Effect of fluconazole on the pharmacokinetics of halofantrine in healthy volunteers.

BACKGROUND: Halofantrine, an antimalarial drug used in endemic areas such as the tropics is mainly metabolized by CYP3A4 to the active metabolite N-desbutylhalofantrine. Fluconazole, an antifungal agent and an inhibitor of CYP3A4 is an established part of the therapy in HIV patients, who in turn are prone to malaria in the tropics. This study investigated the effect of fluconazole on the pharmacokinetics of halofantrine after concurrent administration of the two drugs. METHODS: The effect of fluconazole on the pharmacokinetics of the antimalarial drug halofantrine was evaluated in 15 healthy volunteers in a Latin Square crossover design. The subjects received a single oral dose of 500 mg halofantrine hydrochloride alone or with 50 mg fluconazole after an overnight fast. Venous blood samples were collected during the next 336 h and analysed by HPLC for halofantrine and its active metabolite N-desbutylhalofantrine. RESULTS: Co-administration of fluconazole did not alter the pharmacokinetics of halofantrine significantly with the exception of elimination t(1/2) that was significantly increased by 25% (P < 0.05). In contrast, fluconazole significantly altered the pharmacokinetic parameters of the active metabolite by reducing C(max), AUC and metabolite ratio (N-desbutylhalofantrine/halofantrine) between 35 and 41% (P < 0.05) while increasing t(max) by 50%. The 90% confidence intervals of the ratio of the geometric means (with/without fluconazole) were contained within 80-125% for halofantrine but outside this range for N-desbutylhalofantrine. CONCLUSION: The decreased plasma concentrations of the metabolite are presumably caused by metabolic inhibition of CYP3A4 by fluconazole. Although the therapeutic consequences of this interaction are not clear caution should be exercised when co-administering both drugs to avoid accumulation and subsequent cardiotoxic effects of halofantrine.

Novel determination of nabumetone, a cox-2 inhibitor precursor via its 4-carboxyl-2,6-dinitrobenzene diazonium (CDNBD) derived AZO dye.

A novel colorimetric determination ofnabumetone in tablets has been developed. The assay is based on chemical derivatization (aromatic ring derivatization technique) using newly developed 4-carboxyl-2,6-dinitrobenzene diazonium (CDNBD) ion as the chromogenic derivatizing reagent and resultant formation of azo dye.Optimization studies established an optimal reaction time of 10 minutes at 30 degrees C after mixing the drug/reagent mixture in a vortex mixer for 10 sec. A new absorption maximum (ë(max)) was found at 470 nm, which was selected as analytical wavelength. The assays were linear over 1-6 microg/ml of nabumetone and the optimal reaction required a 2:1 reagent/drug stoichiometric ratio. The developed method has a low limit of detection of 0.39 microg/ml, and is reproducible (1.81% RSD). It has been applied successfully to the assay of nabumetone tablets and is of equivalent accuracy (p > 0.05) with the official (B.P) HPLC method. The new method is simple, has the main advantage of employing a more affordable instrumentation and could find application in routine in-process quality control of nabumetone tablets.

Comparative determination of halofantrine tablets by titrimetry, spectrophotometry and liquid chromatography.

Comparative determination of halofantrine tablets by titrimetry, ultraviolet spectrophotometry and liquid chromatography (LC) is described. Non-aqueous titrimetry on halofantrine hydrochloride tablets was carried out using glacial acetic acid as solvent, perchloric acid as titrant and crystal violet as indicator. Simultaneous potentiometric monitoring of end point delineated an exact color shade of indicator at the end point. Direct measurement of methanol solution, at 254 nm, was adopted for UV spectrophotometric method while reversed-phase liquid chromatographic (LC) method employed a C8 column (4.6 mm x 25 cm) with mobile phase consisting of methanol / 0.05 M NaH2PO4 (76:24, v/v) containing 55 mmol/L perchloric acid (pH 3.4) at a flow rate of 1 ml / min. The three methods gave precise and accurate results. Mean percentage recovery were obtained respectively as 100.73 +/- 0.41, 100.36 +/- 0.79 and 99.93 +/- 3.74% while coefficient of variation were 0.41, 1.36 and 3.74% for non-aqueous. UV spectrophotometry and LC. The three methods were successfully applied to analysis of halofantrine tablets (Halfan) and showed no statistically significant difference in accuracy (P > 0.05, ANOVA). Validated assay methods for halofantrine tablets have been developed. The titrimetric and spectrophotometric methods are of equivalent accuracy with the liquid chromatographic method and could be used for routine quality control of halofantrine tablets where LC method is not readily available.

Bioequivalence study of three generic formulations of co-trimoxazole tablets in human urine.

Many proprietary and generic formulations of co-trimoxazole tablets commercially marketed in Nigeria are mostly from Asian countries. Nigerians buy these products because of their cheaper prices but not confident with regards to therapeutic, quality, safety, and efficacy. Health professionals usually are cautious about drug product selection and substitution during prescription and dispensing. In this paper, the bioequivalence study of three multi-sourced (generic) co-trimoxazole tablets was carried out on the urine of twelve healthy volunteers. The reversed-phase high performance liquid chromatography was employed for the analysis. Sulphadoxine was used as internal standard. The limits of detection were 76.3 ng/mL for trimethoprim, and 61.9 ng/mL for sulphamethoxazole at 0.16 aufs. The linearity (n = 5) for the calibration curve was of the order, 1.0000 for trimethoprim and 0.9998 for sulphamethoxazole; percentage recoveries for trimethoprim and sulphamethoxazole were 89.4 and 87.9% respectively. The relative bioavailabilities of the two generics to the innovator's product were 104.2% (trimethoprim) and 106.8% (sulphamethoxazole); 114.8% (trimethoprim) and 111.8% (sulphamethoxazole) for a product of reputable pharmaceutical company in Nigeria and Indian product respectively. In conclusion, the three generic formulations of co-trimoxazole tablets were biologically equivalent. Interchangeability of drugs in prescription and dispensing may be recommended in this situation.

Some physicochemical properties of 4-amino-3,5-dinitrobenzoic acid (ADBA).

Some physicochemical properties of the aromatic amino acid 4-amino-3,5-dinitrobenzoic acid (ADBA) were determined. This provides, for the first time, quantitative data about this chemical of current pharmaceutical and biomedical interest. The analytical reagent grade of ADBA has 100% purity, determined by potentiometry. The ionization constant (pKa) is 4.00 +/- 0.04. The specific absorbance of ADBA [A(1%, 1 cm)] was determined as 389.42 +/- 51.33 and 381.67 +/- 38.99 (p = 0.05) in water (435 nm) and octanol (415 nm), respectively. The lipophilicity of ADBA is described by its octanol/water partition coefficient (Log P) of -1.50. An analogous parameter descriptive of lipophilicity, the chromatographic hydrophobicity index (Rm), was determined as -0.84 on reversed phase thin layer chromatography (RPTLC). ADBA is more acidic thanp-amino benzoic acid (PABA), the prototype aromatic amino acid of which ADBA is an analogue. It is also about thirty-two times more water soluble than in n-octanol. These findings have a predictive value with respect to absorption and distribution of this compound in living organisms.

Effect of proguanil interaction on bioavailability of cloxacillin.

METHODS: To investigate a potential drug-drug interaction between proguanil (PG) and cloxacillin (Clox). Seven healthy adult volunteers received a single oral dose of Clox plus coadministration of single oral doses of PG and Clox in a simple cross-over manner after a wash-out period of 1 week. Total urine voided was collected at predetermined time intervals over 12 h. Amount of Clox in urine was determined by a reversed-phase high-pressure liquid chromatography method. RESULTS: The mean maximum excretion rate [(dDu/dt)max] of Clox when taken alone was 16.13 +/- 2.92 mg/h at tmax of 1.86 +/- 01.07 hours, whereas in the presence of PG, it was 7.72 +/- 3.24 mg/h at tmax of 2.43 +/- 00.98 hours (P < 0.0001). The total amount of Clox excreted in urine (Du infinity) in 12 h was markedly reduced by coadministration with PG by up to 48% with Du infinity of 49.57 +/- 8.16 mg after Clox alone and 25.81 +/- 8.46 mg in the presence of PG (P < 0.0001). The tmax and t1/2-values obtained from the excretion rate plot were lengthened by 23 and 34%, respectively, in the presence of PG but the differences were not statistically significant (P > 0.05). CONCLUSION: These pharmacokinetic values indicate slowed and diminished absorption (bioavailability) of Clox when concurrently administered with PG. The clinical implication is unknown. However, concomitant administration of the two drugs during antibacterial therapy should be done with caution so as to avoid subtherapeutic levels of Clox, which can lead to treatment failure and facilitate drug resistance.

Evaluation of diazotized 4-amino-3,5-dinitrobenzoic acid (ADBA) as a new derivatizing reagent.

A preliminary evaluation of the reactivity of diazotized 4-amino-3,5-dinitrobenzoic acid (ADBA) towards selected aromatic compounds has been described. Successful diazo coupling of pharmaceuticals possessing aromatic rings of varying reactivities was achieved with the arenediazonium ion of ADBA at room (30 degrees C) or elevated temperature (80 degrees C). The adducts formed in spot-test reactions were coloured for some compounds (e.g, cloxacillin and chloroxylenol), others showed colour at elevated temperature of reaction (e.g., salicylic acid and aspirin), while others showed no detectable change in colour of reaction mixture, even at elevated temperature (e.g., imidazole and tinidazole). The coloured product formed at room temperature decomposed and the colour discharged at elevated temperature in some cases (e.g., beta-naphthol). However, thin layer chromatographic analysis suggested that a more lipophilic derivative, relative to the original compound was formed for some of the compounds studied which did not show any detectable colour change in the spot test reactions. The diazotized ADBA is thus shown to be a reactive coupling reagent with which a suitable derivatization methodology could be developed for a wide range of pharmaceuticals in ultraviolet/visible spectrophotometry and high performance liquid chromatographic (HPLC) analysis.

Mathematical models of antisickling activities of benzoic acid derivatives on red blood cells of sicklers.

A classical drug design technique based on the quantitative structure--activity relationship is applied to a series of synthetic benzoic acid derivatives. Some of the active derivatives tested include; p-toluic acid, p-dimethyl-amino benzoic acid, p-fluorobenzoic acid, p-chlorobenzoic acid, m-chlorobenzoic acid, p-bromobenzoic acid, p-nitrobenzoic acid, and p-iodobenzoic acid. The Hansch lipophilicity, pi, and the Hammett electronic parameters; sigma, were found to predict activities of the agents on the reversal of sickle-shaped deoxygenated sickle red blood cell to normal morphology. A series of equations correlating the biological activities with the structure of the tested compounds were analysed using multiple regression techniques. The most applicable of the equations was found to be; Log BR = -A sigma + B pi--C pi 2 + K Interpretation of this equation in terms of the biological action of the drugs on red blood cells was attempted. In designing a potent antisickling agent, the benzoic acid should have strong electron donating group(s) attached to the benzene ring and should be made averagely lipophilic to satisfy the relationship derived in this study.

Bioequivalence of pyrantel pamoate dosage forms in healthy human subjects.

Drugs that are largely restricted to the gastro-intestinal tract (GIT) for their therapeutic efficacy and that are not substantially absorbed into the body are usually inadequately studied in terms of systemic bioavailability. The possibility of systemic effects requires that bioavailabilities be studied to ensure against enhanced toxicity resulting from formulation differences. Pyrantel pamoate falls into this category. High-performance liquid chromatography was employed in this study to determine plasma levels of pyrantel in nine healthy human subjects after administration of tablet and suspension dosage forms. Mean peak plasma concentrations of 37.56 +/- 9.37, 35.89 +/- 8.94, and 36.22 +/- 10.10 ng mL-1 were obtained following administration of 750 mg pyrantel pamoate in three different formulations. The mean tmax values were 2.02 +/- 0.12, 2.05 +/- 0.356, and 2.05 +/- 0.339 h respectively for the above dosage forms; the respective AUC0-9 values were 81.01 +/- 12.97, 94.59 +/- 17.18, and 101.47 +/- 19.59 h ng mL-1. There was no statistically significant difference between the bioavailabilities of the dosage forms tested. Large inter-subject variations were observed. One subject experienced abdominal discomfort and one experienced dizziness. It was not possible to clearly correlate individual variations in absorption with the observed adverse effect because the number of incidents was low (two out of 27 treatments).

Comparative bioavailability studies on brands of diazepam tablets.

The chemical and biological equivalence of two brands of diazepam tablets marketed in Nigeria were compared to that of Valium (Roche) tablets. The tablets used were Relanium (Polfa) and Tropium (Biode). Bioequivalence studies of the brands were carried out on nine healthy volunteers by monitoring the cumulative diazepam excreted as oxazepam (both free and conjugated) in urine over 48 h. The bioequivalence of Relanium was found not to be significantly different from that of Valium while that of Tropium was significantly different from that of Valium (P less than 0.05). The results of the investigation showed that the drug products were all chemical equivalents but not biological equivalents.

Two new arylnaphthalide lignans from Justicia flava roots.

Orosunol and 8-demethylorosunol, two new 1-aryl-2,3-naphthalide lignans, have been isolated from Justicia flava root. Structures IV and V respectively have been proposed for them by spectral (UV, IR, PMR, (13)C NMR, and MS) and chemical evidence.

Some new decussine-type alkaloids from Strychnos decussata, Strychnos dale and Strychnos elaecocarpa.

From the stem bark of Strychnos decussata (Pappe) Gilg (Loganiaceae), four tertiary indole alkaloids have been isolated: bisnordihydrotoxiferine and three new alkaloids. The structures of two of the new alkaloids, 3,14-dihydrodecussine (III) and 10-hydroxy-3,14-dihydrodecussine (IV), have been ascribed on the basis of their spectral data. The muscle-relaxant activity of these new compounds is discussed. Further studies of the alkaloids present in the stem bark of Strychnos dale and Strychnos elaeocarpa revealed the presence of decussine (V) and dihydrodecussine in S. dale and decussine, dihydrodecussine, and bisnordihydrotoxiferine in S. elaeocarpa.

New tertiary alkaloids of Strychnos decussata.

From the stem bark of Strychnos decussata (Pappe) Gilg (Loganiaceae), five tertiary indole alkaloids have been isolated and identified. Previously known alkaloids, but new to this plant, were: akagerine (1) and 17-O-methylakagerine (2), while alkaloids newly found in nature were 10-hydroxy-21-O-methylkribine (3a), 10-hydroxyepi-21-O-methylkribine (3b) and 10-hydroxy-17-O-methylakagerine (4). Structures have been ascribed to the new compounds on the basis of their spectral, particularly nmr, data. The pharmacological activity of the alkaloids is also discussed.