Cryptosporidium canis n. sp. from domestic dogs.

Oocysts of Cryptosporidium, from the feces of a naturally infected dog and from an HIV-infected human, were identified as the previously reported canine genotype of Cryptosporidium parvum, hereafter referred to as Cryptosporidium canis n. sp. Also among the oocysts from the dog, a trace amount of C. parvum bovine genotype was detected. Cryptosporidium canis oocysts from both the dog and human were infectious for calves. Oocysts excreted by calf 1 (dog source) were approximately 90% C. canis and 10% C. parvum, whereas those excreted by calf 3 (human source) were 100% C. canis. Oocysts from calf 1 infected calf 2 resulting in excretion by calf 2 of oocysts approximately 90% C. parvum and 10% C. canis. Oocysts of C. canis were not infectious for BALB/c neonatal mice or immunosuppressed C57 juvenile mice, although all control mice became infected with the C. parvum Beltsville isolate. Oocysts of C. canis from calf 1 and the human were structurally indistinguishable from oocysts of the C. parvum Beltsville isolate (bovine). However, C. canis oocysts differed markedly at the molecular level from all known species of Cryptosporidium based on sequence data for the 18S rDNA and the HSP 70 gene. The differences in genetics and host specificity clearly differentiate C. canis as a new species.

Pharmacokinetics of gammahydroxybutyrate (GHB) in narcoleptic patients.

Sodium gammahydroxybutyrate (GHB) is an endogenous compound that has been under investigation in the management of narcolepsy for about two decades. The data confirm that GHB treatment decreases daytime sleepiness and episodes of cataplexy, sleep paralysis, and hypnagogic hallucinations. The current study evaluated the pharmacokinetics of GHB, given twice in one night to six narcoleptic patients who had been chronically taking GHB nightly on a similar basis. Results confirmed earlier reports and showed nonlinear pharmacokinetics. Maximum concentrations were reached in 40 +/- 6.2 and 35.7 +/- 7 minutes after the first and second dose respectively. Mean AUCinf was 17731.6 +/- 4867 mg/mL/m. Mean GHB T1/2 was 53 +/- 19 minutes. GHB elimination appears to be capacity-limited in some patients when administered at a fixed dose of 3 g twice nightly at a 4-hour interval.

Lamotrigine high-dose tolerability and safety in patients with epilepsy: a double-blind, placebo-controlled, eleven-week study.

PURPOSE: This study was undertaken to evaluate the dose tolerability and safety of a chronic ascending twice-daily (b.i.d.) dosage regimen of < or = 700 mg/day lamotrigine (LTG) and to include determination of the LTG pharmacokinetic profile at doses > or = 500 mg/day in patients receiving concomitant enzyme-inducing antiepileptic drugs (AEDs). METHODS: Twelve adult male epileptic patients treated with enzyme-inducing AEDs received < or = 700 mg/day (b.i.d.) oral LTG (n = 8) or placebo (controls, n = 4). For 3 weeks, as outpatients they had their LTG dosage increased from 100 to 400 mg/day. Then, in a clinical research study unit, patients received regimens of 500, 600, and 700 mg/day for 1 week each. Controls received matching placebo in the same sequence. At study end, dosages were tapered in 2 weeks. Follow-up evaluations were made 7 days later. RESULTS: Five LTG patients tolerated 700 mg/day for 1 week. LTG was reduced to 600 mg/day in a patient with mild diplopia and to 500 mg/day in a patient with mild oscillopsia and diplopia. One patient discontinued 300 mg/day therapy with a moderately intense diffuse papular skin rash, attributed to LTG. Headache, drowsiness, faintness, and diplopia, the common adverse events (AEs), were mild to moderate in intensity and occurred in 50-75% of patients in both groups (except for diplopia, occurring only with LTG). Concomitant AED plasma concentrations were not markedly changed by LTG. LTG pharmacokinetics were linear over the range of 500-700 mg/day. CONCLUSIONS: LTG doses < or = 700 mg/day can be tolerated in patients receiving concomitant enzyme-inducing AEDs.

Bidirectional interaction of valproate and lamotrigine in healthy subjects.

OBJECTIVE: To evaluate the steady-state pharmacokinetics of lamotrigine and valproate at three dosing levels of lamotrigine in normal volunteers receiving steady-state therapeutic doses of valproate. METHODS: This was an open-label, randomized, three-way crossover study of 18 normal male volunteers. Subjects received oral valproate (500 mg Depakote twice a day) throughout the study. Each subject subsequently received three oral dosage regimens of lamotrigine (50, 100, or 150 mg/day) for 1 week each, with a 2-week washout period between lamotrigine treatment periods. Valproate and lamotrigine trough plasma samples were determined by a capillary gas chromatography method and immunofluorometric assay, respectively. Urine samples were assayed for 11 valproate metabolites by gas chromatography/mass spectrometry. RESULTS: When compared to other studies in which lamotrigine was administered with no concurrent antiepileptic drug, concomitant valproate markedly increased the half-life of lamotrigine and decreased lamotrigine clearance, without substantial alteration in the linear kinetics of the drug. The addition of lamotrigine was associated with a small but significant 25% decrease in steady-state valproate plasma concentration. Oral clearance of valproate was increased (from 7.2 +/- 1.1 ml/hr/kg before lamotrigine treatment to 9.0 +/- 2.0 ml/hr/kg on day 28; p < 0.05). The formation clearance of the hepatotoxic valproate metabolites, 2-n-propyl-4-pentenoic acid (4-ene-valproate) and 2-propyl-2,4-pentadienoic acid [2(E),4-diene-valproate], was unaffected by lamotrigine administration. CONCLUSIONS: As a consequence of the interaction between lamotrigine and sodium valproate, a dosage reduction of lamotrigine should be considered in patients taking a combination of valproate and lamotrigine.

Pharmacokinetics of mivacurium in normal patients and in those with hepatic or renal failure.

We have determined the pharmacokinetics and duration of action of a bolus dose of mivacurium (0.15 mg kg-1) during isoflurane and nitrous oxide anaesthesia in nine patients with normal renal and liver function, nine patients undergoing cadaveric kidney transplantation and nine patients undergoing cadaveric liver transplantation. Total plasma concentrations of mivacurium were measured for 2.5 h after administration using a high-pressure liquid chromatographic assay. Plasma concentration vs time data for what were presumed to be the two active mivacurium isomers were analysed by a non-compartmental method based on statistical moments. Neuromuscular block was assessed by measuring the electromyographic evoked response of the adductor pollicis muscle to train-of-four stimulation of the ulnar nerve. The mean time to recovery of 25% neuromuscular transmission, T25, was greater in the patients with liver failure (57.2 min) than in control patients (18.7 min). The volume of distribution at steady rate (Vdss) was comparable in the three groups. Patients with impaired liver function had significantly longer mean residence time and smaller plasma clearance than did patients with renal failure or control patients. There were significant negative correlations between plasma cholinesterase activity and both T25 (r = 0.79) and mean residence time (r = 0.62).

Pharmacokinetics and safety of lamotrigine (Lamictal) in patients with epilepsy.

In a double-blind parallel study, patients with epilepsy on stable regimen of antiepileptic drugs (AEDs) were given lamotrigine (8 pts) or placebo (3 pts). Patients were sequentially dosed with 100, 200 and 300 mg/day given as a b.i.d. regimen. After steady state was achieved, timed plasma lamotrigine levels were obtained post dose. No medical, psychogenic, neurologic, or hematologic changes were observed and no subjective effects were detected as a result of treatment with lamotrigine. No changes in heart rhythm or blood pressure were observed related to lamotrigine. Pharmacokinetic parameters were calculated using 1-compartment and non-compartment models. The results were similar using both models. Area under the plasma concentration vs. time curves increased linearly with dose. Mean half life (13.5 h), volume of distribution (1.36 l/kg) and clearance (1.27 ml/min/kg) were similar to previously reported results and did not change with increasing dose. These findings indicate that lamotrigine pharmacokinetics can be described by the 1-compartment model, has linear kinetics, and does not induce its own metabolism in patients on concomitant AEDs.

Pharmacokinetics and pharmacodynamics of doxacurium in normal patients and in those with hepatic or renal failure.

We determined the pharmacokinetics and duration of action of a bolus dose of doxacurium (15 micrograms/kg) in 27 patients anesthetized with isoflurane and nitrous oxide. Nine patients had normal renal and liver functions and were undergoing a variety of surgical procedures, nine were undergoing cadaveric kidney transplantation because of end-stage renal disease, and nine were undergoing cadaveric liver transplantation because of end-stage hepatocellular disease. Plasma concentrations of doxacurium were measured for 6 h after administration using a sensitive and specific capillary gas chromatographic assay. Plasma concentration versus time data were analyzed by a noncompartmental method based on statistical moments. Neuromuscular blockade was assessed by measuring the electromyographic evoked response of the adductor pollicis muscle to train-of-four stimulation of the ulnar nerve. The degree of neuromuscular blockade after doxacurium administration was described as the percent of control of the first train-of-four response. The pharmacokinetic variables were (normal vs hepatic failure vs renal failure, respectively): volume of distribution at steady state (220 +/- 110 vs 290 +/- 60 vs 270 +/- 130 mL/kg [mean +/- SD]), plasma clearance (2.7 +/- 1.6 vs 2.3 +/- 0.4 vs 1.2 +/- 0.7 mL.kg-1.min-1), mean residence time (95.2 +/- 57 vs 129.4 +/- 30 vs 270 +/- 210 min), and elimination half-life (99 +/- 54 vs 115 +/- 31 vs 221 +/- 156 min). Plasma clearance and mean residence time differed significantly between patients with renal failure and control patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and pharmacodynamics of doxacurium in young and elderly patients during isoflurane anesthesia.

Preliminary disposition studies of the investigational, long-acting muscle relaxant doxacurium chloride (Nuromax) have demonstrated dual elimination by renal and hepatobiliary pathways, as well as slow hydrolysis by plasma cholinesterase. The present study compares the kinetics and dynamics of doxacurium in eight ASA physical status I or II elderly patients (67-72 yr of age) and eight ASA I or II young patients (22-49 yr of age). After institutionally approved written informed consent, kinetic and dynamic measurements were made after a 25-micrograms/kg bolus injection of doxacurium during 1.25 MAC nitrous oxide/oxygen/isoflurane anesthesia. Maximum twitch depression was similar in older patients (96.4% +/- 1.3%) to that in the young patients (96.6% +/- 1.8%). The time to achieve this level of block was significantly longer in the elderly than in the young (11.2 +/- 1.1 min versus 7.7 +/- 1.0 min, respectively). Recovery times to twitch heights of 5% and 25% of control tended to be prolonged and were more variable in the elderly (82.6 +/- 17.2 and 97.1 +/- 20.1 min, respectively) than in the young (54.8 +/- 9 and 67.5 +/- 8.2 min, respectively). Elimination half-life (96 +/- 20 min) and clearance (2.47 +/- 0.69 mL.kg-1.min-1) in the elderly patients were not statistically different from values found in the younger group. Volume of distribution at steady state in the elderly (220 +/- 80.2 mL/kg) was significantly larger than in the young (150 +/- 40.0 mL/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Disposition of bupropion in healthy volunteers and subjects with alcoholic liver disease.

Bupropion hydrochloride is a new monocyclic antidepressant. In humans, its disposition results in the formation of three major metabolites: the morpholinol metabolite, the erythroamino alcohol, and the threoamino alcohol metabolite. Bupropion's disposition was monitored following a single oral 200 mg dose in eight healthy volunteers and eight age- (44.5 +/- 8.4 years) and weight- (77.4 +/- 6.7 kg) matched volunteers with alcoholic liver disease. This latter group is of interest because the incidence of depression is more frequent in alcoholics than in the general population, and the liver is the major route of elimination for cyclic antidepressants. The mean elimination half-life of the morpholinol metabolite was significantly prolonged in subjects with alcoholic liver disease (32.2 +/- 13.5 vs. 21.1 +/- 4.9 hours (p less than 0.05), while the differences in bupropion (17.3 +/- 8.6 hours vs. 16.5 +/- 10.4 hours for healthy subjects and subjects with alcoholic liver disease, respectively), erythroamino alcohol (26.1 +/- 13.3 hours vs. 29.8 +/- 6.9 hours for healthy subjects and subjects with alcoholic liver disease, respectively), and threoamino alcohol (25.5 +/- 8.6 hours vs. 23.4 +/- 10.7 hours for healthy subjects and subjects with alcoholic liver disease, respectively) were minimal. Mean area under the plasma concentration time curves for bupropion and metabolites were increased in subjects with alcoholic liver disease; however, clear differences between means of these small groups did not emerge, probably due to the increased variability of bupropion pharmacokinetics in these subjects. As a therapeutic agent for the treatment of depression in chronic alcoholics who may consume alcohol in combination with their antidepressant therapy, the lack of sedation with bupropion could be advantageous.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological significance of the species differences in bupropion metabolism.

Bupropion provided a dose-dependent prevention of tetrabenazine-induced sedation in mice but not rats. Bupropion was extensively metabolized in mice, rats, dogs and man. About 85% of the dose was excreted in urine of rats and man. The predominant metabolites in rat urine were side chain cleavage products of bupropion (m-chlorobenzoic acid) with a minor fraction consisting of basic side chain hydroxylated metabolites. Mice, dogs and man form a major side chain hydroxylated product (BW 306U) which appeared in higher concentration than bupropion in plasma of these species but not rats. The relatively high plasma levels of BW 306U in mice but not rats may account for the species difference in pharmacological response observed with bupropion.