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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Calcified tissue international 16 (1974), S. 145-152 
    ISSN: 1432-0827
    Keywords: EHDP ; Bone ; Chemistry ; Serum ; Rabbits
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Abstract The effects of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) on bone and serum chemistry were investigated in adult rabbits. EHDP was administered by subcutaneous injection at doses of 0.25, 2.5 and 10 mg/kg body weight/day for of 28 days. Blood samples were obtained weekly from each rabbit and serum levels of total calcium, ionized calcium, inorganic phosphate and alkaline phosphatase were determined. At the end of the treatment period all rabbits were sacrificed and the tibiae removed for chemical analysis and histological evaluation. The effect of EHDP administration on serum chemistry was both dose- and time-related. The highest of the three doses, 10 mg/kg/day, resulted in a time-related decrease in total serum calcium. This dose also caused a rapid but transient reduction in serum ionized calcium. The effect of EHDP on serum inorganic phosphate was biphasic. Administration of 2.5 mg/kg/day resulted in a time-related elevation in this parameter, whereas the 10 mg/kg/day dose resulted in a time-related hypophosphatemic response. There were no significant drug-related changes in tibial fat-free dry weight, ash weight, total calcium or total phosphorus values. However, administration of 2.5 and 10 mg/kg/day EHDP resulted in increased osteoid tissue as measured histologically. These results are compared with data from other EHDP studies, and discussed in relation to the maturity and growth-state of the experimental animals.
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Calcified tissue international 14 (1974), S. 3-14 
    ISSN: 1432-0827
    Keywords: Hydroxyapatite ; Mineral ; Phase ; Chemistry ; Synthesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé Des diagrammes de phase d'équilibre ont été déterminés pour le système CaO-P2O5-H2O en utilisant des techniques de synthèse hydrothermique au cours de variatio nsde température allant de 300–600° et 2 Kb H2O de pression. De l'hydroxyapatite bien cristallisé a été synthétisé et caractérisé. De faibles variations de paramètres de la maille cristalline, liées à la température de synthèse et composition globale du matériel initial, ont été déterminées. Des conditions chimiques précises sont nécessaires pour obtenir de l'apatite, en tant que seule phase solide en équilibre dans la solution. Les résultats de diagramme de phase d'équilibre sont comparés avec ceux obtenus dans des milieux synthétiques.
    Abstract: Zusammenfassung Es wurden Gleichgewichts-Phasendiagramme für das System CaO-P2O5-H2O bestimmt, indem hydrothermale Synthese-Techniken im Temperaturbereich von 300–600° und bei einem Druck von 2 Kb H2O verwendet wurden. Es wurde gut-kristallisiertes Hydroxyapatit erzeugt und charakterisiert. Es wurden geringe Unterschiede in den Parametern der Zelleinheiten festgestellt, welche von der angewandten Temperatur und der Zusammensetzung des Startmaterials abhingen. Es waren genaue chemische Bedingungen nötig, um Apatit als die einzige feste Phase im Gleichgewicht mit der Lösung zu erhalten. Die Resultate der Gleichgewichts-Phasendiagramme werden mit früheren Untersuchungen mit der Synthesetechnik verglichen.
    Notes: Abstract Equilibrium phase diagrams have been determined for the system CaO-P2O5-H2 using hydrothermal synthesis techniques in the temperature range 300–600° and 2 Kb H2O pressure. Well-crystallized hydroxyapatite has been produced and characterized. Small variations in unit cell parameters dependent on temperature of synthesis and bulk composition of the starting materials have been determined. Precise chemical conditions were required to obtain apatite as the only solid phase in equilibrium with solution. Equilibrium phase diagram results are compared with previous synthetic investigations.
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  • 3
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    Calcified tissue international 7 (1971), S. 150-162 
    ISSN: 1432-0827
    Keywords: Uranium ; Bone ; Distribution ; Fission ; Chemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé Une concentration moyenne de 2.4×10−8 g U/g de cendre a été obtenue à partir de l'os humain normal. La microdistribution de l'uranium dans l'os indique que cet élément est surtout limité à surface de l'endoste et, en particulier, aux surfaces de l'os lamellaire et aux parois des canaux de Havers, ouverts dans l'os corticol. Cette répartition suggère que l'uranium se présente sous une forme chimique impropre à son incorporation dans l'apatite osseux: il ne semble donc pas exister une distribution diffuse significative de l'uranium dans l'os.
    Abstract: Zusammenfassung Eine mittlere Konzentration von 2,4×10−8 g Uran/g Asche wurde in normalen menschlichen Knochen gefunden. Die Feinverteilung von Uran im Knochen zeigt, daß dieses Element hauptsächlich an der endostalen Oberfläche vorkommt, insbesondere an der Oberfläche des trabeculären Knochens und an den Wänden der offenen Haversschen Kanäle im kortikalen Knochen. Diese Verteilung läßt vermuten, daß Uran in einer chemischen Form vorliegt, welche sich für den Einbau in das Knochenapatit nicht eignet. Daraus folgt, daß keine signifikante diffuse Verteilung des Urans innerhalb des Knochens vorliegt.
    Notes: Abstract A mean concentration of 2.4×10−8 g U/g ash has been obtained for normal human bone The microdistribution of uranium in bone indicates that this element is mainly restricted to endosteal surfaces; in particular the surfaces of trabecular bone and the walls of open Haversian canals in cortical bone. This distribution suggests that uranium is present in a chemical form that is not acceptable for incorporation into bone apatite and consequently there does not appear to be a significant diffuse distribution of uranium throughout bone.
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  • 4
    ISSN: 1432-0827
    Keywords: Morphology ; Glycosaminoglycans ; Cartilage ; Chemistry ; Audioradiography ; Healing
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé Une perte de substance ostéo-cartilagineuse, de taille limitée et identique, est réalisée chez le lapin adulte et la cicatrisation est étudiée histologiquement et par autoradiographie après marquagein vitro au35S-sulfate. Une analyse microchimique est pratiquée pour le contenu et la composition en glycosaminoglycanes. 1. Entre la première semaine et la 4ème et 8ème semaine, un tissu conjonctif non-métachromatique se différencie en un cartilage métachromatique et la quantité de sulfate de chondroitine augmente de façon significative aux dépens des glycoprotéines. 2. Jusqu'à la 4ème semaine, la perte de substance est surtout comblée par de l'os néoformé: après cette période, la région est comblée au delà de la limite de la surface articulaire. 3. Le cartilage hyalin, ressemblant morphologiquement, autoradiographiquement et chimiquement au cartilage articulaire, en ce qui concerne la distribution en glycosaminoglycanes, constitute la surface articulaire de la perte de substance comblée dans un tiers des cas après 8 semaines. Le cartilage hyalin s'observe surtout dans les régions où de l'os néoformé a comblé la cavité médullaire. 4. Dans les deux tiers des cas, après 8 semaines, les surfaces articulaires des zones comblées comportent, non seulement du cartilage, mais aussi du tissu fibreux se formant essentiellement sur les parties latérales et dans les régions, où la cavité médullaire, fliant face, à la surface articulaire, n'a pas été comblée par du tissue osseux. La fraction glycoprotéique augmente par rapport à la fraction chondroitine sulfate. 5. Dans la majorité des cas, après 20 semaines, le cartilage néoformé subit des phénomènes dégénératifs, qui se traduisent par une diminution en chondroitine sulfate.
    Abstract: Zusammenfassung Bei ausgewachsenen Kaninchen wurde ein begrenzter, standardisierter, osteochondraler Defekt hervorgerufen, und das regenerierte Gewebe wurde histologisch und autoradiographisch durch Markierung in vitro mit35S-Sulfat und durch mikrochemische Bestimmung des Gehaltes und der Zusammensetzung der Glykosaminglykane untersucht. Die wichtigsten Befunde waren: 1. Zwischen 1 und 4–8 Wochen veränderte sich nichtmetachromatisches Bindegewebe zu metachromatisch gefärbtem Knorpel, und der Anteil an Chondroitin-Sulfat nahm auf Kosten der Glykoproteine signifikant zu. 2. Bis zu 4 Wochen war der Hauptteil des defekten Gebietes mit neugebildetem Knochen gefüllt; nach dieser Zeit lag dieser Bezirk oberhalb der Verknöcherungsgrenze in Richtung der Gelenkoberfläche. 3. Nach 8 Wochen bestand die Gelenkoberfläche des defekten Gebietes in einem Drittel der Fälle aus hyalinem Knorpel, der morphologisch, autoradiographisch und chemisch dem Gelenkknorpel in Bezug auf die Verteilung von Glykosaminoglykanen glich. Hyaliner Knorpel wurde hauptsächlich an Stellen beobachtet, wo neugebildeter Knochen die Markhöhle geschlossen hatte. 3. Nach 8 Wochen bestand die Gelenkoberfläche des defekten Gebietes in einem Drittel der Fälle aus hyalinem Knorpel, der morphologisch, autoradiographisch und chemisch dem Gelenkknorpel in Bezug auf die Verteilung von Glykosaminoglykanen glich. Hyaliner Knorpel wurde hauptsächlich an Stellen beobachtet, wo neugebildeter Knochen die Markhöhle geschlossen hatte. 4. Nach 8 Wochen bestanden Teile der Gelenkoberfläche des Defektes in zwei Dritteln der Fälle nicht nur aus Knorpel, sondern auch aus fibrösem Gewebe, welches vor allem in den seitlichen Teilen des Defektes und an Stellen vorlag, wo die Markhöhle gegenüber der Gelenkoberfläche nicht mit Knochengewebe verschlossen worden war. Die Glykoproteinfraktion nahm im Vergleich zur Chondroitin-Sulfatfraktion zu. 5. Nach 20 Wochen zeigten sich in den meisten Fällen bei neugebildetem Knorpel degenerative Veränderungen, welche durch eine gewisse Abnahme des Chondroitin-Sulfats wiedergegeben wurden.
    Notes: Abstract A limited, standardized osteochondral defect was created in adult rabbits and the regenerated tissue was examined histologically and autoradiographically after labellingin vitro with35S-sulphate, and microchemically for its content and composition of glycosaminoglycans. The principal findings were: 1. Between 1 week and 4 to 8 weeks, non-metachromatic connective tissue differentiated to metachromatically stained cartilage, and the proportion of the chondroitin sulphate increased significantly at the expense of the glycoproteins. 2. Up to 4 weeks, the major part of the defect area was filled with newly formed bone; after this time, the area lay above the level of the “tidemark”, towards the articular surface. 3. Hyaline cartilage with morphological, autoradiographic and chemical resemblance to the articular cartilage in terms of the distribution of glycosaminoglycans constituted the articular surface of the defect area in one-third of the cases at observation times after 8 weeks. Hyaline cartilage was observed mainly in areas where newly formed bone had closed the medullary cavity. 4. In two-thirds of the cases, after 8 weeks, parts of the articular surface of the defect consisted not only of cartilage but also of fibrous tissue, occurring mainly in the lateral parts of the defect and in areas where the medullary cavity facing the articular surface had not been sealed by bone tissue. The glycoprotein fraction increased relative to the chondroitin sulphate fraction. 5. In most cases after 20 weeks, newly-formed cartilage underwent degenerative changes, which were reflected in some reduction of the chondroitin sulphate.
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  • 5
    Electronic Resource
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    Springer
    Calcified tissue international 8 (1971), S. 228-236 
    ISSN: 1432-0827
    Keywords: Skin ; Calcinosis ; Keratin ; Chemistry ; X-ray diffraction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé Des études histologiques antérieures ont montré que le follicle pileux est particulièrement susceptible de se calcifier, lorsque la peau de rats hypercalcémiques est lésée. Des analyses chimiques et par diffraction aux rayons X du follicule ont confirmé ce résultat. — En se basant sur l'augmentation du calcium et du phosphore, les calcifications débutent dans le tissue folliculaire 6–12 h après une blessure d'intensité moyenne de la peau de rats, ayant reçu du dihydrotachysterol (DHT), et 24–48 h après une blessure similaire chez des rats non injectés. Les diagrammes de diffraction aux rayons X sont diffus. Trois heures après la blessure, on note une augmentation du calcium du tissu folliculaire qui ne semble pas en rapport avec le DHT qui traduit probablement une liaison de calcium plutôt qu'un dépot minéral.
    Abstract: Zusammenfassung Frühere histologische Untersuchungen haben gezeigt, daß der Haarfollikel besonders anfällig für Verkalkungen ist, wenn die Haut von hypercalcämischen Ratten verletzt wird. Dieses Resultat wurde nun durch direkte chemische Bestimmungen und Röntgendiffraktions-analysen von Follikelgewebe bestätigt. Aufgrund der erhöhten Calcium- und Phosphatwerte kann gesagt werden, daß nach einer leichten Quetschung der Haut von Ratten, die mit Dihydrotachysterol (DHT) behandelt wurden, im Haarfollikelgewebe nach 6–12 Std Mineral-ablagerungen stattfanden, wogegen Kontrollratten mit der gleichen leichten Hautverletzung diese Ablagerungen erst nach 24–48 Std zeigten. Röntgendiffraktionsanalysen ergaben ein diffuses Apatit-Muster. Innerhalb 3 Std nach der Verletzung wurde ein Anstieg des Calcium-gehaltes im Follikelgewebe beobachtet, der nicht im Zusammenhang mit der DHT-Behandlung stand, also nicht eine Mineralablagerung, sondern eher eine Bindung von Calcium widerspiegelte.
    Notes: Abstract Previous histological investigations have shown that the hair follicle is particularly susceptible to mineralization when the skin of hypercalcaemic rats is injured. Direct chemical and X-ray diffraction analyses of follicle tissue have now confirmed this finding. As judged by increases in both calcium and phosphorus, mineral deposits began to form in hair follicle tissue 6–12 h after a mild crush injury to the skin of rats dosed with dihydrotachysterol (DHT), and 24–48 h after a similar injury to the skin of non-dosed rats. X-ray diffraction gave a diffuse apatite pattern. Within 3 h of injury there was a rise in the calcium content of follicle tissue which was not related to DHT-dosing and which was probably a reflection of calcium binding rather than mineral deposition.
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  • 6
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    Calcified tissue international 8 (1971), S. 304-319 
    ISSN: 1432-0827
    Keywords: Chemistry ; Calcium ; Phosphate ; Solubility ; Computer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé Un programme d'ordinateur a été mis au point pour calculer les activités ioniques du calcium et l'orthophosphate dans un grand nombre de solutions. Dans le cas de solutions synthétiques, les calculs sont vérifiés en comparant les valeurs de pH, obtenues par ordinateur, avec celles observées expérimentalement. Des essais de ce type, avec des solutions possèdant des concentrations de calcium et d'orthophosphate trouvées dans les liquides biologiques et à des valeurs de pH variant de 3.00 à 10.00, indiquent que le programme est adapté pour des applications biologiques. Le programme n'est pas effectif pour des solutions, dans les lesquelles l'ion bromure est la source principale de la force ionique, sans doute, par manque d'équation étendue de Debye-Hückel dans ces circonstances. Aucune formation de complexe de phosphate de sodium n'a été notée à des concentrations biologiques normales.
    Abstract: Zusammenfassung Es wurde ein Computer-Programm ausgearbeitet, um die Ionenaktivitäten von Calcium und Orthophosphat in einer breiten Varietät von Lösungen zu berechnen. Die Berechnungen wurden bei synthetischen Lösungen durch Vergleiche zwischen den auf diese Weise errechneten pH-Werten und den experimentell gefundenen kontrolliert. Diese Art Kontrollen mit Calcium-und Orthophosphatkonzentrationen, wie sie in biologischen Flüssigkeiten gefunden werden, und mit pH-Werten zwischen 3,0 und 10,0 wies darauf hin, daß das Programm für biologische Anwendungen geeignet war. Das Programm konnte nicht benützt werden für solche Lösungen, bei welchen hauptsächlich das Bromidion zur Einstellung der Ionenstärke verwendet wurde, vermutlich weil die erweiterte Debye-Hückel-Gleichung unter diesen Umständen nicht anwendbar ist. Die Bildung eines Natriumphosphat-Komplexes unter normalen biologischen Konzentrationen konnte nicht nachgewiesen werden.
    Notes: Abstract A computer program has been designed to calculate the ionic activities of calcium and orthophosphate in a wide variety of solutions. In the case of synthetic solutions the calculations were checked by comparing the computed pH values with those observed experimentally. Tests of this type with solutions having the concentrations of calcium and orthophosphate found in biological fluids and with pH values ranging from pH 3.0–10.0 indicated that the program was suitable for biological applications. The program was not effective for solutions in which the bromide ion was a principal source of ionic strength probably because of the failure of the extended Debye-Hückel equation under those circumstances. No evidence for the formation of any sodium phosphate complex at normal biological concentrations could be found.
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  • 7
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    Calcified tissue international 8 (1971), S. 197-210 
    ISSN: 1432-0827
    Keywords: Fluorescence ; Calcium ; Collagen ; Chemistry ; Bone ; Dentine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé Des composants fluorescents de l'os et la dentine sont séparés des hydrolysats alcalins de leur marice sur des colonnes Sephadex C25 CM d'échange cationique. Les concentrations en fluorescence et le spectre d'excitation (λ max 330 nm) et d'émission (λ max 395 nm) sont les mêmes que ceux observés au niveau des matrices intactes et gélatinisées. Les paramètres de fluorescence ne sont pas altérés par hydrolyse. La filtration sur gel à l'aide de colonnes Sephadex G 10 perment de différencier le matériel isolé en deux composants, ayant la même fluorescence et la même absorption UV. La fluorescence est indépendante de pH de 3.5–9.5. Des études de dialyse et de filtration sur gel de matrices gélatinisées indiquent une association étroite du matériel fluorescent avec les chaines polypeptidiques de collagène.
    Abstract: Zusammenfassung Fluorescierende Bestandteile aus Knochen und Dentin wurden in Sephadex C25 CM Kationen-Austauschersäulen von alkalischen Hydrolysaten ihrer Matrices getrennt. Die Fluorescenzintensitäten sowie die Erregungs- (λ max 330 nm) und Emissions- (λ max 395 nm) Spektren waren dieselben wie bei intakten und gelatinisierten Matrices. Die Fluorescenzparameter wurden durch die Hydrolyse nicht verändert. Eine Gelfiltration über Sephadex-G10-Säulen trennte das isolierte Material in 2 Komponenten auf, welche gleiche Fluorescenz- und UV-Absorptionseigenschaften zeigten. Im pH-Bereich zwischen 3,5 und 9,5 war die Fluorescenz unabhängig vom pH. Dialysierversuche sowie Gelfiltrationsexperimente mitden gelatinisierten Matrices zeigten eine starkgefügte Bindung des fluorescierenden Materials mit den Polypeptidketten des Kollagens.
    Notes: Abstract Fluorescent components in bone and dentine were separated from alkaline hydrolysates of their matrices on Sephadex C25 CM cationic exchange columns. The fluorescence levels, and the excitation (λ max 330 nm) and emission (λ max 395 nm) spectra, were the same as those observed in the intact and gelatinised matrices. The fluorescence parameters were unaltered by the hydrolysis procedure. Gel filtration on Sephadex G. 10 columns further resolved the isolated material into two components with the same fluorescence and UV absorption properties. The fluorescence was independent of pH over the range 3.5–9.5. Dialysis and gel filtration studies on the gelatinised matrices indicated a firmly-bonded association of the fluorescent material with the collagen polypeptide chains.
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  • 8
    ISSN: 1432-1041
    Keywords: Chlorthalidone ; spironolactone ; hypertension ; potassium deficiency ; diuretic ; Kühns' test
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Kühns' oral test for potassium deficiency (KDT) has been used to evaluate potassium balance after treatment with diuretics. The test was first standardised in 23 patients, both with and without known potassium deficiency. Subsequently, 18 patients with essential hypertension were investigated before and after the use of 3 different diuretics, each for a period of 6 weeks; all patients received all three forms of treatment but in different sequence. Before treatment the patients excreted an average of 121 mEq potassium a day in urine after oral administration of potassium 127 mEq (citrate). After treatment with chlorthalidone (Hygroton®), 50 mg a day, the excretion of potassium decreased significantly to 83 mEq, suggesting an intracellular deficit of it. Treatment with chlorthalidone 50 mg and potassium chloride 2 g daily (Hygroton — K®), led to potassium excretion of 100 mEq after loading, which was distinctly, but not significantly, larger than in the period of treatment with chlorthalidone alone. After chlorthalidone 50 mg daily and spironolactone (Aldactone “Searle”®), 25 mg q. i. d., the excretion of potassium was 121 mEq, which was the same as before treatment. The mean serum potassium before treatment was 4.4 mEq/l, after chlorthalidone 3.8 mEq/l, after chlorthalidone plus potassium chloride 3.9 mEq/l, after chlorthalidone combined with spironolactone 3.9 mEq/l. The results were in agreement with previously published investigations of “exchangeable potassium” after similar treatments. As the test for potassium deficiency gave better information about the amount of intracellular potassium in the body than analysis of serum potassium, it is suitable for the evaluation of potassium deficiency associated with diuretic therapy.
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  • 9
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    European journal of clinical pharmacology 19 (1981), S. 19-24 
    ISSN: 1432-1041
    Keywords: hypertension ; guanfacine ; central antihypertensives ; withdrawal ; catecholamines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 1. Guanfacine (2–6 mg/day) a centrally acting antihypertensive drug, was effective in controlling blood pressure in 5 essential hypertensives and lowered plasma noradrenaline and urinary catecholamine excretion. 2. Withdrawal of guanfacine by blind substitution of identical placebo tablets under observation in hospital led to a gradual recovery of blood pressure over 2–4 days. 3. Salivary flow, which was reduced on guanfacine, returned to pretreatment levels by 2 days after withdrawal and significantly exceeded control for the next two days. 4. Urinary catecholamine excretion returned to pretreatment levels by 3 days but did not exceed control levels during the period of study. 5. Plasma noradrenaline returned gradually to pretreatment levels, and by day 4 significantly exceeded them. 6. No patient experienced symptoms suggesting catecholamine excess although four out of five reported a headache from the second day onwards. 7. Guanfacine, a centrally acting drug which pharmacologically resembles clonidine, has a slow offset of hypotensive effect over 2–3 days. Symptoms or biochemical evidence of catecholamine excess were not encountered within 48 h of withdrawal, possibly reflecting the longer duration of action and plasma half-life of guanfacine.
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  • 10
    ISSN: 1432-1041
    Keywords: guanfacine ; methyldopa ; hypertension ; rebound hypertension ; withdrawal symptoms ; plasma noradrenaline
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Nine patients with essential hypertension completed a clinical trial designed to study the effects and side effects of administration and withdrawal of guanfacine (2 mg tds) and methyldopa (250 mg tds) on blood pressure, heart rate, and plasma noradrenaline. The study was of randomised doubleblind crossover design with two active therapy phases of eight weeks each, preceded by an initial 4 week placebo phase, separated by an intermediate 2 week placebo phase, and followed by a final 2 week placebo phase. Patients took bendrofluazide 5 mgs daily throughout the entire trial, during both active and placebo periods. Each patient was admitted to hospital at the end of the 8 week active treatment phases, so that the effects of drug withdrawal on blood pressure, heart rate, plasma noradrenaline and side reactions, could be closely observed and monitored. The main conclusions from analysis of the results were that: 1. The hypotensive efficacy of guanfacine and methyldopa was very similar in the doses used, each of the two drugs lowering the supine mean arterial pressure by about 15 mm Hg and the supine diastolic pressure by about 10 mm Hg. 2. The frequency of side effects was greater with guanfacine than with methyldopa. 3. There was no signficant early rebound phenomenon after withdrawal of either methyldopa or guanfacine. 4. There was tendency for the blood pressure to rise slowly and marginally above initial placebo values, 2 weeks after cessation of guanfacine treatment though this was not significant. It was however, accompanied by a significant increase in plasma noradrenaline at 2 weeks. This was not seen 2 weeks after cessation of methyldopa. There was no single incidence of worrying rebound hypertension or withdrawal symptoms either early or late in any patient following cessation of methyldopa or guanfacine.
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  • 11
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    European journal of clinical pharmacology 20 (1981), S. 163-168 
    ISSN: 1432-1041
    Keywords: hypertension ; captopril ; cardiac output ; extracellular fluid volume ; renin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of captopril 450 mg/day for 4 weeks on blood pressure, heart rate, cardiac output and extracellular fluid volume were compared in severe, often drug-resistant hypertension (n=23), mild to moderate hypertension associated with renal artery stenosis (n=10) and mild to moderate essential hypertension (n=20). Plasma renin in the three groups was 52±19, 58±17 and 20±4 µU/ml (mean ± SEM), respectively. Blood pressure fell by 18±4%, 21±2% and 18±1%. The pressure drop was mainly due to a fall in peripheral vascular resistance. Addition of the diuretic hydrochlorothiazide (25–100 mg/day) caused a further fall in resistance. Despite the vasodilator effect of captopril, reflex cardiostimulation and reactive fluid retention were not observed. In severe hypertension, captopril alone was more effective in lowering blood pressure than combined diuretic-betablocker-vasodilator therapy. Moreover, cardiac output in these patients was higher and resistance was lower after captopril than during combined treatment. Thus, captopril was capable of normalising the abnormal haemodynamic state in patients with essential hypertension, and in hypertension associated with renal artery stenosis. Despite marked differences in pre-treatment plasma renin, the effects of captopril on systemic haemodynamics were similar in all the patients.
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  • 12
    ISSN: 1432-1041
    Keywords: vasodilator ; hypertension ; haemodynamic effects ; renal plasma flow ; renal tubular function ; plasma renin activity ; aldosterone ; Ro 12-4713
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Selected cardiovascular and endocrine effects of the new oral vasodilator Ro 12-4713 have been evaluated in an acute single dose study. In five patients with essential hypertension, Ro 12-4713 caused a dose-dependent decrease in supine and upright blood pressure and an increase in heart rate. Initial effects occurred one to 2 h after drug ingestion and maximal effects were noted after five hours and persisted for at least 8 h. Blood pressure was normalized, and the antihypertensive and chronotropic effects persisted for 24 h after a dose of about 300 mg/1.73 m2. Plasma and urinary norepinephrine and plasma renin levels tended to be raised, whereas plasma and urinary epinephrine and plasma aldosterone did not change. Changes in supine heart rate were inversely correlated with changes in mean blood pressure (r=−0.60; P〈0.02), and positively with those in plasma norepinephrine (r=0.55; P〈0.05) and renin (r=0.62, P〈0.01); changes in supine plasma renin level were also inversely correlated with those in mean blood pressure (r=−0.65; P〈0.01), and positively with those in plasma norepinephrine (r=0.58; P〈0.05). 24 h-urinary sodium excretion was significantly (P〈0.001) decreased; it was positively correlated with mean blood pressure (r=0.51; P〈0.05) and inversely with supine plasma renin activity (r=−0.63; P〈0.01). In six normal subjects and six patients with essential hypertension, effective renal plasma flow and the renal clearance of sodium, potassium, calcium and uric acid were not significantly altered five hours after a dose of Ro 12-4713 of about 250 mg/1.73 m2; glomerular filtration rate tended to be slightly decreased, and filtration fraction was significantly (P〈0.05) reduced in the hypertensive patients. At the same time blood pressure was decreased and plasma norepinephrine (P〈0.01) and renin (ns) were slightly increased in both groups. Ro 12-4713 in a single oral dose of about 300 mg appeared to be a potent, long acting, hypotensive vasodilator.
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  • 13
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    European journal of clinical pharmacology 26 (1984), S. 309-313 
    ISSN: 1432-1041
    Keywords: clonidine ; hypertension ; therapeutic window ; steady state concentration ; pharmacokinetics ; cardiovascular effects
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Clonidine was given orally as monotherapy in increasing daily doses from 3.1 to 25.7 µg/kg to patients with essential hypertension (n=6). When a steady state concentration in plasma was reached at each dose level, the blood pressure (BP) and heart rate were measured during a dosage interval. Effect time — plasma concentration data were submitted to nonlinear regression analysis, which showed that the observed BP effects could be dissociated into depressor and pressor components. A window for the antihypertensive effect was established. At a plasma clonidine concentration of 0.65±0.07 ng/ml 50% of the maximal depressor effect was found, and it was only separated by a factor of 2 from the half maximal pure pressor concentration in plasma. No relationship between the change in heart rate and the plasma clonidine was observed. The findings strengthen the importance of close monitoring of clonidine therapy.
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  • 14
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    European journal of clinical pharmacology 26 (1984), S. 331-334 
    ISSN: 1432-1041
    Keywords: metoprolol ; oxprenolol ; hypertension ; beta-blockers ; HDL-cholesterol ; intrinsic sympathomimetic activity ; cardioselectivity
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The aim of the present study was to evaluate whether a reduction in HDL-cholesterol is peculiar to non cardioselective beta blockers or whether it is also produced by cardioselective beta1-blockers. 16 patients with primary arterial hypertension on a balanced isocaloric diet were given oxprenolol 120 to 240 mg/day or metoprolol 100 to 200 mg/day in a random cross-over study. No significant change was observed after either treatment in fasting blood glucose, serum total cholesterol and triglycerides. HDL-cholesterol concentration was significantly decreased on metoprolol, from 41 to 36 mg/dl (p〈0.05), while oxprenolol did not affect it at all. The difference might depend on intrinsic sympathomimetic activity which is possessed by oxprenolol and which metoprolol lacks.
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  • 15
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    European journal of clinical pharmacology 26 (1984), S. 549-553 
    ISSN: 1432-1041
    Keywords: pafenolol ; hypertension ; antihypertensive therapy ; beta1-blocking agent ; exercise tests ; plasma levels
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pafenolol, a new selective adrenergic beta1-blocking agent, has been tested for the first time in 6 hypertensive patients. After single oral doses of pafenolol 25 to 100 mg, there was a marked reduction in heart rate and systolic blood pressure during exercise tests. These effects were dose dependent. A significant positive correlation was found between the reduction in heart rate during exercise and the plasma level of pafenolol 5 hours after drug intake (correlation coefficient r=0.94). Side effects were mild and seemed to be dose dependent. It is concluded that this new beta1-blocking agent was effective in reducing blood pressure and was well tolerated.
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  • 16
    ISSN: 1432-1041
    Keywords: etozolin ; ozolinone ; furosemide ; hypertension ; renin ; catecholamines ; chronic renal failure ; steady state kinetics ; plasma levels
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect on urinary electrolyte excretion, renin release and plasma norepinephrine of single oral doses of 400 mg etozolin (E) and of 40 mg furosemide (F) were studied in hypertensive patients with normal (n=6) and impaired kidney function (n=6). E caused a marked saluresis up to 24 hours, showing its long duration of action. F, however, displayed a brief, brisk peak diuresis, followed by a rebound from the 4th to the 24th hours. The brisk peak diuresis induced by F was associated with pronounced release of renin, almost twice that induced by E. In chronic renal failure the renin release in relation to the magnitude of the diuresis was increased, i.e. the sensitivity of these patients to changes in water homeostasis was increased. E and F stimulated the sympathetic system to roughly the same extent. Patients with essential hypertension had higher plasma levels of norepinephrine than hypertensive patients with chronic renal failure. In addition, hypertensive patients with normal renal function (n=4) and varying degrees of renal impairment (n=11) were also given 400 mg daily for 2 weeks. Effects on blood pressure and electrolyte homeostasis were monitored, as well as the plasma kinetics of metabolite I, ozolinone. At the end of the 2 week treatment E had significantly lowered systolic (−12 mm Hg) and diastolic (−9 mm Hg) blood pressure, and had produced a significant loss of body weight, without altering plasma electrolytes or blood chemistry. There was no accumulation of the effective metabolite ozolinone under conditions of severe impairment of kidney function. It is concluded that E can effectively control high blood pressure in patients with normal and impaired kidney function. Its effective metabolite ozolinone did not accumulate in chronic renal failure.
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  • 17
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    European journal of clinical pharmacology 27 (1984), S. 397-405 
    ISSN: 1432-1041
    Keywords: indapamide ; hypertension ; cardiovascular reflexes ; diuretic effect ; blood pressure variability
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Nine elderly and 11 young hypertensives underwent continuous ambulatory monitoring of blood pressure (BP), assessment of cardiovascular reflexes and M-mode echocardiography as hospital in-patients prior to treatment with once-daily indapamide (2.5 mg). They were followed as out-patients for 4 months during which time casual BP was measured at monthly intervals. The patients were then readmitted to hospital and studied using the same protocol under similar standardised conditions. The results showed that indapamide reduced casual and ambulatory BP in both young and elderly although the most marked effect was seen on systolic BP. Assessment of cardiovascular reflexes indicates that at least part of the hypotensive action of indapamide is due to a diuretic effect. Treatment with indapamide has comparable results on both young and elderly.
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  • 18
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    European journal of clinical pharmacology 19 (1981), S. 25-32 
    ISSN: 1432-1041
    Keywords: clonidine ; hypertension ; baroreceptor reflex ; mode of action ; sympathetic activity ; urinary catecholamines
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Acute studies of clonidine suggest that it lowers blood pressure by central enhancement of baroreflex sensitivity coupled with diminished evidence of sympathetic outflow, but longterm clonidine data have not been conclusive. We examined effects of one month of low dose clonidine (0.4 ± 0.15 mg/day) alone in 13 essential hypertensive men, assessing several biochemical indices of sympathetic function, as well as physiologic parameters, including baroreflex sensitivity, the cold pressor test, and the hypotensive response to alpha adrenergic blockade. Clonidine diminished mean arterial pressure (from 104±5 to 84±3 mmHg;p〈0.01), without associated changes in several biochemical parameters of sympathetic outflow (urinary excretion of catecholamines, metanephrines, and vanillylmandelic acid; allp〉0.1). Circulatory baroreflex function was not enhanced by clonidine, during either the amylnitrite test or the phenylephrine test, before or after parasympathetic blockade with atropine. The cold pressor test, an index of efferent sympathetic pressor function, was also unaltered. The enhanced mean arterial pressure response to phentolamine during clonidine therapy (from a fall of 14.8±4.3 to 39.4±5.2 mmHg,p〈0.01), suggested an increase in alpha adrenergic vascular tone, perhaps mediated by clonidine's alpha agonist properties in vascular smooth muscle. The antihypertensive mechanism of longterm low dose clonidine cannot reliably be ascribed either to baroreflex enhancement or to suppression of sympathetic outflow.
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  • 19
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    European journal of clinical pharmacology 19 (1981), S. 113-118 
    ISSN: 1432-1041
    Keywords: tolmesoxide ; vasodilators ; hypertension ; side-effects ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics, hypotensive effect and tolerability of a new vasodilator, tolmesoxide (T), have been studied in 6 uncontrolled hypertensive patients receiving atenolol and a diuretic. After a 50 mg oral dose mean (± SD) peak plasma concentration of T was 1.13±0.29 µg/ml−1 and occurred 0.79±0.40 h after the dose; mean peak plasma concentration of its sulphone metabolite (M) was 0.37±0.09 µg/ml−1 at 1.92±1.32 h after the dose. Following peak plasma concentrations there was a monoexponential decline in T and M concentrations with half-lives of 2.78±0.77 h and 10.78±7.85 h respectively. There was a linear increase in plasma concentration of T and M during incremental dosing with 50–200 mg t. i. d. During in-patient administration of 600–900 mg T daily (n=6) there was no significant change in blood pressure, pulse rate or body weight. Out-patient administration of 900 mg T daily (n=4) was associated with a significant fall in mean systolic but not diastolic bp (lying −15/+1 mm Hg. standing −25/−8 mm Hg). A further fall was observed in 2 subjects receiving 1200 mg and 1500 mg daily. Supine pulse rate increased (mean ± SD) significantly from 55±5/min to 66±8/min following 900–1500 mg T in 4 out-patients. Severe nausea and other gastro-intestinal side-effects in all subjects receiving 600–900 mg daily eventually necessitated drug withdrawal. In its present from T is not recommended for the treatment of hypertension.
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  • 20
    ISSN: 1432-1041
    Keywords: carteolol ; hydrochlorthiazide ; amiloride ; hypertension ; double-blind clinical trial
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The antihypertensive effect of carteolol, a new β-blocking agent, added to basal diuretic treatment (hydrochlorthiazide 50 mg and amiloride 5 mg) has been assessed in a controlled trial in 17 patients with mild-to-moderate hypertension. The trial was divided into 4 stages: 1) run-in period with no antihypertensive treatment, 2) diuretic period (the diuretic being continued as basal treatment during the two following periods), 3) carteolol titration period, and 4) double-blind cross-over period comparing carteolol with placebo, which lasted 2 times 4 weeks. Although the diuretic effectively reduced the blood pressure, 17 of the 20 patients originally studied still had an elevated diastolic blood pressure (≧ 95 mmHg) after the diuretic period, thus fulfilling the inclusion criteria for the study. During the titration period carteolol 5 to 20 mg b. i. d. significantly reduced the elevated blood pressure. The blood pressure was reduced to normal in all 17 patients, although in two patients this occurred only during the double-blind period. During the double-blind period, the dose of carteolol was used which had given a satisfactory response during the titration period. The blood pressure in the 14 patients who completed the trial remained low both with carteolol and placebo during the double-blind stage, and was only slightly lower with carteolol than with placebo. This is probably due to a “carry-over” effect. Three patients discontinued the trial due to side effects (1 urticaria, 1 insomnia and 1 nausea) while on carteolol. There was no other difference between carteolol and placebo in the number or severity of side effects.
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  • 21
    ISSN: 1432-1041
    Keywords: vasodilator ; hypertension ; antihypertensive treatment ; catecholamines ; renin ; aldosterone ; blood volume
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The antihypertensive efficacy and endocrine profile of the new antihypertensive agent, Ro 12-4713, were evaluated in 23 patients (17 men and 6 women) with moderate to severe arterial hypertension. Following addition of Ro 12-4713 to pre-existing therapy with diuretics and beta-blockers or sympatholytics, blood pressure in most of the patients was normalized within one month by a daily dose of 60 to 120 mg. Heart rate was only slightly increased. Orthostatic hypotension was not observed. Weight gain or oedema formation occurred in 14 patients within the first four weeks, but could be controlled satisfactorily by intensified diuretic therapy. Increased hair growth occurred in most of the patients. After a mean duration of treatment of 2.8 months, plasma volume and plasma and urine sodium were unaltered, and plasma potassium was slightly decreased. Plasma renin activity was doubled, whereas plasma aldosterone concentrations were unaltered. Plasma norepinephrine levels were high before and increased only slightly during chronic Ro 12-4713 treatment, whereas urinary norepinephrine excretion was unchanged. Plasma and urinary epinephrine were unaltered by Ro 12-4713. Ro 12-4713 appears to be a potent vasodilator for the combination treatment of hypertension in men.
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  • 22
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    European journal of clinical pharmacology 20 (1981), S. 335-338 
    ISSN: 1432-1041
    Keywords: atenolol ; atherosclerosis ; hypertension ; serum lipoproteins
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Serum lipoproteins were determined in 15 patients before and during antihypertensive treatment with atenolol 0.1–0.2 g/day for a mean of 8 months. The mean blood pressure fell from 171/103 to 154/93 mm Hg (p〈0.05). Significant lipoprotein changes were an increase in very low density triglycerides (VLDL-TG) from 1.21±0.95 (SD) to 1.62±1.24 mmol/l (p〈0.01) and in low density (LDL) TG from 0.46±0.12 to 0.51±0.12 mmol/l (p〈0.05). Together, these TG increases resulted in development of hypertriglyceridaemia in 7/15 patients during atenolol treatment. No effect on whole serum cholesterol or on the high density lipoprotein cholesterol concentrations were found. Thus, some patients on long term treatment with atenolol seem to receive the benefit of normotension at the cost of hypertriglyceridaemia. This may have practical implications, since hypertriglyceridaemia constitutes an important risk factor for atherosclerosis.
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  • 23
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    European journal of clinical pharmacology 20 (1981), S. 347-349 
    ISSN: 1432-1041
    Keywords: reserpine ; syrosingopine ; prolactin secretion ; hypertension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 20 mild hypertensive women, reserpine induced a significant increase in mean plasma PRL, both under basal conditions (from 6.6±0.9 to 17.9±2.9 ng/ml), and on repeated determinations during the day. In contrast to reserpine, the administration of syrosingopine, a synthetic compound derived from reserpine, to the same subjects was not followed by a significant change in prolactin level. Beyond their pharmacological interest, these results are of clinical importance when considering that rauwolfia alkaloids are used for long term treatment, and that an increase in PRL levels is important in pathology, both in relation to the function of the hypophyseogonadal axis and in view of its possible facilitation of the growth and development of mammary cancer.
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  • 24
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    European journal of clinical pharmacology 26 (1984), S. 315-323 
    ISSN: 1432-1041
    Keywords: captopril ; hypertension ; glomerular filtration ; para-aminohippuric acid ; renal function ; severe drug reaction ; nephrotic syndrome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of captopril up to 450 mg/day on blood pressure and renal function were investigated during sustained treatment of 10 patients whose severe hypertension had not responded to previous therapy. All the patients were kept on diuretics and most of them on β-blockers, too. A control determination of glomerular filtration rate (GFR) and para-aminohippuric acid clearance (CPAH) was performed during the prior treatment. The effect of the addition (or substitution) of captopril were assessed after an average of 25 days (short-term) and 26 weeks (long-term). Short-term treatment produced a 15.5% decrease in mean blood pressure and interindividually variable effects on renal function. On average GFR was somewhat lower and CPAH slightly higher than the control values (not significant). This pattern is quite similar to the effects of most other antihypertensive drugs. On long-term therapy GFR rose by a mean of 9% (NS) and CPAH by 17% (p〈0.02). However, in a patient who developed a captopril-induced nephrotic syndrome, GFR dropped to 56% and CPAH to 50% of the control values. In another patient a transient rise in serum creatinine accompanied a severe drug reaction.
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  • 25
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    European journal of clinical pharmacology 19 (1981), S. 395-401 
    ISSN: 1432-1041
    Keywords: sotalol ; hydrochlorothiazide ; hypertension ; combination fixed ratio ; serum potassium ; long term treatment
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The combination of sotalol and hydrochlorothiazide in a fixed ratio of 6.4:1 was evaluated in thirty patients with uncomplicated hypertension. In the first part of the study, once daily administration of an optimal dose of the combination was significantly more effective than either hydrochlorothiazide or sotalol alone in lowering both the supine and standing systolic and diastolic blood pressure. Blood pressure was still controlled 24 h after the previous dose. Serum potassium fell by 0.37 mEq/l from the mean pretreatment value after treatment with the combination, but it still remained within the normal range. In the second part of the study the long term effect of the combination on blood pressure, heart rate and biochemical parameters was studied in twenty patients. Supine and standing blood pressure fell by 28.7/15.3 mmHg and 29.5/17.6 mmHg, respectively (p〈0.001). Serum potassium was 3.98±0.07 mEq/l after twelve months of therapy; potassium supplements were not administered. Like serum potassium, the other biochemical parameters remained within the normal range. The combination was well tolerated on long term use, and only one patient withdrew from the study.
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  • 26
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    European journal of clinical pharmacology 20 (1981), S. 1-8 
    ISSN: 1432-1041
    Keywords: hypertension ; captopril ; angiotensin ; renin ; aldosterone ; catecholamines ; prostaglandins ; kininase II ; hypotensive action
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The acute hypotensive effect of captopril 25 mg was investigated in 26 hypertensive patients (11 with essential and 15 with renal arterial disease). Intra-arterial blood pressure was recorded continuously and arterial blood was sampled for renin, angiotensin I and II, aldosterone, kininase II, catecholamines and prostaglandins. Captopril led to an increase in plasma renin activity, active and total plasma renin concentration and angiotensin I, a decrease in plasma kininase II activity, angiotensin II, aldosterone, prostaglandins E2 and F2* and no change in plasma (nor)adrenaline, dopamine and inactive renin concentration. The hypotensive effect of captopril was related to the changes in plasma angiotensin II level and inversely to the change in prostaglandin E2; the correlation coefficients were low, respectively 0.61 and −0.44. It is likely that the acute hypotensive effect of captopril to some extent is related to changes in plasma angiotensin II and in prostaglandins E2 and F2*. There is no evidence for a role of the adrenergic systems in the hypotensive response.
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  • 27
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    European journal of clinical pharmacology 20 (1981), S. 399-405 
    ISSN: 1432-1041
    Keywords: alpha-adrenergic blocker ; hypertension ; blood pressure ; pulse rate ; noradrenaline ; plasma renin activity ; plasma aldosterone ; dopamine-beta-hydroxylase ; E-643
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To determine whether E-643, a new α-blocking agent, would reduce the blood pressure, regardless of the posture, a 1 mg dose was given 3 times daily for 7 consecutive days, to 8 male and 7 female inpatients, aged 37–73 years, with essential hypertension. Blood pressure and pulse rate were measured daily in the supine, sitting and standing positions. Before and after the treatment with E-643, plasma levels of noradrenaline, adrenaline, dopamine-β-hydroxylase, renin and aldosterone were determined, samples being obtained with the subjects recumbent and after standing upright for 60 min. A significant reduction in the systolic and diastolic blood pressures was evident in the supine (172±31/100±12 → 151±28/89±14 mmHg), sitting (158±22/101±11 → 138±28/89±15 mmHg) and standing (153±32/103±21 → 129±31/89±20 mmHg) positions. The reduction in blood pressure remained unchanged throughout the period of administration of E-643. Pulse rate was not affected when the subjects were supine (67±10 → 69±10 beats/min), but was increased in the sitting (68±10 → 73±9 beats/min) and standing (73±10 → 81±11 beats/min) positions. The increased pulse rate tended to decline during continued administration of E-643. Treatment with E-643 produced no significant change in plasma levels of adrenaline, noradrenaline, dopamine-β-hydroxylase, renin and aldosterone. The antihypertensive effect of treatment was more prominent in the patients with higher levels of plasma catecholamines and dopamine-β-hydroxylase, and was less prominent in those with higher plasma renin and aldosterone. Two patients had temporary bouts of dizziness and visual disturbances, but there were no subjective complaints during treatment.
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  • 28
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    European journal of clinical pharmacology 20 (1981), S. 407-411 
    ISSN: 1432-1041
    Keywords: chlorthalidone ; hypertension ; dose response
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The dose response curve for 25, 50, 75 and 100 mg doses of chlorthalidone was studied in double blind fashion over an 8 week period in patients who presented with untreated mild hypertension. One hundred and thirty four patients completed this multicentre, family practice study. After 2 week's medication, a decline in blood pressure was noted in all dosage groups and this was maximal by 4 weeks. At 8 weeks all doses of chlorthalidone induced a significant reduction in both systolic and diastolic blood pressures (mean −18 and −10 mmHg respectively). Amongst the 4 dosage groups, no differences in response were noted resulting in a flat dose response curve. During the study, mean blood urea and serum uric acid rose whilst serum potassium fell, the urea and potassium being least affected in the 25 mg dosage group. As the dosage of chlorthalidone increased, so the tendency for abnormal laboratory values increased. Unwanted effects sought during the study were relatively few in number. No clear dose response relationship was evident although the positive responses in the 25 mg dosage group were less than in the higher dosages. These results suggest that 25 mg chlorthalidone is the optimum dosage for initiation of therapy in patients with mild to moderate hypertension. This dosage is associated with less adverse biochemical changes and unwanted effects than the higher dosages studied.
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  • 29
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    European journal of clinical pharmacology 20 (1981), S. 453-457 
    ISSN: 1432-1041
    Keywords: diuretics ; trichlormethiazide ; hypertension ; pharmacokinetics ; renal insufficiency
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of trichlormethiazide (TCZ) was studied in twelve patients after a single 4 mg dose. Seven patients had normal renal function with creatinine clearances greater than 90 ml/min. Five patients had compromised renal function with creatinine clearances averaging 48±29 ml/min. The TCZ plasma half life and area under the plasma concentration-time curve (AUC) were significantly greater in patients with impaired function, compared to patients with normal renal function. There were no significant differences between the two patient groups in terms of either rate of drug absorption or total urinary recovery of unchanged drug. Furthermore, there was no correlation between peak drug levels or AUC and renal excretion of water or electrolytes.
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  • 30
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    European journal of clinical pharmacology 21 (1981), S. 1-8 
    ISSN: 1432-1041
    Keywords: hypertension ; combination therapy ; population survey ; drug treatment ; prescription patterns ; population incidence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a cross-sectional study, antihypertensive drug treatment was studied in a representative population sample of people aged 30–64 years, using a combination of postal survey, personal interview, clinical assessment and drug prescriptions. 11% of the men and 16% of the women were currently taking antihypertensives; 54% of patients used one, 38% used two, and 8% used three or more preparations. Men used slightly more drugs than women. Diuretics were used by 62% and betablockers by 49% of the sample population. Fixed combinations of thiazides and potassium-sparing agents formed 70% of all diuretic preparations used. Only 12% of the patients used fixed antihypertensive combinations, of which over half were diuretic-reserpine-vasodilator combinations; women and older patients used them most often. The most common freely combined preparations were diuretics and betablockers, which formed almost half of all two-drug combinations, and were also present in 70% of all triple combinations. Adequate control of blood pressure (DBP 〈100 mmHg) was achieved by slightly under 50% of the patients, the BP of women being more adequately controlled than that of men. Differences in BP control were found between the different drugs and combinations. Antihypertensive combination therapy is important in successful treatment, but we still cannot be sure whether fixed combination preparations or, as in this study, free combinations of marketed preparations are better alternatives for treatment.
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  • 31
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    European journal of clinical pharmacology 21 (1981), S. 87-92 
    ISSN: 1432-1041
    Keywords: hypertension ; metoprolol ; sotalol ; comparison ; plasma levels ; serum uric acid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 28 patients, aged 35–62 years, with uncomplicated hypertension, entered a double-blind, crossover study, in which the effects of single daily doses of sotalol and metoprolol were compared. Both drugs exerted a clinically useful anti-hypertensive effect as monotherapy, or in combination with a thiazide diuretic. No significant difference in hypotensive effects was noted between the two beta-blocking agents, when the dose was titrated to an optimal clinical effect. Treatment with sotalol and metoprolol was associated with a clinically insignificant increase in serum uric acid concentration. The side-effects observed were few, and in only two cases was therapy discontinued. We regard both sotalol and metoprolol as useful anti-hypertensive drugs.
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  • 32
    ISSN: 1432-1041
    Keywords: frusemide ; saralasin ; hypertension ; reninangiotensin ; sodium ; diet
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The use of tests of the renin-angiotensin system for predicting antihypertensive responses to frusemide combined with dietary sodium deprivation was evaluated in eighteen patients with severe hypertension. No relationship could be shown between changes in blood pressure induced by the angiotensin analogue, saralasin, and the short-term or long-term therapeutic effects of diuretic- and diet-induced sodium depletion. Mean values for saralasin response and initial plasma renin activity in eight patients whose blood pressure was adequately controlled by therapeutic sodium depletion were closely similar to those obtained in the remaining ten patients, who proved refractory to this treatment.
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  • 33
    ISSN: 1432-1041
    Keywords: beta-blocking drugs ; insulin sensitivity ; pancreatic beta-cell function ; hypertension ; propranolol ; atenolol ; insulin secretion ; plasma GIP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of two beta-blocking drugs on endogenous insulin secretion and insulin sensitivity were investigated in a double blind cross-over study in 13 hypertensive patients. The patients were randomly allocated to each of three 2-week treatment periods with propranolol 80 mg b.i.d., atenolol 50 mg b.i.d. and placebo b.i.d. Endogenous insulin secretion was assessed by measuring serum insulin and C-peptide before and 6 min after iv administration of glucagon; insulin sensitivity was determined by measuring insulin binding to erythrocytes, and as the glucose disappearance rate (KITT) after i.v. insulin. Fasting concentrations of serum free fatty acids (S-FFA) and plasma gastric inhibitory polypeptide (P-GIP) were also recorded during the three study periods. Both propranolol and atenolol reduced blood pressure, heart rate and S-FFA concentrations compared to placebo, and all patients showed measurable plasma concentrations of propranolol and atenolol. The results can be considered representative, therefore, of clinical beta-blockade. The two drugs did not significantly influence the fasting blood glucose level. There was an increase in fasting and glucagon-stimulated serum C-peptide concentration during propranolol therapy compared with placebo (p=0.037 and p=0.030, respectively), although this was not reflected by a significant change in serum insulin. Propranolol and atenolol did not significantly influence insulin binding to erythrocytes, but they clearly reduced the glucose disappearance rate KITT was compared to placebo (p=0.0036 and p=0.0003, respectively). The findings support the view that beta-blocking drugs can influence glucose metabolism by mechanisms other than inhibition of endogenous insulin secretion.
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  • 34
    ISSN: 1432-1041
    Keywords: acetylator phenotype ; hydralazine response ; hypertension ; blood pressure control ; lupus syndrome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The role of acetylator phenotype in determining the response to hydralazine when it was added to diuretic and β-blocker at doses not exceeding 200 mg daily was examined in 57 hypertensive patients. 81% of rapid acetylators needed 200 mg hydralazine daily compared to 38% of slow acetylators (p〈0.01). Despite higher doses of hydralazine the blood pressure was controlled in only 27% of rapid acetylators compared to 65% of slow acetylators (p〈0.02). The relation of acetylator phenotype to blood pressure response was statistically independent of initial blood pressure, age, sex, body weight and serum creatinine (p〈0.005). Current recommendations on hydralazine dosage are unsatisfactory for the 40% of hypertensive patients who are rapid acetylators. We suggest measurement of the acetylator phenotype in patients who respond incompletely to 200 mg hydralazine daily. About 70% of these patients will be rapid acetylators in whom the dose of hydralazine can be increased safely.
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  • 35
    ISSN: 1432-1041
    Keywords: Tobanum® ; beta-blocker ; chloranolol ; hypertension ; angina pectoris ; arrhythmia ; detection methods
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The incidence of side-effects on administration of chloranolol (Tobanum®), a beta-adrenergic receptor blocking drug, to 2066 patients with hypertension, angina pectoris or arrhythmias was measured by three different methods. In 600 patients in an efficacy trial (Group 1) both spontaneously reported complaints and objective signs were tabulated. A side effect — directed method, utilising a questionnaire containing a list of possible side-effects was also used, with the questionnaire being completed by the physician. 35 questions referred to anticipated and other side-effects. The trial was performed in two groups: in 537 patients a placebo was also given (Group 2), and in another set of 929 patients (Group 3) the questionnaire inquiry was performed uncontrolled, without placebo. All three groups were comparable in their distribution of sexes, ages and diagnoses, the mean daily dose of chloranolol its use alone or in combination, and in a similar duration of treatment. 55% of all patients received chloranolol therapy for a period of more than 3 months. The ratio of in- and outpatients was 1:5. The side-effect incidence was independent of the age and sex of the patients and of the dose of chloranolol. The incidence was also unaffected whether chloranolol was used alone or in combination. The number of side-effects differed markedly between the three groups, their ratio was 1:10:24 in Groups 1, 2 and 3. Two-thirds of the side-effects subsided spontaneously within 1 month of their onset. The duration of the side-effects varied according to their character: cardiorespiratory side-effects were of the shortest duration and those affecting the central nervous system were the most enduring. The appreciable differences in incidence could be attributed to the methods of collection of the data. It has been stated that placebo controlled trials using a detailed questionnaire are the most suitable for estimating the incidence of side-effects; recording side-effects spontaneously reported by patients are insufficiently sensitive, and uncontrolled trials using a questionnaire have been shown to be too sensitive. The revealed incidence of side effects leading to interruption of treatment is less affected by the method chosen. In 100 patients (4.8%) therapy had to be suspended because of the side-effects of chloranolol (Group 1: 1%, Group 2: 6.20%, Group 3: 6.6%). Comparison of the incidence of cessation of therapy due to side-effects did not show an appreciable difference between the various beta-adrenergic receptor blocking agents, including chloranolol.
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  • 36
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    European journal of clinical pharmacology 26 (1984), S. 1-6 
    ISSN: 1432-1041
    Keywords: hypertension ; beta-blockers ; propranolol ; metoprolol ; labetalol ; exercise ; heart rate ; blood pressure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a double blind, within patient investigation of twenty-four patients (nineteen males and five females) with a mean age of 46.3 years (SD 10.9 years) with mild to moderate essential hypertension a comparison between equipotent beta-blocking doses of propranolol, metoprolol and labetalol was carried out. Blood pressure and pulse rate were measured in lying, sitting and standing positions and before, during and after isometric and dynamic exercise. Peak expiratory flow was recorded before and during dynamic exercise. All the active treatments were better than placebo in reducing blood pressure and heart rate. Comparing the effects of treatment, labetalol lowered sitting diastolic pressure significantly more than propranolol and standing diastolic pressure than both propranolol and metoprolol. Metoprolol and propranolol were more effective in reducing heart rate. Propranolol significantly reduced peak flow rate compared to labetalol. During the exercise, both isometric and dynamic, the heart rate and the blood pressure, both systolic and diastolic, of the treated patients were lower than those on placebo. There was little difference between the drugs in the influence on blood pressure, but metoprolol and propranolol were significantly more effective than labetalol in lowering the heart rate.
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  • 37
    ISSN: 1432-1041
    Keywords: alpha-methyldopa ; propranolol ; hypertension ; side effects ; blood pressure control
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A multicentre study of 6–10 weeks duration was performed in 60 ambulant hypertensive patients aged over 60 years to compare the efficacy of methyldopa and propranolol with particular reference to the occurrence of cold extremities and sleep disturbances. Blood pressure was effectively controlled by both drugs being reduced from a mean of 180/108 mmHg to 161/93 with methyldopa and 180/108 to 162/94 with propranolol. More patients treated with methyldopa (74%) achieved the target diastolic blood pressure of 95 mmHg or below compared with those treated with propranolol (58%). Side effects were more frequent in the propranolol group necessitating the withdrawal of four patients from the study. Only one patient on methyldopa was withdrawn. The incidence of cold extremities was significantly greater with propranolol. The occurrence of sleep disturbances was similar in both groups. In this group of elderly patients methyldopa was better tolerated than propranolol.
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  • 38
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    European journal of clinical pharmacology 26 (1984), S. 543-547 
    ISSN: 1432-1041
    Keywords: indapamide ; hypertension ; glomerular filtration ; arginine vasopressin ; free water clearance ; blood pressure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Renal plasma flow (RPF), glomerular filtration rate (GFR), arginine vasopressin in plasma (AVP), free water clearance ( $${\text{C}}_{{\text{H}}_{\text{2}} {\text{O}}}$$ ) and blood pressure (BP) were determined in 11 patients with essential hypertension at the end of 3 consecutive periods of observation each of 6 of weeks duration; indapamide 2.5 mg daily was given in period 2 and placebo in periods 1 and 3. RPF and GFR were reduced by 9% and BP by 9%/14% supine and 14%/12% standing during indapamide treatment. Changes in renal haemodynamics were not correlated with those in BP. AVP was not significantly altered by indapamide and was not correlated with BP. Indapamide reduced $${\text{C}}_{{\text{H}}_{\text{2}} {\text{O}}}$$ possibly due to the reduction in GFR. It is concluded that indapamide evidently induces redistribution of the cardiac output, with enhanced muscle blood flow and reduced renal perfussion, and that AVP does not seem to be involved in blood pressure regulation in mild to moderate essential hypertension under basal conditions.
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  • 39
    ISSN: 1432-1041
    Keywords: beta-blockers ; hypertension ; ISA ; CS ; cold extremities
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Patients with essential hypertension were interviewed prior to entering therapeutic studies in general practice. Patients' age, sex and details of antihypertensive therapy (if any) were noted, as were their spontaneously reported symptoms. Complaints of cold extremities were highest in those taking a beta-blocker (4.1%). Those untreated or taking other therapies complained less often. Those patients taking a beta-blocker with ISA complained less often (3.1%) of cold extremities than those taking a beta-blocker without ISA (5.2%).
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  • 40
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    European journal of clinical pharmacology 27 (1984), S. 13-17 
    ISSN: 1432-1041
    Keywords: nifedipine ; hypertension ; blood pressure decrease ; drug combination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The medication of patients receiving hydralazine, captopril and minoxidil was replaced by a new galenical form, long-acting nifedipine. An additional decrease in blood pressure was observed in most of the patients. Renal function was maintained in all of them. Adverse reactions may be reduced by the use of long-acting nifedipine, which would permit a reduction in the dosage of captopril and minoxidil.
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  • 41
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    European journal of clinical pharmacology 27 (1984), S. 23-27 
    ISSN: 1432-1041
    Keywords: hypertension ; alpha2-adrenoceptors ; blood pressure ; clonidine ; guanfacine ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The time courses of the changes in plasma growth hormone and noradrenaline concentrations in response to 15 min infusions of clonidine 0.2 mgs and guanfacine 2 mgs, were studied in six normal volunteers, in a double-blind, randomised, crossover study. Plasma noradrenaline fell within 15 min of the commencement of drug administration, by 36±14% after clonidine (p〈0.05) and by 32±11% (p〈0.05) after guanfacine. Plasma growth hormone was not significantly elevated until the 30th minute to 12.0±4.7 lU/ml (p〈0.05) after clonidine and 14.7±11.5 lU/ml (p〈0.05) after guanfacine, having been undetectable prior to both drugs. The reduction in plasma noradrenaline by these α2-adrenergic agonists, prior to activation of central adrenoceptors as detected by changes in plasma growth hormone, is evidence for a peripheral component in their sympatholytic effect.
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  • 42
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    European journal of clinical pharmacology 27 (1984), S. 147-152 
    ISSN: 1432-1041
    Keywords: moxonidine ; clonidine ; hypertension ; double-blind crossover ; side-effects ; withdrawal
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The antihypertensive effect of moxonidine·HCl·H2O (MOX) was compared with that of clonidine·HCl (CLON) in a randomized double-blind crossover study in 20 hypertensive outpatients (BP range 154–178/96–108 mmHg). After 2 weeks without antihypertensive medication, either MOX 0.2 mg daily or CLON 0.2 mg daily was given and the dose was titrated until the diastolic blood pressure fell below 90 mmHg. The first treatment period was continued for 2 weeks and, after crossover without a wash-out period, it was followed by the second treatment for a further 2 weeks. Within the first 4 days of administration 0.2–0.4 mg of either agent caused a significant decrease in BP (p〈0.001) from a mean of 166/100 mmHg to 149/86 mmHg after CLON (approx. −10/−14%), and 163/99 mmHg to 146/84 mmHg after MOX (approx. −10/−15%). No significant difference in the fall in BP or pulse rate was detected between the two drugs. In the mean daily dose of 0.3 mg both drugs showed the same antihypertensive activity, but on CLON a higher incidence of side effects (p=0.003) was noted, and after discontinuation of therapy a more rapid rise in BP (systolic BP p〈0.01, diastolic BP p〈0.02) was found. 17 patients on CLON complained of side effects, especially tiredness and dry mouth, whilst only 6 patients on MOX were affected (p=0.003).
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  • 43
    ISSN: 1432-1041
    Keywords: guanfacine ; hydrallazine ; hypertension ; sympathetic nervous activity ; plasma renin activity ; cardiac and systemic haemodynamics ; blood pressure ; limb blood flow ; limb vascular resistance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of guanfacine and hydrallazine on cardiovascular haemodynamics and on sympathetic nervous activity has been studied in 16 patients with essential hypertension. Two groups of patients were investigated: in Group A guanfacine brought the blood pressure back to normal (diastolic blood pressure ⩽90 mmHg), and in Group B diastolic blood pressure was 〉 90 mmHg and required the addition of hydrallazine. Guanfacine significantly decreased heart rate, plasma renin activity and urinary excretion of noradrenaline, without altering cardiac contractility. In Group B, guanfacine 2 to 6 mg/day produced a significant decrease in blood pressure from 178.7/112.4 to 164.4/102.9 mmHg and in heart rate from 77.1 to 62.7 beats/min after 4 weeks of treatment. Guanfacine did not significantly alter preejection period, cardiac output or total peripheral resistance. Hydrallazine 50 to 300 mg/day caused a further reduction in blood pressure from 164.4/102.9 to 150.7/90.2 mmHg and an increase in heart rate from 62.7 to 72.1 beats/min. Limb blood flow was increased from 4.55 to 5.93 ml/100 g/min and limb vascular resistance was decreased from 39.55 to 23.6 mmHg 100 g·min/ml. Hydrallazine also caused a slight increase in plasma renin activity and urinary excretion of noradrenaline. It is concluded that guanfacine is a useful agent to block a hydrallazine-induced increase in sympathetic nervous activity.
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  • 44
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    European journal of clinical pharmacology 27 (1984), S. 407-414 
    ISSN: 1432-1041
    Keywords: piretanide ; hypertension ; triamterene ; double blind comparison ; potassium ; magnesium ; side-effects ; serum electrolytes ; serum parameters
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a randomized, double blind, parallel group study in out patients with mild to moderate essential hypertension the effects of piretanide on serum electrolytes and on blood pressure were compared with those of triamterene alone and the combination piretanide + triamterene. 136 patients entered the study; 18 patients did not fulfill the inclusion criteria (RRdiast was below 95 mmHg or above 120 mmHg) at the end of the placebo period, 6 dropped out due to side effects, and 1 due to lack of efficacy. Data from 1 patient were not evaluated because the patient did not come regularly for checkups. The results for 110 patients were analyzed. Piretanide 6 mg b.d. and piretanide 6 mg + triamterene 50 mg b.d. produced a significant reduction both in supine and erect blood pressure, which was evident at 2 weeks and which increased over the ensuing 12 week trial period. A mean maximal fall of 16.5% was noted in the piretanide group and 15% in the piretanide + triamterene group. Triamterene alone (50 mg b.d.) also reduced diastolic and systolic blood pressures but the reduction was significantly less (diastolic blood pressure) than in both the piretanide groups, and it showed a more rapid return to pretreatment level during a placebo washout phase at the end of the study. A reduction in standing diastolic blood pressure below 95 mmHg was attained in 84% of patients in the piretanide group, 82% in the piretanide + triamterene group and in only 58% of the triamterene group. There were no significant changes within groups nor differences between the three groups in serum potassium or magnesium. 7 patients were withdrawn from the study because of side-effects due to too marked a clinical action (polyuria, orthostatic disorders and hypotension), one from the piretanide group, and the others in the piretanide + triamterene group. One patient in the triamterene group left the study prematurely due to the lack of effect.
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  • 45
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    European journal of clinical pharmacology 27 (1984), S. 529-534 
    ISSN: 1432-1041
    Keywords: beta-adrenoceptor blocking agents ; hypertension ; adverse reactions ; atenolol ; bopindolol ; pindolol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The efficacy of once-daily bopindolol, a nonselectiveβ-adrenoceptor blocking agent with partial agonist activity, and of pindolol and atenolol in the treatment of essential hypertension has been compared. 369 patients were investigated in a double-blind parallel-group study. The treatment period was 10 weeks. Blood pressure normalisation (diastolic BP equal to or less than 90 mmHg) was to be achieved by a stepwise increase in the dose of the test drugs, and, if required, by addition of a diuretic. Normalisation of blood pressure was achieved in 71 to 76% of the subjects, with no significant differences between bopindolol, pindolol, and atenolol. Special attention was given to evaluation of side effects by using two methods for registration of all adverse events during the study. A low incidence of drug-induced side effects was observed, with no significant difference between bopindolol, pindolol, and atenolol. There was no evidence of unsuspected adverse reactions due to bopindolol.
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  • 46
    ISSN: 1432-1041
    Keywords: hypertension ; captopril ; nifedipine ; plasma renin activity ; aldosterone ; vasopressin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a single-dose crossover study Captopril (SQ 14225), 1 mg/kg body weight, and Nifedipine (Bay a 1040) 20 mg were administered orally to 12 hospitalized patients with essential hypertension (Stage 1 or 2, W. H. O.). Both drugs significantly reduced blood pressure, but each dose acted differently: the mean maximum arterial pressure reduction was faster and greater with Nifedipine than with Captopril: −23±2% at 37±15 min and −17±1% at 86±25 min, respectively. Captopril inhibited angiotensin II and aldosterone production, but did not accelerate heart rate or stimulate vasopressin release. Nifedipine stimulated vasopressin release and increased heart rate, but the renin angiotensin aldosterone system was not significantly affected. The blood pressure reduction was related to the initial level of activation of the renin angiotensin system only for Captopril. The blood pressure reduction induced by one drug was not related to that produced by the other in the same patient.
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  • 47
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    European journal of clinical pharmacology 20 (1981), S. 237-240 
    ISSN: 1432-1041
    Keywords: labetalol ; clonidine ; hypertension ; adverse effects ; plasma catecholamines ; plasma cAMP ; withdrawal
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eleven hypertensive patients in whom clonidine therapy had to be discontinued, were treated prophylactically with labetalol, in order to avoid a possible hypertensive crisis. Most of the known side effects, which are consistent with the withdrawal phenomenon were observed, e.g. tremor, insomnia and apprehension, but headaches and flushing did not occur. Blood pressure levels remained unchanged, despite up to a 20-fold increase in plasma catecholamines. The lack of change in serial measurements of plasma cyclic AMP level appears to indicate that adequate adrenergic blockade was induced by labetalol. Since labetalol is a potent anti-hypertensive drug, and is also effective in avoiding a possible hypertensive crisis due to withdrawal of clonidine, we propose to use it as the drug of choice whenever discontinuation of clonidine therapy is indicated.
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  • 48
    ISSN: 1432-1041
    Keywords: aldosterone ; hypertension ; propranolol ; blood pressure ; plasma level ; renin ; urine level
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Thirty patients with mild or moderate essential hypertension, and a fixed elevation of diastolic blood pressure, were randomly allocated to three groups and treated with propranolol 40 mg×4 (Group 1), 80 mg×4 (Group 2) and 160 mg×4 (Group 3). Blood pressure (BP), pulse rate (PR), plasma renin activity (PRA), plasma aldosterone concentration (PAC), total plasma propranolol (tPP), free plasma propranolol (fPP), and 24 h urinary propranolol excretion (UP) were determined at the end of four consecutive periods: (A) after four weeks without any treatment; (B) after two to three weeks during which the propranolol dose was gradually increased to the intended level; (C) after four weeks, and (D) after eight weeks of unchanged treatment. The maximum reduction in diastolic BP occurred after period B, and in systolic BP after Period C, for Groups 2 and 3, and for all groups together; for Group 1, however, the maximum diastolic BP reduction was first seen after period C. PR was reduced to the same level in all groups after period B. After period B, PRA and PAC fell in all groups, and remained reduced during C and D in Group 1. After periods C and D, PRA and PAC in Groups 2 and 3 did not differ significantly from the levels after period A; tPP, fPP and UP were significantly correlated with the propranolol dose, and were lowest in Group 1 and highest in Group 3; UP was negatively correlated with systolic but not diastolic BP in Periods B, C and D. In contrast neither fPP nor tPP were correlated with systolic or diastolic BP. There was no significant correlation between PRA, PAC and changes in PRA or PAC on the one hand and tPP, fPP, UP, BP or changes in BP on the other. It was concluded that propranolol effectively reduced BP, but diastolic BP reduction was most rapidly obtained at 320 and 640 mg daily, that the activity of the renin-aldosterone system was initially suppressed in all groups, but for unknown reasons it increased towards the control level after seven to eleven weeks of therapy with 320 and 640 mg/day, and that the reduction in systolic BP increased with higher doses of propranolol and with increasing urinary propranolol excretion.
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  • 49
    ISSN: 1432-1041
    Keywords: clonidine ; minoxidil ; hypertension ; sympathetic nervous activity ; plasma renin activity ; cardiovascular responses
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of clonidine and minoxidil on sympathetic nervous activity has been studied in 10 patients with accelerated or resistant hypertension. Clonidine 150 to 900 µg/day caused a significant decrease in blood pressure of 18.6 mm Hg, of heart rate 16.4 beats/min, or plasma renin activity 1.13 ng/ml·h, and of urinary noradrenaline excretion 11.55 µg/day, and a significant lengthening of the pre-ejection period of 12.4 ms. Minoxidil 5 to 22.5 mg/day caused a further significant decrease in blood pressure of 24.2 mm Hg, and significant increases in heart rate 8.2 beats/min, plasma renin activity 1.68 ng/ml·h, and of urinary noradrenaline excretion 5.0 µg/day, and a significant shortening of the pre-ejection period of 20.6 ms. Neither clonidine nor minoxidil altered plasma dopamine β-hydroxylase activity or the cardiovascular responses to treadmill exercise. It is concluded that clonidine is a useful alternative agent to block a minoxidil-induced increase in sympathetic nervous activity.
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  • 50
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    European journal of clinical pharmacology 21 (1981), S. 93-96 
    ISSN: 1432-1041
    Keywords: atenolol ; penbutolol ; hypertension ; beta-blockers ; intrinsic sympathomimetic activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Atenolol 100 mg and penbutolol 40 mg given once a day were both effective in controlling moderate hypertension, as judged by a randomised controlled, double-blind trial in 45 patients treated for six weeks. Both drugs significantly reduced the resting supine and erect blood pressures. No serious adverse effects could be attributed to either drug. Bradycardia occurred more frequently with atenolol than with penbutolol. Penbutolol, which possesses intrinsic sympathomimetic activity, may be useful in the treatment of patients in whom some other beta-blocker has failed to bring about adequate control of the blood pressure, despite marked bradycardia.
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  • 51
    ISSN: 1432-1041
    Keywords: hypertension ; hydrochlorothiazide ; atenolol ; side effects ; therapeutic efficacy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary After screening a local population in the northern part of The Netherlands for hypertension, 119 patients with a diastolic pressure (DP) between 95 and 120 mmHg were randomised and treated either with 50 mg hydrochlorothiazide (n=59) or 100 mg atenolol (n=60). After 1 month of treatment 6 patients in the hydrochlorothiazide group and 24 patients in the atenolol group had reached a DP⩽90 mmHg (p〈0.001). 43 of the 50 non-responders to hydrochlorothiazide were switched to atenolol and 30 of the 35 non-responders to atenolol were changed to hydrochlorothiazide. One month after the switch 19 patients in the atenolol group and 2 patients in the hydrochlorothiazide group had reached a DP⩽90 mmHg (p〈0.001). After 6 months of treatment 32 of the 43 atenolol responders and 7 of the 8 hydrochlorothiazide responders were still receiving the same medication, as their DP was still⩽90 mmHg. Non-responders to either medication were given the combination (n=46). 21 patients now became normotensive as did a further 10 after increasing the dose of atenolol to 200 mg. Thus, in all 70 patients had a blood pressure ⩽90 mmHg after treatment for 4 months. Both drugs induced a significant reduction in the total of number of complaints after 1 month of treatment. They did not differ from each other. The reduction was seen both in responders and non-responders and persisted during treatment for 6 months. It is concluded that in terms of short-term efficacy the cardioselective, hydrophilic beta adrenoceptor-blocking drug atenolol is preferable to hydrochlorothiazide in the treatment of uncomplicated hypertension.
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  • 52
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    European journal of clinical pharmacology 26 (1984), S. 603-608 
    ISSN: 1432-1041
    Keywords: pinacidil ; hypertension ; pinacidil pyridine-N-oxide ; urinary excretion ; protein binding ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Preliminary investigation in 3 healthy volunteers suggested that intravenous pinacidil in a dose of 0.2 mg/kg had a potent but well-tolerated hypotensive action in the supine position. Facial flushing, uncomfortable chest sensation and distressing postural hypotension occurred at serum concentrations above 300 ng/ml. Pinacidil, 0.2 mg/kg, was given intravenously over 4 min to 15 healthy volunteers in the supine position. Maximum fall in mean arterial pressure (MAP) was 15.7±6.0 mmHg. Maximum rise in heart rate was 23.8±6.6 beats/min. Pinacidil serum distribution half-life ( $${\text{T}}_{{\raise0.7ex\hbox{${\text{1}}$} \!\mathord{\left/ {\vphantom {{\text{1}} {{\text{2}}\alpha }}}\right.\kern-\nulldelimiterspace}\!\lower0.7ex\hbox{${{\text{2}}\alpha }$}}}$$ ) was 13.4±8.5 min and elimination half-life ( $${\text{T}}_{{\raise0.7ex\hbox{${\text{1}}$} \!\mathord{\left/ {\vphantom {{\text{1}} {{\text{2}}\beta }}}\right.\kern-\nulldelimiterspace}\!\lower0.7ex\hbox{${{\text{2}}\beta }$}}}$$ ) was 2.13±0.49 h. The apparent volume of distribution (Vdβ) was 90.3±13.21 and total body clearance was 31.1±9.61/h. Pinacidil was approximately 40% bound to plasma protein over the concentration range 40–400 ng/ml. Urinary excretion of unchanged pinacidil accounted for 5.7 ± 1.3% of the administered dose over 24 hours and urinary excretion of the major metabolite, pinacidil pyridine-N-oxide, was 31.6±9.2% of the administered dose. It was concluded that intravenous pinacidil is a potent vasodilator hypotensive compound, with a duration of action between 1.5 and 2 h.
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  • 53
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    European journal of clinical pharmacology 26 (1984), S. 661-661 
    ISSN: 1432-1041
    Keywords: endralazine ; hypertension ; elimination half-liefe ; compartment model
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  • 54
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    European journal of clinical pharmacology 27 (1984), S. 13-17 
    ISSN: 1432-1041
    Keywords: nifedipine ; hypertension ; blood pressure decrease ; drug combination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The medication of patients receiving hydralazine, captopril and minoxidil was replaced by a new galenical form, long-acting nifedipine. An additional decrease in blood pressure was observed in most of the patients. Renal function was maintained in all of them. Adverse reactions may be reduced by the use of long-acting nifedipine, which would permit a reduction in the dosage of captopril and minoxidil.
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    European journal of clinical pharmacology 27 (1984), S. 23-27 
    ISSN: 1432-1041
    Keywords: hypertension ; alpha2-adrenoceptors ; blood pressure ; clonidine ; guanfacine ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The time courses of the changes in plasma growth hormone and noradrenaline concentrations in response to 15 min infusions of clonidine 0.2 mgs and guanfacine 2 mgs, were studied in six normal volunteers, in a double-blind, randomised, crossover study. Plasma noradrenaline fell within 15 min of the commencement of drug administration, by 36±14% after clonidine (p〈0.05) and by 32±11% (p〈0.05) after guanfacine. Plasma growth hormone was not significantly elevated until the 30th minute to 12.0±4.7 lU/ml (p〈0.05) after clonidine and 14.7±11.5 lU/ml (p〈0.05) after guanfacine, having been undetectable prior to both drugs. The reduction in plasma noradrenaline by these α2-adrenergic agonists, prior to activation of central adrenoceptors as detected by changes in plasma growth hormone, is evidence for a peripheral component in their sympatholytic effect.
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  • 56
    ISSN: 1432-1041
    Keywords: beta-blockers ; hypertension ; ISA ; CS ; cold extremities
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Patients with essential hypertension were interviewed prior to entering therapeutic studies in general practice. Patients’ age, sex and details of antihypertensive therapy (if any) were noted, as were their spontaneously reported symptoms. Complaints of cold extremities were highest in those taking a beta-blocker (4.1%). Those untreated or taking other therapies complained less often. Those patients taking a beta-blocker with ISA complained less often (3.1%) of cold extremities than those taking a beta-blocker without ISA (5.2%).
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    European journal of clinical pharmacology 27 (1984), S. 287-289 
    ISSN: 1432-1041
    Keywords: pinacidil ; hypertension ; vasodilator ; patients ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A new vasodilator drug, pinacidil, N″-cyano-N-4-pyridyl-N′-1, 2,2-trimethylpropylguanidine, was studied in an open trial in 15 patients with moderate to severe hypertension. Four patients received pinacidil monotherapy, and in 11 patients it was used with a diuretic or a beta-blocker. In all but one patient normotension was achieved with a mean daily pinacidil dose of 46.7 mg b.i.d. (range 20–100 mg). Side effects were few and were action-related. There was no evidence of early toxicity. Pinacidil is a promising new antihypertensive vasodilator, which deserves further clinical evaluation.
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  • 58
    ISSN: 1573-8221
    Keywords: mesenteric microcriculation ; cardiac output ; Cardiogreen dilution method ; celiac ganglion ; hypertension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
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  • 59
    ISSN: 1573-8221
    Keywords: hypertension ; β-adrenoreceptors ; lymphocytes ; man
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    Bulletin of experimental biology and medicine 91 (1981), S. 18-21 
    ISSN: 1573-8221
    Keywords: arterial pressure ; hypertension ; capillary circulation
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    Bulletin of experimental biology and medicine 98 (1984), S. 1283-1285 
    ISSN: 1573-8221
    Keywords: cerebral microcirculation ; hypertension
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    Journal of Biomedical Materials Research 5 (1971), S. 135-148 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: Hollow fibers have been produced and evaluated for use as membrane oxygenators in an artificial heart device. Gas permeable capillaries now commercially available are unsuitable for this use because of: (1) low percent open cross-sectional area, (2) large internal diameter, and (3) high cost. A number of polymers were initially selected for evaluation because of their reported high gas permeabilities. Those selected include a number of rubbers of various compositions, certain poly-α-olefins and an experimental thermoplastic silicone rubber copolymer. These materials were first evaluated as flat membranes (films) for their gas permeabilities and also for ease of preparation in hollow fiber form. Hollow fibers were prepared from the most promising of those studied, poly-4-methylpentene-1 and the thermoplastic polydimethylsiloxane copolymer. Fibers, ranging in the size from 30 to 300 μ ID, were spun with open cross-sectional areas of 40-65%. Oxygen and carbon dioxide permeabilities measured on these fibers were compared to that of SilasticDow Corning medical grade poly (dimethylsiloxane). rubber membranes. These permeabilities range from 1/20 that of Silastic rubber for unmodified poly-4-methylpentene-1 to 2/3 for the thermoplastic silicone copolymer. Modification of poly-4-methylpentene-1 has made it possible to increase it's permeability by tenfold, while still maintaining physical properties necessary to spin and fabricate this material.
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    Journal of Biomedical Materials Research 5 (1971), S. 41-47 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: Advanced forms of elemental carbon were identified as potential implantable prosthetic materials and a study was conducted to determine specific applications. A survey of the carbon industry established material sources and specifications on available types of material. Specimen materials were supplied to several research organizations for in-vivo evaluation and produced acceptable results. Specific designs have been generated for a broad range of implantable prosthetics and prototypes have been provided for preliminary evaluation. The feasibilty of an organic mechanical attachment between cortical bone tissues and elemental carbon has been successfully demonstrated.
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    Journal of Biomedical Materials Research 5 (1971), S. 69-89 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: The success of material implants in the vascular system has been limited by the fact that the intial events of blood coagulation on foreign material surfaces are not understood. Many materials have been evaluated in the search for a suitable implant material in this system. Recent success of porous ceramic materials in bone-ceramic compatibility studies stimulated the feeling that these materials should be tested in other body tissues such as the blood.Ceramic disks of Al2O3 and TiO2 were evaluated using a contact angle measurement technique to determine the characteristics of these material surfaces before and after exposure to a blood environment. This technique involved measuring the contact angle of sessile drops of various liquids on these surfaces with a microscope fitted with a goniometer eyepiece. By plotting these contact angles according to the procedure of Zisman, the characteristics of the surfaces could be evaluated.The clean ceramic disks were found to be extremely wettable even after exposure to a physiological saline environment. On exposure of these disks to a blood environment, it was observed that some type of film was adsorbed from the blood onto the ceramic surface during the initial minutes of exposure. This film had wetting characteristics consistent with layers of fibrinogen.
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    Journal of Biomedical Materials Research 5 (1971), S. 143-159 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: The skeletal attachment of a limb prosthesis approaches two specific and separate problems in tissue reaction to prosthetic materials: Skeletal fixation and trancutaneous interface.The skeletal fixation problem must be looked upon as a method to distribute the stress concentration of prosthetic material in such a manner so that living tissue is not embarrassed by prolonged excessive pressures. One must consider the functional mechanical stresses separate from the toxicological reaction of living tissues to prosthetic materials. Our current experience identifies the fact that vitreous carbon is extremely benign from the standpoint of living tissue reaction. Moreover, when placed in the configuration of irregular surfaces, it apparently encourages bone growth contiguous with the material. To this point, however, the reaction of living material to broad surfaces contiguous with vitreous carbon has not placed under concentration of functional stresses. Porous ceramic to this date has not supplied an appropriate answer to this problem.Transcutaneous perforation is available in the clinical sense only when a method can be presented which requires no specific hygiene and dressing. No drainage at all must be the rule at a transcutaneous perforation. Vitreous carbon in our experience so far has made contiguous epithealization feasible down the neck of a skin perforation. Four millimeters, from our experience, seems to be an appropriate location of epithelial downgrowth before transition into non epithealized connective tissue is available. The use of fixation skirts is felt to be necessary to provide stable, transcutaneous perforation.This paper presents evidence of the favorable tissue reaction both from a skeletal and cutaneous standpoint to vitreous carbon materials. A specific design for the successful skeletal fixation limb prosthesis is as yet not currently available and must await further clinical experience with human skin reaction to transcutaneous devices.
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    Journal of Biomedical Materials Research 5 (1971), S. 231-249 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: A study has been made of the ceramic-epoxy composite “Cerosium.” Experiments were conducted to evaluate the tissue reaction to such material and the extent of bonding established between ceramic and the tissues in which it was implanted. It was found that this material was well tolerated by the body and obtained definite fixation within the tissues when implanted into both bone and tendon. This occurred, however, not by the active infiltration of tissue but by fibrous encapsulation and it is recommended that for more meaningful stabilization, material of larger pore size is required.When Cerosium was implanted into the knee joints of rabbits, it was found to be unsuitable for intra-articular use because of the abrasive effect on the opposing cartilage and bone surfaces and the susceptibility of the material itself to abrasive wear. Furthermore, a full mechanical evaluation of standard specimens of Cerosium showed it to be degraded within the body due to a breakdown of the impregnating polymer.Ceramic-epoxy composites require a strong matrix and a totally stable impregnating material. While mechanically suited to replacing weight bearing surfaces, a smooth surface glaze is essential to avoid abrasive effects upon the opposing bone surface. Further investigation is required before these materials can be fully accepted into the armamentarium of the implant surgeon.
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    Journal of Biomedical Materials Research 8 (1974), S. 115-126 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: A standardized readily reproducible experimental model has been developed to assess the relative importance of the chemical and physical configuration of sutures as determinants of early infection in contaminated wounds. The chemical structure of the suture appeared to be the most important factor in the development of surgical infection. The incidence of infection in contaminated tissues containing either polypropylene sutures or nylon sutures was lower than the infection rate of tissues subjected to any other nonabsorbable suture. Among the absorbable sutures, polyglycolic acid (PGA) sutures evoked the least inflammatory response. The infection rate of contaminated tissues containing the PGA sutures was not significantly different from the incidence of infection of tissues subjected to the least reactive nonabsorbable sutures. The physical configuration of the suture played a relatively unimportant role in the development of early infection. The infection rate of contaminated tissues containing monofilament nonabsorbable sutures did not differ significantly from the incidence of infection of tissues subjected to multifilament sutures made from the same material. Coating the multifilament suture with either silicone, wax, or Teflon did not alter the incidence of early infection in the contaminated tissue. Finally, the presence of even the least reactive suture in contaminated subdermal tissue potentiated the development of infection.
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    Journal of Biomedical Materials Research 8 (1974), S. 163-173 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: Experiments were conducted to further the understanding of tendon reconstructive surgery.A series of 20 dogs was used for replacement of the forepaw extensor carpi radialis tendon (a single tendon only is present in the dog) with active gliding tendon implants. The implants were attached distally and proximally so that new tendon prosthetic designs could be studied as well as new sheath development under gliding conditions.The results, recorded in this paper, show that a “gliding implant” can convert a nonspecific bed of connective tissue or scar into a specific living envelope comparable to a tendon sheath system. This system has been shown to be capable of lubricating and supporting a gliding artificial implant while augmenting normal tendon function. Degrees of active and passive gliding can take place for indefinite periods, providing the mechanical and dynamic capabilities of the new system are understood and controlled. The mature sheath will show a predictable physiologic response to unfavorable stimuli.Further evidence that the new gliding system functions as a physiologic sheath is borne out by the fact that the implant can be replaced in Stage II by a long free tendon graft. The graft is apparently supported in part by fluid nutrition and filmy adhesions between the distal and proximal anastomosis.
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    Journal of Biomedical Materials Research 8 (1974), S. 365-371 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: The mandibular staple is an endosseous implant that will permit the attachment of a lower deture in cases of severe alveolar bone atrophy. It is placed through a submental incision and inserted into seven parallel holes drilled into the mandible. A curved bar containing seven pins is inserted in the holes and is place against the inferior border of the mandibular symphysis. The two lateral most pins project into the mouth and the five retentive pins remain completely buried in bone. Two fasteners are screwed down on the threading of the intraoral pins. Later a bridge containing Dalbo attachments is cemented to the fasteners which allow attachment to a lower denture. A series of 25 patients have been completed with 20 successful patients for survival rate of 80%. The longest case has been in for five years and the average case has been in for 3 years. Stainless steel, titanium and ceramic coated titanium has been with apparently equal success. Patient acceptance has been excellent.
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    Journal of Biomedical Materials Research 8 (1974), S. 391-399 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: A study sponsored by the National Institute of Dental Research has as its major goal the development of easily fabricated and implantable dental anchors for replacement of missing or extracted teeth. Tissue ingrowth fixes the anchors in the mandibular or maxillary bone where they can serve as a base for future attachment of prefabricated dental caps, bridges, or other dental prostheses. More immediate objectives are to determine the suitability of specific porous titanium and ceramic materials for anchor applications, to develop satisfactory designs and fabrication procedures for producing these devices, and to define material/bone interface bonding characteristics through in vivo studies. The value of the Hanford Miniature Swine as a human analog for dental research is being assessed concurrently.
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    Journal of Biomedical Materials Research 8 (1974), S. 49-64 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: A series of nonporous glasses and glass materials designed with controlled surface ion activities to allow chemical bonding to bone are described. Surface reactivities of these materials in vitro are correlated with biological activities in vivo and in tissue culture. Direct chemical bonding of the materials to bone is demonstrated. The mechanism for development of this bond is through the production of an amorphous ion surface gel on the bioglass. This gel induces osteogenesis by a chemotactic response of osteoblasts.
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    Journal of Biomedical Materials Research 8 (1974), S. 99-113 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: One method of providing an artificial limb for an amputee might be to attach the external prosthesis directly to the skeleton but a major problem is the behavior of the tissues at the point where the prosthesis penetrates the skin surface. Preliminary experiments have been carried out using small flexible implants in porcine skin to study the principles involved. It is confirmed that the epidermis grows down into the dermis around the nonporous materials and the implant-skin junction is unstable and readily becomes infected. It was found that polytetrafluorethylene with pores of 10 μm diameter and hydron sponge with pores of 40 μm diameter became invaded by fibrous tissue and this appeared to prevent the migration of epidermis alongside the implants and a stable ring of epidermal tissue was formed near the skin surface. A review of other situations where epidermal migration is taking place suggests that epidermis is able to migrate through damaged collagenous tissue, possibly with the help of leucocytic enzymes, but that epidermal cell movement is halted when the epidermal sheet is confronted by heathly collagen bundles.
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    Journal of Biomedical Materials Research 8 (1974), S. 145-153 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: Polymeric materials are becoming increasingly popular as prosthetic materials in orthopedic surgery. One of these materials, polyethylene, is capable of being fabricated in a porous form suitable for tissue ingrowth. Porous polyethylene appears to be well suited for prosthesis attachment when bonded to its solid form of other prosthetic materials. Extensive bone growth into porous cylindrical specimens implanted in the canine femur has occurred as early as four weeks. Ingrown tissues appear normal and there is minimal inflammatory response. Mechanical strength of the porous material, though not as great as that of the solid material, does appear to be sufficient for certain orthopedic applications. Current research is directed toward determining interfacial strengths and the mechanical properties of the porous polyethylene-bone composite.
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    Journal of Biomedical Materials Research 8 (1974), S. 185-196 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: An investigation was conducted to determine the general physical characteristics of self-curing acrylic resin systems in terms of their potential utilization in total hip arthroplasty.Exothermic temperature, working and setting times were monitored with thermocouples placed in acrylic masses insulated via a Teflon mold. Mechanical strengths were run in an Instron testing machine. The same trends were noted in all systems studied.As thickness or mass increased, the maximum temperature and the setting time increased. As the powder to liquid ratio increased (thereby relatively less liquid), the maximum temperature, set times and dough times decreased, while the working time was essentially unaffected. As the ambient temperature decreased, the maximum temperature decreased while the dough, working and setting times increased.The mechanical strengths of the systems cured at one atmosphere are low compared to high temperature and pressure curing. Flowability of the materials decreases quickly as final set time is approached.Although trends are similar in many self-curing acylic systems minors shifts in complex proprietary compositions can produce a wide span or working and setting times. Because the surgical team controls such parameters as the mass employed, the amount of liquid introduced, and the ambient temperature it is important that they continuously re-evaluate their handling procedures particularly if new acrylic cements would be introduced.
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    Journal of Biomedical Materials Research 8 (1974), S. v 
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    Keywords: Chemistry ; Polymer and Materials Science
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    Journal of Biomedical Materials Research 8 (1974), S. 271-283 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: Through a survey of hip replacement arthroplasty the paper establishes the case for objective evaluation of these joints in the patient. It then outlines a simple, non-invasive technique, based on Paul's (1967) locomotion studies, to assess pre- and postoperative functional capability. Preliminary results which establish viability of the procedure are presented.
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    Journal of Biomedical Materials Research 8 (1974), S. 319-328 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: A porous titanium alloy called void metal composite (VMC) was investigated for use in knee prosthesis fixation. The interfacial ingrowth fixation of VMC intrameduallary, subchondral, and variable density implants in goat femora was evaluated biomechanically and histologically at six weeks and five months. Biomechanical tests were done under static shear and dynamic, cyclic (fatigue) loading conditions. Readily identifiable bone, strong fixation, and excellent biocompatibility were typical. Some subarticular implants appeared to induce normal hyaline cartilage overgrowth.
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    Journal of Biomedical Materials Research 8 (1974), S. 87-90 
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    Keywords: Chemistry ; Polymer and Materials Science
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    Journal of Biomedical Materials Research 8 (1974), S. 97-117 
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    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
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    Notes: A significant variation occurred in the inflammatory response to polyethylene and polyurethane when embedded subcutaneously in experimental animals. This variation apparently is related to the composition of the plastic and adsorption of proteins. The attraction of polymorphonuclear leucocytes by plastics apparently is related to the electrostatic and/or electrokinetic imbalance that occurs at or near the site of implantation.Polyurethane and polyethylene were selected for this study since preliminary observations had shown a variation in inflammatory response when they were embedded subcutaneously in the mouse. From this study it is evident that: (1) variations occurred in the inflammatory reaction in the subcutaneous tissue of mice and rabbits following the embedding of polyethylene and polyurethane; (2) polymorphonuclear leucocytes began to emigrate within hours after these two plastics were implanted, reaching their maximum number within 24 to 48 hr; (3) polymorphonuclear leucocytes usually were absent after the 6th experimental day in mice with polyurethane, but were present for 232 days in mice with polyethylene; (4) polymorphonuclear leucocytes were present in the rabbit for only a few days following subcutaneous implantation of polyethylene and polyurethane; and (5) leucocytes around the implanted polyurethane in the rabbit began to degenerate within 48 hr. The mechanism for this degeneration is not known.
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    Journal of Biomedical Materials Research 8 (1974), S. 185-188 
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    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
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    Keywords: Chemistry ; Polymer and Materials Science
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    Notes: Two types of dense Al2O3 ceramics (99.6% purity, 96% purity) were tested in the following fields of interest.1Wear resistibility using a pin and disk method under distilled water and human synovial fluid. Both types showed minimal initial corpuscular wear.2Biocompatibility of ceramic wear particles in mice and rats after injection by different ways. The crystal material is permanently deposited in macrophages, after transport via lymphpatic and blood vessels also in the RES without chronic inflammatory and progressive fibrotic response.3Under moderate stress conditions ceramic plates are fixed firmly by new bone formation within 2-3 months according to tetracycline label studies of bone growth in rats.4A new ceramic total hip prosthesis with two different socket designs for cement free fixation in bone is proposed and used in sheep experiments. The results of a 4 month experiment is presented showing firm fixation of the prosthesis under full stress conditions.
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    Journal of Biomedical Materials Research 8 (1974), S. 85-97 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: A study of the tissue compatibility of aluminum oxide implants under different stress conditions in rabbits was performed over four- and eight-week implantation periods. The specific objectives were to examine endosteal bone ingrowth into aluminum oxide coneshaped plugs in amputated tibiae, while additional pellet-shaped implants in the tibiae and femora of rabbits with amputated and nonamputated limbs were studied to determine: (1) if the degree of loading placed on the amputated limb was sufficient to promote bone activity, (2) the degree of inertness and/or toxicity of the aluminum oxide implants, and (3) a possible cause of bone spurs.The results of the radiographic, histologic and microradiographic analyses of the in vivo implants demonstrated that there was little mineralized bone ingrowth into the coneshaped aluminum oxide implants in the amputated tibiae. The study also showed that the aluminum oxide pellet implants in the tibiae and femora of the nonamputated limbs demonstrated excellent mineralized bone ingrowth into surface and internal pores. By comparing these results with the incomplete ingrowth into corresponding pellet implants in the tibiae and femora of amputated limbs, it was determined that a lack of weight bearing and damage to the musculature and vascularity following amputation were interfering with the normal bone activity and therefore bone ingrowth.Angiographs and radiographs of the amputated tibiae demonstrated that bone spurs were present and that they originated at the site of the periosteal damage. Their cause was believed to be associated with an increase in the vascularity of the adjacent tissues.
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    Journal of Biomedical Materials Research 8 (1974), S. 137-144 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: Ceramic materials for permanent implantation in osseous tissue, called osteoceramics, were based on an equimolar mixture of Ca3(PO4)2 and MgAl2O4. Tooth roots with dense regions and with regions of controlled porosity for tissue ingrowth were made from the material. They were implanted submucosally in the mandible and maxilla of dogs. Tissue response was aceptable and strong attachment occurred. Thin sections are presented showing the interface of the alveolar bone and the prosthesis.
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    Journal of Biomedical Materials Research 8 (1974), S. 155-162 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: Clinical studies will permit only small sections of tendon sheaths to be removed for biopsy at restricted levels as the sheaths were to be used for tendon grafting. In active gliding programs, biopsy has been limited to small sheath sections in immediate relation to the distal or proximal anastomosis where gliding motion may be induced or minimal. In the passive gliding programs, biopsy has been limited to the most proximal segments where considerable folding of the sheath occurs or cul-de-sac buckling of the implant may produce irritation.As these were the only practical clinical sources of sheath sections for biopsy and study, the authors felt that a comparison study of sheath development in animals would broaden our understanding in humans. With this objective in mind, three canine laboratory studies were carried out where, for pure purposes of investigation, entire sheath sections were removed at designated time intervals for study.The flexible implants were well accepted, affording the opportunity to observe development of early sheaths in a controlled connective tissue environment, free from the stress of joint motion.The semi-rigid implants showed equal acceptance in side-by-side tissue level of the same dog as the flexible implant. This influenced changes in artificial tendon development from extrusion to the more exacting mold fabrication. It seemed evident that the degree of increase in stiffness of the new artificial tendons to gain a superior surface for gliding and increased strength would not change tissue acceptance providing flexibility was maintained.The cellular response in this study did not seem to represent a foreign body phenomena but an orderly acceptance of the soft tissue environment to the smooth surface of the inert implant.It is concluded that this study confirmed in animals the clinical findings of Mayer, Bunnell, Milgram, and Carroll.The consistent orderly development of the new sheaths formed in response to the static implants is impressive. The authors believe the appearance of these histologic sections are likely correlations with the development of new sheaths around the Hunter Tendon Prosthesis during the three-four week postoperative period when the hand is resting in a functional dressing.
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  • 86
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    Journal of Biomedical Materials Research 8 (1974), S. 197-207 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: Poly-α-amino acids have been investigated for possible use in a wide variety of biomedical applications. These range from dialysis membranes to artificial skin substitutes to degradable sutures. The large number of available α-amino acids potentially provides an extremely large number of poly-α-amino acids. The majority of materials investigated to date are copolymers composed of two components, one of which usually provides the desired property for the given application.This paper deals with the further examination of a series of γ-benzyl-L-glutamate-L-leucine copolymers. Evidence is provided on the effect of these copolymers on the biological environment as determined by implantation in rats up to 200 days. In vitro tests were also performed and the effect of these tests on the stress-strain properties of one of the copolymers is presented.Preliminary evidence on biodegradable copolymer films is also included. These materials have free γ-carboxyl groups on the glutamate components.
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  • 87
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    Journal of Biomedical Materials Research 8 (1974), S. 427-434 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: Following the classification of tissues according to their “dominant” and “interactive” components the paper surveys their load-deformation behavior, highlighting in particular the significance of time dependence. This leads to a discussion of the implant/tissue interaction in which the complexity that could be created by varying load and deformation time rates at the interface is explored.
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  • 88
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
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  • 89
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    Journal of Biomedical Materials Research 4 (1970), S. 145-187 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: The influences of the conditioning treatments, surface topography, and crystal structure of carbonaceous surfaces on their ability to sorb heparin and their in vivo compatibility with blood were investigated. The results of the sorption studies indicated that the adsorption of heparin on the surfaces of turbostratic and graphitic materials is not crystallographically selective and that the amount adsorbed on relatively smooth surfaces is near the amount expected for monolayer formation. Although the adsorption of heparin on relatively smooth carbon surfaces is not influenced by the presence of benzalkonium chloride, the sorption of heparin in porous carbons can be greatly increased by a pretreatment with benzalkonium chloride. This increase was found to be due to the formation and entrapment of the insoluble heparin-benzalkonium complex in the accessible porosity. Since the heparin sorptions in Dag-154 coatings were found to be enhanced by a pretreatment with benzalkonium chloride, it was inferred that these coatings contain accessible porosity and that their initial thromboresistance depends on the formation of the benzalkonium-heparin complex in pores. In vivo tests showed that polished and outgassed, impermeable isotropic carbons deposited at low temperatures were significantly thromboresistant without the exogenous application of heparin. There was no relationship between the amount of heparin sorbed on these materials and their compatibility with blood. Polishing, for example, which reduced heparin sorption, enhanced the thromboresistance of these carbons, and while chemisorption of oxygen markedly reduced their thromboresistance, it did not influence the amount of heparin that could be sorbed. Although the heparin-benzalkonium complex sorbed in a porous carbon conferred excellent thromoboresistance in a 2-hr test, the long-tern (14-day) compatibility was not as good as for carbon surfaces that were deposited at low temperatures and then polished and outgassed prior to implanting. In vivo tests of HTI carbon structures and annealed LTI carbons indicate that the blood compatibility of a turbostratic carbon is not significantly dependent on crystallite size, Le. Limited tests of surfaces that had a preponderance of c-faces oriented parallel to the blood-carbon interface at the surface suggest that orientations of this sort are better than others.
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    Journal of Biomedical Materials Research 4 (1970), S. 259-268 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: The adsorption of radiotagged fibrinogen on modified polytetrafluoroethylene surfaces was measured to shed light on the reason of reduced thrombogenicity. These measurements show that when fibrinogen is adsorbed from a solution in which the molecules are in a coiled, undenatured state, adsorption is greater on sulfonated, etched Teflon - a reduced thrombogenic surface, than on unsulfonated, etched Teflon - a thrombogenic surface. On the other hand, when fibrinogen is picked up from a water-air interface in the form of a monolayer consisting of denatured molecules, the pick-up is independent of the thrombogenicity of the surface.
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  • 91
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    Journal of Biomedical Materials Research 4 (1970) 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
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  • 92
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    Journal of Biomedical Materials Research 4 (1970), S. 269-274 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: The extraordinary stability of the γ1 phase of dental amalgam was believed to indicate that part of the Sn in dental amalgam was contained in this phase. By extending the Hume-Rothery “electron compound” ideas to the three component Ag-Sn-Hg system, an estimate was made of the amount of Sn which could be held in the γ1 structure.A Ag-Sn alloy containing 9.1 weight per cent Sn was prepared, spheroidized, and sized. Portions were amalgamated and molded into tensile specimens, parts of which were subjected to X-ray diffraction, corrosion tests, and tests to determine amalgamation rate and dimensional changes during setting.X-ray diffraction patterns showed a complete absence of the γ2 phase, (thus indicating that all Sn was in the γ1 phase) and a stability intermediate between γ Ag-Hg and the γ1 phase of dental amalgam. Physical tests showed a low amalgamation rate, low 1-hr strength, high 7-day strength, and high corrosion resistance.
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  • 93
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    Journal of Biomedical Materials Research 4 (1970), S. 275-277 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: Autoclave sterilization of paper-wrapped stainless steel implants resulted in slight general surface corrosion and crystalline contamination. Such artifacts may produce microanodes which induce local tissue reactions, thereby lowering the pH and further activating the corrosion process. Implants sterilized in ethylene oxide or benzalkonium chloride did not show artifact corrosion or contamination. Mechanisms are presented to show the effects contaminants have upon both the corrosion behavior and the tissue reaction of implant materials.
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  • 94
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    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
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  • 95
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: Nylon-based membranes of greater dialyzing capacity than Cuprophan have been prepared by solution casting. Good permeability is being achieved by the use of diluents such as dimethylsulfoxide in the casting solution. Modifying resins, primarily epoxies, contribute to higher permeability, good aging stability, and heat-sealing properties. Drying time between film casting and water immersion as well as the temperature and composition of the immersion bath are important factors in membrane performance. Methods for attaching heparin to the film surface have been developed, thus imparting good blood compatibility to the membranes.
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    Journal of Biomedical Materials Research 4 (1970), S. 295-312 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: A thin polymeric film, containing a basic polyelectrolyte, was developed with properties that potentially make it highly suitable for use in a membrane blood oxygenator. Its CO2 absorption capacity was correlated as a function of the CO2 partial pressure, temperature and relative humidity of the processed gas. The correlation showed a linear dependence with CO2 partial pressure and relative humidity and an Arrhenius dependence with temperature. A four-step mechanism for the absorption process was postulated and its parameters were evalutaed. The apparent diffusion constant for CO2 was five times that measured for an ion-exchange resin made from the polyelectrolyte. The capacity and mechanism correlations obtained are suitable for the design of a CO2 removal unit for a recirculated air atmosphere as well as for a blood oxygenator. The permeability of the film to CO2 and O2 was measured and the ratio was found to be far greater than that of most commercial materials. This suggests that a blood oxygenator utilizing such a film would have the controlling resistance to transfer on the oxygen side, rather than on the blood side, thus perhaps avoiding bubbling on the blood side altogether.
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    Journal of Biomedical Materials Research 4 (1970), S. 313-339 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: The objective of this study was to determine the feasibility of using a fluorocarbon liquid in a liquid-liquid contacting device for extracorporeal blood oxygenation. Extraction experiments were carried out wherein blood was gently contacted with FC-43 (a fluorinated tributyl amine) for up to 48 hr. The fluorocarbon caused no significant change in red cell volume, white cell count, plasma hemoglobin, platelet count, plasma fibrinogen, or the relative amounts of thirteen different plasma proteins. To determine toxicity, FC-43 slugs and emulsions were injected intravenously and intraaortically into dogs. No chemical toxicity has been found, but the fluorocarbon is intolerable above about 1.7 mg/kg because it retards the flow of blood through pulmonary capillaries. FC-43 was used for several in vivo tests of a vertical cylindrical blood oxygenator. The hemolysis caused by the falling film of fluorocarbon on the inner Teflon wall of the cylinder was considerably less than that caused by direct contact between blood and Teflon, suggesting that the blood-fluorocarbon interface is quite atraumatic. All these results indicate that this fluorocarbon liquid holds considerable promise for use in a liquid-liquid blood oxygenator.
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    Journal of Biomedical Materials Research 4 (1970), S. 469-485 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: For patients performing hemodialysis at home the assembly of the artificial kidney must be simple. To achieve this, a disposable envelope, consisting of two membranes bonded to a supporting substructure, was developed for the Kiil artificial kidney. This envelope was tested in vitro for metabolite clearance, pressure-flow relationship, ultrafiltration, and priming volume. The clearance of this envelope for different metabolites proved to be higher than that achieved with conventional assembly of the Kiil with wet Cuprophan membranes. Analysis of the resistance to mass transfer indicated that the disposable envelope has decreased the blood- and dialyzate-side resistances and provides an increase in effective membrane area, thereby enhancing overall mass transfer. The envelope also showed higher resistance to blood flow and a lower priming volume. In vitro testing of this envelope has shown the feasibility of practical clinical application.
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    Journal of Biomedical Materials Research 4 (1970), S. 503-524 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: A finite element stress-deformation model of the human aorta was developed based on previously determined constitutive relationships. The model was used to predict the deformations experienced by an arota when subjected to localized pressure distributions. The model was further refined so as to analyze a twolayered vascular system. The stress distribution through the wall, particularly at the layer interface, was studied for composite vascular systems subjected to localized internal pressures.
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    Journal of Biomedical Materials Research 4 (1970), S. 525-547 
    ISSN: 0021-9304
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine , Technology
    Notes: A testing technique was developed that enabled an aortic vascular specimen to be analyzed in a quasi-physiological environment. The data that was gathered from human and bovine aortas provided the basis for the formulation of the time dependent constitutive relationships describing the viscoelastic behavior of an aorta subjected to a “normal” pressure pulse.
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