Paul J. Schechter

Pharmacokinetics of tacrolimus in liver transplant patients

To characterize the pharmacokinetics of the immunosuppressive agent tacrolimus (FK 506) in liver transplant patients.

Biochemical and clinical effects of γ‐vinyl GABA in patients with epilepsy

Article abstract-In a pilot single-blind study, γ-vinyl GABA, an enzyme-activated irreversible inhibitor of GABA-transaminase (GABA-T), was administered orally to 10 epileptic patients who were refractory to conventional anticonvulsant therapy. Daily doses of 1 g and 2 g for 2 weeks each as add-on therapy were followed by 2 weeks of placebo treatment. CSF obtained from suboccipital and lumbar punctures demonstrated dose-related increases in concentrations of free and total GABA and homocarnosine with treatment, but no changes in 5-hydroxyindoleacetic acid or homovanillic acid levels, indicating effective and selective CNS GABA-T inhibition. These biochemical changes were associated with decreased seizure frequency in seven patients, decreased seizure severity in one, no change in one, and possible worsening in one. γ-Vinyl GABA may be useful in the therapy of epilepsy.

Increased gamma-aminobutyric acid (GABA), homocarnosine and β-alanine in cerebrospinal fluid of patients treated with γ-vinyl GABA (4-amino-hex-5-enoic acid)

Abstract γ-Vinyl GABA, an enzyme-activated irreversible inhibitor of GABA transaminase (GABA-T), was administered orally to 15 patients with various neurological conditions at daily doses of 0.5, 1, 2 or 6 g/day for 3 days. CSF samples were obtained by lumbar puncture before treatment and within 24 hours after the last dose and the CSF concentrations of free GABA, total GABA, homocarnosine, β-alanine and γ-vinyl GABA determined by ion-exchange chromatography with fluorometric detection. γ-Vinyl GABA treatment produced dose-dependent increases in free GABA, conjugated GABA (defined as total minus free GABA), homocarnosine and β-alanine. The concentrations of CSF γ-vinyl GABA also depended on the dose administered. These results indicate that γ-vinyl GABA enters the CNS after oral administration and alters GABA metabolism by inhibition of GABA-T and suggest that such treatment may achieve therapeutic benefit in conditions where such neurochemical alterations are desirable.

Abnormalities of taste and smell after head trauma

Abnormalities of taste and smell were studied in 29 patients after head trauma. These abnormalities included decreased taste acuity (hypogeusia), a distortion of taste acuity (dysgeusia), decreased smell acuity (hyposmia), and a distortion of smell acuity (dysosmia). This syndrome can occur even after minimal head trauma and can begin months after the moment of injury. The patients exhibited a significant decrease in total serum zinc concentration (patients, 77 ± 3 μg/100 ml, mean ± 1 SEM, vs controls, 99 ± 2 μg/100 ml, P>0·001) and a significant increase in total serum copper concentrations (113 ± 4 μg/100 ml vs 100 ± 2 μg/100 ml, P<0·001) compared with control subjects. Symptoms of hypogeusia, dysgeusia, and dysosmia are frequent sequelae of head injury and are important to the patients and to their care after trauma.

Kinetics of the enantiomers of vigabatrin after an oral dose of the racemate or the active S‐enantiomer

Six healthy men received single oral doses of 1500 mg of vigabatrin [(R,S)‐γ‐vinyl‐GABA] and 750 mg of S(+)‐γ‐vinyl‐GABA on two occasions. Concentrations of the individual enantiomers were assayed by a stereoselective procedure based on combined GC/MS. At peak, concentrations of the R(−)‐enantiomer exceeded concentrations of the S(+)‐enantiomer, with an approximate ratio of 2:1. The mean terminal t½ ranged from 6 to 8 hours for both enantiomers. Mean urinary recovery of the S(+)‐enantiomer was 49% after both doses and was 65% for the R(—)‐enantiomer. Plasma concentration values obtained for the S(+)‐enantiomer after a dose of the pure S(+)‐enantiomer and an equivalent dose of the racemate showed good agreement for both the concentrations observed at any time point and the elimination characteristics, demonstrating bioequivalence. Renal clearance values for the S(+)‐enantiomer are not affected by concomitant dosing with the pharmacologically inactive R(−)‐enantiomer. No chiral inversion was detected after dosing with the pure S(+)‐enantiomer.

IDIOPATHIC HYPOGEUSIA: A DESCRIPTION OF THE SYNDROME AND A SINGLE-BLIND STUDY WITH ZINC SULFATE

Publisher Summary This chapter describes dysgeusia as any distortion of normal taste perception and describes cacogeusia as the abhorrent, obnoxious taste produced by the introduction and/or mastication of food in the oral cavity. Phantogeusia is the intermittent or persistent salty, sweet, sour, bitter, or metallic taste perceived in the oral cavity independent of any external stimuli, while heterogeusia is an inappropriate taste quality of consistent nature associated with the presence and/or mastication of specific items of food and drink. Dysosmia may be manifested in several different ways, including cacosmia, phantosmia, and heterosmia. Cacosmia is a term used to describe the abhorrent, obnoxious smell produced by the inhalation of odorants. Phantosmia is a term used to describe the intermittent or persistent odor that is perceived when no odorant was inhaled. Heterosmia is an inappropriate smell of consistent nature associated with specific odorants.

Kinetics of α‐difluoromethylornithine: An irreversible inhibitor of ornithine decarboxylase

We gave α‐difluoromethylornithine (DFMO), a selective, irreversible inhibitor of ornithine decarboxylase, to six healthy men in single intravenous doses of 5 and 10 mg/kg body weight and oral doses of 10 and 20 mg/kg. Plasma concentrations were monitored during the 24 hr after each dose. Urine was collected from 0 to 24 hr after drug and amount of unchanged drug excreted was determined. Peak plasma concentrations were reached within 6 hr after oral doses. The decay of the plasma concentrations followed first‐order kinetics with a mean half‐life (t½) for all four doses studied of 199 ± 6 min (±SD). Mean total body clearance (ClT) for the four doses was 1.20 ± 0.06 ml · min−1 · kg−1. Mean renal clearance was determined as 0.99 ± 0.03 ml · min−1 · kg−1, accounting for 83% of drug elimination. Mean apparent volume of distribution (aVD) was 0.337 ± 0.031 l/kg−1, corresponding to 24 l for 70 kg of body weight. The amount of unchanged drug in 24‐hr urine samples was 47 ± 7% and 40 ± 11% after 10 and 20 mglkg orally, and 78% and 81 ± 8% after 5 and 10 mglkg intravenously. Bioavailability of the 10 mg/kg dose was estimated as 58% from the urinary recoveries and as 54% from the areas under the plasma concentration curves (AUC0→∞). Since doubling of the dose resulted in a doubling of the mean AUC0→∞ and since other kinetic parameters, such as aVD, t½, ClT, and the urinary recovery of unchanged drug, were essentially the same at all doses, DFMO kinetics follow a dose‐linear model.

Effects of single doses of vigabatrin on CSF concentrations of GABA, homocarnosine, homovanillic acid and 5-hydroxyindoleacetic acid in patients with complex partial epilepsy

Vigabatrin, as a single oral dose of 50 mg/kg, was administered to 11 patients with drug-refractory complex partial epilepsy. Serial lumbar punctures were performed prior to and 5 times within the first week following treatment. Cerebrospinal fluid (CSF) concentrations of total GABA, free GABA, homocarnosine, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and vigabatrin were determined as well as blood vigabatrin levels. CSF GABA, homocarnosine, HVA and 5-HIAA concentrations increased by 6 h after the single dose and remained elevated for up to 5-7 days. In contrast, CSF and blood vigabatrin levels were maximal within the first 24 h and were no longer detectable thereafter. Hence, these results are consistent with vigabatrin acting as an irreversible inhibitor of GABA-transaminase and suggest that it may also increase biogenic amine turnover.

Pharmacokinetics of vigabatrin: implications of creatinine clearance.

The pharmacokinetics of both enantiomers of vigabatrin after a single oral dose in healthy young subjects (mean creatinine clearance 120 ml/min) were compared with kinetics in two groups of elderly subjects, one group aged 60 to 75 years (mean creatinine clearance 86 ml/min) and one group aged 76 to 97 years (mean creatinine clearance 30 ml/min). At a dose of 1500 mg, the group with the eldest subjects and the lowest creatinine clearance values showed mean increases of 3.3‐fold in the time to reach the maximum concentration, 2.7‐fold in the maximum concentration, and 9.8‐fold in the AUC; a twofold prolongation of the t½; and reduced urinary excretion of the biologically and pharmacologically active S(+)‐enantiomer. Changes in the intermediate group were qualitatively similar but quantitatively less. Parallel observations were made for the inactive R(−)‐enantiomer. Most of these changes can be related to decreased renal clearance of vigabatrin. No interference of either enantiomer in the renal clearance of the other was noted. A nonlinear relationship between renal clearance and creatinine clearance for both enantiomers is suggested. Knowledge of the patients renal function and an appropriate dose adjustment will minimize side effects during vigabatrin therapy, especially in elderly patients.

Preference for NaCl in the spontaneously hypertensive rats

Abstract When given free choice between NaCl and water, spontaneous hypertensive (SH) rats exhibited an increased preference for NaCl (0.15 M and 0.30 M) when compared to either Holtzman or Wistar normotensive controls. Similarly, total fluid intake (NaCl and water) was increased in the SH rats compared to Holtzman or Wistar controls. These results are the first to demonstrate a sustained spontaneously increased NaCl preference in a hypertensive rat.