Using animal data to improve prediction of human decompression risk following air-saturation dives.

To plan for any future rescue of personnel in a disabled and pressurized submarine, the US Navy needs a method for predicting risk of decompression sickness under possible scenarios for crew recovery. Such scenarios include direct ascent from compressed air exposures with risks too high for ethical human experiments. Animal data, however, with their extensive range of exposure pressures and incidence of decompression sickness, could improve prediction of high-risk human exposures. Hill equation dose-response models were fit, by using maximum likelihood, to 898 air-saturation, direct-ascent dives from humans, pigs, and rats, both individually and combined. Combining the species allowed estimation of one, more precise Hill equation exponent (steepness parameter), thus increasing the precision associated with human risk predictions. These predictions agreed more closely with the observed data at 2 ATA, compared with a current, more general, US Navy model, although the confidence limits of both models overlapped those of the data. However, the greatest benefit of adding animal data was observed after removal of the highest risk human exposures, requiring the models to extrapolate.

Establishing the world list of schools of pharmacy.

The development of a world-wide list of schools of pharmacy by the former secretary of the Academic Section of the International Pharmacy Federation (F.I.P.) is described. Four print-based editions have been published since the first "preliminary" edition was made available to F.I.P. members in 1986. In February 1995, a version was launched on the World Wide Web, which has considerably facilitated the process of maintenance of the list through direct e-mail contact of academics around the world with the editor. Links are provided to all schools which have established their own home-pages on the Web. The extent to which this resource will aid international communication between pharmacy academics is yet to be fully realised.

A study of drug compliance, including the effect of a treatment card, in elderly patients following discharge home from hospital.

Compliance with prescribed medication was assessed in 104 mentally alert elderly patients one and two months after discharge from a geriatric medical unit. Of the 82 patients (58 females, 24 males) who completed the study, 72% were compliant by average tablet count after one month and 69% after two months. Using urinary riboflavin excretion as a marker of compliance, 69% were compliant after one month and 59% after two months. These differences were not significant, nor was any significant difference shown when a crossover design was used to study the effect of a treatment card on compliance. No differences in age, sex, social support or number of tablets taken were found between compliant and non-compliant patients. The value of a careful explanation of drug therapy by both a hospital pharmacist prior to discharge, and a research nurse, one and two months after discharge, has been highlighted. A considerable number of patients benefited from the assistance of a relative or home helper in administering their own treatment. It is recommended that a suitable helper be identified and counselled to assist at risk elderly patients with their medication. Thus, elderly mentally alert patients can achieve a satisfactory level of compliance equivalent to younger patients if appropriate counselling is undertaken.

An investigation of the metabolism of S-carboxymethyl-L-cysteine in man using a novel HPLC-ECD method.

The metabolism of an oral dose of S-carboxymethyl-L-cysteine (SCMC) in man has been studied; the quantitative determination of SCMC, S-methyl-L-cysteine (SMC) and their sulphoxide metabolites (SCMCO and SMCO), in urine, was carried out using high performance liquid chromatography (HPLC) with electrochemical detection (ECD); the possibility of stereospecific sulphoxidation was investigated.

In situ liver perfusion techniques: the significance of the anaesthetic procedure used.

Pentobarbitone may not be an appropriate anaesthetic to use on the donor rat of an isolated liver perfusion model intended to study drug-drug interactions, since the anaesthetic was found to remain in the liver in concentrations which may be high enough to modify the disposition of a test drug. A retrospective study to assess the anaesthetic pentobarbitone decay in six perfused rat livers, showed a linear correlation between perfusion medium concentrations of phenytoin and pentobarbitone at the early sample times, suggesting that the anaesthetic was inhibiting the hepatic clearance of phenytoin. Direct evidence for this inhibition was obtained following the addition of pentobarbitone (5 mg) to a standard perfusion experiment with phenytoin at t = 30 min. At the end of these experiments (t = 120 min), the perfusate phenytoin levels had decreased to only 18.6 +/- 3.7% of the initial concentration, compared to 5.6 +/- 2.5% in the control group. Pithing, under light ether anaesthesia, was investigated as an alternative preparatory procedure for the donor rat with potentially less effect on the liver. Phenytoin was found to be cleared from the perfusion medium more rapidly with livers thus prepared, especially in the early stages. Also the precision of the technique was improved; the standard errors for six replicate experiments being considerably less in the pithed group compared to the pentobarbitone anaesthetised group. This is clearly a more appropriate preparatory procedure for rat liver perfusion techniques designed to investigate drug metabolism. There may also be some advantages when the technique is to be used for other investigations.

An assessment of the suitability of a modified technique of in situ rat-liver perfusion for the study of certain hepatic drug-drug interactions.

A modified technique of in situ rat-liver perfusion has been developed. Minor modifications were made for practical purposes to an existing technique including: the use of sterile Krebs Henseleit buffer to reduce contamination of perfusion medium which inhibits perfusion rate at the end of a perfusion period; the use of erythrocytes from 5-10-day-old whole human blood to provide a lysis-free oxygen-carrying component of the perfusion medium; the introduction of a sampling and flow-rate device into the reservoir that allows repetitive and accurate monitoring of hepatic blood flow (+/- 0.1 ml/min) and also simplifies sampling of venous hepatic blood; a magnetic support for the hepatic portal vein cannula to provide an easily adjustable yet firm support for the cannula and thus reduce the risk of damage to the vessel wall. Various physiological parameters of the model were investigated. These include: bile flow rate; bile acid content of bile; K+, Na+, and Ca++ content of bile; percent of a bromosulphophthalein dose excreted; oxygen consumption of perfused livers; phenytoin disposition; glycogen content; acid phosphatase activity; and the fine structure of hepatocytes. These parameters were compared with literature and in vivo experimental values, and the results suggest that the model should be suitable for the study of metabolic drug-drug interactions occurring in the rat liver.

Plasma prednisolone concentrations and kinetics in renal transplant patients.

Plasma prednisolone concentrations were measured in 26 renal transplant (RT) patients and five control subjects. A linear relationship was found between prednisolone dosage in mg/kg and area under the plasma concentration time curve in seven stable RT patients (r = 0.98) and in all subjects (n = 19) with estimated prednisolone clearance rates (CLp) between 0.075 and 0.11 L/kg/hr (r = 0.96). The greatest deviation from this occurred in five patients having reduced CLp with prolonged prednisolone half life (t1/2p) and in one having increased CLp while taking phenytoin. Three of the five with reduced clearance had steroid induced diabetes and one a Cushingoid appearance. There was some correlation between peak plasma prednisolone and dosage (r = 0.77) in all subjects, but none between creatinine clearance and t1/2p or CLp.

In vitro experiments on chloroquine and pyrimethamine absorption in the presence of antacid constituents or kaolin.

A study was made in vitro of the effect of five gastrointestinal medications on the absorption of chloroquine and pyrimethamine, the two most commonly used antimalarial agents in the Sudan. Activated dimethicone did not appreciably affect the absorption of either antimalarial drug. All other agents tested significantly decreased the absorption of both chloroquine and pyrimethamine. The decreases observed were as follows: calcium carbonate (-52.8 and -31.5%), a local remedy, gerdiga (-36.1 and -38.0%), kaolin (-46.5 and -49.9%) and magnesium trisilicate (-31.3 and -37.5%) for chloroquine and pyrimethamine respectively. The results indicate that concomitant therapy of these antimalarials with the implicated antacid and antidiarrhoeal agents will result in poor bioavailability of the antimalarials.

The effect of magnesium trisilicate and kaolin on the in vivo absorption of chloroquine.

An in vitro study indicated that certain antacids and adsorbents may decrease the oral availability of th two widely used antimalarial agents chloroquine and pyrimethamine. To determine if this data was applicable to the clinical (in vivo) situation, plasma levels of one of the antimalarial agents (chloroquine) were followed in six Negro--Arab volunteers both when given alone and when taken with separate doses of two of the implicated interactants (magnesium trisilicate and kaolin). This in vivo work confirmed the in vitro findings; chloroquine area under the plasma concentration-time curve data were decreased by both magnesium trisilicate (18.2%) and kaolin (28.6%). Similar results could be expected for pyrimethamine. It is suggested therefore, to avoid loss of drug, that the antimalarials should not be taken with gastrointestinal medications of this type or that their administration should be separated by at least 4 h to reduce the risk of them interacting in the gut, thus preventing drug adsorption to the antacids/adsorbents, and loss of systemic availability.

The use of buccal partitioning as a model to examine the effects of aluminium hydroxide gel on the absorption of propranolol.

1 A buccal partitioning model showed no absorption interaction between propranolol and aluminium hydroxide gel in three volunteer subjects. 2 The previously reported in vivo interaction is therefore not due to propranolol adsorption to, or complexation with the antacid but is more probably due to a decreased gastric emptying rate caused by the antacid. 2 Buccal partitioning has proved useful in the examination of the mechanism of the propranolol/aluminium hydroxide absorption interaction and may also be a suitable in vivo bioavailability screening model for other drugs which can be partitioned in the buccal membranes.

The N- and alpha- C-oxidation of N,N-dialkylanilines by rabbit liver microsomes in vitro.

1. A method for the determination of N,N-dialkylanilines and their metabolites by g.l.c. is described. 2. N-Demethylation and N-oxidation are important routes of metabolism of N-alkyl-N-methylanilines. 3. N-dealkylation, except the removal of a N-t-butyl group, occurs during the metabolism of N,N-dialkylanilines. 4. N-oxidation was found with N,N-dimethyl and N,N-diethylaniline and all N-methyl-N-alkylanilines examined except N-methyl-N-t-butylaniline. 5. A good correlation was found between the hydrophobic bonding constant (pi) and the extent of demethylation of a series of N-alkyl-N-methylanilines.

A comment on the formation of an N-hydroxymethyl intermediate in the metabolism of N-methylcarbazole.

Interpretation of the mass spectrum of the N-methylcarbazole used in a previous metabolism study suggests that the substrate was grossly contaminated with carbazole. The present study refutes that suggestion.

The formation of an N-hydroxymethyl intermediate in the N-demethylation of N-methylcarbazole in vivo and in vitro.

1. The metabolism of N-methylcarbazole has been studied in several mammalian species, both in vivo and in vitro. 2. An important metabolite after incubation of N-methylcarbazole with liver microsomes in vitro was identified as N-hydroxymethylcarbazole. 3. This metabolite was also found as a conjugate (probably the O-glucuronide) in the urine of some species. 4. N-Hydroxymethylcarbazole decomposed spontaneously in solution at pH 7-4 to formaldehyde and carbazole; this breakdown was enhanced by incubation with liver microsomes from several species, especially the guinea-pig. 5. The role of N-methyl hydroxylation, compared with N-oxidation, in the mechanism of N-dealkylation of non-basic N-methyl compounds is discussed.

The metabolism of N-ethyl-N-methylaniline by rabbit liver microsomes: the measurement of metabolites by gas-liquid chromatography.

1. A method for the determination of N-ethyl-N-methylaniline and its metabolites by g.l.c. is described. 2. Following incubation in N-ethyl-N-methylaniline with rabbit liver microsomes for 60 min, over 95% of the substrate was accounted for as unchanged compound or metabolites. 3. N-Ethyl-N-methylaniline is metabolized in vitro by rabbit tissues mainly by N-oxidation and N-demethylation and to a lesser extent by N-deethylation and di-dealkylation. 4. Both major routes of metabolism were observed in homogenates prepared from rabbit liver and lung; in addition N-oxidation occurred in kidney and bladder tissue homogenates.

The differentiation of N-oxidation and N-dealkylation of N-ethyl-N-methylaniline by rabbit liver microsomes as distinct metabolic routes.

1. N-Oxidation and N-dealkylation were shown to be separate routes of metabolism for N-ethyl-N-methylaniline. 2. N-Dealkylation, but not N-oxidation, is enhanced when NADH is present in addition to the NADPH-regenerating cofactors. 3. Some inhibitors, e.g. p-chloromercuribenzoate, inhibit N-dealkylation to a very much greater extent than they do N-oxidation. 4. N-Dealkylation is affected more by 'ageing' of the microsomal preparation or by the presence of bile salts, than is N-oxidation. 5. N-Oxidation followed by N-O-alpha-carbon migration of oxygen is only implicated to a very minor extent in the N-dealkylation process.

The metabolism of the local anaesthetic fomocaine (1-morpholino-3-[p-phenoxymethylphenyl]propane) in the rat and dog after oral application.

1. The metabolism of fomocaine following its oral administration to male and female Wistar rats and male beagle dogs has been qualitatively investigated. 2. The drug is metabolized in both species by aromatic hydroxylation, N-oxidation, splitting of the ether link and, in the dog, by removal of the morpholine group. 3. The rat and dog excrete some unchanged fomocaine in the urine together with p-hydroxyfomocaine (free and conjugated), fomocaine-N-oxide, p-hydroxyfomocaine-N-oxide and p-(gamma-morpholinopropyl)benzoic acid. In addition, the dog excretes morpholine in the urine.