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Alcohol consumption in the UK has been increasing steadily. We prospectively studied the burden on hospital services caused by overt alcohol misuse, in an inner-city hospital in north-west England. All Accident & Emergency (A&E) patients were assessed to determine whether their hospital attendance was alcohol-related, and whether this resulted in admission and/or generated new out-patient appointments. Over 2 months, 1915 patients attended A&E with alcohol-related problems, accounting for 12% of attendances; 50% were aged 18-39 years, and acute alcohol intoxication was the commonest presenting complaint. Overall, 6.2% of all hospital admissions were due to alcohol-related problems. Over 2800 new out-patient visits were likely to have been generated over an 18-month period from initial attendance with an alcohol-related problem, mostly for orthopaedic clinics. The burden placed by overt alcohol-related problems on hospitals is enormous, both in terms of the emergency and out-patient services. The implementation of education, screening and intervention strategies in A&E departments, and employment of key trained personnel, should be considered, to optimize the clinical management of these patients.

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OBJECTIVE: To investigate the pharmacokinetics of nelfinavir (NFV) administered alone and in combination with nevirapine (NVP) to HIV-positive patients. DESIGN: Seven patients with advanced HIV disease received dual nucleoside analogues in addition to NFV (750 mg three times daily) and subsequently NVP (200 mg daily for 2 weeks followed by 200 mg twice daily) as salvage therapy. On the first study day (day 3), blood samples were taken for assay of NFV. The second study day followed the introduction of NVP for 3 weeks. METHODS: Blood samples were obtained at 0, 1, 2, 3, 4, 6 and 8 h after dosing on both study days. Separated plasma was heated to 58 degrees C for 30 min to inactivate HIV and stored at -80 degrees C until analysis by high performance liquid chromatography for both NFV and NVP. RESULTS: The geometric mean NFV area under the concentration-time curve to 8 h (AUC0-8h) was 23.4 microg x h/ml (range, 13.5-49.2) and 11.6 microg x h/ml (range, 6.6-23.2) on the first and second study days, respectively. The geometric mean ratio was 0.49 (95% confidence interval, 0.33-0.72; P = 0.016). This represented a 50% reduction in plasma NFV concentrations. Maximum and minimum concentrations were also reduced during NVP therapy (from 4.4 to 2.5 microg/ml and from 1.7 to 0.8 microg/ml, respectively). Time to maximum concentration was reduced from 4 to 2 h. NVP concentrations were determined with a maximum concentration of 5.4 microg/ml at 4 h. CONCLUSIONS: NVP is currently being used in combination therapy with protease inhibitors for antiretroviral-experienced patients in the setting of treatment failure. This study demonstrates that when patients are coadministered NVP there is a 50% reduction in the plasma AUC of NFV. Although the mean trough concentrations of NFV remained above the stated minimum effective concentration of 0.4 microg/ml, there is nevertheless concern that some patients will fall below this value when NVP is added to treatment regimens. In the absence of therapeutic drug monitoring we suggest that an increase in the standard NFV dosage of 750 mg three times daily will be required to ensure satisfactory NFV plasma concentrations, thereby maintaining antiviral efficacy.

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OBJECTIVE: The most important hepatic enzyme involved in the metabolism of protease inhibitors is cytochrome P450 3A4 (CYP3A4). Ritonavir (RIT) is a potent inhibitor of CYP3A4 and inhibits saquinavir (SQV) metabolism in healthy volunteers. In this study we investigated the kinetics of SQV when administered alone and in combination with RIT in HIV-infected patients. DESIGN: SQV pharmacokinetics were determined in seven patients who had advanced HIV disease. Steady-state SQV profiles were obtained on two occasions following treatment with SQV 600 mg three times daily alone and when administered with RIT 300 mg twice daily. METHODS: Blood samples were obtained at times 0, 1, 2, 4, 6 and 8 h post-dosing. Following centrifugation, separated plasma was heated at 58 degrees C for at least 30 min to inactivate HIV and stored at -80 degrees C until analysis using high performance liquid chromatography. RESULTS: For patients treated with SQV alone there was a 12-fold variability in the area under the SQV concentration-time curve (AUC0-8h) ranging from 293 to 3446 ng.h/ml. When combined with RIT there was a marked increase in the maximum plasma concentration of SQV [median (range), 146 (57-702) versus 4795 (1420-15810) ng/ml; approximately 95% confidence interval (CI), 2988-6819; P = 0.0006, Mann-Whitney U test]. The AUC0-8h for SQV was also significantly increased in the presence of RIT [median (range), 470 (29-3446) versus 27,458 (7357-108,001) ng.h/ml; approximately 95% CI, 16,628-35,111; P = 0.0006]. CONCLUSIONS: For some patients, administration of SQV 600 mg three times daily results in very low SQV plasma levels and possibly little antiviral effect. Combination of SQV with RIT results in a significant drug interaction mediated by enzyme inhibition which exposes patients to very high SQV concentrations and potential toxicity. If combination therapy with SQV plus RIT is considered then the dose of SQV should be greatly reduced.

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The role of clinical pharmacology in improving the prevention and treatment of malaria is reviewed. A series of general and specific issues is discussed, concentrating on risk-benefit and cost-effectiveness. The techniques of clinical pharmacokinetics play an important role in the optimal use of drugs and this is illustrated by studies on quinine and proguanil. In discussing amodiaquine toxicity, the role of the pharmacologist and the chemist in designing out drug toxicity lends hope for producing a new generation of antimalarial drugs.

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OBJECTIVES: Zidovudine (ZDV) requires intracellular phosphorylation to ZDV triphosphate (ZDV-TP) prior to the inhibition of HIV replication. The effect of ZDV dose on the formation of intracellular phosphorylated metabolites may help define the optimum daily dose of ZDV, which is still unknown. DESIGN AND METHODS: The plasma and intracellular phosphorylated metabolite concentrations of ZDV were determined over a 12 h period following oral administration of 100 and 300 mg ZDV to 10 HIV-seropositive patients at steady state during two dosing regimens (i.e., 100 mg three times daily and 300 mg twice daily). The intracellular ZDV phosphates, ZDV monophosphate (ZDV-MP), ZDV diphosphate (ZDV-DP) and ZDV-TP were measured in peripheral blood mononuclear cells using a combination of high-performance liquid chromatography and radioimmunoassay. RESULTS: There was a greater than threefold increase in maximum plasma concentration (Cmax) following 300 mg ZDV when compared with 100 mg ZDV (mean +/- SD, 2.59 +/- 0.52 versus 0.70 +/- 0.14 mumol/l). The area under the concentration time curve (AUC0-12 h) was also significantly increased (4.59 +/- 0.79 versus 1.42 +/- 0.51 mumol/l x h) following 300 mg ZDV dose. For total intracellular ZDV phosphate metabolites the AUC0-12 h was doubled (7.64 +/- 3.67 versus 3.71 +/- 1.83 pmol/10(6) cells x h) in patients taking 300 mg ZDV compared with 100 mg. The AUC0-12 h for ZDV-MP was significantly increased at the higher dose (6.47 +/- 3.14 versus 2.77 +/- 1.70 pmol/10(6) cells x h), whereas the active moiety ZDV-TP was variable and not significantly different (0.42 +/- 0.42 versus 0.61 +/- 0.81 pmol/10(6) cells x h) following 100 and 300 mg ZDV. CONCLUSIONS: Administration of 100 mg ZDV orally produces significantly less of the potentially toxic metabolite, ZDV-MP, and comparative, although variable, concentrations of the active metabolite ZDV-TP when compared with 300 mg ZDV orally. This finding supports clinical data indicating the efficacy of low-dose (300 mg daily) ZDV. The measurement of intracellular phosphorylated metabolites advances our understanding of the clinical pharmacology of ZDV.

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OBJECTIVE: To determine whether HIV-infected patients have a deficiency of intracellular glutathione (GSH) in peripheral blood mononuclear cells (PBMC) and erythrocytes. DESIGN: Initial experiments determining the stability of intracellular GSH preceded the measurement of GSH levels in 33 HIV-positive patients and 40 control subjects within 1 h of isolation of their blood cells. In addition, the susceptibility of erythrocytes to dapsone hydroxylamine-induced methaemoglobinaemia was evaluated. METHODS: GSH levels were determined by an high-performance liquid chromatography method utilizing a fluorescent probe, monobromobimane. The bimane-GSH adduct formed in PBMC was also characterized by mass spectrometry. Methaemoglobin formation on exposure to dapsone hydroxylamine was determined spectrophotometrically. RESULTS: GSH levels remained stable for only 1 h after cell isolation, thereafter showing a decrease of 20 and 60% at 4 and 24H, respectively, There was no difference in the GSH levels in PBMC and erythrocytes of the HIV-positive patients compared with controls. The GSH levels were not related to the disease stage or to CD4+ cell counts. There was no difference in GSH levels in PBMC taken from trimethoprim-sulphamethoxazole-hypersensitive and non-hypersensitive patients. Methaemoglobinaemia on exposure of erythrocytes to dapsone hydroxylamine was concentration-dependent, but there was no significant difference between patients and controls. CONCLUSION: In contrast to previous studies, no deficiency of intracellular GSH in the PBMC and erythrocytes of HIV-infected patients was found. The discrepancy between studies may be methodological reflecting the instability of GSH, which requires prompt sample analysis.

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The potency of antimalarial dihydrofolate reductase inhibitors, alone and in synergistic combination with dihydropteroate synthetase inhibitors, against the Kenyan K39 strain of Plasmodium falciparum (pyrimethamine resistant) and against normal replicating human bone marrow cells in in vitro culture has been studied. Therapeutic indices and rank order of synergistic potency were derived. Trimethoprim, pyrimethamine, and the quinazolines WR159412 and WR158122 had the smallest therapeutic indices (1.39, 4.38, 2.56, and 90.0, respectively), while the three triazines clociguanil, WR99210, and chlorcycloguanil had the largest (3,562, 3,000, and 2,000, respectively). In rank order of decreasing activity against P. falciparum, the six most potent drug combinations were WR99210-dapsone, chlorcycloguanil-dapsone, WR158122-dapsone, WR159412-dapsone, WR159412-sulfamethoxazole, and chlorcycloguanil-sulfamethoxazole; pyrimethamine-sulfadoxine was the least potent combination. These experiments form a basis for the selection of rapidly eliminated antifolate combinations for further clinical testing.

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The reproducibility and reliability of cardiac output (CO) measurement by transthoracic electrical bioimpedance (TEB) and dual beam Doppler ultrasound methods were compared in 9 uremic patients during treatment with continuous ambulatory peritoneal dialysis (CAPD). CO was measured simultaneously by each method during supine rest and 70 degree passive head-up tilt on two separate days. The effect on CO after the infusion of dialysate was also studied on day 1. CO, stroke volume (SV) and heart rate (HR) measurements were reproducible by each method. The median day to day differences (95% confidence intervals) in CO and SV were 0.6 (-0.3, 1.8) l/min and 10 (-1.5, 24.5) ml for TEB and 0.7 (-0.5, 2.2) l/min and 13 (-1.0, 30.5) ml for Doppler at supine rest; 0.4 (-0.2, 0.9) l/min and 11 (-0.5, 19.0) ml for TEB and 0.5 (-0.3, 1.2) l/min and 8 (-5.0, 16.0) ml for Doppler during tilt (p > 0.05 in each case). Data were unobtainable by TEB at five time points while none were lost by Doppler. This is due to incorrect HR or poor quality signals detected by TEB. CO and SV measured by Doppler were higher than that by TEB during supine rest (p < or = 0.01) but not during passive tilt. As a result, there was significant change (p < or = 0.01) in CO and SV from supine to tilt measured by Doppler but not by TEB. Neither TEB nor Doppler detected significant change (p > 0.05) in CO or SV after the infusion of dialysate, in either the supine or tilt positions.(ABSTRACT TRUNCATED AT 250 WORDS)

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1. Zidovudine (ZDV) has proved unsuccessful in controlling disease progression over extended periods of time in patients with AIDS. Combination of ZDV with another reverse transcriptase inhibitor, dideoxyinosine (ddI) may improve the duration of effectiveness of antiretroviral therapy. The aim of this study was to investigate the possibility of a pharmacokinetic drug interaction between ZDV and ddI. 2. The pharmacokinetics of ZDV and ddI were determined in eight patients with AIDS who were randomised to receive ZDV 250 mg orally, ddI 250 mg orally or a combination of ZDV 250 mg plus ddI 250 mg orally on 3 study days separated by 1 week. 3. The administration of ZDV did not significantly alter ddI pharmacokinetics. The mean AUC was 6.8 +/- 2.0 s.d. and 7.6 +/- 2.5 s.d. mumol l-1 h and oral clearance was 2766 +/- 686 and 2660 +/- 1297 ml min-1 in the presence and absence of ZDV, respectively. 4. In the presence of ddI the elimination half-life of ZDV was increased significantly by 18% from 1.1 +/- 0.3 to 1.3 +/- 0.3 h (P < 0.05) and the mean AUC increased significantly by 35% from 4.8 +/- 1.5 to 6.5 +/- 1.5 mumol l-1 h (P < 0.05). The clearance was decreased by 29% from 3518 +/- 1123 to 2505 +/- 575 ml min-1, but this difference was not significant. The renal clearance of ZDV was not altered by ddI. 5. Administration of ddI also resulted in a significant 22% increase in the AUC of GZDV, from 28.5 +/- 15.7 to 34.9 +/- 12.8 mumol l-1 h (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

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1. The major adverse effect of zidovudine (ZDV) is haematological toxicity which results in anaemia and granulocytopenia. The aim of the present study was to investigate if HIV-positive patients developing erythroid aplasia/hypoplasia are exposed to higher plasma concentrations of ZDV owing to impaired hepatic metabolism to the major metabolite, 3'-azido-3'-deoxy-5'-beta-D-glucopyranuronosylthymidine (GZDV). 2. Twelve HIV-positive male patients were studied, six having developed bone marrow aplasia/hypoplasia within the first 6 months of ZDV therapy. Each of the patients exhibiting toxicity were matched for age, weight, risk factors for HIV infection and disease stage with patients who had no evidence of early bone marrow toxicity. 3. ZDV was administered orally in doses of 3-10 mg kg-1 and blood samples taken at intervals to 6 h. Urine was collected over the whole 6 h period. ZDV and GZDV were assayed by h.p.l.c. 4. There were no significant differences in the pharmacokinetic parameters between the two groups of patients. For patients with early bone marrow toxicity the elimination half-life of ZDV was 1.10 +/- 0.16 h with an oral clearance of 2752 +/- 1031 ml min-1 compared with values of 1.06 +/- 0.18 h and 2843 +/- 730 ml min-1 seen in the control group. Similarly there was no significant difference in the pharmacokinetics of GZDV or the urinary ratio of GZDV to ZDV. 5. Therefore, despite the fact that ZDV toxicity to haematopoietic progenitor cells has been previously shown to be dose related, there was no indication from this study that it is directly related to plasma concentrations of ZDV.

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The possible cardiovascular pharmacodynamic interactions at rest and during exercise of combining oral flosequinan (100 mg) with xamoterol (200 mg) was investigated in a four-way randomised double-blind placebo-controlled crossover trial in eight healthy male volunteers. Xamoterol was better tolerated than flosequinan. The most common adverse events were mild to moderate headache and facial flushing. One volunteer developed headache and vomiting following flosequinan treatment and was replaced. Compared to placebo, at supine rest, flosequinan significantly increased heart rate (HR) by 5 beats.min-1, but had no effect on cardiac output (CO), stroke volume (SV) and mean blood pressure (MBP). Xamoterol significantly increased CO by 1.5 l.min-1, HR (5 beats.min-1) and MBP (6 mmHg) but not SV. The combined treatment (flosequinan + xamoterol) significantly increased CO (1.7 l.min-1) and HR (10 beats.min-1), but had no effect on SV and MBP. During exercise, flosequinan had no significant effect on any variable compared to placebo. Both xamoterol and combined treatment reduced the increase in CO (-4.6 l.min-1 after xamoterol and -3.4 l.min-1 after combined treatment vs. 0.1 l.min-1 after placebo), but had no effect on other variables. The effect of the combined treatment on each haemodynamic variable were no more than the anticipated additive effects of the two drugs. Thus, no cardiovascular pharmacodynamic interaction was found between flosequinan and xamoterol in healthy volunteers.

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Proguanil, a prophylactic antimalarial agent, is metabolised by the polymorphic isoenzyme CYP2Cmep in man. In this study the multiple dose pharmacokinetics of proguanil were investigated in subjects who were phenotyped previously as extensive (n = 6) or poor (n = 2) metabolisers of the drug. Steady-state plasma concentrations of proguanil were achieved within 48 h in extensive metaboliser subjects and chronic administration of the drug did not appear to alter the disposition of proguanil or that of its active metabolite, cycloguanil. The currently recommended dosage regimen appears to be appropriate for extensive metabolisers of proguanil. Poor metabolisers of proguanil had significantly lower plasma concentrations of the active metabolite cycloguanil compared with extensive metabolisers. Thus, even on multiple dose administration these subjects may not achieve adequate plasma concentrations of cycloguanil. Deficient metabolism of proguanil to cycloguanil leads to an increased appearance of the N-dealkylated metabolite p-chlorphenylbiguanide in the urine of poor metabolisers.

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The interaction between sulphasalazine and cimetidine has been studied, a drug combination which is quite likely in view of the higher incidence of peptic ulceration in patients with RA. Nine patients with RA on sulphasalazine (group I) were given cimetidine 400 mg three times daily and followed up for 18 weeks. In addition, five patients on sulphasalazine alone (group II), who served as a control group, were also followed up in the same manner as group I. Monitoring included assessment of disease activity and haematological variables, and measurement of plasma and urinary levels of sulphapyridine and its metabolites. There was no significant change in either the haematological parameters or sulphapyridine pharmacokinetics upon administration of cimetidine. We therefore conclude that cimetidine may be safely used in patients with RA who are being treated with sulphasalazine.

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