Double-Blind, Randomized, Placebo-Controlled Phase II Dose-Finding Study To Evaluate High-Dose Rifampin for Tuberculous Meningitis.

High doses of rifampin may help patients with tuberculous meningitis (TBM) to survive. Pharmacokinetic pharmacodynamic evaluations suggested that rifampin doses higher than 13 mg/kg given intravenously or 20 mg/kg given orally (as previously studied) are warranted to maximize treatment response. In a double-blind, randomized, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg, or 1,350 mg (10, 20, and 30 mg/kg) oral rifampin combined with other TB drugs for 30 days. The endpoints included pharmacokinetic measures, adverse events, and survival. A double and triple dose of oral rifampin led to 3- and 5-fold higher geometric mean total exposures in plasma in the critical early days (2 ± 1) of treatment (area under the concentration-time curve from 0 to 24 h [AUC0-24], 53.5 mg · h/liter versus 170.6 mg · h/liter and 293.5 mg · h/liter, respectively; P < 0.001), with proportional increases in cerebrospinal fluid (CSF) concentrations and without an increase in the incidence of grade 3 or 4 adverse events. The 6-month mortality was 7/20 (35%), 9/20 (45%), and 3/20 (15%) in the 10-, 20-, and 30-mg/kg groups, respectively (P = 0.12). A tripling of the standard dose caused a large increase in rifampin exposure in plasma and CSF and was safe. The survival benefit with this dose should now be evaluated in a larger phase III clinical trial. (This study has been registered at ClinicalTrials.gov under identifier NCT02169882.).

Prevention and treatment of HIV addicted patients: a biopsychosocial approach.

Injecting drug use is the main route of HIV transmission in many parts of Indonesia. Efforts to prevent HIV-transmission through injecting drug use mostly focus on subjects who actively inject. In scientific publications, the term 'injecting drug users' tends to be used without a clear definition and without specifying the pattern of drug use as current or former drug use, frequency, duration, type of injected drug(s) or context (e.g. imprisonment). Actually, injecting drug users (IDUs) have different drug use patterns, risk behavior, somatic co-morbidity, psychiatric co-morbidity, and psychosocial problems. In fact, these patients are suffering from addiction as a chronic brain disease in co-occurrence with somatic and psychiatric disorder and many social problems. Failing in addressing the problems comprehensively will lead to the failure of drug treatment. This is why addiction can be best studied and treated from a biopsychosocial perspective. Accordingly, treatment goals can be differentiated in crisis intervention, cure or recovery (detoxification, relapse prevention), and care or partial remission (stabilization and harm reduction). In summary, injecting drug use in Indonesia is not a single entity and patient oriented prevention and care for IDUs, especially focusing on their addiction, should be addressed to prevent the transmission of HIV/AIDS.

Oxidized low density lipoprotein acts on endothelial cells in culture to enhance endothelin secretion and monocyte migration.

Monocyte deposition on the endothelium is the initial step in atherogenesis. Oxidized low density lipoprotein (Ox-LDL) is involved in the development of the fatty streak which progresses to the atherosclerotic lesion. Our interest focussed on the question, does the endothelium react to Ox-LDL to produce humoral substances that might influence the migration of human blood monocytes? Chemotaxis of monocytes was assessed by the modified membrane-filter technique based on the Boyden chamber principle. Exposure of porcine aorta endothelial cells (ECs) to Ox-LDL (100 micrograms/ml) increased the directional migration of monocytes by 25% (p < 0.01) over that of ECs in the absence of Ox-LDL. Radioimmunoassay of the EC culture media revealed the presence of immunoreactive endothelin-1 (ir-ET-1). The endothelin converting enzyme inhibitor, phosphoramidone (10 microM), when incubated together with ECs and Ox-LDL, suppressed the synthesis of ir-ET-1 by 53% (p < 0.05) and the migration decreased by 12% (p < 0.05). Preincubation of monocytes with the ETA receptor-selective antagonist, BQ-123 (1 microM), followed by exposure to ECs plus Ox-LDL, lead to a decrease in their migration by 12% (p < 0.05) compared to monocytes not treated with BQ-123. These results show that Ox-LDL acts on ECs to enhance the synthesis of ir-ET-1 which in turn increases the directional migration of monocytes. Phosphoramidone decreased the synthesis of ir-ET-1 but migration was affected only modestly; monocyte ETA receptor blockade by BQ-123 also suppressed migration toward EC chemoattractants to a small extent. Both results suggest that in addition to ir-ET-1 other chemotactic factors are being released by the ECs; Ox-LDL appears to enhance their release or synthesis.

Telomerase activity in different clinical staging of colorectal adenocarcinoma.

Increased telomerase activity is proposed to be related with the proliferation of some gastrointestinal cancers, including colorectal adenocarcinoma. To date, little is known about the activity of telomerase in different clinical stagings of colorectal adenocarcinoma, which may reflect its association with the progression of colorectal adenocarcinoma. We will examine the activity of telomerase enzyme in different clinical stagings of colorectal adenocarcinoma to know whether it has diagnostic and prognostic value as a tumor marker in the management of colorectal adenocarcinoma. The telomerase activities of primary tumor and normal adjacent mucosa in 17 cases with different clinical stagings of colorectal adenocarcinoma were measured by TRAP assay during the period of 28 September 1998 to 28 February 1999. The activities of the enzyme were measured both qualitatively and quantitatively, and the diagnostic value was assessed by diagnostic test using 2 x 2 table contingency. The association between telomerase activities and other related factors were assessed by multivariate analysis. Increased telomerase activities were found in 82.4% (14/17) of colorectal adenocarcinoma, but in only 23.5% (4/17) of normal adjacent mucosa, which was significantly higher (p = 0.008) compared to that of normal mucosa. The mean values of telomerase activity between different clinical stagings were 0, 0.661, and 1.449 units/410 (g protein for Dukes' stage B, C, and D, respectively, which gave p value of 0.025 with ANOVA. Using a cut off level of 0.2-units/410 (g protein for positive activity, we revealed that the accuracy, sensitivity, and specificity were 77.77%, 82.35%, and 76.47%, respectively. There was no association found between the histopathologic grading of the tumor and telomerase activity. Increased telomerase activity was found in colorectal adenocarcinoma compared to the adjacent normal mucosa. Telomerase activity correlates well with the progression of colorectal adenocarcinoma. Therefore, telomerase enzyme may have a potential diagnostic and prognostic values in the management of colorectal adenocarcinoma.

Chemotaxis of human blood monocytes toward endothelin-1 and the influence of calcium channel blockers.

The adherence of monocytes to the arterial endothelium followed by its migration into the arterial intima is the earliest event in atherogenesis. The vasoconstrictive peptide, Endothelin-1 (ET-1), is elevated in patients with atherosclerosis. We were interested to know whether ET-1 was a chemoattractant for blood monocytes. Using the modified membrane filter technique for chemotaxsis assessment, ET-1 increased monocyte chemotaxis in a dose-dependent manner. Ca2+ channel blockers, Nifedipine, Diltiazem and Verapamil (5 microM), reduced ET-1 chemotaxsis more than 60% (P < 0.001). Aspirin and Indomethacin (1 mM and 100 microM, respectively) reduced migration by 23% (P < 0.05). Alpha-Lipoic acid, Probucol and Neomycin (100 microM) were also migration inhibitory (37%, P < 0.01). These results suggest that ET-1 is a strong chemoattractant for blood monocytes; Ca2+ influx is probably the major stimulus for the accelerated migration induced by ET-1.