ALBERT

Notes: Summary Previous ultrafiltration studies indicated that up to one-half of the calcium and two-thirds of the phosphate in human salivary secretions may be bound by salivary proteins. Since this binding is an important variable in determining the extent of salivary supersaturation with respect to calcium phosphate salts, and since the amount of binding reported is surprisingly large, calcium and phosphate ion-binding by salivary macromolecules has been reexamined. From experiments using equilibrium dialysis, it was found that (1) the fraction of salivary calcium involved in macromolecular complexes ranges from a few percent for unstimulated secretions, to no more than about 10% for stimulated glandular salivas, and (2) salivary proteins do not bind phosphate ions to any significant extent. These findings, and experiments using an improved ultrafiltration membrane, indicate that the earlier results were artifacts of the ultrafiltration technique. Fractionation of salivary proteins, followed by equilibrium dialysis measurements, showed that the anionic proline-rich proteins and a basic proline-rich glycoprotein are responsible for most of the calcium binding now observed. The finding that macromolecular complexes of salivary calcium and phosphate have been overestimated in the past, leads to the conclusion that salivary calcium and phosphate ion activities in stimulated salivary secretions may be up to 50 to 100% higher than previously thought. Revised values were therefore used to recalculate the degree of salivary supersaturation with respect to calcium phosphate salts. The results indicate that stimulated salivary secretions are supersaturated with respect to dicalcium phosphate dihydrate; this is a substantially greater degree of supersaturation than previously reported.

Notes: Summary Adult male rats were fed a diet containing 0.15% calcium, 0.3% phosphorus, and either 100, 50, or 20 mg of prednisolone per kg of diet. All these levels of prednisolone led to osteopenia, decreased intestinal absorption of calcium, slightly lower serum calcium and phosphorus, and a decreased level of serum 1,25-dihydroxyvitamin D3. Exogenous parenteral 1,25-dihydroxyvitamin D3 corrected steroid-induced changes in serum calcium and phosphorus, but could not completely correct the low intestinal calcium transport; nor did it prevent the development of osteopenia. The prednisolone-induced osteopenia seems at least in part to be caused by impaired intestinal calcium transport. The impaired calcium transport may be the result of low levels of 1,25-dihydroxyvitamin D3 and a direct effect of presnisolone on the intestine.

Notes: Summary Experiments were performed to study the effect of inorganic phosphate (Pi) on phosphatidylserine-mediated Ca2+ transport utilizing two- and three-compartment lipid-aqueous phase model systems. When the three-compartment model was used, the rate of Ca2+ transport from an aqueous donor compartment to an aqueous receiver compartment, separated by a nonaqueous phospholipid phase, was determined. This experiment showed that the rate of Ca2+ transport was proportional to the phosphatidylserine concentration and the pH. Pi modulated the rate of Ca2+ transport; even when the Pi concentration of the donor aqueous phase was low, there was a marked enhancement of transport. To determine whether the Pi-mediated rise in the Ca2+ transport rate was due to an increase in the uptake of Ca2+ into the lipid phase, or to an increase in the ability of the lipid phase to release Ca2+, a two-compartment model was used. It was found that the ability of the phosphatidylserine phase to take up Ca2+ increased as the Pi concentration of the aqueous donor phase was raised. With the increase in Ca2+ uptake there was a concomitant elevation in the rate of Ca2+ transport into an aqueous receiver phase. However, Pi did not stimulate Ca2+ release from the phosphatide. Thus it was concluded that Pi enhanced the interaction between Ca2+ and phosphatidylserine, possibly by forming a Ca-phospholipid-Pi complex. Once this interaction had taken place, Ca2+ release into the aqueous receiver compartment was independent of the Pi concentration.

Notes: Summary Bone Gla protein (BGP) was measured in the plasma by radioimmunoassay (RIA) during treatment of 59 patients with bone diseases including Paget's disease (N=9), primary hyperparathyroidism (N=25), chronic renal failure (N=20), and cancer involving bone (N=5). Plasma BGP was increased above normal in all patients. BGP decreased in the patients with Paget's disease following the acute and chronic administration of salmon calcitonin. Plasma BGP was higher in women then in men with primary hyperparathyroidism. Following parathyroidectomy, BGP decreased in both sexes but the decrease was significant in women only. Plasma BGP was increased in patients with renal osteodystrophy and did not change after hemodialysis. In the patients with bone cancer, plasma BGP decreased during treatment of the attendant hypercalcemia with salmon calcitonin. Although plasma BGP and serum alkaline phosphatase (AP) levels were generally correlated in these studies, there were examples of dissociation between the two. The measurement of plasma BGP appears to provide a specific index of bone metabolism that may in some circumstances be more sensitive than serum alkaline phosphatase measurement. However, further studies are necessary to establish the clinical value of plasma BGP measurement by RIA in the management of patients with bone diseases.

Notes: Abstract Migration of differentiated cells to a capillary containing cyclic AMP was enhanced in the presence of 1 mM CaCl2 and was virtually absent in the presence of 1 mM EGTA. Furthermore, the cells contracted and extended pseudopods to a capillary filled with the calcium ionophore A 23187. At short distances, migration to the tip of the capillary was observed. The ionophore also induced transient decreases of the optical density of suspended cells indicating changes of cell shape. These findings support the hypothesis that cyclic AMP-binding to cell surface receptors causes a local influx of calcium ions. These in turn lead to an increase of the cytosolic calcium concentration and subsequently to an activation of cell migration. Perturbing pulses of the ionophore induced permanent phase shifts of free-running light scattering oscillations. This result indicates that cytosolic calcium is an intrinsic component of the oscillatory system.

Notes: Summary Plasma concentrations of orphenadrine were measured by a specific gaschromatographic method in 5 healthy male volunteers after a single oral dose of orphenadrine hydrochloride 100mg. The single dose pharmacokinetic profile of orphenadrine was evaluated from these data. The elimination half-life ranged from 13.2–20.1 h after the commercial tablet formulation. Plasma concentrations, determined in volunteers and patients under different conditions of repeated oral administration of the same formulation of orphenadrine hydrochloride exceeded the theoretical values, predicted from the single dose pharmacokinetics, by a factor 2 to 3. The elimination half-lives after discontinuation of treatment showed a 2 to 3-fold increase over the single dose values. This demonstrates a clear discrepancy between the multiple and single dose pharmacokinetics of orphenadrine. Experiments in dogs suggested competition for biotransformation between orphenadrine and its metabolite N-demethylorphenadrine. Product inhibition of this type could explain the observed discrepancy.

Notes: Summary Two formulations of indapamide tablets (2.5 mg) were given as a 5.0 mg dose and the subsequent blood levels were compared to those obtained after administration of a 5.0 mg solution. The study was conducted as a randomized three-way crossover design using healthy male volunteers. The drug was well tolerated by all the subjects involved. The area under the blood concentration versus time curve, extrapolated to infinity was essentially the same for all three formulations (4.2, 4.7, and 4.4 µg-h/ml). Statistical comparison of the blood levels from the two tablets showed that one tablet had a significantly greater maximum blood concentration (263 vs 231 ng/ml) and a significantly shorter time of maximum blood concentration (2.3 vs 3.5 h). Cmax (333 ng/ml) and tmax (0.7 h) values for the solution were significantly higher than either tablet. The average half-life (β-phase) for all three formulations was 15 h, while the average systemic clearance was 20 ml/min. Indapamide has a low clearance rate and there was no evidence that the drug undergoes a first-pass effect.

Notes: Summary 21 healthy women undergoing gynaecological operations received rectal premedication with morphine 0.3 mg/kg body weight. Plasma concentrations of morphine were followed for 4 h by a GC/MS technique. In most patients the peak plasma concentration was reached after 30 min; the mean peak plasma level of morphine was 18 ng/ml (range 8.5–57 ng/ml). The bioavailability of rectal morphine was determined in 6 patients, who received an i.m. injection of morphine at a second operation. The mean bioavailability of rectal morphine was 31% (range 12%–61%). None of the patients showed any clinical sign of respiratory depression, and there was no increase in end-tidal carbon dioxide tension measured in 5 patients operated under spinal block.

Notes: Summary The kinetics of ergotamine has been investigated in migrainous patients using a new, specific, sensitive HPLC assay (detection limit 100 pg/ml plasma). 10 patients were given ergotamine tartrate 0.5 mg i.v. and 5 of them received the same dose i.m. 2–3 weeks later. Blood samples were collected for up to 54 h following administration and the plasma concentration were analysed. After intravenous administration the plasma ergotamine declined rapidly, with an initial distribution half-life of 3 min followed by a mean terminal half-life of 1.86 h (range 90–155 min). The mean total plasma clearance was 11.0 ml kg−1 min−1, and the volume of distribution (Vdβ ) was 1847.6 ml kg−1. Individual t1/2β showed a positive linear correlation with the individual Vdβ . The intramuscular absorption of ergotamine was rapid and maximum plasma levels were usually obtained 10 min following administration. The biological availability was incomplete and variable at 46.6% (range 28.3–60.8%).

Notes: Summary The pharmacokinetic parameters of deacetyl metipranolol were determined after i.v. infusion of increasing doses (6–25 mg) in 17 normal volunteers. In a second cross-over trial, deacetyl metipranolol 10 and 20 mg were infused in a further 10 subjects, and in a third trial another 20 volunteers received metipranolol 40 mg orally. Metipranolol is very rapidly and completely deacetylated in man, so all pharmacokinetic data refer to deacetyl metipranolol, which was assayed by gas chromatography-mass spectrometry. The pharmacokinetic analysis was performed using a recently developed model, using a volume of distribution which is variable with time. The following data were obtained after oral administration: (mean values); lag-time 7.3 min; tmax 50 min, invasion half-life 6.3 min; elimination half-life 3 h; urinary excretion of unchanged drug approximately 4% of the dose. The experiments with infusion of increasing doses, as well as the cross-over study with 10 and 20 mg i.v., showed dose-linearity of the kinetics. The respective mean half-lives of elimination were 2.6, 2.9 and 2.8 h. The mean total, renal and extra-renal clearances amounted to 1237 ml/min, 149 ml/min and 1068 ml/min, respectively. The distribution coefficient was 3.5 l/kg, and protein binding amounted to 70% within the range of therapeutic concentrations. Absolute bioavailability was found to be approximately 50% by several different evaluation procedures. Thus, the pharmacokinetic profile of metipranolol shares features of both the lipophilic and the hydrophilic groups of β-blocking agents.

Notes: Summary 16 premature infants suffering from neonatal apnoea received orally an aqueous solution of theophylline 5 mg/kg bodyweight under fasting conditions and immediately before a milk feed. Bioavailability up to 7 h after administration was determined from the serum concentration-time course. The rate of absorption was significantly decreased if the drug was given with food; mean maximum serum concentrations were reached after 4.7 h instead of 1.6 h under fasting conditions. The area under the curve did not differ between the two patient groups which indicates that only the rate but not the amount of absorption was affected by food intake. The influence of feeding on the rate of absorption of theophylline by premature infants, which is more pronounced than in adults, can be related to particular functional factors in the gastrointestinal tract during the neonatal period.

Notes: Summary Acetylsalicylic acid (ASA) is a strong, irreversible inhibitor of platelet aggregation, but loses this activity following first-pass deacetylation to salicylic acid (SA). In order to compare the bioavailability of unchanged ASA from rapid- and slow-release formulations, the single-dose concentration profiles of ASA and SA were studied in healthy volunteers following intake of two different rapid-release (conventional and effervescent tablets) and three different slow-release (microencapsulated ASA in tablets and in capsules, and enteric-coated tablets) formulations of ASA, and of one slow-release formulation of sodium salicylate. Since anti-platelet therapy with ASA is often combined with dipyridamol, the influence of this drug was also examined. The concentrations of ASA and SA were measured by high-pressure liquid chromatography. While the bioavailability of SA from the 5 ASA formulations was essentially equal and similar to that of the salicylate formulation, the bioavailability and peak concentrations of ASA appeared to be the much greater after rapid-release than after slow-release formulations. Indeed, ASA was only rarely detected in systemic blood following intake of slow-release ASA. Co-administered dipyridamol did not significantly influence the kinetics of ASA or SA. It appears that rapid-release formulations of ASA should be prefered in anti-platelet therapy, either alone or in combination with dipyridamol.

Notes: Summary For drugs with a high hepatic clearance, bioavailability is low due to the so-called “first pass effect”. Prediction of the bioavailability for these drugs has been only lossely tested. It is proposed that by plotting the reciprocal of bioavailability versus the oral clearance, a straight line with intercept of unity and slope of reciprocal of hepatic blood flow should ensue. For lignocaine and verapamil, this relationship was found to be strong and gave good predictability, whereas for propranolol this relationship was weak and gave poor predictability. The proposed method may be of value in determining whether the low bioavailability of a drug is due to hepatic first pass metabolism.

Notes: Summary Plasma and urinary levels of chlorpheniramine (CPM) and its 2 demethylated metabolites were measured by HPLC after i.v. and oral dosing. In 5 mg (maleate) i.v. bolus studies in 2 subjects, plasma CPM levels were fitted to triexponential equations with terminal half-lives (t 1/2) of 23 and 22 h and area of 3.6 and 3.21/kg, respectively. Intravenous data predicted hepatic blood extraction ratios for the 2 subjects to be 0.06 and 0.07, respectively. Absolute bioavailability from oral solution (10 mg) was 59 and 34%, and from tablets (8 mg) 44 and 25%, respectively, indicating extensive gut first-pass metabolism. Mean t 1/2 from 7 oral fasting studies in 5 subjects was 28 h (19–43 h). Mean absorption lag time was 0.7 h (0.4–1.3 h), and mean peak time was 2.8 h (2–4 h). In 2 subjects, 6 mg solutions were given every 12 h for 9 doses; good correlation between single and multiple dose kinetics was found. Significant accumulation was demonstrated in simulation studies with frequent daily dosing. Estimated accumulation ratios vary from 4.1 to 9.4 (mean 6.5). The t 1/2 from urinary data (collected for 12 days) was consistent with plasma data. The above results suggest the need to reexamine the current practice of frequent daily dosing and the use of sustained or controlled release dosage forms of this drug. The possible cause of reduced plasma clearance of CPM in renal patients is discussed.

Notes: Summary The effect of food on the rate and extent of absorption of tolbutamide in diabetic patients was studied by varying the time of drug administration in relation to the ingestion of a standard meal. Serum levels of tolbutamide, insulin and glucose and related bioavailability parameters were compared following the administration of a single dose of tolbutamide 0.5 g to diabetic patients 30 min prior to and immediately before a standardized meal. A placebo dosage form was also administered to determine baseline glucose and insulin response to the meal. The 700 calorie standard meal was composed of 41% carbohydrate, 18% protein, and 41% fat. Administration of the drug with the meal resulted in a 6% (statistically significant) decrease in the extent of absorption, as determined by measurement of the area under the tolbutamide serum level-time curve from zero to infinity. Serum levels of tolbutamide were also significantly higher 0.5 h after drug administration when the drug was taken with the meal. Except for these two minor effects, no other differences between the drug treatments were observed in any other parameters of tolbutamide absorption or in the postprandial glucose and insulin serum levels. Therefore, the small differences found were judged to be clinically meaningless. These findings demonstrate that administration of tolbutamide 0.5 g tablets 30 min prior to or with a standard meal results in equivalent therapeutic actions.

Notes: Summary The kinetics of phenobarbital (PB) were evaluated in six normal subjects and six epileptic patients treated with phenytoin or carbamazepine. Each normal subject received three single doses of PB: PB-sodium 130 mg i.v. (IV), PB sodium 130 mg i.m. (IM), and PB acid 100 mg orally (PO), in random order at least one month apart. After IV PB distributive half-lives varied from 0.13 to 0.70 h, disposition half-lives were 75 to 126 h, steady state volume of distribution (Vss) was 0.54±0.03 l/kg, and clearance (CL) was 3.8±0.77 ml/h/kg. Absolute bioavailability of IM PB was 101±13%, of PO PB (corrected for dose) 100±11%. Peak serum PB concentrations were achieved from 2 to 8 h after IM administration, and from 0.5 to 4 h after PO administration. Epileptic patients exhibited similar PB kinetics: disposition half-lives were 77 to 128 h, Vss 0.61±0.05 l/kg, and Cl 3.9±0.76 ml/h/kg. Phenobarbital appears to represent an exception among antiepileptic drugs, in that pharmacokinetic data obtained in normals can reasonably be extrapolated to the epileptic population.

Notes: Summary The bioavailability of chloroquine in 7 healthy adult male volunteers was assessed with and without a standard breakfast. Chloroquine (600 mg base) was administered orally and timed blood samples were obtained for determination of plasma concentrations. The results suggest that the AUC and peak plasma levels were significantly higher when chloroquine was administered together with food, although the rate of absorption was not different. It appears, therefore, that food facilitates chloroquine absorption and the extent of absorption is significantly modified. Hence administration of chloroquine together with food appears to be an advisable clinical practice.

Notes: Summary 7-3H-phenylephrine was given to 15 volunteers by a short-infusionn=4) or p.o. (10 volunteers, 1 patient with porto-caval anastomosis). Analysis of serum for free3H-phenylephrine and fractionation of urinary radioactivity was performed by ion-exchange and thin-layer chromatography. As almost the same3H-activity was excreted in urine after i.v. and p.o. administration, 86% and 80% of the dose respectively, complete enteral absorption can be assumed. A considerable difference was seen in the fraction of free phenylephrine, i.v. 16% of the dose versus p.o. 2.6%, which suggested reduced bioavailability. This was confirmed by comparison of the areas under the serum curve, which showed a bioavailability factor of 0.38. The result for the patient with porto-caval anastomosis was comparable to that in the normal volunteers. The biological half-life of 2 to 3h was comparable to that of structurally related amines, as were the total clearance of 2 1/h, and the volume of distribution of 340l. Metabolism to phenolic conjugates mainly after oral ingestion, and tom-hydroxymandelic acid after i.v. injection, again demonstrated thatm-hydroxylated amines are predominantly conjugated during the “first-pass” metabolism.

Notes: Summary The elimination and bioavailability of two beta-blocking agents, propranolol and sotalol, were studied in 10 thyrotoxic patients, both before and after treatment with iodine-131. Each subject received in random order propranolol 160 mg and sotalol 160mg as single oral doses both while hyperthyroid and after euthyroidism had been achieved. The pharmacokinetics of sotalol was not affected by hyperthyroidism, whereas serum propranolol concentrations were significantly lower during hyperthyroidism than in the euthyroid state. During hyperthyroidism, the bioavailability of propranolol was significantly reduced (p〈0.05) and its clearance was increased (p〈0.005), whereas there was no difference in its serum t1/2. This indicates that the bioavailability of propranolol in hyperthyroidism is reduced by a mechanism which may depend on increased first-pass metabolism in the liver, or on an increased distribution volume of the drug. Both propranolol and sotalol caused a slight decrease in serum tri-iodothyronine concentration. As the effects of beta-blocking agents on the symptoms of hyperthyroidism are correlated with the serum concentration of the drugs, sotalol, with its long half-life and unaltered elimination in hyperthyroidism, has certain advantages over propranolol in the treatment of thyrotoxicosis.

Notes: Summary Two multiple-units controlled-release indomethacin capsule formulations containing enteric-coated pellets were bioequivalent to a standard capsule formulation (taken as the reference) in respect of extent of bioavailability in a crossover study with normal human subjects. However, drug absorption from the enteric-coated pellet formulations was slower, when compared to that from the standard reference capsule. The standard reference capsule released 85% of its drug content in vitro during 10 min at pH 6.5 and 98% during 1 h at pH 7.5. One enteric-coated pellet capsule formulation (I) released 77% during 1 h at pH 6.5 and the other (II) released 10% during 1 h at pH 6.5. Release of drug from each capsule of enteric-coated pellets was complete during 1 h at pH 7.5. Although differences in areas under the plasma indomethacin concentration-time curves were not significantly different, the peak plasma levels and the times of their occurrence indicated that the absorption rates of indomethacin decreased in the order, reference formulation 〉 pellet formulation I 〉 pellet formulation II, which was the same rank order as that of their dissolution rates in vitro. The data indicated that multiple units controlled-release formulations represent a reliable and reproducible source of indomethacin, which by avoiding extremes of local or systemic drug concentrations also should be better tolerated by individuals susceptible to unwanted gastrointestinal and centrally-mediated side-effects.

Notes: Summary Three different pivmecillinam preparations, a conventional 200 mg tablet (P tablet) and two new formulations containing respectively pivmecillinam 200 mg and 400 mg plus Avicel® (microcrystalline cellulose) as a disintegrator (PA tablet), were compared in vitro and in a gastroscopic study in 8 healthy volunteers. Disintegration of the PA tablet was significantly more rapid both in vitro and in the stomach. Following disintegration, the content of the PA tablet was spread over a larger area of the gastric mucosa (1088 mm2) than was observed with the P tablets (408 mm2). Three of the 8 volunteers taking the P tablet developed hyperaemia, interstitial bleeding or erosions of the mucosa of the stomach. No such reactions were seen with the PA tablets. Serum concentrations of mecillinam following ingestion of pivmecillinam tablets were determined in three groups of subjects; fasting volunteers, both supine and ambulant, and in ambulant subjects who took the preparation with a light meal. There was a tendency for the new PA tablets to produce a higher peak serum level as well as greater bioavailability of mecillinam. Administration of the PA tablets with a meal significantly increased the peak serum level and total bioavailability of the drug. On the basis of our observations we recommend adoption of the new PA tablet, because of its quick passage through the oesophagus and its more rapid and complete disintegration in the stomach.

Notes: Summary An high-pressure liquid chromatographic method was used to measure allopurinol and oxipurinol in plasma and urine in 6 healthy volunteers after a single intravenous or oral dose of allopurinol. The influence of coadministrated benzbromarone and hydrochlorothiazide on the pharmacokinetics of allopurinol and oxipurinol was also investigated. After intravenous injection of allopurinol 300 mg the plasma disappearance was biexponential, with a mean distribution half-life of 2.32±1.08 min $$(\bar x \pm SD)$$ and an elimination half-life of 47.8±10.6 min. The total clearance of allopurinol was 11.37±2.70 ml/min/kg, whereas its renal clearance was only 1.73±0.79 ml/min/kg. Oxipurinol disappeared monoexponentially from plasma ith a mean half-life of 12.2±2.6 h. Its renal clearance was 0.42±0.091 ml/min/kg. After oral administration of allopurinol 300 mg the peak plasma concentration of 2.1±0.6 µg/ml (1.5×10−5 M) was reached within 30 to 120 min. The peak level of oxipurinol of 5.8±1.5 µg/ml (3.8×10−5 M) was found within 2 to 5 h after intravenous and oral allopurinol. The bioavailability of oral allopurinol computed from plasma data was 90.4±8.7%. The total recovery from urine was 77% (allopurinol 8%, oxipurinol 69%) after oral and 88% after i.v. administration. It was concluded that about 10% of the oral dose was not absorbed and that 12% was eliminated by an unknown mechanism, presumably as riboside. The pharmacokinetics of allopurinol and oxipurinol were not significantly influenced by coadministration of benzbromarone or hydrochlorothiazide.

Notes: Summary Noscapine was administred to five healthy volunteers in a randomized crossover design, as an intravenous infusion of 66 mg, and as an oral 150 mg dose of either rapidly dissolving tablets or a tablet containing ion exchange resin-bound noscapine. After i.v. administration, the disposition of noscapine was bi-exponential with an elimination half-life of 2.6 h; the total plasma clearance was 22 ml/min/kg and the volume of distribution (Vdarea) was 4.7 l/kg. The absolute oral bioavailability was 30%, with a 3.6-fold interindividual variation. There was no pharmacokinetic evidence to support a prolonged action of the ion exchange resin tablet.

Notes: Summary The pharmacokinetics of bacmecillinam and pivmecillinam were studied in healthy fasting volunteers given tablets in a cross-over, randomized order. The mean (±SD) peak levels of plasma mecillinam were 1.43±0.34, 2.73±0.43, and 4.62±1.41 mg/l after bacmecillinam 100, 200, and 400 mg and 2.38±0.65 mg/l after pivmecillinam 400 mg. The corresponding areas under plasma Vs time curves (AUC) were 2.21±0.19, 3.99±0.63, and 7.74±1.38 mg·h·l−1 for bacmecillinam and 5.35±0.93 mg·h·l−1 for pivmecillinam. The elimination half-lives were 0.8–1.1h for bacmecillinam and 0.7h for pivmecillinam. The 12 h urinary recovery of unchanged mecillinam after the 400 mg doses was 41% for bacmecillinam and 30% for pivmecillinam. The 400 mg dose of bacmecillinam gave a significantly higher plasma peak (p〈0.001), AUC (p〈0.001) and urinary recovery (p〈0.001) than did pivmecillinam 400 mg. The plasma peaks appeared earlier and the rate of absorption was higher after bacmecillinam than after pivmecillinam (p〈0.05). In conclusion, bacmecillinam had a better bioavailability than pivmecillinam in the tablet formulations studied. The AUC increased linearly with increasing doses of bacmecillinam.

Notes: Summary The pharmacokinetics of terodiline HCl was studied in nine healthy volunteers given 12.5 mg i.v. and p.o. or 20 mg i.v. and 25 mg p.o. on two different occasions. The serum concentrations were measured by gas chromatography — mass spectrometry, using deuterated terodiline HCl as the internal standard. After i.v. administration the kinetics could be described by a two-compartment model with a mean distribution half life of 0.3 h and a mean elimination half life of 63 h. The serum clearance and apparent volume of distribution varied about 4-fold with mean values of 4.8 l/h and 417 l, respectively. After oral administration, the mean half life of absorption was 0.7 h and that of elimination 65 h. The absolute bioavailability varied between 64% and 105% with a mean of 92%. The long serum half life of terodiline should permit its once daily administration.

Notes: Summary Differences in the plasma concentrations of drugs after oral administration are caused by two main factors: variation in absorption ratios and in the distribution processes in the body. A new method for the dissection of both types of factors is discussed. The method uses a reference regression of the AUC-values to the corresponding values after intravenous infusion of graded doses. The reference regression is estimated from an appropriate trial. Deviation of the determined AUC-values from the regression curve afford an estimate of the residual variance due to varying distribution volumes or similar random biological effects. For the estimation of absorption ratios after oral administration the drug is given orally to another sample of subjects and their AUC-values are calculated. The deviation of these AUC values due to the above mentioned random effects are simulated using the residual variance of the reference regression, and are subtracted from the observed AUC-values. Then, the differences in the corresponding absorbed doses are transformed by inverting the reference regression. From these doses the empirical distribution function and statistical parameters (e.g. quantiles) are determined. The method has the advantage that no restrictive assumptions are required, such as first order processes, dose linearity, homogeneity of variance or normal distribution of absorption ratios. Its applicability to substances with qualitative differences in their pharmacokinetics is demonstrated by appropriate examples.

Notes: Summary Etilefrine undergoes considerable first-pass metabolism through conjugation in the gut wall. In six volunteers bioavailability was reduced to 35% for a fast release tablet and to 17% for a sustained release preparation. The addition fo dihydroergotamine (DHE) to the sustained release preparation surprisingly increased bioavailability to 61%. The plasma levels of the main metabolite formed during the passage through the gut wall indicated an increase in the rate of enteric absorption and therefore also in bioavailability by DHE. This might be due to the influence of DHE upon the vascular resistance of the vessels in the gut wall or a change in gastro-intestinal motility with a prolongation of drug contact time within the absorbing gut segment.

Notes: Summary The structure and topography of flagellar scales (underlayer scales, rodshaped scales, hair-scales) in the green flagellateTetraselmis cordiformis has been studied in detail and the effect of divalent cations and fixation conditions on scale structure and topography was followed quantitatively. Hair-scales occur in two rows on opposite sides of a flagellum and are linked to the flagellar membrane and to two axonemal doublets by B-tubule-flagellar membrane connectives. Underlayer scales form about 24 longitudinal rows along the flagellum and occur in two distinctive shapes (pentagonal and square). The square shaped underlayer scales are related in position to the attachment sites of the hair-scales. Rod-shaped scales occur in about 20 longitudinal rows along the flagellum and are characteristically positioned as “double scales”. Calcium in the culture medium is necessary to retain rod-shaped scales on the flagellum, absence of calcium or chelation with EGTA or pyrophosphate leads to disappearance of rod-shaped scales from the flagellum. Other divalent cations can only partially substitute for calcium. It is suggested that calcium provides the linkage between underlayer scales and rod-shaped scales inTetraselmis. Flagellar scales inTetraselmis apparently fall into two categories: a) hair-scales (not affected by fixation or absence of divalent cations, firmly bound to axonemal microtubules via the flagellar membrane), b) underlayer scales and rod-shaped scales (affected by fixation and absence of divalent cations, kept on the flagellum mainly by electrostatic forces). The function of flagellar scales inTetraselmis is discussed.

Notes: Summary Discophrya collini is a suctorian protozoan with contractile tentacles containing a microtubule-lined canal and microfilaments. The effects of a range of cations on tentacle contraction and ultrastructure have been determined. Treatment with 80 mM CaCl2 and 95 mM MgCl2 causes contraction to 28% and 57% of the control length respectively. Re-extension takes over 4 hours in the culture medium, but CaCl2-treated tentacles are re-extended after a 5 minutes treatment with 10−2 M EDTA or 5 × 10−3 M EGTA. CuCl2 causes a significant contraction at 10−5 M (to 77%); LaCl3 at 10−4 M (to 65%); ZnCl2 at 10−2 M (to 65%), but BaCl2, CoCl2, MnCl2, NiCl2, and SrCl2 cause significant changes only at 10−1 M. The cytoplasm of CaCl2-treated cells contains two forms of membraneous structures when viewed in TEM; that of MgCl2-treated cells reveals granular areas of medium electron density. None of these features are seen in control cells. The microtubules of the tentacle canal appear to be intact upon its retraction into the cell with no change occurring in the numbers or relative positions of the microtubules. The tentacle cortex is wrinkled. It is suggested from this and previous work that tentacle contraction may be mediated by a microfilament-based mechanism, and that calcium may be involved.

Notes: Abstract Plasma concentrations of total and unbound sulfisoxazole were followed after single intravenous and oral doses of 1 g sulfisoxazole and during a 500-mg, four-time-a-day dosing regimen in six healthy males, using a specific high pressure liquid Chromatographic assay method. Saturable plasma protein binding was observed at total concentrations above 80–100 mg/liter. The clearance of sulfisoxazole was 18.7±3.9ml/min for total drug and 232±64ml/min for unbound drug. Renal elimination, on the average, accounted for 49% of the clearance of sulfisoxazole. The apparent volume of distribution for total drug was 10.9±2.0 liters and 136±36 liters for unbound drug, indicating that sulfisoxazole is primarily distributed extracellularly. Accumulation of N4-acetyl-sulfisoxazole during multiple dosing did not affect the disposition of sulfisoxazole. Adjusting for variable renal clearances between oral and intravenous administration and using the unbound plasma concentrations, the bioavailability for an oral dose of sulfisoxazole was found to be 0.95±0.04.

Notes: Abstract The bioavailability of phenytoin from rapid release capsule and oral solution formulations relative to that of a slow release capsule formulation was assessed in five patients who had participated in a three-way crossover study performed at steady state. The subjects then underwent dosage adjustment utilizing the slow release formulation, and estimates of their Michaelis-Menten parameters thus obtained were utilized in calculating the relative bioavailabilities. In addition, expected changes in steady-state plasma phenytoin concentrations were calculated assuming initial levels of 15 mg/liter, with increases and decreases in bioavailability of 10%. The consequences of such alterations in the extent of phenytoin absorption or average content of the dosage form may be clinically significant, particularly where the initial phenytoin level is equal to or greater than the patient's operative Km.

Notes: Abstract Current information on the pharmacokinetics of disopyramide is reviewed with emphasis on the implications for antiarrhythmic therapy. The absolute bioavailability, the disposition half-life, the plasma clearance, and the renal clearance for normal subjects and patients are discussed. Drug-drug interactions are discussed, and a new flexible intravenous dosing schedule is proposed.

Notes: Abstract The literature growth in pharmacokinetics and bioavailability between the years 1964 and 1980 is analyzed. During much of this period, the literature doubled approximately every 1.6 years. However, during the period 1978–1980, little or no growth was observed. During the period 1950–1967, the total chemical literature increased exponentially with a half-life of 8.28 years; between 1968 and 1980, the half-life was 12.4 years. Thus, the pharmacokinetic literature increased at a much more rapid pace than did the total chemical literature in general. The subject of growth is considered in a general context, particularly as influenced by psychological, sociological, political, and economic factors. It is concluded that while mathematical functions may adequately describe past literature trends, they have little if any utility in predicting future trends in specific research areas such as pharmacokinetics.

Notes: Abstract The pharmacokinetics of chloramphenicol (CAP) and total chloramphenicol succinate (CAPS) were studied in eight hospitalized adult patients with normal renal and hepatic function receiving intravenous chloramphenicol sodium succinate therapy. The steady-state peak concentrations of CAP (8.4–26.0 μg/ml) occurred at an average of 18.0 min (range 5.4–40.2) after cessation of the chloramphenicol sodium succinate infusion. Unhydrolyzed CAPS prodrug, representing 26.0±7.0% of the dose, was recovered unchanged in the urine indicating that the bioavailability of CAP from a dose of intravenous chloramphenicol succinate is not complete. A pharmacokinetic model was developed for simultaneous fitting of CAP and CAPS plasma concentration data. Pharmacokinetic parameters determined by simultaneous fitting were: V, 0.81±0.18 liters/kg; t1/2, 3.20 ±1.02 hr; CLB, 3.21±1.27 ml/min/kg for chloramphenicol; and V, 0.38±0.13 liters/kg; t1/2, 0.57±0.12hr; CLB, 7.72±1.87 ml/min/kg for total chloramphenicol succinate.

Notes: Abstract The pharmacokinetics and bioavailability of nitrazepam following intravenous, oral (tablet), and rectal (solution) administration were studied in seven healthy, young male volunteers. Nitrazepam plasma concentrations were determined by electron-capture GLC; pharmacokinetic evaluations were made by compartmental analysis (NONLIN) and compared with the results obtained by a less stringent modelling of the data. The plasma concentration-time profile was similar for all three routes of administration. Mean kinetic parameters as obtained by compartmental analysis of i.v. nitrazepam were: distribution half-life 17 min; volume of distribution after equilibrium 2.14 liters/kg; total plasma clearance 61.6 ml/min; elimination half-life 29.0 h. The mean protein unbound fraction of nitrazepam in plasma was 12.3% and the clearance of the unbound fraction was 506 ml/min. Absorption of oral nitrazepam started after the elapse of a lag time (mean value 12 min) and occurred as an apparent first-order process in all but one subject, with a mean absorption half-life of 16 min. Distribution and elimination half-lives were comparable with those following i.v. administration. Following rectal administration of the nitrazepam solution, rapid first-order absorption occurred with a mean lag time of 4 min and a mean absorption half-life of 9 min. Peak times (median 18 min) were significantly shorter than following oral administration (median 38 min), but there was little difference in peak concentrations. The distribution half-life was similar to i.v. and oral administration, but the elimination half-lives were longer with a mean value of 33.1 h. Following i.v. administration a good agreement was found between the results obtained by compartmental analysis using NONLIN and those obtained by a less stringent modelling of the data. Following oral and rectal administration, a good agreement between the two procedures was found for the elimination half-life; estimation of bioavailability, however, was higher by compartmental analysis. The mean bioavailability data showed that absorption is complete when nitrazepam is given orally and almost 20% lower when it is given rectally, but considerable interindividual differences were observed.

Notes: Summary The amount of copper extracted from soils by EDTA was found to increase with the temperature of extraction. Under controlled conditions of extraction, the amount of applied copper extracted from soils by EDTA decreased during incubation of soils under both moist and dry conditions. The recovery of applied copper by EDTA appeared to be related to the amounts of manganese and iron oxides in the soil. On the basis of comparisons with calcium chloride-extractable copper and isotopically-exchangeable copper it is suggested that EDTA extraction could over-estimate the availability of soil copper to plants.

Notes: Summary Fertility levels in soils beneathPinus caribaea trees were examined in the Mountain Pine Ridge savannas, Belize, where fire control has precipitated the development of pine woodland. Slight surface soil enrichment was recorded beneath pine canopies, but to levels well below those found beneath associated hardwoods. Estimates of total nutrient pools beneath trees showed modest cation accumulation beneath a 73 year old tree but some defecits in Ca and Mg beneath a 24 year old tree. A tap root cutting experiment on trees of the same species revealed no significant declines in foliar nutrient levels after 19 months. It is concluded that no pronounced long-term deterioration in soil fertility levels is developing beneath stands ofP. caribaea in the savanna, although some temporary nutrient declines may exist beneath young pine stands. Atmospheric inputs are the most likely source of nutrient accretion and it is suggested that the establishment of hardwood associates with pine may enhance the rates of nutrient capture from this source.

Notes: Summary In order to study the reasons for poor peanut (Arachis hypogaea L.) performance on an Avalon medium sandy loam, a three year field study was undertaken to investigate the effects of lime and gypsum applications on growth, yield and quality. Rates of up to 2,400 kg agricultural lime/ha/annum significantly increased soil pH (1N KCl) and exch. Ca and decreased levels of exch. Al and Al saturation in the soil (0–150 mm). The effect of the same rates of gypsum was much less marked, only exch. Ca increasing and Al saturation decreasing to any substantial extent. In the absence of lime (i.e. even where gypsum was applied). nodulation was poor and the plants developed a general chlorosisc. 90 days after planting. Liming markedly improved nodulation whereas annual applications of gypsum had the opposite effect. Liming significantly increased the hay, pod and kernel yields by up to 73, 105 and 117%, respectively. On average, gypsum applications had no significant effects. Liming increased shelling percentage, the percentage mature pods, 100-kernel mass and protein concentration in the kernel, and decreased the incidence of pops and kernels with black plumule. Applications of gypsum had little effect on quality except for a decreased incidence of black plumule. It appeared that the improved crop performance with liming resulted from a reduction in Al toxicity which improved nodulation. Calcium deficiency did not appear to be a major cause of poor peanut growth and quality in the unameliorated soil.

Notes: Summary Concentrations of P, N, K, Ca, and Mg in above-ground tissues ofP. caribaea were sampled in the species'native savanna habitat. Concentrations were relatively low, but some evidence of higher consumption of K and Ca was found in trees grown on more fertile soils. Regressions were developed to predict the quantities of nutrients sequestered in above-ground tree tissues, and estimates made of the quantities stored in above-ground stands of this species in its native habitat and in several plantations elsewhere. Estimates were also made of the nutrient removals to be expected by harvesting these stands in different ways. Nutrient quantities stored in stands generally exceed those extractable from savanna surface soils, and it is suggested that inputs from the atmosphere are the most probable alternate nutrient source. A comparison of these inputs for tropical areas with the quantities required for stand growth in the savanna, and harvesting removals, suggests that an adequate supply of all elements except P exists, provided that capture by pine is effective. However, atmospheric inputs generally fall below the storage and harvest removal rates for fast growing exotic plantations of this species suggesting that multiple rotations of these plantations at current growth rates may not be feasible without artifical fertilization.

Notes: Summary We report a study of the mechanism by which the response of plants to waterlogging can be modified by soil temperature. Wheat was grown initially in well-aerated soil in a controlled environment room before the soil was flooded with aerated, deionized water. The soil temperature was maintained constant in the range 6–18°C while the air temperature was at 14°C. Waterlogging damage was greater in plants at the higher soil temperatures when the plants were compared at the same chronological age. However, when compared at the same growth stage, the response to soil temperature was little differenti.e. plants subjected to waterlogging for a long time at low soil temperatures exhibited a similar reduction in growth and other properties as those subjected briefly at higher temperatures. The concentration of dissolved oxygen in the soil solution declined rapidly at all temperatures, being almost zero after 36 h waterlogging. Temperature affected rates of change of the concentrations of dissolved carbon dioxide, ethylene, nitrous oxide, nitrite, nitrate, calcium and potassium. The importance of soil-and plant-determined properties in the waterlogging response of plants at different temperatures are discussed.

Notes: Summary A comparative study of two populations ofE. obliqua has shown that germination of an acidic population is severely reduced at high levels of Ca, whereas a calcareous population maintained high germinability over a wide range of Ca concentrations. In contrast, seedlings of both populations showed a similar overall response in yield to an increasing supply of external Ca. However, plants from the acidic population tended to show a lower survival rate and poorly growing plants accumulated higher levels of Ca and P at high external concentrations of Ca than the calcareous population. Plants showing severe chlorosis and symptoms of P and Ca toxicity also exhibited low K/Ca ratios.

Notes: Abstract Seasonal and regional variations in the speciation, sediment-water partitioning, and dynamics of mercury (Hg) were studied at selected sites along the Hg-polluted Wabigoon River, and at unpolluted headwater and tributary sites, during April–September, 1979. ‘Dissolved’ and ‘particulate’ forms of Hg in the water were separated by continuous-flow centrifugation in the field. The Hg and other pollutants such as wood chips and salt had been discharged from a chlor-alkali plant and paper mill at Dryden, Ontario. Concentrations and loadings of particulate methyl mercury (CH3Hg+) and total particulate Hg (and loadings of total ‘dissolved’ Hg) were greatest during the spring flood (April-May) owing to accelerated resuspension and transport of sediments. Concentrations of ‘dissolved’ CH3Hg+, however, were highest in the summer (July–September), probably reflecting stimulation of microbial methylating activity by elevated temperatures, together with factors such as reduced levels of metal-scavenging particulates and minimal dilution by runoff. Total dissolved Hg concentrations were relatively high in September at polluted sites only, possibly because of desorption from sediments due to elevated concentrations of Cl− ions. Loadings of dissolved CH3Hg+ tended to be high in the summer but were generally depressed (suggesting sorption by suspended particles) during the major spring-flood episode in May. During July–August dissolved CH3Hg+ was a function of total dissolved Hg, suggesting rapid biomethylation of desorbed inorganic Hg; but in general dissolved and suspended CH3Hg+ levels depended on environmental variables and were unrelated to total Hg concentrations. In the summer only, total dissolved Hg was a function of dissolved Cl−. Hg species in particulates were associated with sulfides, hydrated Fe and Mn oxides, organic matter (notably high molecular weight humic and humic-Fe components), and selenium (Se); but CH3Hg+ and total Hg differed in their specific preferences for binding agents, implying that binding sites discriminate between CH3Hg+ and Hg2+ ions. CH3Hg+ was associated with sulfide and (in the spring only) with Fe oxides, whereas total Hg was associated with organic matter and Se and with DTPA- and NaOH-extractable Fe in the spring but with Mn oxide and NaOH-extractable organics in the summer. Sulfides were most abundant in May, indicating that they were eroded from bottom sediments, but Fe and Mn oxides were most abundant in the summer, probably owing to activities of filamentous iron bacteria and other micro-organisms. Particulate Hg was 98–100% nonextractable by mild solvents such as Ca acetate, CaCl2, dilute acetic acid, and (at polluted sites only) DTPA solutions, suggesting that the particulate Hg mobilized in the spring may not be readily available to organisms; association with Se and high molecular weight humic matter also supports this hypothesis. Hg probably becomes more bio-available in the summer, as suggested by the upsurge in dissolved CH3Hg+ and total dissolved Hg levels, and by increases in the solubility of particulate Hg in acetic acid, DTPA, H2O2, and NaOH solutions, as well as an increase in the relative importance of lower molecular weight fractions of NaOH-extractable Hg (in September). Regional variations in Hg speciation and partitioning reflected a gradient in sediment composition from wood chips near Dryden to silt-clay mud further downstream. Hg in silt-clay mud relatively far (〉 35 km) downstream from the source of pollution or in unpolluted areas appeared to be more readily solubilized by Cl− ions or chelators such as DTPA, more readily methylated (as indicated by downstream increases in dissolved CH3Hg+ levels and CH3Hg+/total Hg ratios), and was to a greater degree organically bound (H2O2-extractable), and thus was probably more bio-available, than Hg in wood-chip deposits. Possible explanations include weaker binding of Hg by the mud, the more finely divided state of the mud, and improved microbial growth at lower concentrations of toxic pollutants. Owing to enrichment in sulfides and Fe oxides, resuspended wood-chip sediments were especially efficient scavengers of CH3Hg+. The results indicate that in any pollution abatement plan aimed at lowering the Hg levels in the biota of lakes fed by the Wabigoon River, immobilization, removal, or detoxification of dissolved as well as particulate forms of Hg in the river would probably have to be considered. Possibly, Hg species could be ‘scrubbed’ from the river water by increasing the suspended load and by sedimentation and treatment with Hg-binding agents in special receiving basins.

Notes: Abstract Seasonal and regional variations in the speciation, sediment-water partitioning, and dynamics of mercury (Hg) were studied at selected sites along the Hg-polluted Wabigoon River, and at unpolluted headwater and tributary sites, during April–September, 1979. ‘Dissolved’ and ‘particulate’ forms of Hg in the water were separated by continuous-flow centrifugation in the field. The Hg and other pollutants such as wood chips and salt had been discharged from a chlor-alkali plant and paper mill at Dryden, Ontario. Concentrations and loadings of particulate methyl mercury (CH3Hg+) and total particulate Hg (and loadings of total ‘dissolved’ Hg) were greatest during the spring flood (April-May) owing to accelerated resuspension and transport of sediments. Concentrations of ‘dissolved’ CH3Hg+, however, were highest in the summer (July–September), probably reflecting stimulation of microbial methylating activity by elevated temperatures, together with factors such as reduced levels of metal-scavenging particulates and minimal dilution by runoff. Total dissolved Hg concentrations were relatively high in September at polluted sites only, possibly because of desorption from sediments due to elevated concentrations of Cl− ions. Loadings of dissolved CH3Hg+ tended to be high in the summer but were generally depressed (suggesting sorption by suspended particles) during the major spring-flood episode in May. During July–August dissolved CH3Hg+ was a function of total dissolved Hg, suggesting rapid biomethylation of desorbed inorganic Hg; but in general dissolved and suspended CH3Hg+ levels depended on environmental variables and were unrelated to total Hg concentrations. In the summer only, total dissolved Hg was a function of dissolved Cl−. Hg species in particulates were associated with sulfides, hydrated Fe and Mn oxides, organic matter (notably high molecular weight humic and humic-Fe components), and selenium (Se); but CH3Hg+ and total Hg differed in their specific preferences for binding agents, implying that binding sites discriminate between CH3Hg+ and Hg2+ ions. CH3Hg+ was associated with sulfide and (in the spring only) with Fe oxides, whereas total Hg was associated with organic matter and Se and with DTPA- and NaOH-extractable Fe in the spring but with Mn oxide and NaOH-extractable organics in the summer. Sulfides were most abundant in May, indicating that they were eroded from bottom sediments, but Fe and Mn oxides were most abundant in the summer, probably owing to activities of filamentous iron bacteria and other micro-organisms. Particulate Hg was 98–100% nonextractable by mild solvents such as Ca acetate, CaCl2, dilute acetic acid, and (at polluted sites only) DTPA solutions, suggesting that the particulate Hg mobilized in the spring may not be readily available to organisms; association with Se and high molecular weight humic matter also supports this hypothesis. Hg probably becomes more bio-available in the summer, as suggested by the upsurge in dissolved CH3Hg+ and total dissolved Hg levels, and by increases in the solubility of particulate Hg in acetic acid, DTPA, H2O2, and NaOH solutions, as well as an increase in the relative importance of lower molecular weight fractions of NaOH-extractable Hg (in September). Regional variations in Hg speciation and partitioning reflected a gradient in sediment composition from wood chips near Dryden to silt-clay mud further downstream. Hg in silt-clay mud relatively far (〉 35 km) downstream from the source of pollution or in unpolluted areas appeared to be more readily solubilized by Cl− ions or chelators such as DTPA, more readily methylated (as indicated by downstream increases in dissolved CH3Hg+ levels and CH3Hg+/total Hg ratios), and was to a greater degree organically bound (H2O2-extractable), and thus was probably more bio-available, than Hg in wood-chip deposits. Possible explanations include weaker binding of Hg by the mud, the more finely divided state of the mud, and improved microbial growth at lower concentrations of toxic pollutants. Owing to enrichment in sulfides and Fe oxides, resuspended wood-chip sediments were especially efficient scavengers of CH3Hg+. The results indicate that in any pollution abatement plan aimed at lowering the Hg levels in the biota of lakes fed by the Wabigoon River, immobilization, removal, or detoxification of dissolved as well as particulate forms of Hg in the river would probably have to be considered. Possibly, Hg species could be ‘scrubbed’ from the river water by increasing the suspended load and by sedimentation and treatment with Hg-binding agents in special receiving basins.

Notes: Abstract Control of phytoplankton production in the Great Lakes can be achieved most efficiently by limiting inputs of biologically available P. We report the results of studies performed to characterize the chemical forms and availability of particulate P in wastewater and tributaries which enter the lower Lakes, the eroding bluffs which border Lake Erie, and bottom samples from the near-shore of western Lake Erie. Rates of release of available P were estimated from a simple first-order model of the process, as observed during algal bioassays. Available P in wastewater samples, as a fraction of total particulate P, was affected minimally by wastewater treatment, including chemical precipitation and filtration; it correlated well with levels of total particulate P. Available particulate P levels in fluvial suspended sediments showed regional uniformity, but appeared to be strongly dependent on levels of both NaOH-P and CDB-P. Rates of release of available P decreased during wastewater treatment to values which were similar in magnitude to those observed for fluvial sediments. Release rates, however, were not related to any of the particulate P fractions which were measured. Analysis of the bluff and bottom samples indicated that P availability in the former was negligible, but the latter contained levels which approached those of wastewater particulates, though available P was released from the bottom sediments at relatively low rates.

Notes: Abstract Control of phytoplankton production in the Great Lakes can be achieved most efficiently by limiting inputs of biologically available P. We report the results of studies performed to characterize the chemical forms and availability of particulate P in wastewater and tributaries which enter the lower Lakes, the eroding bluffs which border Lake Erie, and bottom samples from the near-shore of western Lake Erie. Rates of release of available P were estimated from a simple first-order model of the process, as observed during algal bioassays. Available P in wastewater samples, as a fraction of total particulate P, was affected minimally by wastewater treatment, including chemical precipitation and filtration; it correlated well with levels of total particulate P. Available particulate P levels in fluvial suspended sediments showed regional uniformity, but appeared to be strongly dependent on levels of both NaOH-P and CDB-P. Rates of release of available P decreased during wastewater treatment to values which were similar in magnitude to those observed for fluvial sediments. Release rates, however, were not related to any of the particulate P fractions which were measured. Analysis of the bluff and bottom samples indicated that P availability in the former was negligible, but the latter contained levels which approached those of wastewater particulates, though available P was released from the bottom sediments at relatively low rates.

Notes: Abstract Seasonal and regional variations in the speciation, sediment-water partitioning, and dynamics of mercury (Hg) were studied at selected sites along the Hg-polluted Wabigoon River, and at unpolluted headwater and tributary sites, during April–September, 1979. ‘Dissolved’ and ‘particulate’ forms of Hg in the water were separated by continuous-flow centrifugation in the field. The Hg and other pollutants such as wood chips and salt had been discharged from a chlor-alkali plant and paper mill at Dryden, Ontario. Concentrations and loadings of particulate methyl mercury (CH3Hg+) and total particulate Hg (and loadings of total ‘dissolved’ Hg) were greatest during the spring flood (April-May) owing to accelerated resuspension and transport of sediments. Concentrations of ‘dissolved’ CH3Hg+, however, were highest in the summer (July–September), probably reflecting stimulation of microbial methylating activity by elevated temperatures, together with factors such as reduced levels of metal-scavenging particulates and minimal dilution by runoff. Total dissolved Hg concentrations were relatively high in September at polluted sites only, possibly because of desorption from sediments due to elevated concentrations of Cl− ions. Loadings of dissolved CH3Hg+ tended to be high in the summer but were generally depressed (suggesting sorption by suspended particles) during the major spring-flood episode in May. During July–August dissolved CH3Hg+ was a function of total dissolved Hg, suggesting rapid biomethylation of desorbed inorganic Hg; but in general dissolved and suspended CH3Hg+ levels depended on environmental variables and were unrelated to total Hg concentrations. In the summer only, total dissolved Hg was a function of dissolved Cl−. Hg species in particulates were associated with sulfides, hydrated Fe and Mn oxides, organic matter (notably high molecular weight humic and humic-Fe components), and selenium (Se); but CH3Hg+ and total Hg differed in their specific preferences for binding agents, implying that binding sites discriminate between CH3Hg+ and Hg2+ ions. CH3Hg+ was associated with sulfide and (in the spring only) with Fe oxides, whereas total Hg was associated with organic matter and Se and with DTPA- and NaOH-extractable Fe in the spring but with Mn oxide and NaOH-extractable organics in the summer. Sulfides were most abundant in May, indicating that they were eroded from bottom sediments, but Fe and Mn oxides were most abundant in the summer, probably owing to activities of filamentous iron bacteria and other micro-organisms. Particulate Hg was 98–100% nonextractable by mild solvents such as Ca acetate, CaCl2, dilute acetic acid, and (at polluted sites only) DTPA solutions, suggesting that the particulate Hg mobilized in the spring may not be readily available to organisms; association with Se and high molecular weight humic matter also supports this hypothesis. Hg probably becomes more bio-available in the summer, as suggested by the upsurge in dissolved CH3Hg+ and total dissolved Hg levels, and by increases in the solubility of particulate Hg in acetic acid, DTPA, H2O2, and NaOH solutions, as well as an increase in the relative importance of lower molecular weight fractions of NaOH-extractable Hg (in September). Regional variations in Hg speciation and partitioning reflected a gradient in sediment composition from wood chips near Dryden to silt-clay mud further downstream. Hg in silt-clay mud relatively far (〉 35 km) downstream from the source of pollution or in unpolluted areas appeared to be more readily solubilized by Cl− ions or chelators such as DTPA, more readily methylated (as indicated by downstream increases in dissolved CH3Hg+ levels and CH3Hg+/total Hg ratios), and was to a greater degree organically bound (H2O2-extractable), and thus was probably more bio-available, than Hg in wood-chip deposits. Possible explanations include weaker binding of Hg by the mud, the more finely divided state of the mud, and improved microbial growth at lower concentrations of toxic pollutants. Owing to enrichment in sulfides and Fe oxides, resuspended wood-chip sediments were especially efficient scavengers of CH3Hg+. The results indicate that in any pollution abatement plan aimed at lowering the Hg levels in the biota of lakes fed by the Wabigoon River, immobilization, removal, or detoxification of dissolved as well as particulate forms of Hg in the river would probably have to be considered. Possibly, Hg species could be ‘scrubbed’ from the river water by increasing the suspended load and by sedimentation and treatment with Hg-binding agents in special receiving basins.

Notes: Summary A conspicuous feature of freeze-dried cryosections of male Schistosoma mansoni is the presence of groups of electron-dense granules. X-ray analysis in the TEM of these granules shows them, in comparison with the adjacent cytoplasm, to contain significantly greater amounts of sodium and calcium. In glutaraldehyde-fixed material, these granules have been correlated with the membrane-bounded, electron-dense granules found within the axons of the peripheral nervous system.