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R A Carr

Publications and source records attributed to R A Carr.

30 records · Page 2Linked to original sources
PubMed1995

Stereospecific high-performance liquid chromatographic assay of ketoprofen in human plasma and urine.

A high-performance liquid chromatographic (HPLC) assay suitable for the analysis of the enantiomers of ketoprofen (KT), a 2-arylpropionic acid (2-APA) non-steroidal antiinflammatory drug (NSAID), in plasma and urine was developed. Following the addition of racemic fenoprofen as internal standard (I.S.), plasma containing the KT enantiomers and I.S. was extracted by liquid-liquid extraction at an acidic pH. After evaporation of the organic layer, the drug and I.S. were reconstituted in mobile phase and injected into the HPLC system. The enantiomers were separated at ambient temperature on a commercially available 250 x 4.6 mm amylose carbamate-packed chiral column (Chiralpak AD) column with hexane-isopropyl alcohol-trifluoroacetic acid (80:19.9:0.1, v/v/v) as the mobile phase pumped at 1.0 ml/min. The enantiomers of KT were quantified by ultraviolet detection with the wavelength set at 254 nm. The assay described allows for the direct quantitation of KT enantiomers without pre-column derivatization, and is suitable for clinical studies of KT enantiomers in human plasma and urine after administration of therapeutic doses.

Chromatography, High Pressure Liquid↗
PubMed1995

Protein binding of sotalol enantiomers in young and elderly human and rat serum using ultrafiltration.

The protein binding of sotalol (STL) enantiomers was evaluated using an ultrafiltration technique with serum from young (32 +/- 2 years, n = 5) and elderly (73 +/- 6 years, n = 5) male and female humans, and young (8 weeks, n = 4) and elderly (60 weeks, n = 3) male Sprague-Dawley rats. Serum samples were collected and immediately frozen at -20 degrees C. Within 1 week, the serum samples were thawed at room temperature, and adjusted to pH 7.4 using 0.05 M phosphate buffer, pH 5.0. Aliquots were spiked with 250 ng mL-1 and 500 ng mL-1 of each STL enantiomer, placed in ultrafiltration sets (Microsep, 30K molecular weight cut-off), capped, equilibrated to 37 degrees C, and centrifuged at 1850g for 1.5 h at 37 degrees C. Aliquots of ultrafiltrate and unspun serum were analysed for STL enantiomer concentration using a stereospecific HPLC assay. In all groups, bound fraction was less than 7% for both STL enantiomers. There were no significant differences in bound fraction between groups, or between enantiomers. Adsorption of STL enantiomers to the ultrafiltration device and membrane, evaporative loss of serum samples during centrifugation, and protein concentration in each ultrafiltrate sample were all negligible. It is concluded that the binding of STL in human and rat serum at therapeutic concentrations and physiological temperature and pH is negligible and non-stereoselective.

Adrenergic beta-Antagonists↗
PubMed1995

Stereospecific high-performance liquid chromatographic assay of lomefloxacin in human plasma.

This report describes an HPLC assay developed for the quantification of the enantiomers of lomefloxacin (LFLX), a quinolone antibiotic, in plasma. Following addition of racemic acebutolol (internal standard, IS), plasma samples were extracted at pH 7 with a mixture of chloroform-isopentyl alcohol-diethyl ether (71.25:3.75:25, v/v/v). The organic layer was evaporated, and LFLX and IS enantiomers in the resulting residue were derivatized with chloroform solutions of 1% triethylamine and 1% (S)-(+)-(1-naphthyl)ethyl isocyanate, followed by 2% ethyl chloroformate (ECF) 1 min later. Ethanolamine was added 30 s after the addition of ECF. The enantiomers were separated as diastereomers on an 8 x 100 mm Radial Pak normal phase column using a mobile phase of hexane-chloroform-methanol (64.5:33:2.5, v/v/v) pumped at 2.0 ml min-1. The IS was detected by fluorescence at 245 and 420 nm (excitation and emission, respectively) during the first 12 min, after which time the wavelengths were 280 and 470 nm for detection of LFLX. The method: (1) was sensitive and showed excellent linearity (10-1000 ng ml-1, r2 > 0.99) between added enantiomer concentrations and peak-area-ratio (LFLX/IS); and (2) separated LFLX and IS enantiomers within 25 min. The assay is suitable for the quantification of LFLX enantiomers in plasma samples.

Anti-Infective Agents↗
PubMed1994

Stereospecific evaluation of sotalol pharmacokinetics in a rat model: evidence suggesting an enantiomeric interaction.

Sotalol (STL) is a chiral beta-adrenergic blocking drug, which is useful clinically as the racemate in treating hypertension, and is also useful as a class III antiarrhythmic when administered as the pure S-enantiomer. Utilizing a stereospecific high-performance liquid chromatographic (HPLC) assay, the enantiomeric disposition of STL is reported after administration of racemate and both pure enantiomers to a rat model. After administration of the racemate, enantiomers of STL had similar plasma concentration-time profiles. Following administration of the pure S-enantiomer of STL, however, systemic clearance was significantly reduced; R-STL disposition after pure enantiomer administration was not significantly altered. Changes in systemic clearance of S-STL after either racemate or enantiomer dosing were explained by corresponding changes in renal clearance. Renal clearance values of S-STL were significantly reduced from 33.7 +/- 6.0 to 28.9 +/- 5.6 ml min-1 kg-1 for administration as racemate and pure enantiomer, respectively. As clearance of STL approximates reported values of renal blood flow, renal perfusion changes caused by the beta-blocking effects of R-STL may explain changes in S-STL disposition. It is suggested that dosing of STL as either racemate or pure enantiomer, depending on the clinical indication for use, may result in significantly altered enantiomer disposition.

Animals↗
PubMed1994

Intracapillary glomerular metastases in a nephrectomy specimen removed for ipsilateral renal cell carcinoma.

A case of intraglomerular metastases observed in a nephrectomy specimen removed for primary renal cell carcinoma is reported. The intraglomerular metastases arose by dissemination of malignant cells into the systemic circulation via invasion of the renal veins. Intraglomerular metastases are therefore an indicator of malignant dissemination which in turn should be associated with a poor prognosis. It is recommended that in nephrectomies undertaken for primary renal cell carcinoma at least one random block of renal cortex should be examined to confirm or exclude intraglomerular metastases.

Carcinoma, Renal Cell↗
PubMed1992

Pharmacokinetics of sotalol enantiomers in humans.

The chiral beta-blocker, sotalol (STL), is marketed as a racemic mixture. Although both STL enantiomers have equal Class III antiarrhythmic activity, beta-blocking activity has been ascribed mainly to the R-enantiomer. The pharmacokinetics of STL enantiomers were studied in young (mean age 32 +/- 3 years), healthy male volunteers after oral administration of 160 mg. Subsequent plasma and urine samples were collected over 24 hours, and STL enantiomer concentrations were determined using a stereospecific high-performance liquid chromatography assay. There were no significant differences between pharmacokinetic parameters of enantiomers. The area under the time-concentration curves (mean +/- standard deviation [SD]) were 6.95 +/- 0.85 and 6.76 +/- 1.2 (mg/L)hour for S- and R-STL, respectively. Maximal plasma concentrations of S- and R-STL were 615 +/- 167 and 619 +/- 164 ng/mL, respectively, which were obtained on average, 3.13 +/- 0.60 hours after dosing. The mean residence time (mean +/- SD) was 13.2 +/- 1.2 and 12.9 +/- 1.8 hours for S- and R-STL, respectively. Respective renal clearance values for S- and R-STL were 8.98 +/- 1.5 and 9.46 +/- 2.3 L/hour, and were approximately 1.5 times greater than creatinine clearance. Renal clearance constituted approximately 76% of the oral clearance. Although stereoselective disposition of STL was absent after racemate administration, these results should not be extrapolated to patients with significantly altered physiology, or to the pharmacokinetics of S-STL after administration of pure-S-STL.

Adult↗
PubMed1991

Stereospecific high-performance liquid chromatographic determination of tocainide.

A sensitive high-performance liquid chromatographic assay was developed for the determination of tocainide enantiomers in plasma. Following extraction of tocainide from plasma, the enantiomers were derivatized with S-(+)-1-(1-naphthyl)ethylisocyanate. The resulting diastereomers were separated and quantified using normal-phase chromatography with fluorescence detection set at 220/345 nm (excitation/emission). The peaks, resolved with a resolution factor greater than 1.5, were free from interference. Linearity was established over the concentration range 0.25-10.0 mg/l for each enantiomer in plasma (r2 greater than 0.998). The inter-assay variability was less than 10% at all concentrations examined. The method can be used to determine the pharmacokinetics of tocainide enantiomers in man.

Adult↗
PubMed1991

Stereospecific high-performance liquid chromatographic assay of sotalol in plasma.

A convenient high-performance liquid chromatographic (HPLC) assay was developed for determination of sotalol (STL) enantiomers in plasma. Following addition of the internal standard (IS; racemic atenolol), enantiomers of STL and IS were extracted using ethyl acetate. After evaporation of the organic layer, samples were derivatized with a solution of S-(+)-1-(1-naphthyl)ethyl isocyanate (NEIC). The resulting diastereomers were chromatographed with normal-phase HPLC with chloroform:hexane:methanol [65:33:2 (v/v)] as the mobile phase at a flow rate of 2 ml/min. The fluorescence detection wavelength was set at 220 nm for excitation with no emission filter. The suitability of the assay for pharmacokinetic studies was determined by measuring STL enantiomers in the plasma of a healthy subject after administration of a single 160-mg oral, racemic dose of STL.

Adult↗
PubMed1990

Retinal ganglion cell death during regeneration of the frog optic nerve is not accompanied by appreciable cell loss from the inner nuclear layer.

We estimated cell numbers in the ganglion cell and inner nuclear layers of adult frog (Hyla moorei) retinae, examining normal animals and those with regenerated optic nerves. Analysis of sections stained with cresyl violet showed that cell numbers in a nasotemporal strip, which included the area centralis and visual streak, were comparable between sides for both these cellular layers in normal animals. In line with our previous observations, after optic nerve regeneration cell numbers in the ganglion cell layer had fallen by 35-43% compared to the unoperated sides. By contrast cell numbers remained similar for the inner nuclear layers on the two sides. We conclude that retrograde transneuronal degeneration had not taken place in the inner nuclear layer in response to ganglion cell death.

Animals↗
PubMedDate not supplied

Correlation of retinal haemorrhages with brain haemorrhages in children dying of cerebral malaria in Malawi.

Retinal haemorrhages increase in number with severity of Plasmodium falciparum malaria and occur in 35-40% of children with cerebral malaria. We performed clinical retinal examinations and histopathological examinations of retina, and parietal and cerebellar sections of the brains, in 33 children in Malawi who died with cerebral malaria, severe malaria anaemia, or coma of other causes. Haemorrhages were counted in a standardized fashion: the Spearman correlation coefficient between the number of haemorrhages in retina and brain was 0.741 for parietal tissue and 0.703 for cerebellar (P < 0.01 for both). Severity of haemorrhage in the retina correlates well with that in the brain. Retinal examination in cerebral malaria is a useful tool in predicting some of the pathophysiological processes occurring in the brain.

Autopsy↗
PubMedDate not supplied

Solid-phase development of a L-hydroxybenzotriazole linker for heterocycle synthesis using analytical constructs.

The development of a 1-hydroxybenzotriazole linker for the synthesis of heterocyclic derivatives is described, utilizing analytical construct methodology to facilitate the analysis of resin samples. A UV-chromophore-containing analytical construct enabled the accurate determination of resin loading and the automated monitoring of key reactions using only small quantities of resin. The syntheses of an array of isoxazole derivatives are reported.

Journal Article↗