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ABSTRACT: Halofantrine (HF) is a poorly water-soluble antimalarial drug with low bioavailability. Complex formation of HF.HCl and 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) in aqueous solution and in solid state as well as the possibility of improving the solubility and dissolution rate of the drug though complexation with the cyclodextrin were investigated. Phase-solubility profile indicated that the solubility of the drug was significantly increased in the presence of HP-beta-CD and was classified as AL-type, indicating 1:1 stoichiometric inclusion complexes and an apparent stability constant value of 2300 M(-1). Solid inclusion complexes of HF, HCl and the cyclodextrin at 1:1 molar ratios were prepared by physical mixture, kneading, co-evaporation and freeze-drying methods and characterized by X-ray diffraction and Infra-red spectroscopy. The solubility and dissolution rates of HF.HCl from the complexes were determined and found to be dependent on the preparation method of the complexes. Dissolution profile of the drug was markedly enhanced by complex formation with the cyclodextrin and the product prepared by the freeze-drying method exhibited the most superior dissolution properties compared to the other methods used in this study. The results suggest that the complexation of HF.HCl with HP-beta-CD could improve therapeutic efficacy of the drug though enhanced absorption expected from increased drug dissolution.
Pharmazie 12/2007; 62(11):858-63. · 1.01 Impact Factor
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ABSTRACT: The significance of a pharmacokinetics basis in chloroquine (CQ)-induced pruritus was investigated by determining the disposition of the drug in two groups of volunteers; pruritus positive and pruritus negative. Single oral dose of 600 mg CQ was administered to each of 36 volunteers, 18 for each of the two groups. After a washout period of 9 months, 150 mg single oral dose of the drug was given to 12 of the same volunteers, six each from the two groups. Blood and urine samples were collected at predetermined times following administration of each dose. Concentrations of CQ and its major metabolite, desethylchloroquine (CQM), were measured in plasma and urine using an established HPLC method. Results showed that the ratio, AUC (CQ)/AUC (CQM), as well as AUC(0-48 h) and 24-h urinary CQ excretion were all significantly higher (P<0.05) in pruritus-positive compared to pruritus-negative volunteers, following administration of the 600-mg CQ dose. Also, urinary drug-metabolite ratios monitored over 0-48 h postdose were markedly higher in the pruritus positive group. However, after administration of the 150-mg dose, 24-h urinary CQ collection and urinary drug-metabolite ratios were highly comparable between the two groups (P>0.1). This study indicates that there might be a decreased metabolism of CQ in subjects susceptible to CQ-induced pruritus following ingestion of a therapeutic dose. It also suggests that the extent of metabolism of CQ in this group may be influenced by the dose of the drug. Comparatively higher CQ levels in pruritus susceptible subjects may possibly be responsible for the pruritus experienced by such individuals when given therapeutic regimen.
European Journal of Pharmaceutical Sciences 05/2001; 13(2):195-201. · 3.21 Impact Factor
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ABSTRACT: The need to develop chloroquine suppository formulations that yield optimal bioavailability of the drug has been emphasized. This study demonstrates the effects of incorporation of known absorption-enhancing agents (nonionic surfactants and sodium salicylate) on the in vitro release characteristics of chloroquine from polyethylene glycol (1000:4000, 75:25%, w/w) suppositories. The release rates were determined using a modification of the continuous flow bead-bed dissolution apparatus for suppositories. Results showed that the extent of drug release from suppositories containing any of three surfactants (Tween 20, Tween 80 and Brij 35) was 100%, whereas 88% release was obtained with control formulation (without enhancer) (P<0.05). However, Tween 20 was more effective than Brij 35 and Tween 80 in improving the drug release rate. There was a concentration-dependent effect with Tween 20, and 4% (w/w) of this surfactant was associated with the highest increase in the rate of drug release from the suppositories. Sodium salicylate at a concentration of 25% (w/w) also significantly enhanced the drug release rate, but a higher concentration of the adjuvant markedly reduced both the rate and extent of drug release. Combined incorporation of Tween 20 and sodium salicylate did not significantly modify (P0.05) the rate of drug release when compared to the effect of the more effective single agent. Due to their effects in improving the drug release profiles coupled with their intrinsic absorption-promoting properties, it is suggested that incorporation of 4% (w/w) Tween 20 and/or 25% (w/w) sodium salicylate in the composite polyethylene glycol chloroquine suppository formulations, may result in enhancement of rectal absorption of the drug. This necessitates an in vivo validation.
European Journal of Pharmaceutical Sciences 12/1999; 9(2):131-6. · 3.21 Impact Factor
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ABSTRACT: This study investigated the in vitro adsorption of halofantrine (Hf) by some antacids. Magnesium carbonate showed the highest adsorptive effect, the extent of adsorption being up to 83%. Only 4% of Hf adsorbed by the antacid could be eluted with 0.1 M HCl while no detectable elution occurred with water. Other antacids investigated were magnesium trisilicate and aluminium hydroxide and these had Hf-adsorption capacities of 23 and 43%, respectively. The effect of magnesium carbonate on the bioavailability of Hf was evaluated in seven healthy volunteers. The subjects were administered with 500 mg oral dose of Hf-HCl or the same dose of the drug in combination with 1 g of magnesium carbonate, in a crossover fashion. Blood samples were collected at predetermined time intervals and were analysed for Hf and its major metabolite, desbutylhalofantrine (Hfm), using high-performance liquid chromatography method. The results showed that magnesium carbonate significantly prolonged (P<0.05) the time to reach maximum plasma concentration (Tmax) of Hf. Also the maximum plasma concentrations (Cmax) of Hf and Hfm were significantly reduced (P<0.05). Furthermore, there was a reduction in the area under the curve (AUC) values of Hf and this was as high as 56% (range 1-56%). Results of this study suggest that it may not be advisable to concomitantly administer Hf with an antacid like magnesium carbonate.
European Journal of Pharmaceutics and Biopharmaceutics 11/1998; 46(3):299-303. · 4.27 Impact Factor
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ABSTRACT: A new ion-pair reversed-phase high-performance liquid chromatographic (HPLC) method for the simultaneous measurements of halofantrine (HF) and its major metabolite, desbutylhalofantrine (Hfm), in human plasma is described. Sample treatment involved protein precipitation with acetonitrile followed by extraction with hexane-diethylether (ratio, 1:1; vol/vol) under alkaline condition. Chromatographic separation was achieved on a 10-microm particle size C-18 column (200 x 4.6 mm internal diameter) using a mobile phase consisting of methanol-0.05 M potassium dihydrogen phosphate (70:30, vol/vol) with 55 mmol/l perchloric acid (pH 3.1). Retention times for Hfm, Hf, and the internal standard were 5.3, 7.5, and 11.5 minutes, respectively. Detection limits of Hf and Hfm were 2.5 and 2.0 ng/ml, respectively (1 ng/ml = 2 nmol/l for Hf; 1 ng/ml = 2.25 nmol/l for Hfm). Intraassay and interassay coefficients of variation for both compounds were less than 7%, with an accuracy of no greater than 8% at concentrations of 40 and 400 ng/ml, respectively. The new HPLC method is sensitive, selective, and rapid. Relative to previous HPLC methods, it is simple and cost-effective. In addition, the internal standard is readily accessible. Application of this method in pharmacokinetic studies was demonstrated.
Therapeutic Drug Monitoring 01/1998; 19(6):682-7. · 2.49 Impact Factor
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ABSTRACT: Chloroquine has been reported to be secreted into human saliva. This is a report of a study designed to underscore the importance of the finding. It involved the administration of 600 mg chloroquine per oral to seven volunteers and 150 mg by intramuscular route to six others. Blood and simultaneous saliva samples were collected and analyzed for the drug by an HPLC method. The results showed that chloroquine reaches peak concentration at the same time in both plasma and saliva after oral administration of the drug. A good correlation was obtained between the AUC values derived from saliva and plasma level data. Saliva to plasma concentration ratios obtained after administration of the drug by both routes were high (mean > 11) and exhibited a time-dependent variability. These results suggest that an active process, among other mechanisms, may be involved in the transfer of chloroquine into human saliva. Caution should be exercised in the use of saliva for therapeutic monitoring of chloroquine.
Pharmacy World amp Science 12/1996; 18(6):211-6. · 1.22 Impact Factor
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ABSTRACT: A simple and sensitive HPLC method for the determination of drotaverine in human plasma and urine has been developed. Alkalinized plasma or urine was extracted with organic solvent and the basic components in the organic phase were back-extracted into 0.1 M HCl. An aliquot of the aqueous layer was injected onto the column and the eluent was monitored at 254 nm. Separation was performed on a C18-column with 0.02 M sodium dihydrogen phosphate-methanol (30:70, v/v) containing perchlorate ion at pH 3.2 as mobile phase. Drotaverine was well resolved from the plasma constituents and internal standard. An excellent linearity was observed between peak-height ratios and plasma concentrations and the intra- and inter-assay coefficients of variation were always < 10%. The lowest limit of detection (signal-to-noise ratio 3:1) was 6 ng/ml. The method is suitable for therapeutic monitoring and pharmacokinetic studies of drotaverine in humans as well as in animal models.
Journal of Chromatography 12/1993; 622(1):93-7. · 4.53 Impact Factor
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ABSTRACT: The pharmacokinetic interaction between chloroquine (CQ) and imipramine was investigated in six healthy volunteers who received 300 mg of CQ, 50 mg of imipramine, and combined doses of both drugs in a randomized, crossover design. Blood and urine samples were collected at predetermined time intervals and were analyzed for the drugs and their metabolites by high-performance liquid chromatography methods. The results revealed that the plasma concentrations of CQ and its pharmacokinetic parameters were not significantly altered when CQ was coadministered with imipramine (p > 0.1). The plasma concentration-time profiles and the disposition characteristics of imipramine also were not altered after coadministration with CQ. The results suggest that there appears to be no pharmacokinetic interaction between CQ and imipramine given as single oral doses.
Therapeutic Drug Monitoring 03/1993; 15(1):43-6. · 2.49 Impact Factor
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ABSTRACT: Aetiologically different models of experimental acute renal failure were induced in rats by the administration of glycerol, mercuric chloride and gentamicin, respectively, to different groups. Quinine levels in plasma and urine of the rats with induced renal failure were determined and pharmacokinetic parameters (elimination t1/2, CLp, V, CLR AUC0-infinity) of the drug were derived and compared with values obtained from control rats following intraperitoneal administration of a 10 mg/kg body-weight dose of quinine. Results showed that each of the three compounds caused an up to 25-fold increase in the plasma levels of the drug and a marked decrease in the levels of the metabolite 3-hydroxyquinine. All the pharmacokinetic parameters determined for the rats with renal impairment were markedly different when compared to control. The high plasma quinine levels observed in the rats with renal failure could be largely due to the marked decrease in V and reduced metabolism. Also, in the rats with renal impairment, no correlation was observed between the increased plasma urea levels and plasma quinine levels or disposition of the drug. The results of the study suggest that quinine should be used with caution in patients with renal impairment. The plasma urea levels, as a measure of renal function, might not provide a suitable index for determining quinine dosage.
Pharmaceutisch Weekblad Scientific Edition 09/1992; 14(4):185-90.
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ABSTRACT: The uptake and efflux of chloroquine by the rat submaxillary gland in-vitro were studied under various incubation conditions. Variations in the extracellular pH significantly affected both the uptake and efflux of the drug. Increasing chloroquine concentration significantly decreased the uptake. Uptake was also decreased significantly (P less than 0.05) when compared with control conditions (pH 7.40, 37.5 degrees C, O2 aeration, 6 x 10(-6) M chloroquine) by the following experimental variations: aeration of the incubation medium with N2 instead of O2; decrease of bath temperature from 37.5 to 4 degrees C; addition of metabolic inhibitors, cyanide (10(-3) M), iodoacetic acid (10(-3) M) and o-nitrophenol (10(-3) M). Cimetidine (10(-3) M), a known organic cationic inhibitor, had no significant effect on chloroquine uptake when compared with control values. These results show that the uptake of chloroquine by the rat submaxillary gland in-vitro is concentration-dependent and this is indicative of possible saturable binding sites for the drug in the gland. These results suggest that the transfer of chloroquine across the submaxillary gland may be mediated by an active transport process. On the other hand, it is possible that the apparent active transport process implicated in this study could be a consequence of chloroquine ion trapping in the acidic interior of lysosomes.
Journal of Pharmacy and Pharmacology 03/1992; 44(2):136-8. · 2.17 Impact Factor
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ABSTRACT: After a single oral administration of a 300 mg dose of proguanil to six volunteers, the presence of the drug in saliva was established by chromatographic and spectrophotometric methods. The tmax and elimination half-life of proguanil derived from salivary levels were 4.0 +/- 1.26 h and 15.1 +/- 1.8 h, respectively. These results are in agreement with values previously reported for the drug using plasma level data. The mean saliva: plasma proguanil concentration ratio was 0.41 +/- 0.17 and this was not time dependent. There was a correlation (r = 0.82) between the saliva and simultaneous plasma proguanil concentration. The results suggest that proguanil is passively secreted into saliva and that saliva levels may be useful in the determination of pharmacokinetic parameters and the therapeutic monitoring of the drug.
Journal of Pharmacy and Pharmacology 01/1990; 41(12):872-3. · 2.17 Impact Factor
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ABSTRACT: The excretion of chloroquine and the major metabolite, desethylchloroquine, in breast milk was investigated in eleven lactating mothers following a single oral dose of chloroquine (600 mg base). The average milk to plasma concentration ratio at the 24th hour was 6.6 +/- 2.4 for chloroquine and 1.5 +/- 0.6 for desethylchloroquine in five of the volunteers. In five other volunteers the elimination half-life of chloroquine in milk was 8.8 +/- 4.7 days which was longer than that in saliva (3.9 +/- 1.0 days) from the same volunteers. The maximum daily dose of the drug that the infant can receive from breastfeeding was about 0.7% of the maternal start dose of the drug in malaria chemotherapy. It is, therefore, suggested that it is safe for mothers to breastfeed their infants when undergoing treatment for malaria with chloroquine.
British Journal of Clinical Pharmacology 05/1987; 23(4):473-6. · 2.96 Impact Factor
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Journal of Chromatography 09/1986; 380(2):425-30. · 4.53 Impact Factor
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ABSTRACT: The presence of chloroquine in saliva from seven healthy volunteers for 21 days after a single 600 mg oral dose of the drug was established by chromatographic and spectroscopic methods. The results showed the drug to be rapidly absorbed with a tmax in saliva of 3.9 +/- 1.6 h. A long elimination half-life of 7-20 days, calculated from the saliva concentration-time profile, is in agreement with values previously reported for the drug using plasma level data. In three of the volunteers from whom simultaneous blood samples were obtained, the mean Cs/Cp value was 1.20 +/- 0.27. It is suggested that saliva level determination may be used in evaluating patient compliance, therapeutic drug monitoring and pharmacokinetic parameters of chloroquine.
Journal of Pharmacy and Pharmacology 08/1986; 38(7):535-7. · 2.17 Impact Factor
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ABSTRACT: A simple and sensitive HPLC method for the determination of drotaverine in human plasma and urine has been developed. Alkalinized plasma or urine was extracted with organic solvent and the basic components in the organic phase were back-extracted into 0.1 M HCl. An aliquot of the aqueous layer was injected onto the column and the eluent was monitored at 254 nm. Separation was performed on a C18-column with 0.02 M sodium dihydrogen phosphate—methanol (30:70, v/v) containing perchlorate ion at pH 3.2 as mobile phase. Drotaverine was well resolved from the plasma constituents and internal standard. An excellent linearity was observed between peak-height ratios and plasma concentrations and the intra- and inter-assay coefficients of variation were always < 10%. The lowest limit of detection (signal-to-noise ratio 3:1) was 6 ng/ml. The method is suitable for therapeutic monitoring and pharmacokinetic studies of drotaverine in humans as well as in animal models.
Journal of Chromatography B: Biomedical Sciences and Applications.
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ABSTRACT: The in vitro adsorption of proguanil by some antacids was investigated. Results showed that magnesium trisilicate exhibited the highest adsorptive capacity, with the extent of adsorption being up to 88%. At 37.1°C only partial elution of the adsorbed drug on magnesium trisilicate could be achieved. The bioavailability of proguanil after a single oral administration of a 200 mg dose of the drug to eight volunteers was evaluated from saliva level data. The results were compared with the corresponding data obtained following concomitant administration of the same dose of the drug with magnesium trisilicate. The aucTs values of the drug were 3256 ± 990 and 1148 ± 619 (ng h ml−1; ± S.D.) after administration of proguanil alone and proguanil-antacid combination, respectively. The results indicate that magnesium trisilicate markedly reduced the extent of absorption of proguanil. However, the rate of absorption was unaffected. The results of this study suggest that concomitant administration of proguanil with a non-systemic antacid like magnesium trisilicate should be discouraged.
International Journal of Pharmaceutics. 100:249-252.
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ABSTRACT: The pharmacokinetics and bioavailability of drotaverine was studied in 10 healthy volunteers after administration of single 80 mg oral and intravenous doses of the HCl salt of the drug, in a crossover fashion. Plasma and urine samples were analyzed for the unchanged drug by HPLC. The pharmacokinetic parameters, such as elimination half-life, plasma clearance, renal clearance and apparent volume of distribution, were not influenced by the route of drug administration. The drug was mainly eliminated by non-renal routes since renal clearance accounted for only 0.31 +/- 0.13% of the total plasma clearance. The absolute bioavailability was variable and ranged from 24.5-91% with a mean of 58.2 +/- 18.2% (mean +/- SD). It is suggested that the high variation in the bioavailability of drotaverine HCl after oral administration may result in significant interindividual differences in therapeutic response.
European Journal of Drug Metabolism and Pharmacokinetics 21(3):217-21. · 0.36 Impact Factor
