Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients.

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.

Interaction of sildenafil and indinavir when co-administered to HIV-positive patients.

OBJECTIVES: The prevalence of erectile dysfunction in HIV-infected men is estimated to be 33%. Sildenafil citrate (Viagra; Pfizer Ltd, Sandwich, Kent, UK) is the first oral drug for this condition. Since sildenafil and the protease inhibitors are both metabolized by, and act as inhibitors of cytochrome P450 3A4, we evaluated the pharmacokinetics of the combination sildenafil plus indinavir in HIV-infected patients. DESIGN AND METHODS: Six patients at steady state in treatment with indinavir participated in the study. On the first day blood samples for indinavir assay were drawn at times 0, 1, 2, 3, 4, 6 and 8 h after dosing. On the second study day patients received a single dose of 25 mg of sildenafil in addition to their routine morning medication. Blood samples were taken as described. Separated plasma was stored at -80 degrees C until analysis by high performance liquid chromatography. In a parallel study, the effect of indinavir, ritonavir, saquinavir and nelfinavir on the in vitro hepatic metabolism of sildenafil was assessed. RESULTS: The geometric mean area under the concentration curve for 0-8 h (AUC0-8h) and maximum plasma concentration (Cmax) for indinavir were 19.69 microg/ml h (range, 9.19-31.99 microg/ml h) and 7.02 microg/ml (range, 2.33-16.17 microg/ml), respectively, on the first study day. In the presence of sildenafil, the mean AUC0-8h and Cmax of indinavir were 22.37 microg/ml h [range, 10.08-37.25 microg/ml h; 95% confidence interval (CI) for difference between means, -15 to 13.25) and 9.11 microg/ml (range, 3.41-22.78 microg/ml; 95% CI, -13 to 6.37), respectively. The geometric mean AUC0-8h and Cmax for sildenafil were 1631 ng/ml h (range, 643-2970 ng/ml h) and 384 ng/ml (range, 209-766 ng/ml) respectively. The AUC for sildenafil was 4.4 times higher than data from historical controls given either 50 mg or 100 mg of sildenafil and dose normalized to 25 mg. Indinavir was a potent inhibitor of sildenafil hepatic metabolism in vitro [concentration producing 50% inhibition of control enzyme activity (IC50) = 0.39 +/- 0.17 microM, mean +/- SD]. CONCLUSIONS: Co-administration of sildenafil 25 mg did not significantly alter the plasma indinavir levels. However, plasma sildenafil AUC was markedly increased in the presence of indinavir compared with historical controls. From the in vitro data, the mechanism of increase is indinavir inhibition of the hepatic metabolism of sildenafil. The magnitude of this interaction suggests a lower starting dose of sildenafil may be more appropriate in this clinical setting.

The pharmacokinetics of combination therapy with nelfinavir plus nevirapine.

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.

Effect of recombinant human bone morphogenetic protein-2 on fracture healing in a goat tibial fracture model.

Bone morphogenetic proteins (BMPs) are considered to have important regulatory roles in skeletal embryogenesis and bone healing. Recombinant human BMPs (rhBMPs) have been shown to heal critical size defects and promote spinal fusion. We studied the effects of rhBMP-2 in an absorbable collagen sponge (ACS) on bone healing in a large animal tibial fracture model. Bilateral closed tibial fractures were created in 16 skeletally mature goats and reduced and stabilized using external fixation. In each animal, one tibia received the study device (0.86 mg of rhBMP-2/ACS or buffer/ACS), and the contralateral fracture served as control. The device was implanted as a folded onlay or wrapped circumferentially around the fracture. Six weeks following fracture, the animals were sacrificed and the tibiae harvested for torsional testing and histomorphologic evaluation. Radiographs indicated increased callus at 3 weeks in the rhBMP-2/ACS treated tibiae. At 6 weeks, the rhBMP-2/ACS wrapped fractures had superior radiographic healing scores compared with buffer groups and controls. The rhBMP-2/ACS produced a significant increase in torsional toughness (p = 0.02), and trends of increased torsional strength and stiffness (p = 0.09) compared with fracture controls. The device placed in a wrapped fashion around the fracture produced significantly tougher callus (p = 0.02) compared with the onlay application. Total callus new bone volume was significantly increased (p = 0.02) in the rhBMP-2/ACS fractures compared with buffer groups and controls regardless of the method of device application. The rhBMP-2/ACS did not alter the timing of onset of periosteal/endosteal callus formation compared with controls. Neither the mineral apposition rates nor bone formation rates were affected by rhBMP-2/ACS treatment. The increased callus volume associated with rhBMP-2 treatment produced only moderate increases in strength and stiffness.

The effect of genetic polymorphisms in CYP2C9 on sulphamethoxazole N-hydroxylation.

Sulphamethoxazole undergoes CYP2C9-mediated bioactivation to a hydroxylamine. In this study, we investigated the effect of the CYP2C9Arg144 to Cys (CYP2C9*2) and CYP2C9Ile359 to Leu (CYP2C9*3) polymorphisms on sulphamethoxazole N-hydroxylation. Human livers were genotyped using polymerase chain reaction amplification and restriction fragment length polymorphism analysis. Formation of sulphamethoxazole hydroxylamine and methylhydroxy tolbutamide in microsomes prepared from cell lines and the genotyped human livers was determined by high-pressure liquid chromatography. Microsomes prepared from the cell line expressing the allelic variants CYP2C9-Cys144 and CYP2C9-Leu359 displayed a threefold and 20-fold decrease in intrinsic clearance (Cl(int)) for sulphamethoxazole, respectively, when compared with the wild-type, CYP2C9-Arg144. A significant decrease (P < 0.05) in Cl(int) was also observed with tolbutamide for both mutations. Of the 26 human livers genotyped, 61.5% were homozygous wild-type, 26.9% were heterozygotes for CYP2C9*2 and 15.4% were heterozygotes for CYP2C9*3. No homozygous mutant livers were detected. There was a good correlation between sulphamethoxazole N-hydroxylation and tolbutamide methyl hydroxylation (r = 0.825). However, there was no difference in the kinetic parameters for either sulphamethoxazole N-hydroxylation or tolbutamide methyl hydroxylation between the wild type livers (n = 6) and either the livers heterozygous for the CYP2C9*2 (n = 5) or the livers heterozygous for the CYP2C9*3 mutation (n = 3). The CYP2C9*2 and CYP2C9*3 polymorphisms may have some influence on the bioactivation of sulphamethoxazole, particularly in individuals who are homozygous mutants, and this could act as a protective factor against sulphamethoxazole hypersensitivity. However, given the rarity of homozygous mutants, it is likely that other metabolic and immunological risk factors will dominate individual susceptibility.

Inhibition of tolbutamide metabolism by substituted imidazole drugs in vivo: evidence for a structure-activity relationship.

Tolbutamide has been used as a model drug for an examination of the effects of eleven substituted imidazole compounds on hepatic metabolism in vivo. The 1-substituted compounds 1-methylimidazole, miconazole, clotrimazole and ketoconazole produced marked alterations in tolbutamide kinetics (increased half-life, decreased clearance). However, if there was substitution in the 2- position, irrespective of a substituent on N-1, then the compound did not appear to inhibit metabolism (e.g. 2-methylimidazole, 1,2-dimethylimidazole, methimazole, metronidazole). The 4- substituted compounds, 4-methylimidazole and cimetidine were inhibitors. A structure-activity relationship for the inhibitory actions of the substituted imidazoles is thus evident in vivo.

Tolbutamide as a model drug for the study of enzyme induction and enzyme inhibition in the rat.

The effects of various drugs on the pharmacokinetics of tolbutamide have been examined in the rat. Phenobarbitone pretreatment caused a significant decrease in half life and area under the curve (AUC) and a significant increase in clearance and volume of distribution (Vd). Acute administration of primaquine significantly increased half life and AUC and decreased clearance. In contrast, the related animoquinolone chloroquine, was without effect. Acute administration of cimetidine produced similar changes to primaquine but of lesser magnitude. Formation of the major metabolite hydroxytolbutamide, was markedly enhanced by phenobarbitone and reduced by primaquine and cimetidine. We conclude that due to its single pathway of metabolism, tolbutamide is a good substrate to use when examining pharmacokinetic interactions involving hepatic enzyme induction and inhibition.

The in-vitro mucosal conjugation of ethinyloestradiol and the bioavailability of oral contraceptive steroids in patients with treated and untreated coeliac disease.

The 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 less than 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.

PIP: Physicians took several small intestinal mucosal samples from female patients with or with out celiac disease at the Royal Liverpool and Broadgreen Hospital in Liverpool, England, to determine in vitro the mucosa's ability to metabolize ethinyl estradiol and levonorgestrel. They compared this in vitro ability with the pharmacokinetics of the 2 steroids in 5 women with celiac disease. The percentage conjugation of ethinyl celiac mucosa (17.1% mg dry weight vs. 6.3% mg dry weight; p .01); it was also greater than it was for celiac mucosa from patients treated with a gluten-free diet (12.1% mg dry weight; p .05). The percentage of conjugate as sulphate was 85% for untreated celiac mucosa. Among the 5 celiac disease patients, no significant differences in any of the pharmacokinetic parameters for levonorgestrel or ethinyl estradiol existed between pre- and post-gluten free diet treatment. These parameters included area under the curve, volume of distribution, and bioavailability. The physicians were able to compare the in vitro ability of intestinal mucosa to metabolize ethinyl estradiol with 1st in vivo pharmacokinetics in 2 patients. In both cases, the in vitro mucosal conjugation rose while the in vivo bioavailability fell (4.4% to 12.1% and 75.4% to 43.2% for patient 1, and 3.6% to 9.1% and 86.7% to 55.2% for patient 2). These findings suggest that celiac disease weakens the ability of intestinal mucosa to conjugate ethinyl estradiol, but a gluten-free diet can adequately improve this ability.

Substrate-adsorbed collagen and cell secreted fibronectin concertedly induce cell migration on poly(lactide-glycolide) substrates.

Limited epithelial cell migration on synthetic polymeric biomaterials, such as polyesters, presents a serious challenge to their use as scaffolds for artificial skin analogs. The mechanisms by which a physiologic matrix interface on such polymers may regulate and promote cell migration under 'activated conditions' were the focus of this study. We have quantified the migration behavior of epidermal growth factor (EGF) stimulated epidermal keratinocytes on 50:50 poly-D,L(lactide-glycolide) (PLGA) substrates, following exogenous and cell-derived substrate conditioning based on the model matrix proteins, collagen and fibronectin. We report that 'non-conditioned' PLGA substrates elicited poor levels of keratinocyte migration. However, keratinocyte migration was significantly enhanced upon the adsorption of type I collagen, and was only weakly enhanced with fibronectin adsorption. Molecular analysis of the mechanism of enhanced migration on collagen-PLGA substrates showed that keratinocyte migration was sensitive to cell-derived fibronectin conditioning, but not to cell-secreted collagen conditioning. Fibronectin control of cell migration on collagen-PLGA was found to be both stoichiometric and biologically specific, mediated via adhesion involving keratinocyte alpha v integrin receptors. Based on our results, we propose a unique paradigm for induction of cell migration on a non-physiologic synthetic polymer using concerted interactions between primary, polymer-instructed matrix remodeling and secondary, cell-derived matrix remodeling.

Effect of the progestogens, gestodene, 3-keto desogestrel, levonorgestrel, norethisterone and norgestimate on the oxidation of ethinyloestradiol and other substrates by human liver microsomes.

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 microM 3-keto desogestrel). Ki values determined for GSD and 3-KD were 98.5 +/- 12.3 and 93.2 +/- 10.3 microM (mean +/- SD; n = 4), respectively. Preincubation of progestogens in a small volume (50 microliters) incubation for 30 min in the presence of an NADPH-generating system enhanced the inhibitory potential of all the steroids (at 100 microM, 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 greater than 3-KD greater than NET greater than 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.

Effect of fluconazole on the interactions between human neutrophils and Candida albicans.

The effects of fluconazole on the candidacidal activity of human neutrophils were investigated. Three clinical isolates of Candida albicans were studied in a colony count assay and the presence of fluconazole during incubation of yeasts with neutrophils had no effect on neutrophil candidacidal activity. These results, using a different assay and three additional isolates, confirm previous studies showing that fluconazole does not interfere with the ability of neutrophils to kill C. albicans.

Analysis of surface microtopography of biodegradable polymer matrices using confocal reflection microscopy.

Currently, synthetic degradable polymers are frequently employed as culture substrates prior to cell transplantation and as implantable scaffolds for cellular infiltration during soft and hard tissue repair. The surface microstructure of matrices based on such polymers may be important in controlling cellular anchorage, spreading, and growth on the external surface, as well as infiltration into the voids of porous polymer scaffolds. While the chemistry, bulk structure, and mechanical properties of such polymers have been extensively studied, the surface microstructure has not yet been systematically examined, particularly following polymer degradation. In this study, we present the first account of the use of confocal laser-scanning reflection microscopy (CLSM) to visualize and quantitate the microtopography of the surface of porous matrices of poly(lactic acid)/poly(glycolic acid) (PLAGA) copolymers following polymer degradation. Utilizing this technique, we report that the surface morphology of PLAGA matrices changes significantly upon degradation, with increased local clustering of textured regions. Our quantitative analysis suggests that polymer degradation results in a lower spatially-averaged surface roughness, with significant cyclical variations observed at later time points. The computed surface correlation function was observed to increase upon degradation, confirming the results from our morphological studies. Finally, we demonstrate the efficacy of CLSM to concomitantly image both the polymer surface and locally attached cells, in real time.

The lack of effect of sodium valproate on the pharmacokinetics of oral contraceptive steroids.

Patients taking anticonvulsants such as phenobarbitone, phenytoin and carbamazepine together with their oral contraceptive steroid may suffer contraceptive failure because of the enzyme-inducing properties of these anticonvulsants. We have examined, in six women, the effect of sodium valproate, an effective broad spectrum anticonvulsant, on the area under the plasma concentration versus time profile (AUC) of ethinyloestradiol (EE2) and levonorgestrel (Ng). Prior to sodium valproate therapy the mean AUC for EE2 was 880 +/- 109 pg/ml X h (+/- S.E.) and for levonorgestrel it was 29.1 +/- 2.9 ng/ml X h (n = 4). Between two and four months after sodium valproate therapy the mean AUC figures had not changed significantly, the figure for EE2 being 977 +/- 130 pg/ml X h and for levonorgestrel 29.2 +/- 1.9 ng/ml X h (p greater than or equal to 0.1 in each case). We conclude that sodium valproate in the dose used (200 mg b.d.) does not interact with oral contraceptive steroids.

The bioavailability of ethinyloestradiol and levonorgestrel in patients with an ileostomy.

The bioavailability of ethinyloestradiol and levonorgestrel has been studied in 5 young women with an ileostomy following surgery for ulcerative colitis and compared to that in 5 control subjects. Single i.v. and oral doses of both drugs were administered and the bioavailability calculated from the ratio of the two areas under the plasma concentration versus time curve for the two drugs. The mean bioavailability of ethinyloestradiol in the patients with an ileostomy was 55.4 +/- 10.9% (+/- S.D.) compared to a control value of 45.0 +/- 6.1% (p greater than or equal to 0.1). The mean bioavailability of levonorgestrel in the ileostomy patients was 85.2 +/- 13.1% compared to 104.6 +/- 22.3% in the controls (p greater than or equal to 0.1). Women who have an ileostomy following lower bowel surgery can rely on their oral contraceptive preparations being absorbed in the normal way.

The lack of interaction between temafloxacin and combined oral contraceptive steroids.

In view of the considerable debate concerning the possible failure of contraception in women taking broad spectrum antibiotics, we have examined a group of 12 women aged 22-32 in a controlled study. Each woman had been on long-term therapy with oral contraceptive steroids (OCS) containing ethynylestradiol (EE2) and levonorgestrel (Ng) for at least 6 months and all were in good general health. Blood samples were taken about 11.0 hours after dosing with their OCS on days 5, 6, 7 and 8 of their contraceptive cycle, for measurement of EE2, Ng, FSH and LH by radioimmunoassay. In addition blood samples were taken on days 19, 20 and 21 of the contraceptive cycle for assay of progesterone concentrations in plasma. The study was repeated in the next cycle of use of their OCS during which they took temafloxacin, a broad spectrum quinolone antibiotic in a dose of 600 mg twice daily for 7 days starting on day 1 of the cycle. All women completed the study satisfactorily as judged by diary cards, tablet counts and plasma temafloxacin concentrations. In the early part of the study some nausea and headaches were seen due to taking temafloxacin on an empty stomach but these effects were not seen when the antibiotic was later given with food. There was no evidence of any interaction between temafloxacin and the OCS. The plasma concentration of EE2 was 61.4 +/- 21.1 pg/ml in the control cycle and 68.5 +/- 26.6 pg/ml in the temafloxacin cycle.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: In view of the considerable debate concerning the possible failure of contraception in women taking broad spectrum antibiotics, the authors examined a group of 12 women ages 22-32 in a controlled study. Each had been on longterm therapy with oral contraceptives (OCs) containing ethinyl estradiol (EE) and levonorgestrel (Ng) for at least 6 months and all were in good general health. Blood samples were taken about 11.0 hours after dosing with OCs on days 5, 6, 7, and 8 of their contraceptive cycle, for measurement of EE2, Ng, FSH, and LH by radioimmunoassay. In addition, blood samples were taken on days 19, 20, and 21 of their contraceptive cycle for assay of progesterone concentrations in plasma. The study was repeated in the next cycle of OC use during which the patients took temafloxacin, a broad spectrum quinoline antibiotic in a dose of 600 mg twice daily for 7 days, beginning on day 1 of the cycle. All women completed the study satisfactorily as judged by diary cards, tablet counts, and plasma temafloxacin concentrations. In the early part of the study, some nausea and headaches were experienced; this was due to the taking of the drug on an empty stomach. When the antibiotic was administered with food, this problem was no longer a concern. There was no evidence of any interaction between temafloxacin and OCs. The plasma concentration of EE2 was 61.4 +or- 21.2 pg/ml in the control cycle and 68.5 +or- 26.6 pg/ml in the temafloxacin cycle. The plasma progesterone concentration was 0.53 +or- 0.1 ng/ml in the control cycle and 0.6 +or- 0.24 ng/ml in the temafloxacin cycle (p0.01). No woman demonstrated any significant rise in plasma FSH or LH concentrations during temafloxacin therapy. The authors conclude that there is no evidence for a systematic interaction between temafloxacin and OCs and that there is no need for use of alternative contraceptive methods in women taking OCs who are also being treated with temafloxacin.

The effect of cotrimoxazole on oral contraceptive steroids in women.

Nine women taking long-term oral contraceptive steroids (Trinordiol) were studied during a cycle while taking cotrimoxazole (1 gm twice daily) and the results were compared to the previous control cycle. During the cotrimoxazole cycle, there was a significant increase in the plasma concentration of ethynylestradiol (EE). In plasma samples taken on 4 successive days 10-12 hours after dosing, the plasma EE concentration rose from 29.3 +/- 5.0 pg/ml to 38.2 +/- 5.8 pg/ml (mean +/- S.E. P less than or equal to 0.02). In samples taken 24 hours after dosing, the increase was from 18.9 +/- 2.5 pg/ml to 27.8 +/- 4.0 pg/ml (P less than or equal to 0.05). Plasma F.S.H. values in these latter samples, decreased from 4.8 +/- 0.6 mIu/ml to 3.4 +/- 0.5 mIu/ml (P less than or equal to 0.01). No significant changes were noted in the plasma concentrations of levonorgestrel or progesterone. The rise in plasma concentration of EE during cotrimoxazole therapy is attributed to an inhibition of the metabolism of EE by cotrimoxazole as has been shown with other drugs. Short courses of cotrimoxazole are unlikely to cause any adverse effects on contraceptive control when given to women taking long-term oral contraceptive steroids.

The effect of some benzimidazoles on the disposition of antipyrine and tolbutamide from the rat isolated perfused liver.

The anthelmintic benzimidazoles, mebendazole, albendazole and flubendazole have been screened for any propensity to alter the disposition of antipyrine and tolbutamide in the rat isolated perfused liver preparation. The benzimidazoles were added as a 2.5 mg bolus dose into the perfusate reservoir 5 min before the administration of either antipyrine or tolbutamide. Neither mebendazole or albendazole produced any significant effect on the pharmacokinetics of either of the substrate drugs. In contrast, flubendazole significantly decreased the clearance of antipyrine (by 40%) indicating inhibition of mixed function oxidase activity. However, flubendazole did not alter the disposition of tolbutamide. The results suggest that not all benzimidazoles inhibit hepatic drug metabolizing enzymes and that different forms of cytochrome P-450 are involved in the metabolism of antipyrine and tolbutamide.