Involvement of intracellular calcium stores in Giardia lamblia induced diarrhoea in mice

The transmucosal fluxes of Na+ and Cl- were studied in Giardia lamblia-infected mice in the presence of absence of dantrolene (1-(5(p-nitrophenyl)furfurilidene-amino) hydantoinsodiumhydrate). There was net secretion of Na+ and Cl- in infected animals, while in control animals there was net absorption of these ions. The addition of dantrolene resulted in significant net increase in absorption of Na+ and Cl- in control and experimental groups. Further, mouse intestinal epithelial cells were labelled with [32P]Pi and then treated with G. lamblia trophozoites and their excretory secretory products separately. The optimum time for inositol triphosphate formation was 15 min in control enterocytes as well as in treated enterocytes. A plateau was formed at higher concentrations. Since raised inositol triphosphate levels mobilize Ca2+ from intracellular stores and dantrolene traps Ca2+ within intracellular calcium stores, the present study thus suggests that intracellular calcium stores are involved in G. lamblia-induced diarrhoea in mice

Low dose lopinavir/ritonavir tablet achieves adequate pharmacokinetic parameters in HIV-infected Thai adolescents.

Item does not contain fulltextBACKGROUND: Lopinavir/ritonavir (LPV/r) is an effective and commonly used protease inhibitor in HIV-infected adolescents. Previous data showed high plasma concentrations of LPV in Thai patients. This study determined the pharmacokinetic (PK) parameters of a low-dose LPV/r tablet (70% of standard dose) in HIV-infected Thai adolescents. METHODS: A total of 24 adolescents on LPV/r-containing HAART regimens with HIV RNA35 kg, respectively. On the fourth week of treatment, PK was performed for all doses at 0 (pre-dose), 2, 4, 6, 8, 10 and 12 h. LPV and ritonavir concentrations were measured using the HPLC method. RESULTS: The median (IQR) age was 13.5 (12-15) years. The median LPV doses of standard and low doses were 290 and 208 mg/m(2). The mean (sd) area under the concentration-time curve at 0-12 h, maximum concentration and plasma concentration at 12 h for the standard dose were 97.6 (25.7) mg*h/l, 11.1 (2.6) mg/l and 4.1 (2.0) mg/l, and for the low dose were 87.4 (29.0) mg*h/l, 11.0 (3.1) mg/l and 3.2 (1.9) mg/l, respectively. No significant differences were detected between the groups. One child had plasma concentration at 12 h <1.0 mg/l while on low-dose LPV/r but HIV RNA was undetectable. CONCLUSIONS: The low-dose LPV/r tablet provides adequate PK parameters in HIV-infected Thai adolescents. A randomized study to assess the efficacy of low and standard doses of LPV/r among Thai HIV-infected adolescents should be explored

Plasma concentrations of generic lopinavir/ritonavir in HIV type-1-infected individuals.

Contains fulltext : 81956.pdf (publisher's version ) (Closed access)BACKGROUND: Generic drugs can contribute to access to treatment for HIV-infected patients. However quality and safety remains an issue of concern. Therefore, we evaluated minimal plasma concentrations and short-term safety of a generic lopinavir/ritonavir 200/50 mg tablet formulation. METHODS: In a single-centre prospective pilot study, patients receiving protease-inhibitor-based antiretroviral treatment were switched to a generic lopinavir/ritonavir tablet at the standard dose (400/100 mg twice daily). Minimum drug concentrations (C(min)) of lopinavir and ritonavir were performed before switching (in 16 patients who were on Kaletra((R)) soft-gel capsules) and after 4 weeks (in all patients). Plasma levels of lopinavir and ritonavir were determined by a validated HPLC method. Either the Wilcoxon signed-rank or Mann-Whitney U test was used to compare the groups. RESULTS: A total of 37 patients (18 females) were included in the study. Two stopped their study medications prematurely because of intolerance. The median (interquartile range) lopinavir C(min) was 7.2 mg/l (5.8-8.3) and no patients had subtherapeutic levels <1.0 mg/l. No significant difference of lopinavir C(min) levels was found between Kaletra((R)), and the generic product (P=0.224). By contrast, the C(min) of generic ritonavir was higher (P=0.012). Food did not affect the drug levels. Mild gastrointestinal complaints were reported in 12 patients. CONCLUSIONS: The generic lopinavir/ritonavir tablet showed C(min) plasma concentrations similar to what is described for the branded product, with good stability, independent of food intake. These data support the efforts in scaling up access to generic second-line treatment in middle- and low-income countries

Pharmacokinetics and 48-week efficacy of nevirapine: 400 mg versus 600 mg per day in HIV-tuberculosis coinfection receiving rifampicin.

Item does not contain fulltextBACKGROUND: We aim here to determine the appropriate dose of nevirapine (NVP) in Thai HIV-tuberculosis (TB)-coinfected patients receiving rifampicin. METHODS: Thirty-two HIV-infected adults with CD4+ T-cell counts <200 cells/mm3 and active TB, receiving rifampicin for 2-6 weeks were randomized to receive either NVP 400 mg (NVP400) or 600 mg (NVP600) per day plus two nucleoside reverse transcriptase inhibitors; a 2-week NVP lead-in was performed at 200 mg once daily (OD) and 200 mg twice daily, respectively. Plasma NVP levels were determined at weeks 2, 4 and 12. Twelve-hour pharmacokinetics (PK) were obtained (n=20) at week 4. RESULTS: Baseline body weight was comparable. There were more patients with NVP plasma concentration at 12 h (C12) <3.1 mg/l at week 2 in NVP400 than in NVP600 (79% versus 19%, respectively; P=0.002). However, the proportions were comparable at weeks 4 and 12. From week 4, 12 h PK studies showed that NVP400 had lower median NVP area under the plasma concentration-0-12 h (AUC0-12 h, maximum concentration in plasma (Cmax) and C12 than NVP600 (P<0.05). Four patients in NVP600 developed NVP hypersensitivity. At week 48, the median CD4+ T-cell count rise and proportion with viral load <50 copies/ml (intention-to-treat analysis 56% versus 50% and as-treated analysis 75% versus 89%) were comparable. CONCLUSIONS: In rifampicin-treated patients, 200 mg NVP OD lead-in led to a significant short-term suboptimal NVP C12 level, while NVP 400 mg lead-in then 600 mg/day was associated with a high rate of NVP hypersensitivity. Forty-eight week efficacy was comparable. Thus, NVP 600 mg/day in rifampicin-treated patients is not recommended

Pharmacokinetics and 48 week efficacy of low-dose lopinavir/ritonavir in HIV-infected children.

Contains fulltext : 79493.pdf (publisher's version ) (Closed access)BACKGROUND: Lopinavir/ritonavir is a common protease inhibitor (PI) used for second-line regimens in children. Several studies have shown higher plasma concentrations of antiretroviral agents in Thai adults than in Caucasians, suggesting that lower doses may be used. METHODS: An open label study in 24 HIV-infected children between the age of 2 and 18 years, naive to PIs, randomized to receive either the WHO-recommended dose of lopinavir/ritonavir or a low dose (70% of the standard dose) twice daily in combination with zidovudine and lamivudine. A 12 h pharmacokinetic study was done at 4-6 weeks after starting treatment. Treatment outcomes were evaluated at week 48. The clinical trial number of the study is NCT00887120. RESULTS: The medians [interquartile ranges (IQRs)] of age, body surface area, percentage CD4 and plasma HIV RNA were 9.5 years (7.0-12.3), 0.9 m(2) (0.8-1.1), 17% (11%-24%) and 4.6 log(10) copies/mL (4.1-4.9), respectively. The median (IQR) lopinavir dose was 279 mg/m(2)/dose (263-294) and 194 mg/m(2)/dose (176-206) in the standard and low-dose arms, respectively. Median (IQR) AUC(0-12) and C(trough) of lopinavir were 117.6 mg.h/L (74.0-128.5) and 4.9 mg/L (2.7-8.0) for the standard arm and 83.8 mg.h/L (56.0-112.9) and 3.4 mg/L (2.7-5.4) for the low-dose arm. One child in the low-dose arm had a lopinavir pre-dose level of <1.0 mg/L. At week 48, the median percentage CD4 was 22% (15%-28%) and 27% (21%-31%) in the standard and low-dose arms, respectively, while 50% and 83% of children had HIV RNA <50 copies/mL, respectively (P = 0.19). CONCLUSIONS: Low-dose lopinavir displayed adequate pharmacokinetic parameters and good efficacy as compared with standard-dose lopinavir in Thai children. A larger study to investigate the efficacy of low-dose lopinavir is warranted