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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 9 (1976), S. 429-432 
    ISSN: 1432-1041
    Keywords: Drug-protein binding ; hepatic disease ; salicylate ; sulphadiazine ; phenylbutazone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The binding of 3 drugs to serum proteins of patients with chronic hepatic disease has been studied by an ultrafiltration technique, and compared to that of normal subjects. The binding of phenylbutazone was reduced in all patients, salicylate in patients with inactive liver disease and sulphadiazine in patients whose disease was active. Analysis of binding data showed a real reduction in the capacity of albumin to bind the drugs in the majority of patients. Addition of bilirubin to normal plasma caused a reduction in sulphadiazine binding, but had no effect on the binding of salicylate or phenylbutazone. The possible causes of this reduction in binding are discussed.
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 31 (1987), S. 655-660 
    ISSN: 1432-1041
    Keywords: epilepsy ; anticonvulsants ; psychomotor function ; therapeutic drug monitoring
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Using a battery of simple tests, psychomotor performance was assessed in 11 healthy subjects, 14 untreated epileptic patients and 66 epileptics on chronic anticonvulsant medication. Significant differences were found between controls and untreated patients for choice reaction time, card sorting and Simple Simon memory game. Treated patients performed less well than both untreated epileptics and controls in choice reaction time (p〈0.05; p〈0.001), card sorting (p〈0.01; p〈0.001), Simple Simon (p〈0.05; p〈0.001) and finger tapping (p〈0.05; p〈0.001). Patients with centrencephalic epilepsy were slower than those with discrete focal EEG abnormalities in reaction time and card sorting. Patients receiving treatment with carbamazepine, phenytoin or sodium valproate alone all performed similarly to each other and to those patients taking anticonvulsant polypharmacy. Monotherapy patients with potentially “toxic” plasma anticonvulsant concentrations did no worse than those within or below the “therapeutic” range. Both the disease and its treatment reduce psychomotor performance. All major anticonvulsants appear to cause a similar degree of impairment across a wide range of concentrations. The effect of chronic anticonvulsant medication on “quality of life” should not be neglected in the pursuit of perfect seizure control.
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 30 (1986), S. 37-42 
    ISSN: 1432-1041
    Keywords: carbamazepine ; psychomotor function ; anticonvulsants ; epilepsy ; healthy subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of a single dose of carbamazepine (CBZ), 10 mg kg−1, on a battery of simple psychomotor tests was investigated in 12 healthy subjects (6 male, 6 female) in a balanced randomised double blind placebo controlled cross-over study. Psychomotor testing and blood sampling for total and free plasma CBZ, and CBZ 10, 11 epoxide concentration were performed at 10, 12, 14, 16, 18 and 34 h after oral dosing (23.00 h the previous evening). CBZ impaired i) critical flicker fusion threshold frequency at all time points up to 18 h (p〈0.005); ii) total choice reaction time at 10 h (p〈0.005) and 18 h (p〈0.008); iii) card sorting at 14 h (p〈0.001). No significant effect on finger tapping was noted. Subjects adjudged themselves more sedated on CBZ as compared to placebo at 12, 14 and 16 h (p〈0.008). Plasma total and free CBZ concentrations (mean ± SD) peaked at 10 h (8.8±0.2 mg l−1) and 16 h (1.88±0.3 mg l−1) after dosing respectively. CBZ 10, 11 epoxide values were all less than 10% of total CBZ concentrations and, therefore, were unlikely to contribute to the pharmacodynamic effect. Total choice reaction time was significantly more impaired in females (p〈0.05) but no sex difference occurred with the other tests or CBZ concentrations at any time point. No significant correlations were found between individual total or free CBZ concentrations and corresponding test performances at each time point. This study has demonstrated impairment of psychomotor function following CBZ in healthy subjects using a series of simply performed tests. This approach can now be applied to patients with epilepsy receiving long-term treatment with CBZ and other anticonvulsants.
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 35 (1988), S. 241-247 
    ISSN: 1432-1041
    Keywords: carbamazepine ; porphyria ; epilepsy ; haem biosynthesis ; enzyme induction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The anticonvulsant drug carbamazepine has been reported to produce a condition clinically and biochemically similar to acute intermittent porphyria (AIP). We have determined the effect of chronic carbamazepine treatment on the activities of the enzymes of haem biosynthesis in circulating blood cells and on the urinary excretion of porphyrins and their precursors in 53 epileptic patients receiving monotherapy and in 42 age- and sex-matched controls. In the patients the mean activity of leucocyte 5-aminolaevulinic acid (ALA) synthase, the rate-limiting enzyme of the pathway, was 218% of control values (p〈0.001) and ALA-dehydratase activity was reduced by 37% (p〈0.001). Circulating carbamazepine concentrations correlated negatively with ALA dehydratase (r s=−0.45;p〈0.01). Porphobilinogen deaminase and uroporphyrinogen decarboxylase appeared unaffected by carbamazepine treatment. Significant quantitative increases in the urinary excretion of porphobilinogen and total porphyrins (bothp〈0.05) accompanied the changes in enzyme activity. Similar dose-dependent effects on ALA synthase and ALA dehydratase were shown to occur in rats treated for 5 days with 3 different doses of carbamazepine. These findings further support the porphyrinogenicity of carbamazepine, but the pattern of enzyme alteration differs from that found in AIP.
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 20 (1981), S. 39-46 
    ISSN: 1432-1041
    Keywords: liver disease ; environmental factors ; cytochrome P-450 ; NADPH-cytochrome c reductase ; aryl hydrocarbon hydroxylase ; caffeine ; alcohol ; cigarette smoking ; meat consumption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of liver disease and environmental factors on hepatic microsomal cytochrome P-450 content, NADPH-cytochrome c reductase (reductase) activity and aryl hydrocarbon hydroxylase (AHH) activity have been simultaneously investigated in 70 patients undergoing diagnostic liver biopsy. The activity of reductase was not significantly affected by the presence of liver disease or any of the environmental factors studied. Cytochrome P-450 content decreased with increasing severity of liver disease whereas AHH activity was only significantly reduced in biopsies showing hepatocellular destruction. None of the parameters of monooxygenase activity varied significantly with the age or sex of the patients. Alcohol excess was associated with decreased cytochrome P-450 content and AHH activity and this effect was independent of the histological status of the biopsy. Both high caffeine intake and cigarette smoking increased AHH activity in the absence of any change in cytochrome P-450 content. There was a positive correlation between the number of meat meals eaten per week and cytochrome P-450 content. Chronic treatment with enzyme-inducing anticonvulsants appeared to increase both cytochrome P-450 content and AHH activity. Despite differential effects of liver disease and environmental influences on cytochrome P-450 content and AHH activity there was a highly significant correlation between the two parameters. The results of the present study correlate well with the known effects of disease and environment on drug metabolism in vivo.
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  • 6
    ISSN: 1432-1041
    Keywords: stanozolol ; porphyria ; aplastic anaemia ; anabolic steroids ; haem biosynthesis ; monooxygenases ; cytochrome P 450 ; vascular thrombosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Stanozolol is an anabolic steroid which is used in the treatment of aplastic anaemia and has been recently advocated for the prophylaxis of vascular thrombosis. Similar steroid substances stimulate the activity of δ-aminolaevulinic acid synthase (ALA S), the rate limiting enzyme of haem biosynthesis, in rat hepatocytes and chick embryo liver cell cultures and activate acute hepatic porphyria. In the present study stanozolol (10 mg daily for 14 days) has been shown to increase significantly leucocyte ALA S activity in 9 healthy male subjects. There was a concomitant rise in urinary ALA and total porphyrin excretion but no change in antipyrine kinetics or urinary 6 B hydroxycortisol excretion. In a complementary study in male Sprague Dawley rats, stanozolol administered intraperitoneally, produced a dose-dependent increase in hepatic ALA S activity without changing hepatic cytochrome P 450 content. Stanozolol has been clearly shown to elevate ALA S activity, probably directly, and, thereby, porphyrin production without affecting hepatic monooxygenase activity. This porphyrinogenic effect may be relevant to the successful treatment of aplastic anaemia with anabolic steroids. Leucocyte ALA S activity may provide a human system for the study of drug porphyrinogenicity in vivo.
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 31 (1986), S. 195-199 
    ISSN: 1432-1041
    Keywords: carbamazepine ; epilepsy ; anticonvulants ; psychomotor function
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of an additional dose of 400 mg carbamazepine (CBZ) on a series of simple psychomotor tests was investigated in 8 patients with epilepsy receiving chronic CBZ monotherapy in a balanced randomised double-blind placebo controlled cross-over study. Psychomotor testing and blood sampling for total and free CBZ and CBZ 10,11 epoxide (CBZ-E) concentrations were performed at 10, 12, 14, 16 and 18 h after the extra dose which was administered at 23.00 h on the previous evening. The CBZ increment produced significant impairment of (i) choice reaction recognition time from 10–16 h after the dose (ii) total choice reaction time at 12 h (iii) card sorting at 12 h (iv) sedation scoring at 12 h. No significant effect on critical flicker fusion threshold, finger tapping or simple memory testing was noted. No patient reported increased side-effects in the placebo phase while 5 noted new symptoms likely to be attributable to the additional CBZ. Areas under the concentration-time curves from 10–18 h were higher following CBZ than placebo for total and free CBZ and CBZ-E concentrations. This study has demonstrated decrements in performance of a series of simple psychomotor tests in epileptic patients receiving a supplemental CBZ dose. Patients with epilepsy who require high CBZ concentrations for optimal control of seizures may be at risk of concurrent impairment of psychomotor function. Simple objective measures of performance may help in assessing the benefit-risk ratio.
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 34 (1988), S. 605-611 
    ISSN: 1432-1041
    Keywords: oxprenolol ; hypertension ; osmotic delivery system ; blood pressure control
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of two oxprenolol oral osmotic (OROS) delivery systems on heart rate and blood pressure before and during recovery from exercise at a predetermined load were examined in twelve patients with hypertension previously responding to beta-blocker monotherapy. Haemodynamic responses were attenuated during the 24 h after single and repeated (15 days') once daily administrations of 10/170 and 16/260 oxprenolol OROS. At 24 h after repeated doses, compared to placebo there were significant reductions in resting blood pressure and in heart rate immediately following exercise. Attenuation of heart rate after exercise was dose related but differences between the systems with respect to resting heart rate and blood pressure were inconsistent. Antihypertensive responses after repeated doses were greater than those after single doses. However, reductions in resting and exercise heart rates were consistently less on chronic therapy. This may reflect enhanced expression of the partial agonist activity of oxprenolol due to altered receptor sensitivity after prolonged beta-blockade. The plasma oxprenolol profiles after both systems indicated slow absorption and substantial concentrations were apparent 24 h after drug administration. These observations suggest that both oxprenolol OROS systems display sustained drug release and on once daily dosing provide 24 h beta-blockade and control of blood pressure at rest and following exercise.
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  • 9
    ISSN: 1432-1041
    Keywords: cefuroxime ; peritonitis ; peritoneal dialysis ; toxicity ; increased permeability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The distribution of cefuroxime (250 mg) was studied in patients with renal failure undergoing continuous ambulatory peritoneal dialysis (CAPD). 10 uninfected patients received the drug intravenously and intraperitoneally, while 9 patients with peritonitis were randomly allocated to intravenous or intraperitoneal administration. Samples were taken over the first 6 hour dialysis period. In the infected patients, more drug (p〈0.01) crossed into the peritoneal cavity following intravenous injection and reached the systemic circulation following intraperitoneal administration than in the uninfected group. This increased permeability of the peritoneal membrane during infection may result in unexpected systemic toxicity in patients treated with intraperitoneal antibiotics.
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 26 (1984), S. 453-456 
    ISSN: 1432-1041
    Keywords: carbamazepine ; thyroid hormones ; antipyrine ; enzyme induction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of short-term hepatic enzyme induction with carbamazepine (CBZ) on circulating thyroid hormone concentrations was studied in 10 healthy male subjects. CBZ 400 mg per day was given for 21 days in 6 subjects and for 14 days in a further 4. In the former group the effect of therapy on the pituitary/thyroid axis was also assessed by measuring thyroid stimulating hormone (TSH) response to thyrotrophin-releasing hormone. CBZ therapy resulted in induction of hepatic monooxygenase activity, evidenced by a fall in antipyrine half-life (11.1±0.7 to 7.6±0.7 h; p〈0.001), and a rise in antipyrine clearance (0.72±0.06 to 0.98±0.1 ml min−1 kg−1; p〈0.001). A significant fall in total serum thyroxine (T4) (81.9±2.9 to 75.1±2.9 nmol l−1), and triiodothyronine (T3); (1.59±0.07 to 1.37±0.05 nmol l−1) and free T4 (16.03±0.82 to 14.2±0.8 pmol l−1) was seen after CBZ therapy. (all p〈0.05). No significant change in reverse T3 or thyroid binding globulin occurred. In the 6 subjects studied for 21 days, maximal changes were found following 14 days' treatment. Basal and stimulated TSH remained unaltered. These effects on circulating thyroid hormone concentrations are likely to be secondary to hepatic enzyme induction leading to accelerated nondeiodinative hepatic hormone disposal. The reason for the failure of pituitary TSH secretion to rise in response to the fall in circulating T4 and T3 is unclear but may have implications for chronic treatment with CBZ in epileptic patients.
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