Three pharmacokinetic studies were conducted in Ghanaian patients in support of investigations of albendazole and its combination with ivermectin in the treatment of onchocerciasis. These included dose-finding studies, investigations into the influence of a fatty meal on the relative bioavailability of albendazole as assessed by the measurement of concentrations of albendazole sulphoxide and the effect of prior treatment with ivermectin on antiparasitic efficacy and plasma concentrations of albendazole suphoxide. Increasing the dose of albendazole from 800 mg x 3 daily to 1200 mg x 3 daily produced no additional antiparasitic effects although plasma concentrations of albendazole sulphoxide were increased in proportion to dose size. Moreover, the plasma concentration vs time profiles suggest that most of the effects observed may have been due to the first 800 mg dose. Administration of ivermectin had no effect on the pharmacokinetics of albendazole sulphoxide and there was no additive effect on the parasite. Albendazole was well tolerated and its administration 5-7 days after ivermectin produced little additional reaction. Although it is not macrofilaricidal, it does possess important chemosterilant properties which are enhanced by its administration with a fatty breakfast. Under these conditions, the relative bioavailability of albendazole is increased four-fold. These studies support further work with albendazole administered with food either as a single dose, as multiple single doses repeated at intervals of several months and its coadministration with ivermectin. They also encourage the belief that a more potent and bioavailable benzimidazole may be macrofilaricidal or a permanent chemosterilant for Onchocerca volvulus on single dosage.

SUMMARYThe ethinyloestradiol (EO2) component of oral contraceptive steroids is extensively conjugated with sulphate by the gut wall. The ability of gastrointestinal mucosa to conjugate EO2 has been examined in vitro in samples of mucosa taken from normal women as well as from women with coeliac disease. The percentage conjugation per mg dry weight for normal tissue (n= 11) was 17.1 ± 6.4 (mean ± s.d.) while in untreated coeliac tissue (n= 6) the figure was 6.3 ± 3.6% (P < 0.01). In tissue from patients with treated coeliac disease (n= 5) the figure was 12.1 ± 3.2%.Thus the ability of intestinal mucosa to conjugate ethinyloestradiol was significantly reduced in patients with coeliac disease, and restored towards normal following treatment. However, in patients with coeliac disease the pharmacokinetics of ethinyloestradiol were not significantly different from normal controls.

hospital are often still recovering from infection when discharged and may not be fit for immunisation. Indeed, children may be discharged less than 30 hours after fever subsides, which would preclude immunisation by the criteria of Dr Riley and colleagues. As already occurs in Oxford, and as suggested by Dr Reeve and colleagues, suitably trained health visitors could catch up missed immunisations. The single most important finding in our study was that once parents have decided against a particular vaccine, often following inappropriate advice, it is difficult to persuade them otherwise. Attention to the clear and concise recommendations in the "green book" should ensure that health professionals give appropriate advice from the outset.4

A number of different progestogens, levonorgestrel (LNG), norethisterone (NET), gestodene (GSD), desogestrel (DG) and norgestimate (NORG) are used in combination with the oestrogen ethinyloestradiol (EE2) in oral contraceptive steroid preparations. All the progestogens are acetylenic steroids and previous studies have indicated the potential of acetylenic steroids to cause mechanism-based or "suicide" inactivation of cytochrome P-450.We have compared the effects of the different progestogens on EE2 2-hydroxylation (a reaction catalyzed by enzymes from the P-450IIC, P-450IIIA and P-450IIE gene families) and also the oxidative metabolism of other drug substrates (cyclosporin, diazepam, tolbutamide) by human liver microsomes. On coincubation with EE2 as substrate, GSD, 3-keto desogestrel (3-KD, the active metabolite of desogestrel) and LNG produced some concentration-dependent inhibition of EE2 2-hydroxylation (maximum 32% inhibition at 100-mu-M 3-keto desogestrel). Ki values determined for GSD and 3-KD were 98.5 +/- 12.3 and 93.2 +/- 10.3-mu-M (mean +/- SD; n = 4), respectively. Preincubation of progestogens in a small volume (50-mu-l) incubation for 30 min in the presence of an NADPH-generating system enhanced the inhibitory potential of all the steroids (at 100-mu-M, inhibition was for GSD 39%, 3-KD 46%, LNG 46%, NET 51% and NORG 43%). Inhibitory effects were therefore comparable and also similar to the macrolide antibiotic troleandomycin. The most marked inhibition seen was of diazepam N-demethylation and hydroxylation by GSD (71 and 57%, respectively) and 3-KD (62 and 50%, respectively).In preincubation studies involving cyclosporin as the substrate, the order of inhibitory potency was GSD > 3-KD > NET > LNG for production of both metabolite M17 and M21.The results of the study indicate that all the progestogens in common use have the propensity to inhibit a number of oxidative pathways but there is little evidence for one progestogen being more markedly inhibitory than others.

A sensitive and selective reversed-phase high-performance liquid chromatographic method for the determination of albendazole and its active metabolite albendazole sulphoxide in plasma has been developed. It involves single-step extraction of plasma with dichloromethane, evaporation of the solvent and chromatography on a mu-Bondapak phenyl column with a mobile phase of water containing 1% (v/v) triethylamine-methanol-acetonitrile (70:10:20, v/v) at pH 3.1. Run time is 12 min. The assay satisfies all of the criteria required for use in clinical pharmacokinetic studies and possesses important advantages, notably speed and expense, over current methods.

The metabolism of the progestogen oral contraceptive desogestrel (Dg) has been studied in vitro using human liver microsomes. Metabolites have been separated using radiometric high performance liquid chromatography and identified by co-chromatography with authentic standards and by mass spectrometry. All the livers examined (n = 6) were able to form 3-keto desogestrel as the main identifiable metabolite and also the presumed intermediates 3α-hydroxydesogestrel (3α-OHDg) and 3β-hydroxydesogestrel (3β-OHDg). In addition, a large polar heterogenous peak was evident on the radiochromatograms which did not co-chromatograph with any known metabolites of desogestrel. Inter-individual variability in metabolite formation was seen. A number of drugs were examined for their propensity to inhibit desogestrel metabolism. Primaquine was the most potent tested having an IC50 value (inhibitory concentration reducing overall metabolite production by 50%) of 30 μM. Cimetidine, trilostane and levonorgestrel failed to inhibit at 250 μM.

1. Oral amodiaquine (AQ) has been used to treat patients with symptomatic malaria in Zambia (n = 14) and Nigeria (n = 5). Clinical cure was obtained in all patients and no serious adverse drug reactions were seen. 2. As in healthy subjects, AQ achieved low plasma concentrations. Plasma concentration vs time profiles of desethylamodiaquine (AQm) from the present study did not differ from those obtained from healthy subjects. 3. In contrast to previous results from healthy subjects, the mean ratio of red cell (RBC): plasma AQm concentration in the present study was 0.80: 1 at the start of the study and rose in a linear manner (r = 0.873; P less than 0.01) to 3.04: 1 by the end (n = 10; P less than 0.01). The final mean value was similar to that seen in healthy subjects. 4. These data show that there are differences in the disposition of orally administered AQ between healthy subjects and patients with clinical malaria. The relevance of this observation to the frequency of adverse reactions to AQ in these two groups is not established.

A reversed-phase high-performance liquid chromatographic method is described for determination of the antimalarial agent arteether in blood plasma based on its decomposition in acidic medium and measurement of the major decomposition product, which has been identified as an α,β-unsaturated decalone. Linear calibration curves were obtained in the range 0–250 ng/ml arteether and the recovery of the drug from plasma was found to be quantitative. There is no interference from desoxyarteether, the putative major metabolite of arteether. The method has been applied to the measurement of arteether in the plasma of rats given 110 mg/kg by intramuscular injection of the drug as a solution in sunflower oil.

1. Plasma concentrations of halofantrine (Hf) and its putative principal plasma metabolite desbutyl halofantrine (Hfm) have been measured in two separate studies after oral administration of the hydrochloride salt. 2. Six healthy male volunteers each received single oral doses of 250, 500 and 1000 mg administered after an overnight fast. A washout period of at least 6 weeks was allowed between each dose. A further 250 mg single oral dose was administered to the same six subjects in a fasting state and after a standardised fatty meal in a randomised study, again with a washout period of at least 6 weeks. 3. AUC and maximum plasma concentration (Cmax) for Hf increased in proportion to the dose from 250-500 mg. This increase was non-proportional when the dose was increased from 500 to 1000 mg. For Hfm, in the dose range 250-500 mg, AUC but not Cmax increased in proportion in the increase in dose size. The increase in these parameters was non-proportional when the dose was increased from 500 to 1000 mg. Time to reach peak concentrations for Hf and Hfm and the elimination half-life of Hf remained unchanged across the dosage range. 4. Following a fatty meal, Cmax for Hf was increased from 184 +/- 115 micrograms l-1 (fasting) to 1218 +/- 464 micrograms l-1 (fed). AUC for Hf was increased from 3.9 +/- 2.6 mg l-1 h (fasting) to 11.3 +/- 3.5 mg l-1 h following a fatty meal.(ABSTRACT TRUNCATED AT 250 WORDS)

British Journal of Clinical PharmacologyVolume 28, Issue 6 p. 621-628 Free Access The effects of food on drug bioavailability. PA Winstanley, PA Winstanley Department of Pharmacology and Therapeutics, University of Liverpool.Search for more papers by this authorML Orme, ML Orme Department of Pharmacology and Therapeutics, University of Liverpool.Search for more papers by this author PA Winstanley, PA Winstanley Department of Pharmacology and Therapeutics, University of Liverpool.Search for more papers by this authorML Orme, ML Orme Department of Pharmacology and Therapeutics, University of Liverpool.Search for more papers by this author First published: December 1989 https://doi.org/10.1111/j.1365-2125.1989.tb03554.xCitations: 85AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. 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Millions of women around the world use combined oral contraceptives (OCs), yet surprisingly little is known about their central nervous system (CNS) effects. This article provides a short overview of the basic pharmacology of OCs, emphasizing features that may be relevant to understanding their effects in the CNS. Historical and recent findings from studies of cognitive function, mood, and negative affect (depressive changes under OC use) are then reviewed. We also present data from an archival dataset from our own laboratory in which we explore dysphoric changes in women using four generations of contraceptive progestins. Current data in the field are consistent with a modest effect of OC use on CNS variables, but conclusions based on current findings must be made very cautiously because of multiple methodological issues in many published studies to date, and inconsistencies in the findings. Directions for future research over the next 10 years are suggested. (150 words)

A pharmacy‐based adverse drug reaction (ADR) reporting scheme, using pharmacists, nurses and medical practitioners as initiators of reports, was set up at the end of 1984 in the Royal Liverpool Hospital in order to encourage reporting. New reports were inspected at weekly intervals by a staff pharmacist, and a clinical pharmacologist. Reports were forwarded to the Committee on Safety of Medicines if the reaction was considered to be serious by the clinicians, or the ADR team or involved 'black triangle' drugs. The total number of ADR reports was increased eightfold by the introduction of the scheme (from 14 in 1984 to 76, 102 and 94 in 1985, 1986 and 1987 respectively), and this rate of reporting has been sustained.

The effect of a single dose of paracetamol (1 g) on plasma concentrations of the oral contraceptive steroids ethinyloestradiol (EE2) and levonorgestrel (LNG) has been studied in six healthy female volunteers. The area under the plasma concentration-time curve (AUC0-24) of EE2 was significantly increased following paracetamol administration by 22% (control 2221 +/- 291; following paracetamol, 2702 +/- 452 pg ml-1 h; mean +/- s.d.; P less than or equal to 0.05). The greatest effect was evident in the time period 0-3 h. There was a significant decrease in the AUC of EE2-sulphate after paracetamol (7736 +/- 3791 pg ml-1 h) compared with control (13161 +/- 4535 pg ml-1 h; P less than or equal to 0.05). Plasma concentrations of LNG were unaltered by concurrent paracetamol administration. We conclude that the administration of a single 1 g dose of paracetamol causes an increase in plasma concentrations of EE2 as a result of a reduction in the sulphation of the steroid. This interaction may be of clinical significance in women on oral contraceptive steroids who regularly take paracetamol.

The kinetics and elimination of pethidine (meperidine) after intravenous administration (150 μg/kg) to ten healthy volunteer subjects were compared with those obtained from 18 patients who suffered from varying degrees of renal dysfunction. In both groups of subjects, pethidine was eliminated triexponentially from plasma. However, plasma concentrations in the patients (who were subdivided into patients with severe dysfunction, moderate dysfunction, and mild dysfunction) were consistently higher. The mean ± SEM elimination half‐life (t1/2) of pethidine was significantly longer in the three groups of renal patients: 7.9 ± 1.1, 20.2 ± 13.6, 16.6 ± 5.4, and 14.3 ± 3.1 hr, respectively, for healthy volunteers, patients with severe, moderate, and mild dysfunction; their mean ± SEM creatinine clearances were 97.3 ± 7.5, <9.5, 30.0 (3.7), and 63.3 ± 8.5 mL/min respectively. The mean plasma clearance of the drug was higher in healthy subjects (342.7 ± 62.5 mL/min) than various groups of renal patients (99.9 ± 11.6, 120.9 ± 45.8, and 123.8 ± 34.1, respectively, for patients with severe, moderate, and mild dysfunction). Impairment of renal function also reduced total plasma protein binding: 58.2 ± 5.0% in healthy subjects and 31.8 ± 3.9%, 44.5 ± 5.0%, and 42.5 ± 5.6%, respectively, for the three renal patient groups. The percentage of pethidine recovered in the urine was significantly lower in the severe dysfunction group while norpethidine recovery was significantly lower in all three groups of renal patients. These observations suggested that the longer elimination t1/2 of pethidine in renal patients may be attributable to a more extensive distribution of pethidine in the body (with a decrease in plasma protein binding) and a lower plasma clearance of the drugs.

The intestinal mucosal metabolism of ethinyloestradiol (EE2) and paracetamol (P) has been studied in vitro in Ussing chambers. Histologically normal jejunum or ileum was obtained from 19 patients undergoing various resections. The muscularis externa was stripped off the mucosa and the mucosal sheets mounted between two perspex chambers. Tissue viability was routinely assessed by measurement of the transmural potential difference. The percentage of steroid in the serosal chamber, 2 h after addition of EE2 (2 microCi; 80 ng) to the mucosal chamber was 2.3 +/- 0.8% (mean +/- s.d.) which comprised unconjugated drug (0.4 +/- 0.3%), sulphate conjugates (0.7 +/- 0.5%) and glucuronides (0.9 +/- 0.8%). In the mucosal chamber, 56.6 +/- 11.4% was unconjugated steroid, 33.3 +/- 12.4% sulphate conjugates and 2.1 +/- 2.3% glucuronides. Small amounts of the oxidation products 2-hydroxy and 16-hydroxy-EE2 were present. At 2 h, the percentage of paracetamol in the serosal chamber was 3.2 +/- 1.4% (of added P; 2 microCi; 50 ng) of which 0.5 +/- 0.3% was paracetamol sulphate (PS) and 0.1% was paracetamol glucuronide (PG). In the mucosal chamber 2.4 +/- 0.8% and 1.0 +/- 0.2% was present as PS and PG respectively. The total amount of paracetamol conjugated was approximately 4.0%. When paracetamol in the mucosal chamber was increased to 50 micrograms (i.e. by a factor of 1000) there was a decrease in the percentage of added drug metabolized to PS and an increase in formation of PG. The glucuronide:sulphate ratio was increased from 0.34 to 3.56. Competition for sulphation was evident when both paracetamol and EE2 were presented to the intestinal mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

1 To compare the haemodynamic effects of secondary characteristics of beta-adrenoceptor blockers with an angiotensin converting enzyme inhibitor forty patients with previously untreated mild to moderate hypertension were prescribed either atenolol 50-100 mg day-1, labetalol 200-800 mg day-1, pindolol 10-30 mg day-1 or captopril 25-100 mg day-1 and observed for 6 months. 2 Over this period: (a) All four drugs produced similar reductions in blood pressure at rest (P less than or equal to 0.01) and after exercise (P less than or equal to 0.01). (b) All four drugs significantly decreased resting forearm (P less than or equal to 0.01) and calf blood flow (P less than or equal to 0.01). They all also caused a significant reduction in the increased calf blood flow following exercise (P less than or equal to 0.01). (c) No drug produced a change in resting forearm vascular resistance, while resting calf vascular resistance was decreased by captopril and pindolol, unaltered by labetalol and increased by atenolol. Post-exercise calf vascular resistance was increased by atenolol, labetalol and pindolol but unaltered by captopril. (d) Although all four drugs produced a fall in resting heart rate this was significantly greater for atenolol and labetalol (P less than or equal to 0.01). All four treatments however significantly reduced the increase in heart rate following exercise (P less than or equal to 0.01). (e) No drug produced any significant change in resting and post-exercise stroke volume/ejection fraction. 3 It is concluded that despite differing modes of action all four drugs reduce limb blood flow. This primarily appears to be a consequence of reduced perfusion pressure associated with limited autoregulation of skeletal muscle circulation. The reduction in arterial vascular resistance produced by captopril and pindolol is inconsistent and does not appear of major benefit in preserving limb blood flow. The reduction in perfusion with the agents studied may in part be related to a fall in cardiac output associated with decreased heart rate. This suggests that captopril may exert antisympathetic activity when used as an antihypertensive agent.

The pharmacokinetics of low dose pethidine (150 micrograms kg-1) after intravenous administration were determined in 10 Caucasian, 10 Chinese and 10 Indian healthy volunteers under conditions of acidic urinary pH. Plasma and urine concentrations of pethidine and norpethidine were measured by gas liquid chromatography. In all 3 ethnic groups, the disappearance of pethidine from plasma was best described by a tri-exponential function. No significant differences were observed in the elimination half life, renal clearance and total plasma clearance of the drug. The significantly lower AUC and higher (approaching significance) apparent volume of distribution in the 2 Asian groups may be explained in terms of more readily distribution of the drug (significantly higher K21 rate constants were obtained from both Chinese and Indian subjects according to a 3-compartment open model) due possibly to more frequent movement of these subjects during the early part of experiment. More norpethidine was recovered in the urine of the Chinese and Indian subjects; this may suggest an interethnic difference in the oxidative demethylation of pethidine.