Pharmacokinetic interaction of megestrol acetate with zidovudine in human immunodeficiency virus-infected patients

This nonrandomized, two-period crossover study was performed to assess whether concomitant administration of megestrol acetate influences the steady-state pharmacokinetics of zidovudine and its inactive 5'-O-glucuronide metabolite. Twelve HIV-positive, asymptomatic male volunteers received a 100-mg oral capsule dose of zidovudine at least 30 min before meals five times a day at 0700, 1100, 1500, 1900, and 2300 h on study days 1 to 3 and a single 100-mg dose at 0700 h on day 4. On days 5 to 17, 800 mg of megestrol acetate, as a 40-mg/ml aqueous suspension, was administered orally immediately before the 0700 h dose of zidovudine. On days 5 to 16, zidovudine was also administered at 1100, 1500, 1900, and 2300 h. Serial blood samples were collected for 12 h after the single 100-mg dose of zidovudine on days 4 and 17; trough samples were also obtained just before the 0700 h dose on days 2 to 4 and 15 to 17. Levels of zidovudine and its glucuronide in plasma were assayed by a validated radioimmunoassay. Statistical analysis of trough plasma level data indicated that steady-state levels of zidovudine and its glucuronide in plasma had been attained when pharmacokinetic assessments were made on days 4 and 17. When megestrol acetate and zidovudine were coadministered for 13 days, differences of -14, -6.5, and -4.6% in mean zidovudine peak concentration and areas under the curve at 0 to 4 and 0 to 12 h, respectively, +22.5% in mean trough concentration, +2.6% in mean plasma half-life, and no change in median time to peak were observed compared to conditions when zidovudine was administered alone; for zidovudine 5'-O-glucuronide the respective differences were -9, -7.3, -4.4, +2.3, and +10% and no change. None of the differences were statistically significant (P > 0.05). Concomitant therapy with megestrol acetate, at the dose employed to treat anorexia, cachexia, or an unexplained, significant weight loss in AIDS patients, did not alter the steady-state pharmacokinetics of zidovudine or its 5'-O-glucuronide metabolite.     

Pharmacokinetic and clinical evaluations of fluconazole in pediatric patients

Fluconazole (FLCZ) is a novel antifungal agent and available both in oral and intravenous forms. It is characterized by a long plasma half-life and a good absorbability into tissues. Because of these, it is expected to be used safety and to exhibit good clinical efficacy in the deep seated mycosis of children. We evaluated the efficacy of FLCZ given orally or intravenously to 6 patients. Pathogenic fungi isolated from all patients were Candida, and diagnosises made were candidemia in 3 cases, gastro-intestinal candidiasis in 2 and skin candidiasis. The clinical efficacies of FLCZ in 5 cases were excellent in 2 cases of gastro-intestinal candidiasis and poor in 3 cases of candidemia. None of the patients reported any side effect. In clinical laboratory tests, no abnormalities that were judged to be related to FLCZ were noted. In the study, clinical efficacy was shown to be poor in candidemia, because these cases had severe underlying diseases and the proper therapy was started too late. Thus earlier diagnosis and earlier treatment seem to be important for FLCZ to exhibit good clinical efficacy in the treatment of deep-seated mycosis.     

Effect of fluconazole on zidovudine pharmacokinetics in patients infected with human immunodeficiency virus

The effect of a therapeutic dose of fluconazole on the disposition of zidovudine was evaluated in 12 men infected with human immunodeficiency virus. The study was designed as a randomized, two-period, two-treatment, crossover trial. On two occasions, 21 days apart, patients received either zidovudine alone or zidovudine (each, 200 mg every 8 h) and fluconazole (400 mg daily) for 7 days. Fluconazole coadministration decreased (P < .001) the apparent oral serum clearance of zidovudine by 43% and the apparent oral formation clearance to zidovudine glucuronide (GZDV) by 48%, resulting in increases (P < .002) in the area under the serum concentration time curve (74%), the maximum serum concentration (84%), and the terminal half-life (128%) of zidovudine. The molar ratio of GZDV to zidovudine recovered in urine was reduced by 34% with fluconazole (P < .001). These pharmacokinetic changes suggest that 400 mg of fluconazole inhibited the conversion of zidovudine to GZDV. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions.     

Hepatic steatosis during treatment with zidovudine and lamivudine in an HIV-positive patient

BACKGROUND: Polydipsia-hyponatremia is a poorly understood disorder that causes considerable mortality and morbidity. Hyponatremia in polydipsia-hyponatremia has been attributed to disturbances in antidiuretic hormone (ADH) function. Improvements in polydipsia-hyponatremia during clozapine treatment offered the chance to see if levels of ADH and other hormones associated with osmoregulation changed with improvement in biochemical and clinical measures of polydipsia-hyponatremia. METHOD: In this preliminary, longitudinal study, we studied 2 male schizophrenic patients (DSM-III-R) who had polydipsia-hyponatremia. Measures were (1) biochemical and clinical: serum sodium and osmolality, urine osmolality and specific gravity, normalized diurnal weight gain, and estimated urine volume and (2) endocrine: ADH, angiotensin II, atrial natriuretic peptide, and prolactin. Measures were collected during 2 months of baseline (typical neuroleptic) and 6 months of clozapine treatment. RESULTS: Single-case statistical procedures showed significant changes in sodium levels (a.m. and p.m.), estimated urine volume, and a.m. urine specific gravity in both patients and significantly decreased diurnal weight gain in 1 patient. Both serum and urine osmolality showed improvement, but values did not reach statistical significance. Low baseline ADH levels persisted through 6 months of clozapine treatment and showed no changes in the context of improvements in serum sodium and osmolality. No significant changes were seen in levels of angiotensin II and atrial natriuretic peptide. CONCLUSION: Given the limitations of this study, there is some evidence to suggest that the improvements in serum sodium and osmolality during clozapine treatment of polydipsia-hyponatremia may not be related to serum levels of ADH, although altered ADH receptor function cannot be ruled out. These data need to be extended in larger samples.     

Pharmacokinetic interaction between oral cyclosporin and mibefradil in stabilized post-renal-transplant patients

BACKGROUND: The potential for interaction between oral cyclosporin (Sandimmun) and the new calcium antagonist mibefradil was assessed as part of the clinical development of the new compound. METHODS: Six stable renal transplant patients on long-term, oral, twice-daily (Q 12 H) cyclosporin (CsA) therapy received 25 mg mibefradil on Day 1, followed by 50 mg once daily for 5 or 6 days. At baseline, as well as on the last day of mibefradil dosing, complete steady-state CsA blood concentration-time profiles were characterized over a dosing interval. RESULTS: Mibefradil led to mean increases in minimum and maximum CsA blood concentrations and area under the curve of CsA by 2.7-, 2.1-, and 2.3-fold, respectively (all significantly different from CsA alone, P < 0.02). Mibefradil is therefore associated with a clinically relevant increase in CsA blood concentrations. The mechanism of elevation of CsA blood concentrations is probably mibefradil and/or metabolite inhibition of the cytochrome P-450 isoenzyme 3A4. CsA had no clinically significant effect on mibefradil plasma concentrations. CONCLUSIONS: These results confirm previous findings of cytochrome P-450 3A4 inhibition by mibefradil and suggest that, for patients receiving CsA, its dose must be adjusted and its plasma concentration must be monitored when adding or stopping mibefradil.     

Pharmacokinetic interaction between itraconazole and rifampin in Yucatan miniature pigs

The objective of this study was to examine the effects of rifampin on itraconazole pharmacokinetics, at steady state, in three Yucatan miniature pigs. Daily for 3 weeks, the pigs received 200 mg of itraconazole orally at the beginning of each meal, and for the following 2 weeks they received itraconazole orally combined with intravenous administration of rifampin at 10 mg/kg/day. Coadministration of rifampin resulted in an 18-fold decrease in the maximum concentration of itraconazole in serum, from 113.0 (standard deviation [SD] 17.2) to 6.2 (SD, 3.9) ng/ml and a 22-fold decrease in the area under the concentration-time curve, from 1,652.7 (SD, 297.7) to 75.6 (SD, 30.0) ng.h/ml. The active metabolite of itraconazole, hydroxyitraconazole, was undetectable. This study demonstrates that rifampin affects itraconazole kinetics considerably at steady state in this miniature-pig model, probably by inducing hepatic metabolism of itraconazole.     

Pharmacokinetic interaction between itraconazole and ceftriaxone in Yucatan miniature pigs

Since ceftriaxone and itraconazole are highly protein bound, are excreted via a biliary pathway, and are in vitro modulators of the efflux pump P glycoprotein, a pharmacokinetic interaction between these antimicrobial agents can be hypothesized. Therefore, we evaluated the pharmacokinetics of itraconazole and ceftriaxone alone and in combination in a chronic model of catheterized miniature pigs. Itraconazole does not influence ceftriaxone kinetic behavior. The mean areas under the concentration-time curve (AUC) were 152.2 microg x h/ml (standard deviation [SD], 22.5) and 129.2 microg x h/ml (SD, 41.2) and the terminal half-lives were 1.1 h (SD, 0.3) and 0.9 h (SD, 0.2) when ceftriaxone was given alone and combined with itraconazole, respectively. Regarding itraconazole kinetics, ceftriaxone was shown to alter the disposition of the triazole. Contrary to what was expected, the AUC (from 0 to 8 h) decreased from 139.3 ng h/ml with itraconazole alone to 122.7 ng h/ml with itraconazole and ceftriaxone combined in pig 1, from 398.5 to 315.7 ng x h/ml in pig 2, and from 979.6 to 716.6 ng x h/ml in pig 3 (P of <0.01 by analysis of variance).     

Candida albicans morphotypes and in vitro adhesivity to cells of the human oral mucosa in HIV-positive and AIDS patients after exposure of blastospores to fluconazole. II

BACKGROUND: Oro-pharyngeal candidosis is a frequently initial clinical manifestation of HIV infection and the adhesive properties of Candida spp. represent a very important pathogenicity factor. METHODS: In this study the adhesivity rate of Candida albicans to the oral epithelial cells of 33 HIV-positive patients and 12 healthy volunteers, have been assessed before and after the exposure of blastospores to inhibitory concentrations of fluconazole, in relation to 11 morphotypes obtained from 13 C. albicans strains. RESULTS: Results can be summarized as follows: 1) the number of blastospores adhering to the HIV-positive donor' cells is higher than that of blastospores adhering to the healthy donors' cells (rate is 2.7:1); 2) blastospores from strains producing rough or very coarse fringes show adhesive properties higher than those of strains with different morphology; 3) in the group of HIV-positive patients the adhesivity inhibition of blastospores from strains producing rough or very coarse fringes was higher (38.3%) than that of strains with different morphology (33.8%); 4) overall, adhesivity inhibition due to exposure to fluconazole is higher for epithelial cells from healthy donors. CONCLUSIONS: These results can suggest the validity of an antimycotic pretreatment of persons at risk of oro-pharyngeal candidiasis.     

Sexually transmitted diseases in HIV-positive patients

The complex interaction between sexually transmitted diseases (STDs) and HIV has been demonstrated in many epidemiological studies and clinical trials over the last number of years. Herpes simplex virus, human papilloma virus, and syphilis are all accepted to have different manifestations, effects, and therapeutic responses in HIV positive patients. These and other issues are discussed in this article.     

Pharmacokinetic basis of nifedipine-digoxin interaction: a commentary

Elevation of plasma digoxin levels following concurrent administration of nifedipine have previously been reported. The mechanism for this interaction has not been fully explained, but may include a reduction in volume of distribution of digoxin and/or reduction in the renal or non-renal clearance of digoxin by nifedipine. The end result is probably an elevation of plasma concentrations of free (pharmacologically active) digoxin, which may lead to manifestation of side effects of digoxin. This communication highlights the possible pharmacokinetic basis of the reported digoxin-nifedipine interaction.     

Multidose pharmacokinetics of ritonavir and zidovudine in human immunodeficiency virus-infected patients

The effect of coadministration of ritonavir and zidovudine (ZDV) on the pharmacokinetics of these drugs was investigated in a three-period, multidose, crossover study. Eighteen asymptomatic, human immunodeficiency virus-positive men were assigned randomly to six different sequences of the following three regimens: ZDV (200 mg every 8 h [q8h] alone for 4 days, ritonavir (300 mg q6h) alone for 4 days, and ZDV with ritonavir for 4 days. Ritonavir pharmacokinetics were unaffected by coadministration with ZDV. However, ZDV exposure was reduced by about 26% (P < 0.05) in the presence of ritonavir. The maximum concentration in (Cmax) of ZDV plasma decreased from 748 +/- 375 (mean +/- standard deviation) to 546 +/- 296, and area under the concentration-time curve from 0 to 24 h (AUC0-24) decreased from 3,052 +/- 1,007 to 2,261 +/- 715 when coadministered with ritonavir. In contrast, the ZDV elimination rate constant was unaffected by ritonavir, suggesting that there was no change in ZDV systemic metabolism. Correspondingly, differences in ZDV-glucuronide Cmax and AUC were not statistically significantly different between regimens (P > 0.31). Also, there were no apparent differences in the formation of 3'-amino-3'-deoxythymidine or in the adverse event profiles between the regimens. The lack of change in ritonavir pharmacokinetics suggests that dosage adjustment of ritonavir is unnecessary when it is administered concurrently with ZDV. The clinical relevance of a 26% reduction in ZDV exposure when ZDV is administered with ritonavir is unknown. In addition to other multidrug regimens, the long-term safety and efficacy of coadministration of ritonavir and ZDV is being investigated.     

Candidal meningitis in HIV-infected patients: treatment with fluconazole

Although mucocutaneous candidiasis is a common occurrence in HIV-infected patients, candidal meningitis is uncommon. We report 3 cases of candidal meningitis in HIV-positive patients, all intravenous drug abusers, and we discuss the clinical course and outcome, the treatment with fluconazole and possible prophylaxis.     

Pharmacokinetic interaction between finasteride and terazosin, but not finasteride and doxazosin

The alpha 1-adrenoceptor antagonists doxazosin and terazosin and the 5 alpha-reductase inhibitor finasteride are used in the treatment of benign prostatic hyperplasia. The aim of this study was to assess the potential pharmacokinetic interaction of doxazosin or terazosin when coadministered with finasteride. This was a randomized, placebo-controlled, multi-center study. Ninety healthy men were assigned to one of six treatment groups: doxazosin; doxazosin plus finasteride; terazosin; terazosin plus finasteride; placebo; and placebo plus finasteride. Plasma concentrations, maximum plasma concentration (Cmax), time to maximum concentration (tmax), and area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24) of doxazosin, terazosin, and finasteride were determined. Ratios of Cmax and AUC for doxazosin and terazosin were not significantly altered by coadministration with finasteride. The Cmax and AUC0-24 of finasteride were not significantly altered by coadministration with doxazosin. However, Cmax and AUC0-24 of finasteride were significantly higher after coadministration with terazosin. There is no statistically significant pharmacokinetic interaction between finasteride and doxazosin; however, there is a statistically significant interaction between finasteride and terazosin, which affects the pharmacokinetics of finasteride but not those of terazosin. The clinical significance of this interaction remains to be determined.     

Variation in incidence of indinavir-associated nephrolithiasis among HIV-positive patients

BACKGROUND: Nephrolithiasis may be an important consequence of indinavir therapy; however little has been published on the variation in incidence between different populations of patients or the possible mechanisms of calculus formation. OBJECTIVE: To examine variation in the incidence of indinavir-associated nephrolithiasis (IAN) in HIV-positive patients in relation to hemophilia and hepatitis C virus (HCV) infection. METHODS: Clinical data were abstracted retrospectively from the medical records of all adult patients treated with indinavir from September 1995 to September 1997. Occurrence of first IAN, defined as flank pain and hematuria after initiation of therapy, was analyzed in relation to hemophilia status and HCV infection. RESULTS: There were 17 episodes of IAN (22%) among 79 patients treated with indinavir. Of 10 patients with hemophilia, 50% developed IAN as compared with 17% of patients without hemophilia (P = 0.03). Median days to first IAN was 22 (range 7-110 days) for hemophiliacs and 156 (range 5-611 days) for those without hemophilia. Data for HCV status were available for 74 out of 79 patients: 10 out of 27 (37%) patients with HCV developed IAN compared with six out of 42 (14%) without HCV (P = 0.02). CONCLUSION: Overall incidence of IAN was higher than that previously reported and was significantly greater in hemophiliacs than in non-hemophiliacs. HCV may be a contributing factor.     

Pharmacokinetic and pharmacodynamic evaluation of the potential drug interaction between venlafaxine and ethanol

Venlafaxine is a new antidepressant with a unique mode of action. Because many patients taking antidepressant therapy may self-medicate with ethanol, this study was undertaken to assess the possible pharmacokinetic and pharmacodynamic interactions between venlafaxine and ethanol. This randomized, double-blind, placebo-controlled, two-period crossover study was conducted with 16 healthy men. Multiple doses of venlafaxine (50 mg every 8 hours) or placebo were administered for 7 days. On days 5 and 7 a single dose of 0.5 g/kg of ethanol or a placebo solution was administered in a randomized fashion. Pharmacokinetic data indicated that ethanol administration did not affect the disposition of venlafaxine or O-desmethylvenlafaxine. Similarly, venlafaxine administration did not affect the pharmacokinetic disposition of ethanol. Ethanol produced its expected effects on the eight psychometric tests administered. Venlafaxine produced small effects on the results of the Digit Symbol Substitution Test, the Divided Attention Reaction Time, and the Profile of Mood States. No pharmacodynamic interaction was detected between venlafaxine and ethanol.     

Pharmacokinetic and clinical evaluation of cefozopran in premature and newborn patients

Cefozopran (SCE-2787, CZOP), which is already on the market with a variety of approved indications in infectious diseases for adult patients, was administered to premature and newborn patients to evaluate the pharmacokinetics and the clinical efficacy. 1. Pharmacokinetics CZOP was intravenously administered at doses of 10.0 mg/kg, 21.4 mg/kg and 40.0 mg/kg to premature and newborn patients, and the blood concentrations and urinary excretion rate were examined. The blood CZOP concentrations were 31.7 and 65.5 micrograms/ml at 30 minutes after administration of 10.0 mg/kg and 40.0 mg/kg, respectively. The elimination half life was 1.78 hours and 2.31 hours, and the urinary recovery was 110.7% and 53.7% within 6 hours after administration, respectively. In the patient given 21.4 mg/kg, the blood CZOP concentration was 36.4 mg/kg at 1 an hour after administration and the elimination half life was 3.97 hours. The urinary recovery was 29.6% within 5 hours after administration. 2. Clinical results The clinical efficacy was evaluated in 19 patients and judged "good" or better in 13 of them with the efficacy rate or 68.4%. The bacteriological response was evaluated in 10 patients from whom Gram-positive cocci of S. aureus (6 strains), S. pneumoniae (1 strain) and E. faecalis (1 strain) and Gram-negative bacilli of H. influenzae (2 strains) and E. coli (2 strains) were isolated as possible causative organisms. With exception of 1 strain each of S aureus and H influenzae, which were not tested after the treatment with CZOP, all of these strains were found to be eradicated. 3. Adverse drug reactions (ADRs) of signs and symptoms and abnormal alterations of laboratory test values. Safety evaluation was made in 24 patients. ADRs of signs and symptoms were recognized in none of them. As abnormal alterations of laboratory test values, increased eosinophils in 3 patients, elevated GOT in one and elevated GPT in one were recognized. These results indicate that CZOP is a drug useful for treatment of infections in premature and newborn patients.