Enantioselective disposition of hydroxychloroquine after a single oral dose of the racemate to healthy subjects.

1. Stereoselectivity in the disposition of hydroxychloroquine was investigated in 23 healthy males following a single oral dose of 200 mg racemic HCQ (rac-HCQ) sulphate. Total concentrations (R+S) and R/S ratios of HCQ and its metabolites were measured by stereoselective h.p.l.c. 2. HCQ was detected in whole blood and urine, up to 91 and 85 days after dosing, respectively. Metabolites could not be detected in whole blood while in urine detectable concentrations were still present after 85 days. The blood concentrations of HCQ enantiomers were measurable until 168 h post-dose. 3. R(-)-HCQ accounted for 62 +/- 3% (mean +/- s.d.) of the AUC of rac-HCQ AUC. The elimination half-life of S(+)-HCQ (457 +/- 122 h) was significantly shorter than that of R(-)-HCQ (526 +/- 140 h), partly due to its faster urinary excretion and hepatic metabolism. Its renal clearance was twice that of R(-)-HCQ (4.61 +/- 4.01 vs 1.79 +/- 1.30 1 h-1), and metabolites derived from the S-isomer represented 80-90% of the urinary recovery of the dose. 4. Over 85 days, 4.4 +/- 2.9 and 3.3 +/- 1.8% of the dose was recovered in urine as unchanged S(+)-HCQ and R(-)-HCQ, respectively. For the first 2 weeks, S(+)-HCQ excretion rate clearly surpassed that of R(-)-HCQ whereas afterwards the inverse was observed. However, since the first 2 weeks account for 95% of rac-HCQ renal excretion, the total urinary excretion of S(+)-HCQ clearly surpassed that of R(-)-HCQ.(ABSTRACT TRUNCATED AT 250 WORDS)

Distribution of the enantiomers of hydroxychloroquine and its metabolites in ocular tissues of the rabbit after oral administration of racemic-hydroxychloroquine.

The disposition of the enantiomers of hydroxychloroquine (HCQ) and its major metabolites in ocular tissues of rabbits has been studied. Both albino, New Zealand White (NZW), and pigmented animals were administered daily oral doses of rac-HCQ, (S)-HCQ or (R)-HCQ (20 mg/kg) over 1, 6, or 8 day periods or for 8 days followed by a 7-day washout period. At the end of the study periods, plasma and whole blood samples were collected and the rabbits were sacrificed. The eyes were collected, the aqueous humor removed with a syringe, and the eyes separated into the cornea, lens, vitreous body, iris, choroid-retina, sclera, and conjunctiva. The concentrations of (R)-HCQ, (S)-HCQ, and their respective metabolites were determined using a validated enantioselective liquid chromatographic assay. The data from these studies indicate that HCQ accumulated in both pigmented and nonpigmented ocular tissues. In the pigmented tissues, HCQ and its metabolites were bound to melanin and the binding was not enantiospecific. In the nonpigmented tissues and in the iris and retina-choroid of the NZW rabbits, the accumulation appeared to be the result of a reversible and enantioselective binding of HCQ and its metabolites to an unidentified biopolymer present in these ocular tissues.

Direct analysis of the enantiomers of mexiletine and its metabolites in plasma and urine using an HPLC-CSP.

A high-performance liquid chromatographic assay has been developed for the quantification of the enantiomers of mexiletine and its four major metabolites, in plasma and in urine. Mexiletine and all metabolites were determined, after derivatization of mexiletine and its hydroxymetabolites, p-hydroxymexiletine and hydroxymethylmexiletine, using a Chiralpak AD chiral stationary phase, based on a carbamoyl derivative of amylose. o-phthalaldehyde was chosen as derivatization reagent to increase the sensitivity of detection, to achieve separation of all compounds in one chromatographic system, and to avoid interferences.

Determination of the stereoisomers of hydroxychloroquine and its major metabolites in plasma and urine following a single oral administration of racemic hydroxychloroquine.

Plaquenil (hydroxychloroquine, HCQ; Sanofi Winthrop Pharmaceuticals, New York, NY) is a stereoisomeric drug administered as a racemic (50: 50) mixture of two isomeric forms--(+) and (-) HCQ. To correlate clinical efficiency accurately with dose, it is necessary to determine the fate of both isomers. This will allow for the optimization of clinical dosing. A method has been developed for the quantitation of (+) and (-) HCQ and its major metabolites, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bisdesethylchloroquine (BDCQ), in plasma and in urine. Application of this method in a preliminary study in four human volunteers is reported. After a single oral dose of 200 mg of Plaquenil, the average enantiomeric ratio of (+) to (-) HCQ was approximately 1 over an 8-hour period. However, the average cumulative 48-hour excretion of HCQ, DHCQ, and DCQ showed stereoselective excretion.

Enantioselective determination of hydroxychloroquine and its major metabolites in urine and the observation of a reversal in the (+)/(-)-hydroxychloroquine ratio.

A sequential achiral-chiral high-performance liquid chromatographic system has been developed for the quantitation in urine of the enantiomers of hydroxychloroquine (HCQ), and of its 3 major metabolites, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bisdesethylchloroquine (BDCQ). HCQ and its metabolites were separated and quantified on a cyano-bonded phase, and the enantiomeric ratios were determined using a Chiral-AGP chiral stationary phase. The assay validation and application of this method to a preliminary study in a human volunteer are presented. In this subject, the initial 0-4 h urine contained the 2 HCQ enantiomers in a ratio of (+)-HCQ:(-)-HCQ of 3:2; by the 2,064 h of the study, this ratio had reversed to (+)-HCQ:(-)-HCQ of 3:7.

Direct determination of the enantiomeric ratio of verapamil, its major metabolite norverapamil and gallopamil in plasma by chiral high-performance liquid chromatography.

Two methods for the determination of the enantiomeric ratio of verapamil in plasma by high-performance liquid chromatography have been developed. On an alpha 1-acid glycoprotein chiral stationary phase (Chiral-AGP) verapamil was separated after the acetylation of the main metabolite norverapamil, which interferes with the resolution of verapamil. On an amylose tris-3,5-dimethylphenylcarbamate column (Chiralpak AD) verapamil and norverapamil were determined simultaneously without prior derivatization. Gallopamil was separated on both columns under similar conditions.

Cardiopulmonary bypass, profound hypothermia, and circulatory arrest for neurosurgery.

Six female and 4 male patients (age, 23 to 75 years) underwent operation for difficult intracranial lesions. Preoperative diagnoses included four giant intracranial aneurysms, three base of skull glomus jugulare tumors, two arteriovenous malformations, and one cerebellar hemangioblastoma. All lesions were inoperable or nearly so by standard neurosurgical techniques. All patients were placed on total bypass via groin cannulations. Bypass times ranged from 111 to 269 minutes (mean, 174 minutes) with cooling times of 26 to 83 minutes (mean, 48 minutes) and warming times of 68 to 110 minutes (mean, 83 minutes). Circulatory arrest times ranged from 1.25 to 60 minutes with 1 patient not requiring arrest. The lowest core temperatures recorded varied from 8.4 degrees to 13.7 degrees C. There was one postoperative death and one major complication, both in patients with arteriovenous malformations. Eight patients (80%) have achieved an excellent result. Profound hypothermia with the option of circulatory arrest and exsanguination has been an indispensable adjunct to the safe management of intracranial aneurysm, glomus jugulare tumor, and hemangioblastoma.

Arachnoid cyst producing recurrent neurological disturbances.

A patient with an arachnoid cyst of the posteriro fossa experienced repeated episodes of transient right upper extremity numbness and weakness. Review of the literature indicates that arachnoid cysts of the posterior fossa and spinal canal as well as extradural spinal cysts may present with symptoms of transient neurological deficit which often suggest the diagnosis of multiple sclerosis.

Duplication-deficiency of the short arm of chromosome 8 following artificial insemination.

A chromosomally abnormal child with psychomotor retardation and multiple anomalies, including agenesis of the corpus callosum and cleft palate, was born following artificial insemination by donor. Chromosomal and conventional markers were used to ascertain paternity. Various banding techniques were employed to identify the origin of the extra chromosomal material as most likely a duplication-deficiency of the short arm of chromosome No. 8.

PIP: A case study of a chromosomally abnormal child, conceived through artificial insemination, with psychomotor retardation and multiple anomalies, including agenesis of the corpus callosum and cleft palate, is reported. Paternity was established through chromosomal and conventional markers. Various banding techniques were used to determine the origin of the extra chromosome. It is likely that the extra chromosomal material was the result of a duplication-deficiency of the short arm of chromosome No. 8.