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O Eradiri

Publications and source records attributed to O Eradiri.

9 recordsLinked to original sources
PubMed2000

Dual effects of L-3,4-dihydroxyphenylalanine on aromatic L-amino acid decarboxylase, dopamine release and motor stimulation in the reserpine-treated rat: evidence that behaviour is dopamine independent.

The comparative effects of L-3,4-dihydroxphenylalanine (L-DOPA) on dopamine synthesis, release and behaviour were studied in the reserpine-treated rat. Acute administration of L-DOPA (25-200 mg/kg) dose-dependently inhibited the activity of aromatic L-amino acid decarboxylase (AADC) in the substantia nigra and corpus striatum. The antiparkinsonian drugs budipine (10 mg/kg) and amantadine (40 mg/kg) enhanced AADC activity in these regions, and prevented or reversed AADC inhibition by L-DOPA. Dual probe dialysis revealed that low doses of L-DOPA (25-50 mg/kg) dose-dependently stimulated the release of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in nigra and striatum, whilst high doses of L-DOPA (100-200 mg/kg) completely suppressed the release of dopamine, but not DOPAC. Sulpiride (50 microM) administered via the probes antagonized dopamine release in response to 25 mg/kg L-DOPA, but greatly facilitated release by 200 mg/kg L-DOPA. Dopamine release was blocked by the centrally acting AADC inhibitor NSD 1015, but facilitated by the central AADC activator budipine. In behavioural tests L-DOPA (plus benserazide, 50 mg/kg) only reversed akinesia at 200 mg/kg, and not at 25-100 mg/kg. Pretreatment with either NSD 1015 (100 mg/kg) or budipine (10 mg/kg) markedly potentiated the motor stimulant action of a threshold dose of L-DOPA (100 mg/kg). A combination of NSD 1015 (100 mg/kg) and benserazide (50 mg/kg) potentiated L-DOPA behaviour more effectively than either inhibitor alone. NSD 1015-facilitated L-DOPA behaviour was antagonized by sulpiride (100 mg/kg) and not by SCH 23390 (1 mg/kg), whereas budipine-facilitated L-DOPA behaviour was fully antagonized by SCH 23390 and only partially by sulpiride. These results show that behaviourally active doses of L-DOPA in the reserpinized rat are not accompanied by significant increases in extracellular dopamine and are therefore probably not dopamine mediated. We propose that L-DOPA is capable of directly stimulating dopamine D2 and possibly non-dopamine receptors, thereby inhibiting dopamine efflux presynaptically and promoting motor activation postsynaptically. A stimulant action of L-DOPA on motor behaviour, preferentially mediated by D1 > D2 receptors, suggests that L-DOPA may also be capable of yielding a dopamine-like response in the absence of detectable dopamine release. These findings are incorporated into a new model of L-DOPA's actions in the reserpinized rat, and their possible implications for our understanding of L-DOPA in Parkinson's disease are discussed.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Scale effect in bioequivalence evaluations.

OBJECTIVE: The objective of the study was to evaluate the relationship between the magnitude of the sample means for a bioavailability measure and the ratio of the sample means in bioequivalence evaluations. METHODS: We assumed that bioavailability data were obtained from crossover trials on a test and a reference drug products. The true test-reference ratio was constructed as a function of dosage strength under certain dose-response relationship assumptions, and was used for deriving analytical results of assessing the scale effect due to dosage strength. In addition, the test-reference ratio of sample means was constructed as a function of the true test-reference ratio and the correlated sampling deviation in the sample means, and was used in a deterministic simulation for quantifying the scale effect due to the correlated sampling deviation. RESULTS: The major systematic factors that influence the magnitude of the sample means include the dosage strength, dose-response relationship, and the positively correlated sampling deviation in the sample means. RESULTS of this study showed that the true test-reference ratios can be improved with increasing dosage strength in most of the situations studied, but at a diminishing rate. The correlated sampling deviation can alter the test-reference ratio of the sample means through changing magnitude of the sample means, especially for drug products with low bioavailability. CONCLUSIONS: For extended release drug products with multiple dosage strengths, the development efforts should focus on the lowest strength if there is little or no formulation by dose interaction effect. Pilot studies should be conducted for both the highest and the lowest strength instead for possible formulation by dose interaction effect. The magnitude of observed means for bioavailability measures on the reference drug product can indicate the degree of systematic variation in the ratio of means. The expected mean values of the reference drug product can be derived from previous trial(s) and/or from other information sources. If the sample mean for the reference drug product in a failed bioequivalence trial is lower than expected, the investigator should consider repeating the trial.

Algorithms↗
PubMed1997

Comparison of diltiazem bioavailability from 3 marketed extended-release products for once-daily administration: implications of chronopharmacokinetics and dynamics.

Diltiazem has proven to be an effective antihypertensive and antianginal agent, due to its potent calcium channel blocking activity. The present study was conducted to compare the bioavailability of a new extended release diltiazem HCl capsule formulation (Tiazac) with 2 other currently marketed products (Cardizem CD and Dilacor XR). Fourteen healthy male subjects participated in this randomized, 3-period, multiple daily dose (240 mg for 7 days), crossover bioavailability study. ANOVA and multiple comparison tests showed the parent drug AUC0-tau to be significantly higher after daily dosing with Tiazac than with the other 2 marketed products, but the diltiazem Cmin values were not significantly different between the 3 formulations. Between 5 and 12 hours after drug administration, mean plasma diltiazem levels for Tiazac capsules were found to be significantly higher than those of the 2 other products tested. Comparison of plasma concentrations of metabolites for the 3 capsule formulations by ANOVA and multiple comparison tests showed similar trends as in the case of parent drug concentrations. These findings may be clinically important as higher and more consistent plasma concentrations of diltiazem, and its active metabolite during daytime are needed to counteract higher blood pressures in hypertensive patients due to circadian variations. The new extended release product of diltiazem HCl was found to exhibit significantly differing pharmacokinetics of the parent compound compared to either of the other 2 products tested.

Adult↗
PubMed1988

Application of a stereospecific high-performance liquid chromatography assay to a pharmacokinetic study of etodolac enantiomers in humans.

An HPLC assay suitable for pharmacokinetic analysis of enantiomers of etodolac [(+/-)-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b] indole-1-acetic acid] was developed. Following addition of internal standard (IS), (+/-)-2-(4-benzoylphenyl)butyric acid, the constituents were extracted from the specimen into a mixture of isooctane:isopropanol (95:5). The organic layer was evaporated and the drug and IS were sequentially derivatized with ethyl chloroformate and iota(-)-alpha-phenylethylamine. The diastereoisomers thus formed were extracted and chromatographed on a normal-phase column, with a mobile phase consisting of hexane:ethyl acetate:isopropanol (85:15:0.2) at a flow rate of 2 mL/min. The etodolac diastereoisomers were separated with a resolution factor of 6.4 and detected at a wavelength of 280 nm. Excellent linear relationships were found between the peak area ratios (etodolac:IS) and the plasma and urine concentrations (0.2-20 mg/L), with intra- and interday variations of less than 10.1%. The assay was applied to a preliminary pharmacokinetic study following seven repeated oral administrations of 200 mg/12 h of racemic etodolac to two healthy subjects. The plasma concentrations of the active S-(+)-enantiomer were considerably less than those of the inactive antipode (AUC S:R, 2.5:30.9 mg.L-1.h-1) due to a greater volume of distribution of the latter (S, 101 and 135 L versus R, 24 and 17 L). Considerable concentrations of conjugated enantiomers were also found in plasma (AUC conjugated: intact: S, 1.1; R, 0.23).

Adult↗
PubMed1985

Temperature effects on the binding efficiency of starch pastes.

The effect of temperature on the binding efficiency of yam starch and cassava starch pastes has been investigated. Starch pastes prepared at different temperatures were used to granulate lactose powder and the resulting granules and tablet properties were evaluated. Increased average granule size and decreased percentage fines were observed as the pasting temperature was increased upto a certain level and then there was a decrease in average size and increase in amount of fines as the pasting temperature was further increased. Granules prepared with yam starch pastes exhibited relatively lower amount of fines and larger average granule size. The corresponding tablets also showed higher crushing strength values and were less friable. Although the disintegration time of tablets was found to increase with the temperature of pasting of both the starches, no relationship between the pasting temperature and the crushing strength of tablets was observed. The release of amylose/amylopectin from starch grains, the amylopectin chain length and the amount of free molecular components as the pasting temperature increased are believed to be the factors contributing to the increased binding efficiency of the starch pastes.

Chemistry, Pharmaceutical↗
PubMedDate not supplied

Steady-state pharmacokinetics of metronidazole in Crohn's disease.

The pharmacokinetics of metronidazole (MTZ) were studied in six Crohn's disease patients after multiple oral daily doses of 250, 500, 750, and 1000 mg day-1. Pharmacokinetic indices were found to be independent of the dose administered. The half-life, volume of distribution and oral clearance of metronidazole were 9.5 +/- 2.1 h, 0.732 +/- 0.094 l kg-1 and 0.921 +/- 0.175 (ml min-1) kg-1 (mean +/- SD), respectively. A strong linear correlation (r = 0.95) was found between the volume of distribution of MTZ and the patients' total body weight. The percentage of dose of metronidazole excreted in urine as the intact drug and metabolites as well as glucuronic acid conjugates ranged from 34.7 +/- 7.4 to 58.9 +/- 5.2. Both plasma and urine data exhibited very large inter-patient variations. However, intra-patient variations were negligible. Strong positive linear correlations were observed between the dose and the areas under the plasma concentration versus time curves, peak plasma concentrations as well as cumulative urinary excretion of the drug and its metabolites. It is concluded that in Crohn's disease, the pharmacokinetics of MTZ and its metabolites are linear and that the drug concentrations are dependent on the total body weight.

Adult↗
PubMedDate not supplied

Interaction of metronidazole with phenobarbital, cimetidine, prednisone, and sulfasalazine in Crohn's disease.

The influence of prednisone(PR), sulfasalazine(SZ), cimetidine(CM), and phenobarbital(PB) on the pharmacokinetics of metronidazole was investigated in six Crohn's patients. Metronidazole was first administered alone (250 mg bid, po) and then with prednisone (10 mg bid, po), sulfasalazine (1 g bid, po), cimetidine (600 mg bid) or phenobarbital (60 mg bid, po). Each regimen was followed for 6 days and sampling of blood and urine was carried out on the 7th day after the first dose of each regimen. Plasma and urine samples were analysed for the drug and its two principal metabolites, hydroxymetronidazole and metronidazole-1-acetic acid, by HPLC. When given alone, metronidazole had a mean volume of distribution of 0.667 +/- 0.15 lkg-1, a half-life of 9.7 +/- 3.1 h and an oral clearance of 0.852 +/- 0.23 (ml-1 min) kg-1. The disposition kinetics of metronidazole and its metabolites was not altered by CM and SZ. Induction of metabolism of metronidazole by PR was made manifest in significant increases in oral clearance of the former and urinary excretion of the hydroxy metabolite, and significant decrease in AUC of the parent compound. PB also induced the metabolism of metronidazole. This induction was reflected in significant increases in the oral clearance of metronidazole and AUC of the hydroxy metabolite as well as significant decreases in AUC, half-life, and urinary excretion of the parent drug.

Chromatography, High Pressure Liquid↗