Serum concentration and urinary excretion of ethambutol administered alone and in combination with isoniazid in patients of pulmonary tuberculosis

Ethambutol (20 mg/kg) was administered orally to 10 patients of pulmonary tuberculosis for seven consecutive days at 8 a.m. after over night fast. On 7th day serum levels were measured at 2, 4, 6, 8 and 24 hr intervals and urinary excretion was estimated at 2, 4, 6 and 24 hr following ethambutol administration. Simultaneous administration of isoniazid (300 mg, orally) for next seven days to the same patients significantly raised the serum levels of ethambutol at 4, 6 and 8 hr and the cumulative per cent dose excreted was decreased significantly at 4, 6 and 24 hr. The serum levels and urinary elimination was not significantly different at 2 hr.     

Challenges in containing the burden of hepatitis B infection in dialysis and transplant patients in India

Aim: Whether or not completing the hepatitis B vaccination in patients who have undergone kidney transplantation in the middle of incomplete vaccination schedule leads to development of protective antibody titres is not known. This study was designed to determine whether the strategy of completing hepatitis B virus (HBV) vaccination after transplantation is efficacious. Methods: Sixty‐four end‐stage renal disease (ESRD) patients were screened for hepatitis B surface antigen (HBsAg), antibodies to hepatitis B surface antigen (anti‐HBs), hepatitis B e‐antigen (HBeAg) and HBV DNA. HBsAg negative patients received four doses of 40 µg recombinant HBV vaccine. Schedule was continued in after transplantation period if it was incomplete before transplant. Anti‐Hbs titres were evaluated at 1, 3, 6, 9 and 12 months. Results: Past HBV infection was noted in 12 patients: 10 by serology plus viraemia and two by viraemia alone. Of the 46 patients without current or past HBV infection who had received at least two doses of the vaccine before transplant, 17 each had received two and three doses and 12 had completed the schedule. Seventeen (37%) exhibited protective titres. Patients who had completed vaccination were more likely to have protective titres than those incompletely vaccinated (P = 0.02). Five patients responded to post‐transplant vaccination. Conclusion: Partially vaccinated patients do not mount an adequate antibody response despite continued vaccination in the post‐transplant period, whereas complete vaccination provides protection in 60%. The present study data highlights the need of administration of a full schedule of HBV vaccination before kidney transplantation. Nucleic acid‐based tests can identify occult HBV infection.     

The pediatric hydroxyurea phase III clinical trial (BABY HUG): Challenges of study design

Evidence of the laboratory benefits of hydroxyurea and its clinical efficacy in reducing acute vaso‐occlusive events in adults and children with sickle cell anemia has accumulated for more than 15 years. A definitive clinical trial showing that hydroxyurea can also prevent organ damage might support widespread use of the drug at an early age. BABY HUG is a randomized, double‐blind placebo‐controlled trial to test whether treating young children ages 9–17 months at entry with a liquid preparation of hydroxyurea (20 mg/kg/day for 2 years) can decrease organ damage in the kidneys and spleen by at least 50%. Creation of BABY HUG entailed unique challenges and opportunities. Although protection of brain function might be considered a more compelling endpoint, preservation of spleen and renal function has clinical relevance, and significant treatment effects might be discernable within the mandated sample size of 200. Concerns about unanticipated severe toxicity and burdensome testing and monitoring requirements were addressed in part by an internal Feasibility and Safety Pilot Study, the successful completion of which was required prior to enrolling a larger number of children on the protocol. Concerns over recruitment of potentially vulnerable subjects were allayed by inclusion of a research subject advocate, or ombudsman. Finally, maintenance of blinding of research personnel was aided by inclusion of an unblinded primary endpoint person, charged with transmitting endpoint data and monitoring blood work locally for toxicity (ClinicalTrials.gov number, NCT00006400). Pediatr Blood Cancer 2010;54:250–255. © 2009 Wiley‐Liss, Inc.     

The prevalence and molecular basis of hemoglobinopathies in Cambodia

Blood counts, hemoglobin (Hb) high performance liquid chromatography (HPLC), and DNA analyses were performed on 260 children, aged 5 months to 16 years, at Siem Reap to assess the prevalence of thalassemia and other hemoglobinopathies in regional Cambodia. Hemoglobinopathies were present in 134 children (51.5%) with 20 abnormal genotypes identified. alpha-Thalassemia (thal) (35.4%) was the most prevalent disorder and the -alpha3.7 gene deletion was the most common alpha-globin gene abnormality. The - -SEA deletion and nondeletional forms of alpha-thal, Hb Constant Spring [Hb CS, alpha142, Term-->Gln, TAA-->CAA (alpha2)], Hb Paksé [alpha142, Term-->Tyr, TAA-->TAT (alpha2)] and triplicated alpha genes, were also present but at low frequencies. Hb E [beta26(B8)Glu-->Lys, GAG-->AAG] (28.8%) was the most common beta-globin gene abnormality, whilst beta-thal was only detected in two children (0.8% of cases). Although hemoglobinopathies were common, the majority of abnormalities detected (heterozygous -alpha3.7 and Hb E) were not clinically significant. On the basis of these findings, and with the majority of abnormalities being mild, it seems improbable that thalassemia represents a major health burden in this region of Cambodia.     

Relapse of herpes simplex encephalitis presenting as choreoathetosis

We report a case of herpes simplex virus (HSV) encephalitis (HSE) in an 11-year-old boy who recovered with acyclovir therapy but developed relapse after 2 weeks. Choreoathetosis was the presenting feature of relapse. Response to antiinflammatory treatment was excellent. To the best of our knowledge, this is the first case of HSE relapse presenting with choreoathetosis reported from India. We describe the patient and review the literature on HSE and HSE relapse.     

Metabolic differences between Asian and Caucasian patients on clozapine treatment

OBJECTIVE: To establish if there are ethnic differences in the various metabolic disturbances that are common with clozapine treatment. METHOD: Forty subjects (20 Asians and 20 Caucasians) with a diagnosis of schizophrenia were recruited for the study. Clozapine blood levels as well as fasting blood glucose, lipid levels, and liver function tests were established. Other clinical parameters such as blood pressure and Body Mass Index (BMI) were recorded for each patient. RESULTS: The mean clozapine dose was significantly higher in the Caucasian subjects (432.5+/-194.7 mg) as compared to the Asian subjects (175.6+/-106.9 mg) (p<0.001) while the mean weight-corrected dose for Asian patients was lower (3.0+/-1.9 and 5.0+/-2.1 mg/kg, respectively, p=0.005). There were, however, no ethnic differences in the mean plasma clozapine concentration (415.3+/-185.8 ng/ml in Caucasians and 417.1+/-290.8 ng/ml in Asians). BMI were significantly higher in Caucasians, as were the number of subjects with hypertension; levels of hepatic enzymes were higher in the Asian group. CONCLUSIONS: Not only are there pharmacokinetic differences between Asian and Caucasian patients receiving clozapine, but there may also be differential emergence of certain metabolic abnormalities like hypertension and weight gain in these two ethnic groups. However, the effects of life style including diet and exercise cannot be excluded.     

Pharmacogenetics of CYP1A2, novel polymorphisms and haplotypes in three distinct Asian populations

CYP1A2 play an important role in the metabolism of many carcinogens and clinically important drugs. CYP1A2 activity has been found to be influenced by the presence of polymorphic variants which were reported to display wide interethnic variation. This study investigates the frequency distribution and linkage disequilibrium patterns of CYP1A2 genetic polymorphisms, and characterize their haplotype structures in three healthy Asian populations in Singapore (Chinese, Malay, and Indian). The entire CYP1A2 gene was screened in 126 healthy subjects from all three ethnic groups (N=42 each). A total of 25 polymorphisms was identified, of which nine were novel. The polymorphisms, -2467delT and -163C>A were detected at high frequencies in all Asian ethnic groups. Significant interethnic differences were observed in the genotypic frequency distribution of IVS2-99G>A (P<0.01) and 1548C>T (P=0.05) across the three ethnic groups while -163C>A (P=0.02) was found to differ between Chinese and Malays. Haplotype analyses revealed four to six major haplotypes in each ethnic population which accounted for more than 60% of the cumulative haplotype frequencies. Future studies should be done to investigate the functional roles of these haplotypes.     

Inhibitors of catechol-O-methyltransferase sensitize mice to pain

BACKGROUND AND PURPOSE

Catechol-O-methyltransferase (COMT) inhibitors are used in Parkinson''s disease in which pain is an important symptom. COMT polymorphisms modulate pain and opioid analgesia in humans. In rats, COMT inhibitors have been shown to be pro-nociceptive in acute pain models, but also to attenuate allodynia and hyperalgesia in a model of diabetic neuropathy. Here, we have assessed the effects of acute and repeated administrations of COMT inhibitors on mechanical, thermal and carrageenan-induced nociception in male mice.

EXPERIMENTAL APPROACH

We used single and repeated administration of a peripherally restricted, short-acting (nitecapone) and also a centrally acting (3,5-dinitrocatechol, OR-486) COMT inhibitor. We also tested CGP 28014, an indirect inhibitor of COMT enzyme. Effects of OR-486 on thermal nociception were also studied in COMT deficient mice. Effects on spinal pathways were assessed in rats given intrathecal nitecapone.

KEY RESULTS

After single administration, both nitecapone and OR-486 reduced mechanical nociceptive thresholds and thermal nociceptive latencies (hot plate test) at 2 and 3 h, regardless of their brain penetration. These effects were still present after chronic treatment with COMT inhibitors for 5 days. Intraplantar injection of carrageenan reduced nociceptive latencies and both COMT inhibitors potentiated this reduction without modifying inflammation. CGP 28014 shortened paw flick latencies. OR-486 did not modify hot plate times in Comt gene deficient mice. Intrathecal nitecapone modified neither thermal nor mechanical nociception.

CONCLUSIONS AND IMPLICATIONS

Pro-nociceptive effects of COMT inhibitors were confirmed. The pro-nociceptive effects were primarily mediated via mechanisms acting outside the brain and spinal cord. COMT protein was required for these actions.     

Determination and evaluation of solubility parameter of satranidazole using dioxane-water system

Satranidazole, a potent broad spectrum antiprotozoal, is a poorly water-soluble drug and has low bioavailability on oral administration. One of the important methods to improve the solubility and bioavailability of a less water-soluble drug is by the use of cosolvents. The solubility enhancement produced by binary blends with a cosolvent (dioxane) was studied against the solubility parameter of solvent blends (δ(1)) to evaluate the solubility parameter of drug (δ(2)). Solubility parameter of drug (δ(2)) was evaluated in blends of dioxane-water system. The results obtained were compared with the δ(2) values obtained using Molar Volume Method and Fedor's Group Substitution Method. The binary blend water-dioxane (10:90) gave maximum solubility with an experimental δ(2) value of 11.34 (Cal/cm(3))(0.5) that was comparable to the theoretical values of 11.34 (Cal/cm(3))(0.5) determined by Molar Volume Method and 11.3928 (Cal/cm(3))(0.5) when determined by Fedor's Group Substitution Method, which is in good agreement with solubility measurement method.