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F Jamali

Publications and source records attributed to F Jamali.

At least 109 records · Page 6Linked to original sources
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↗
PubMed1988

Pharmacokinetics of ibuprofen enantiomers in humans following oral administration of tablets with different absorption rates.

Ibuprofen (IB) is a racemic drug and is administered as such. While activity is due mainly to the S enantiomer, pharmacokinetic interpretations, as well as criteria to assess the bioequivalence of IB formulations, are based on measurements of the total (S + R) drug concentrations. IB enantiomers possess different disposition properties mainly as a result of R-to-S isomeric bioinversion. Inversion is maximal during the absorption phase, suggesting, perhaps, involvement of a presystemic process. This concept was evaluated in healthy subjects by crossover administration of four IB tablets having different absorption rates. The plasma concentrations of the individual isomers were measured using a stereospecific gas chromatographic assay. Differences among the products were insignificant with respect to the extent to the absorption. The S:R concentration ratios rose for 4 to 6 hr and then remained relatively unchanged. This observation was consistent with equal terminal t1/2 values for the enantiomers. There were significant differences between the peak times (Tmax) of the products. The S:R ratios of the concentrations at Tmax of S and AUC also differed; significant positive correlations were found between Tmax and the S:R ratios of Cmax. Thus the extent of R-to-S inversion, and hence the potency of a racemic dose of IB, may be absorption rate dependent.

Administration, Oral↗
PubMed1988

Stereospecific high-performance liquid chromatographic (HPLC) assay of fenoprofen enantiomers in plasma and urine.

A new high-performance liquid chromatographic (HPLC) assay suitable for pharmacokinetic studies of enantiomers of fenoprofen (FEN) was developed. Following the addition of internal standard (IS; racemic ketoprofen), the plasma or urine constituents are extracted into a mixture of isooctane:isopropanol (95:5), back extracted into water, and finally, extracted into chloroform. After evaporation of the organic layer, the drug and IS are derivatized with l-leucinamide hydrochloride via ethyl chloroformate intermediate. The formed diastereoisomers are chromatographed on a reversed-phase HPLC with a mobile phase consisting of monopotassium phosphate solution:acetonitrile:triethylamine (65:35:0.02) at a flow rate of 1 ml/min. The detection UV wavelengths are 232 and 275 for the drug and IS, respectively. The suitability of the assay for pharmacokinetic analysis of FEN enantiomers was examined by analysis of the plasma and urine samples taken from a healthy subject, following peroral administration of a single 300-mg dose of racemic FEN.

Chromatography, High Pressure Liquid↗
PubMed1988

Pharmacokinetic analysis of the enantiomeric inversion of chiral nonsteroidal antiinflammatory drugs.

Equations describing plasma concentration-time courses of the individual enantiomers of chiral 2-arylpropionic acid nonsteroidal antiinflammatory drugs were derived from a general model. The model assumes first-order absorption and elimination of the enantiomers with presystemic and/or systemic R-to-S enantiomeric inversion. Utilizing reported pharmacokinetic parameters, plasma concentrations of the enantiomers of ibuprofen (IB) were simulated. In the case of presystemic inversion, S:R plasma concentration ratios remained constant after an initial rise; the ratio progressively increased with time, however, when systemic inversion was assumed. Under the assumption of simultaneous systemic and presystemic inversion, the increase in the ratio in the postabsorptive phase was preceded by a steeper increase during absorption. Furthermore, it was shown that perturbation of IB absorption from the gastrointestinal tract may serve as an important discriminative measure for identification of the inversion site. For systemic and presystemic inversions, negative and positive sigmoidal relationships, respectively, were observed between the S:R concentration ratio 5 hr after drug administration and the time to reach the maximum plasma concentration. The applicability of the model to previously reported IB data is discussed.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1988

Doxapram dosage regimen in apnea of prematurity based on pharmacokinetic data.

To 18 premature apneic patients refractory to theophylline, doxapram (0.5-2.5 mg/kg/h) was administered in combination with therapeutic doses of theophylline. Doxapram concentrations in serum were measured 48 h after commencement of the infusion and then in 2-hour intervals during a 6-8 h withdrawal. Total body clearance (dose/Css) of the drug ranged from 0.20 to 0.56 liter/h in 13 patients and 1.14 to 1.75 liter/h in 4 patients suggesting a binomial distribution in the disposition kinetics of the drug. Other pharmacokinetic indices, although variable, did not exhibit binomial distribution. The mean volume of distribution and half-life of doxapram were 7.33 +/- 4.55 liter/kg and 8.17 +/- 4.13 h, respectively. Based on our calculations to accelerate the attainment of a steady-state plasma concentration (Css) of approximately 1.5 mg/l, a loading dose of 5.5 mg/kg and a maintenance dose of 1 mg/kg/h along with serum concentration monitoring are recommended.

Apnea↗
PubMed1988

Treatment of tardive dyskinesia: preliminary report on use of tetrabenazine.

Tetrabenazine has been used for treatment of tardive dyskinesia sporadically over the past twenty years. Dose has usually been decided empirically without assaying blood levels. This report describes 23 cases treated successfully with tetrabenazine. Our method of measuring levels of tetrabenazine and its metabolites in biological samples is described briefly.

Adult↗
PubMed1988

Longer plasma half-life for procainamide utilizing a very sensitive high performance liquid chromatography assay.

The reported biological half-life of the antiarrhythmic drug procainamide (PA) is between 2 and 4 h. To reassess this, the disposition kinetics of the drug and its pharmacologically active metabolite, N-acetyl procainamide (NAPA), were determined using a newly developed high performance liquid chromatography (HPLC) method. The assay involved extraction from plasma of PA and NAPA with methylene chloride, followed by a brief washing of the extract with water, separation and evaporation of the organic layer, reconstitution in the mobile phase [water/methanol/acetic acid/triethylamine (74:25:1:0.03)], and injection into the HPLC system. At an ultraviolet light detection wavelength of 280 nm, the samples were chromatographed on a reverse-phase column. The minimum quantifiable concentration was 0.005 microgram/ml for both the drug and its metabolite. With this sensitivity it was possible to measure PA and NAPA plasma concentrations in samples taken as late as 24 h after single 375-mg oral doses of PA HCl to 13 healthy volunteers. When only the data points up to 12 h were included in the calculation, the drug t1/2 was 3.50 +/- 0.82 h (mean +/- SD) and in agreement with those reported previously. However, the t1/2 became significantly longer (8.52 +/- 3.58 h) when the 16- and 24-h data points were also included. The t1/2 of NAPA was 8.06 +/- 1.33 h and close to the reported values.

Acecainide↗
PubMed1988

Research methodology in NSAID monitoring: plasma concentrations of chiral drugs.

The poor concentration-efficacy correlation generally observed with chiral nonsteroidal antiinflammatory drugs administered as racemates may, in part, be the result of conclusions based on the correlation of total drug concentration (R- plus S-enantiomers) with efficacy. The disposition kinetics of the enantiomers may be stereoselective. The extent of this stereoselectivity may range from substantial for fenoprofen and ibuprofen to small or negligible for flurbiprofen, ketoprofen and tiaprofenic acid. Pathophysiological factors such as gastrointestinal residence time and age may influence the stereoselectivity. Thus basic and clinical pharmacological data generated without considering stereoselectivity may be misleading.

Aging↗
PubMed1988

Liquid-chromatographic assay of ibuprofen enantiomers in plasma.

This stereospecific "high-performance" liquid-chromatographic (HPLC) assay is suitable for pharmacokinetic studies of ibuprofen (IB). Very efficient extraction of the drug and internal standard, (+/-)-2-(4-benzoylphenyl)butyric acid, from plasma with isooctane/isopropanol (95/5, by vol) is followed by sequential reaction of the enantiomers with ethyl chloroformate and (S)-(-)-1-(1-naphthyl)ethylamine. The reactions take place at ambient temperature in less than 4 min. The naphthylethylamide derivatives of IB enantiomers and internal standard are then extracted into chloroform. After the organic layer is evaporated, the reconstituted residue is chromatographed at ambient temperature on a C18 reversed-phase column with a mobile phase of acetonitrile/water/acetic acid/triethylamine (55/45/0.1/0.02 by vol) at a flow rate of 1 mL/min. The IB diastereoisomers, detected at 232 nm, are free of interfering peaks and have a resolution factor of 2.2. Within the examined enantiomer concentration range of 0.1 to 20 mg/L in plasma, the peak-area ratios varied linearly with the corresponding IB concentrations. We used the assay to study the pharmacokinetics of IB enantiomers in plasma of a subject who took a single 600-mg dose of racemic drug.

Chromatography, High Pressure Liquid↗
PubMed1987

Microbiological systems in organic synthesis: preparation of racemic prenalterol utilizing Cunninghamella echinulata.

The fungal microorganism Cunninghamella echinulata was utilized to para-hydroxylate the synthetic substrate (+/-)-1-isopropylamino-3-phenoxy-propan-2-ol (1). The resulting product, (+/-)-1-(4-hydroxyphenoxy)-3-isopropylamino-propan-2-ol, or (+/-)-prenalterol, (2) was formed in greater than 85% yield. Extracts from incubates were derivatized with trifluoroacetic anhydride and the concentrations of 1 and 2 were determined by GC on a fused silica methyl silicone capillary column with nitrogen-phosphorus detection. At substrate concentrations of 100 and 200 mg/L, the biotransformation proceeds with apparent first-order kinetics. With higher concentrations, the kinetics of prenalterol formation and substrate uptake appear to be nonlinear with a Km value of 427.8 micrograms/mL and a Vmax value of 232.3 micrograms/mL/d. This suggests that the biotransformation may proceed through a single-capacity limited pathway. The microbial product was isolated and identified as (+/-)-prenalterol by comparison (mp, IR, MS, 1H NMR) with an authentic specimen.

Biotransformation↗
PubMed1987

Concentration-effect relationships of tetrabenazine and dihydrotetrabenazine in the rat.

To investigate the pharmacodynamics of tetrabenazine [1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-2-H-benzo(a)quinol izine-2- one; 1], the drug of choice in the control of Huntington's chorea and tardive dyskinesia, and its major metabolite, dihydrotetrabenazine (2), ip doses of 3 mg/kg of the drug and the metabolite were administered to rats. Animals were decapitated at 0.0, 0.5, 2, 5, and 12 h. Brain and serum concentrations of 1 and 2, and brain concentrations of dopamine, norepinephrine, and serotonin were measured. Time courses of 1 and 2 in the brain (site of action) were parallel to those in serum, indicating that the brain is a part of the central compartment for both compounds. Despite its greater polarity, 2 was able to readily cross the blood-brain barrier. The monoamine depletions at any time following the administration of 2 were at least equal to or greater than those observed following the administration of the same dose of 1. After both compounds, the maximum serum and brain concentrations and maximum depletions were observed with the first sample at 0.5 h, with dopamine and serotonin being the most and least affected, respectively. The brain levels of the amines returned to the control values a maximum of 12 h after ip injections of either 1 or 2. Sigmoidal relationships were found between the monoamine levels and the corresponding log brain or serum concentrations of 1 or 2. The concentration-response curves of 2 following the administration of 1 and 2 were superimposable, suggesting that the observed activity after tetrabenazine injection is mainly, if not entirely, due to the formation of the active metabolite.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Dose-response relationship of doxapram in the therapy for refractory idiopathic apnea of prematurity.

Eighteen infants with idiopathic apnea of prematurity refractory to therapeutic levels of aminophylline were treated with incremental doses of doxapram beginning at 0.5 mg/kg/h. Continuous recording of heart rate, thoracic impedance, and transcutaneous PO2 demonstrated that 47% of the infants satisfied objective response criteria at the lowest dose, 53% responded at 1.0 mg/kg/h, 65% at 1.5 mg/kg/h, 82% at 2.0 mg/kg/h, and 89% at the highest allowed dose of 2.5 mg/kg/h. The mean serum doxapram concentration at the response dose was 2.9 +/- 1.3 micrograms/mL, and all infants who responded had levels greater than 1.5 micrograms/mL. BP was significantly elevated at doses higher than 1.5 mg/kg/h (P less than .05). Minute ventilation significantly increased and PCO2 significantly decreased as the doxapram dosage was increased (P = .02). Terminal elimination half-life was 9.9 +/- 2.9 hours. When doxapram is used for treatment of refractory neonatal apnea the starting dosage should be no more than 0.5 mg/kg/h.

Apnea↗
PubMed1986

Gas chromatographic separation of optically active anti-inflammatory 2-arylpropionic acids using (+)- or (-)-amphetamine as derivatizing reagent.

A method is described for the derivatization of several non-steroidal anti-inflammatory arylalkanoic acids (ibuprofen, ketoprofen, naproxen, fenoprofen, flurbiprofen, pirprofen, cicloprofen, tiaprofenic acid, etodolic acid) with optically active amphetamine. The usefulness of this reagent compared to alpha-methylbenzylamine is described. The enantiomers are separated as diastereoisomers using capillary gas chromatography with nitrogen-phosphorus detection. The procedure is readily applied to the quantification of the enantiomers in urine and plasma samples.

Amphetamine↗
PubMed1986

Pharmacokinetics of the enantiomers of tiaprofenic acid in humans.

A gas chromatographic method was utilized to study stereoselective pharmacokinetics of the nonsteroidal anti-inflammatory drug, tiaprofenic acid (5-benzoyl-alpha-methyl-2-thiopheneacetic acid), in four arthritic patients receiving 200 mg/8 h of the racemic drug. Synovial concentrations of the enantiomers were also measured following administration of single 200-mg doses of the drug to six other patients. In the analytical procedure, racemic tiaprofenic acid was coupled to (S)-(+)-amphetamine and the corresponding diastereoisomeric amide derivatives were resolved. Analysis of serial blood and urine samples at steady state, and single synovial samples, revealed that tiaprofenic acid enantiomers had superimposable plasma concentration-time and urinary excretion-time profiles and equivalent synovial concentrations. These results indicate that, unlike most 2-arylpropionic acid anti-inflammatory drugs, tiaprofenic acid enantiomers do not have different disposition kinetics, and the metabolic chiral inversion of one to the other does not occur or is so slow that the drug is eliminated before significant inversion takes place.

Anti-Inflammatory Agents↗