Effects of the antimigraine compound zolmitriptan ('Zomig') on psychomotor performance alone and in combination with diazepam in healthy volunteers

Zolmitriptan (Zomig^TM) is a 5HT_1B/1D agonist which has the ability to cross the intact blood-brain barrier to access central as well as peripheral receptors. Because of the potential for central nervous system side effects, this randomized, double-blind, placebo-controlled, 6-period crossover study evaluated the effects of 2.5 and 5 mg doses of zolmitriptan on psychomotor performance and investigated any pharmacodynamic or pharmacokinetic interaction with diazepam. Twelve healthy volunteers received the following "treatments" as single doses: zolmitriptan 2.5 mg, zolmitriptan 5 mg, diazepam 10 mg, zolmitriptan 2.5 mg+diazepam 10 mg, zolmitriptan 5 mg+diazepam 10 mg and placebo. Pre-dose and at 1, 4, 8, and 24 h post-dose, the following validated battery of psychomotor tests was performed: Bond-Lader visual analogue scales (calmness, contentedness, and alertness factors), critical flicker fusion test, choice reaction time (recognition, motor, and total reaction times), finger-tapping test, number cancellation test and digit symbol substitution test. Plasma concentrations of zolmitriptan, its active metabolite, and diazepam and its active metabolites were measured at the same timepoints. Zolmitriptan 2.5 and 5 mg had no effect on psychomotor function when given alone. In contrast, diazepam 10 mg had profound effects, consistent with its sedative properties, but there was no synergism on concomitant administration of either dose of zolmitriptan. Plasma concentrations of zolmitriptan, diazepam, and their respective active metabolites were similar when the two drugs were given alone or in combination.     

Association between chronic hepatitis B virus infection and diabetes among Asian Americans and Pacific Islanders

BACKGROUND: Asians have a higher prevalence of both diabetes (diabetes mellitus) and chronic hepatitis B virus infection compared to Caucasians. The aim of this study was to investigate whether hepatitis B virus infection was associated with diabetes mellitus among Asian Americans and Pacific Islanders. METHODS: We reviewed the electronic medical records of 411 Asian and 424 Pacific Islanders seen at our medical centre over a 5-year period. Diabetes mellitus was defined by the presence of two or more random blood glucose levels > or =200mg/dL, an ICD-9 diagnostic code of diabetes mellitus, or use of medications for diabetes mellitus. Hepatitis B virus infection was defined by a positive HBsAg test. RESULTS: Diabetes mellitus was diagnosed in 223 of the 835 subjects (26.7%), whereas hepatitis B virus infection was diagnosed in 56 (13.8%) of the 407 subjects tested for HBsAg. Overall, the prevalence of diabetes mellitus was significantly higher in patients with hepatitis B virus than in those without hepatitis B virus (58.9% vs. 33.3%, P<0.001), and this remained significant after adjustment for potential confounding variables (OR=3.17; 95% CI, 1.58-6.35). When Asians and Pacific Islanders were analysed separately, the prevalence of diabetes mellitus in patients with hepatitis B virus was significantly higher than in those without hepatitis B virus among Asians (65.0% vs. 27.5%, P<0.001) but not in Pacific Islanders (43.8% vs. 37.1%, P=0.60). Among the 390 subjects who were tested for both hepatitis B virus and hepatitis C virus, the prevalence of diabetes mellitus was 29.4% in uninfected subjects, 44.4% in patients with hepatitis B virus monoinfection, 47.2% in patients with hepatitis C virus monoinfection and 85.0% in patients with hepatitis B virus and hepatitis C virus coinfection (P<0.001). CONCLUSIONS: Hepatitis B virus infection is strongly associated with diabetes mellitus among Asian Americans, but not in Pacific Islanders, whereas hepatitis C virus infection was associated with diabetes mellitus in both ethnic groups.     

Indapamide inhibits endothelium-dependent contractions in the aorta of the spontaneously hypertensive rat

Summary— Experiments were designed to determine whether or not indapamide, an antihypertensive agent with vasodilator properties, inhibits endothelium-dependent contractions. Rings of aortae with and without endothelium from spontaneously hypertensive rats (SHR) were suspended in conventional organ chambers for the measurement of isometric force. Acetylcholine and adenosine diphosphate-β-S in the presence of a nitric oxide synthase inhibitor, caused endothelium-dependent contractions, which were inhibited by indapamide. The compound (10⁻⁴M) also slightly reduced the contractions of rings without endothelium evoked by U-46,619, which activates thromboxane-endoperoxide receptors. These results demonstrate that indapamide inhibits endothelium-dependent contractions in the SHR aorta, and suggest that the inhibition is due, at least in part, to the action of the drug on the hypertensive vascular smooth muscle.     

Needle biopsy of renal allografts: comparison of two techniques

Two techniques for renal allograft biopsy were retrospectively evaluated to compare relative safety and efficacy. After ultrasound (US) localization of the kidney and biopsy with a hand-held 14-gauge cutting needle, an adequate specimen was obtained in 74 of 77 cases (96%). Major complications occurred in six of these 77 cases (8%). One hundred four biopsies were performed by using a smaller 18-gauge cutting needle with a spring-loaded biopsy "gun" and real-time US guidance. With this newer technique, specimens adequate for diagnosis were obtained in 99 biopsies (95%). There was a single major complication with this technique (1%). The 18-gauge needle with real-time US guidance yields comparably adequate specimens with a lower frequency of complications.     

Pharmacokinetics and protein binding of intravenous ibuprofen in the premature newborn infant

The elimination, disposition and protein binding of ibuprofen (IBU) in premature infants were studied for use in the prevention of intraventricular hemorrhage and closure of patent ductus arteriosus. The kinetic profile of i.v. IBU lysine (10 mg/kg bolus) given within the first 3 h after birth was studied in 21 premature neonates (mean birthweight = 944.7 g, range: 575–1450 g; gestational age: 26.8 weeks, range: 22–31 weeks). Blood samples (0.3 ml/sample) were obtained at time 0 and at 1, 3, 6, 12, 24, 48, and 72 h post-dose for IBU by high-performance liquid chromatography (HPLC). Kinetic analyses assumed applicability of one open-compartment model and calculations from the model-independent areas under the time concentration curve (AUC). Data (mean ± SEM) show that apparent volume of distribution (AVd) was 62.1 ± 3.9 ml/kg, plasma t _1/2 beta was 30.5 ± 4.2 h, elimination rate constant (k_el) was 0.032 ± 0.004 h^-1plasma clearance was 2.06 ± 0.33 ml/kg/h and plasma concentration (Cp) at 1 h was 180.6 ±11.1 mg/1. Gestational age and birthweight were not related to drug elimination. In 10 neonates, IBU maintenance dose of 5 mg/kg once daily on days 2 and 3 generated mean Cp of 116.6 ± 54.5 mg/1 and 113.6 ± 58.2mg/1, respectively. Protein binding by ultrafiltration and capillary electrophoresis showed that the percentage bound IBU was significantly lower in full term cord plasma (94.98 ± 0.39%, n = 26) compared to adult plasma protein (mean ± SE = 98.73 ± 0.31%, n = 8, p < 0.0001). Compared to data from adults and older children, IBU elimination is markedly prolonged in neonates and protein binding is slightly lower. Thus, investigational and clinical therapeutic regimens should be adjusted to account for decreased drug disposition to ensure safe and effective therapy.     

Screening for medium chain acyl-CoA dehydrogenase deficiency using electrospray ionisation tandem mass spectrometry

OBJECTIVE: To establish criteria for the diagnosis of medium chain acyl-CoA dehydrogenase (MCAD) deficiency in the UK population using a method in which carnitine species eluted from blood spots are butylated and analysed by electrospray ionisation tandem mass spectrometry (ESI-MS/MS). DESIGN: Four groups were studied: (1) 35 children, aged 4 days to 16.2 years, with proven MCAD deficiency (mostly homozygous for the A985G mutation, none receiving carnitine supplements); (2) 2168 control children; (3) 482 neonates; and (4) 15 MCAD heterozygotes. RESULTS: All patients with MCAD deficiency had an octanoylcarnitine concentration ([C8-Cn]) > 0.38 microM and no accumulation of carnitine species > C10 or < C6. Among the patients with MCAD deficiency, the [C8-Cn] was significantly lower in children > 10 weeks old and in children with carnitine depletion (free carnitine < 20 microM). Neonatal blood spots from patients with MCAD deficiency had a [C8-Cn] > 1.5 microM, whereas in heterozygotes and other normal neonates the [C8-Cn] was < 1.0 microM. In contrast, the blood spot [C8-Cn] in eight of 27 patients with MCAD deficiency > 10 weeks old fell within the same range as five of 15 MCAD heterozygotes (0.38-1.0 microM). However, the free carnitine concentrations were reduced (< 20 microM) in the patients with MCAD deficiency but normal in the heterozygotes. CONCLUSIONS: Criteria for the diagnosis of MCAD deficiency using ESI-MS/MS must take account of age and carnitine depletion. If screening is undertaken at 7-10 days, the number of false positive and negative results should be negligible. Because there have been no instances of death or neurological damage following diagnosis of MCAD deficiency in our patient group, a strong case can be made for neonatal screening for MCAD deficiency in the UK.