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Background: Abacavir is a potent, novel 2′-deoxyguanosine analogue reverse transcriptase inhibitor (NRTI) which effectively suppresses HIV-1 replication. To date, there is no pharmacokinetic study in patients with renal impairment. Methods: Five HIV-1-infected patients with various degrees of renal dysfunction (creatinine clearance 60, 40, 25, 20 and 1 haemodialyzed patient) were evaluated after being treated for at least 2 months with multi-antiretroviral therapy including abacavir. After an overnight fast, the subjects received their abacavir dosage (600 or 300 mg). Blood samples were withdrawn and plasma concentrations determined. A nonparametric pharmacokinetic analysis was then performed. The dialysability of abacavir was also evaluated. Results: Time of maximum plasma concentration (Tmax) was constant among the subjects with a mean value of 0.7 ± 0.27 h (range 0.33–1). Maximum plasma concentration (Cmax) ranged from 2.76 to 4.15 mg/l (mean 3.44 ± 0.59). The elimination half-life ranged from 1.31 to 2.67 h (mean 2.08 ± 0.51). Normalized Cmax/dose ranged from 0.007 to 0.014 mg/l and normalized AUC(0-inf)/dose ranged from 0.014 to 0.035 mg·h/l. In haemodialysis the dialysance was 60–80 ml/min with a fractional drug removal of 24% during a 4-hour haemodialysis session with a high permeability membrane. Discussion: In our patients, absorption, elimination and distribution phases were not altered by renal insufficiency. Furthermore, our pharmacokinetic data are similar to those obtained in patients with normal renal function. Therefore, dosage adjustment is not necessary in patients with renal insufficiency. In haemodialyzed patients, treatment can be administered independently to the dialysis session because of the negligible elimination of abacavir in the dialysate.

Objective To determine whether diarrhea and intestinal malabsorption during HIV infection alter oral ganciclovir systemic exposure. Methods We studied the oral disposition of ganciclovir in 42 HIV-infected patients stratified into three groups: A (n = 15), HIV (stage A and B); B (n = 13), AIDS (stage C); and C (n = 14), AIDS with chronic diarrhea and wasting syndrome (10% or more weight loss). Each patient was evaluated for nutritional (body mass index, serum albumin and transferrin), immunologic (CD4 count, plasma viral load) and intestinal status (D-xylose test, fecal fat and nitrogen excretion, and intestinal permeability). Following an overnight fast, 1 g oral ganciclovir was given to patients. Six blood samples were collected over 24 hours. Serum was analyzed for ganciclovir by high performance liquid chromatography. Drug disposition was characterized using a population pharmacokinetic approach. Results Mean intestinal permeability increased as HIV disease progressed (0. 05, 0.1, and 0.2 for groups A, B, and C, respectively). Average weight-adjusted maximum concentration (Cmax) in group C was twofold more than that in group A and B patients (12.5 versus 6 and 6.4 ng/ml/kg), and average area under the curve (AUC0-infinity) was threefold greater in group C patients (193 versus 59 and 65 ng. hour/ml/kg in groups A and B, respectively). Mean oral clearance was threefold lower in group C (96 versus 258 and 212 L/hour in groups A and B, respectively). Conclusion Because systemic exposure of oral ganciclovir is enhanced in AIDS patients with diarrhea and wasting syndrome, oral ganciclovir therapy may benefit these patients.

A new high-performance liquid chromatography (HPLC) with UV detection assay was developed for the simultaneous determination of protease inhibitors (PIs), nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs, NNRTIs) using a single 1-ml plasma samples. A solid-liquid extraction procedure without internal standard was coupled with two separate reversed-phase HPLC systems; one for the determination of amprenavir, efavirenz, indinavir, nelfinavir, ritonavir, saquinavir (run time=32 min) and one for the determination of abacavir, didanosine, lamivudine, stavudine, nevirapine, zidovudine (run time=40 min). The first requires a mobile phase containing sodium phosphate buffer+ion pair-acetonitrile (50:50, v/v) through a C18 Symmetry column (250x4.6 mm I.D., 5 microm particle size), using variable wavelengths (241, 254 and 261 nm). The second system requires three mobile phases (potassium phosphate buffer+ion pair-acetonitrile) for different elution through a C18 Symmetry Shield column (250x4.6 mm I.D., 5 microm), using a single wavelength (260 nm). Peak-areas are linear; correlation coefficients are better than 0.998 for all compounds, with both inter- and intra-day relative standard deviations lower than 12%. Extraction recoveries are higher than 93% for PIs and NNRTIs and higher than 70% for NRTIs. The method is specific and sensitive and was used to determine trough and peak levels of antiretroviral drugs in HIV infected patients under various combinations of RTIs and PIs.

Oral anticoagulants and pulse high-dose intravenous methylprednisolone are often administered concomitantly, but no data on potential interactions are available.To assess possible potentiation of oral anticoagulation by high-dose intravenous methylprednisolone.Prospective cohort study.University hospital in Paris, France.10 consecutive patients concomitantly receiving methylprednisolone and oral anticoagulants (fluindione and acenocoumarol) and 5 consecutive controls receiving methylprednisolone alone.Serial determinations of the international normalized ratio (INR) and clotting factors during administration of pulse methylprednisolone. The total plasma fluindione concentration was determined in 3 patients.The mean INR was 2.75 (range, 2.02 to 3.81) at baseline and increased to 8.04 (range, 5.32 to 20.0) after methylprednisolone administration. Plasma fluindione concentrations and the INR increased after methylprednisolone administration. Methylprednisolone alone did not increase prothrombin time.The action of oral anticoagulants is potentiated by intravenous high-dose methylprednisolone. The INR should be monitored daily during concomitant administration of these medications.

The genotype of the receptor with which a particular drug interacts may be a between- subject factor that modifies the pharmacodynamic and consequently the therapeutic response to drugs. Subjects with A1 allele (Taq IA restriction fragment length polymorphism) of the gene encoding for the dopamine D2 receptor (DRD2) seem to express lower number of DRD2 compared to subjects who do not have this allele. We investigated whether subjects homozygous for the A1 allele of the DRD2 gene have decreased response to DRD2 stimulation by apomorphine when compared with those homozygous for the A2 allele. Two hundred and two Caucasian subjects were genotyped for DRD2 Taq IA polymorphism, 6.9 % had the genotype A1A1 and 65% A2A2. Nine homozygous subjects/group were selected for the apomorphine study. Five, 10 and 20mgr;g/kg of apomorphine were administered subcutaneously according to a randomized crossover design. The main pharmacodynamic criterion was the plasma growth hormone increase induced by apomorphine. Secondarily, we measured oral temperature responses and yawns in response to apomorphine. Plasma apomorphine concentrations were similar for the two matched and only genotypically different groups. Apomorphine dose-dependently increased serum growth hormone concentration, and significant effect of time, dose by time interaction but no effect of genotype or genotype by dose interaction was shown. Apomorphine decreased body temperature, significant effect of dose, time, dose by time interaction but no effect of genotype or genotype by dose interaction were observed. The number of apomorphine-induced yawns increased dose-dependently but no significant difference between groups occurred. Thus, in this study apomorphine-induced responses were not modified by DRD2 Taq IA polymorphism although the power of the study could be insufficient to detect subtle differences.

Cigarette smoking has been suspected to increase the risk and the activity of systemic lupus erythematosus (SLE)1 2 and cutaneous lupus.3 4 Some data indicate that cigarette smoking might interfere with the effectiveness of hydroxychloroquine and chloroquine in cutaneous lupus.3 4 As these antimalarial agents are partly metabolised via the cytochrome P450 enzyme system and as the constituents of cigarette smoke are known potent inducers of cytochrome P450, it has been hypothesised that the resistance of cutaneous lupus might be explained by a modification of the metabolism of these …

A new high-performance liquid chromatographic (HPLC) assay without any extraction procedure was developed for the quantification of fluindione in plasma using a 100-microl sample volume and coumarin as the internal standard. A deproteinization procedure was coupled with a reversed-phase HPLC separation using a 250x4.6 mm I.D. C18 column and a UV detector set at 280 nm. Peak height ratios were linear over the range 0.05 to 10 microg/ml (correlation coefficient0.998). The method was found to be highly reproducible, as indicated by the low value obtained for the coefficient of variation: C.V.or = 6.1% (n = 10). The limit of quantification, estimated under the described conditions at a signal-to-noise ratio of three and with a C.V. lower than 20% for precision and accuracy, was 0.025 microg/ml. The total turnaround time was 25 min. After storage of blood samples at concentrations of 0.1, 0.5 and 2.5 microg/ml at room temperature and exposition to light for 120 h, no degradation of fluindione occurred. This micromethod is simple (no extraction step), fast and currently is being used for drug monitoring.

A high-performance liquid chromatographic method with diode array detection (HPLC-DAD) has been developed for the simultaneous separation and quantification of imipramine, amitriptyline, maprotiline, fluoxetine, clomipramine and their respective metabolites using a 500-μl plasma sample and clovoxamine as the internal standard. The substances were eluted on a Symmetry C 18 5-μm column (250×4.6 mm, I.D.). Full UV spectra from 200 to 450 nm were recorded on-line during the entire analysis and were automatically compared to spectra stored in a library. The quantification was performed at 226, 254, and 400 nm. Peak height ratios were linear over a concentration range of 10–3000 ng/ml: the correlation coefficient ( r ) was better than 0.998 for all substances at each wavelength. Acceptable coefficients of variation are demonstrated for both within-run and day-to-day assays. The method is simple, highly specific and currently being used for drug monitoring and toxicological studies in children and adult patients.

Accessible online at: www.karger.com/journals/nef Dear Sir, Tramadol is a centrally acting analgesic agent which is extensively metabolized in the liver. However, 30% of a dose is excreted unchanged in urine [1] and renal impairment may alter the pharmacokinetics of tramadol. However, there are no data for patients with end-stage renal disease undergoing hemodialysis. We thus report a pharmacokinetic study of tramadol in a patient requiring chronic hemodialysis. The patient was a 70-year-old male (65 kg, 170 cm) with a long history of multiple myeloma. He suffered from renal failure with the following laboratory values within the last 6 months: serum creatinine 180 Imol/l, urea 25 mmol/l, and normal liver enzymes. He was treated with ibuprofen for acute pain secondary to pathologic thigh bone fracture and developed end-stage renal disease. On admission, the patient complained of pain and leg cramps. Analgesic treatment with tramadol was instituted (50 mg twice daily) with a good analgesic efficacy. Because of persistent anuric renal insufficiency, hemodialysis was started. The study of tramadol pharmacokinetics was performed 1 week after starting hemodialysis, after oral administration of a 50-mg dose in the pattern of a long-term twice-daily treatment. Blood samples were collected just before and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6 and 8 h after oral administration. The study was conducted on a hemodialysis-free day. Paired arterial and venous blood samples were also obtained simultaneously 2 h after starting a hemodialysis session, on a hemodialysis day. On that day, the patient was administered tramadol 1 h before the session was started. Hemodialysis was performed for 4 h using a F60 polysulfone dialyzer (surface area 1.6 m2) with a double-needle access to a double lumen catheter with a constant dialysate flow rate of 500 ml/min and blood flow rate between 250 and 300 ml/min. Pharmacokinetic parameters were compared to those of subjects with normal renal function [2], FHD, which represents the participation of hemodialysis clearance in total body clearance of the drug during the session was calculated using the formula: FHD = CLHD/(CLHD + CLER) [3], where CLHD is hemodialysis clearance and CLER is ‘extrarenal’ clearance, equal to interdialytic total body clearance of the drug. Neither clinical side effects, nor overdosage symptoms, such as obnibulation, respiratory system depression, nor constipation, were observed. Our results (table 1) showed that Tmax and T1/2 were the same in our patient and in healthy subjects. However, total body clearance was decreased in our patient as compared to healthy subjects. Since the apparent total body clearance of a drug CL/F is linked to its volume of distribution Vd/F with the relation CL/F = (0.693/T1/2) ! Vd/F, the decrease in CL/F in our patient was due to an Table 1. Pharmacokinetic parameters of tramadol in an hemodialysis patient

Accessible online at: www.karger.com/journals/nef Dear Sir, Protease inhibitor therapy is one of the most important recent advances in the treatment of HIV infection [1]. Hepatic clearance is the major route of elimination of ritonavir and saquinavir (95%). Therefore, it has been suggested that no dosage adjustment is necessary in patients with renal insufficiency [2, 3]. However, no study is available on these drugs administered in patients with renal insufficiency. We report on the pharmacokinetics of these drugs in a HIV-1-infected patient undergoing haemodialysis. A 50-year-old man, haemodialyzed for 4 years for HIV-associated nephropathy, was treated with multitherapy including ritonavir 200 mg every 12 h and saquinavir 600 mg every 12 h for 1 year without side effects and with a decrease of his viral load from 22,400 copies/ml to undetectable levels (!200 copies/ml). Blood samples were collected just before and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 h after oral drug administration. Our patient was studied between and during dialysis sessions. Paired arterial and venous blood samples were also taken simultaneously 2 h after the start of haemodialysis. Also