Telmisartan inhibits the progression of cardiomyopathy in daunorubicin treated rats: the role of advanced glycation end products.

Background: Anthracyclines have been reported to induce cardiotoxicity through mechanisms involving formation of advanced glycation end-products (AGEs), including pentosidine and Nє-(carboxymethyl) lysine (CML). We investigated the potential utility of telmisartan (TML), an angiotensin II receptor antagonists (ARB) on anthracycline-induced cardiotoxicity. Methods: Three groups of Sprague-Dawley rats were treated as follows: The first group received daunorubicin (DNR) 3 mg/kgBW every alternating day to reach a cumulative dose of 9 mg/kg DNR . The second group received DNR plus TLM at a dose10 mg/kgBW, by oral gavage for 6 weeks, and the third group served as control group (CTL) which only received vehicle of DNR. Mean blood pressure (MBP) peak left ventricular pressure (LVP), LV end-diastolic pressure (LVEDP), and intra-ventricular contractility (±dP/dt) were recorded by using Powerlab instrumentation. Ejection fraction (EF), and fractional shortening (FS) were measured by echocardiography. Expression of receptor of AGE (RAGE), pentosidine and CML were measured by immunohistochemistry and Western blot in LV tissue. Results: DNR treatment was associated with significant weakening of some hemodynamic parameters which could be reversed by TML (LVP: 124.3 ± 6.0; 111 ± 7; and 115.1 ± 5.4 mmHg, respectively in CTL, DNR and DNR-TLM groups; LVEDP: 7.5 ± 0.9; 10.7 ± 0.3; 8.7 ± 0.4 mmHg, respectively; +dP/dt: 6813 ± 541; 4800 ± 345; 5950 ± 398 mmHg/s, respectively). The same phenomenons were also observed on echocardiographic parameters (EF: 78.9 ± 1.8; 59.6 ± 1.4; 76.2 ± 2.75 %, resepectively; FS: 42.8 ± 1.7; 29.1 ± 1.3; 41 ± 2.7 %) respectively. Expression of RAGE as well as pentosidine and CML were increased in DNR-rats. TML treatment ameliorated these changes. Conclusion: These results suggested the role of AGE formation in DNR-induced cardiotoxicity and telmisartan could inhibit the progression of cardiac toxicity at least in part by reduction RAGE expressiom.

Primaquine decreased plasma concentration of ritonavir: single- and repeated-dose study in Sprague Dawley rats.

Background: The present study was aimed to explore the effects of ritonavir and primaquine combination given as a singledose or repeated-dose compared to ritonavir alone on ritonavir plasma concentration in the rats. Methods: In single-dose study, 30 male Spraque Dawley rats were randomly allocated to receive ritonavir 20 mg/kg BW or ritonavir 20 mg/kg BW + primaquine 1.2 mg/kg BW or ritonavir 20 mg/kg BW + ketokonazole 10 mg/kg BW. Ketokonazole was used as positive control of ritonavir metabolism inhibitor. In the repeated-dose study, thirty Spraque Dawley male rats were randomly allocated to receive ritonavir 20 mg/kg BW/day or ritonavir 20 mg/kg BW/day + primaquine 1.2 mg/kg BW/day or ritonavir 20 mg/kg BW/day + rifampicin 100 mg/kg BW/day. Rifampicin was used as a positive control of ritonavir metabolism inducer. Results: In the single-dose study, ketokonazole increased the area under the plasma concentration (AUC) of ritonavir (↑114.8%, p< 0.05), while primaquine tended to decrease the AUC of ritonavir (↓ 32.6%, p> 0.05). Repeated-dose study showed that rifampicin decreases the AUC of ritonavir (↓ 42.8%, p< 0.001), and primaquine decreased the AUC of ritonavir plasma concentration (↓ 46.6%, p< 0.001). Conclusion: Concomitant administration of primaquine and ritonavir decreases the AUC of ritonavir. This effect may result in the insufficient concentration of ritonavir as anti-HIV, which may lead to treatment failure with ritonavir.

Incretin-based therapies for type 2 diabetes mellitus in Asian patients: Analysis of clinical trials.

Aim To review the effi cacy and safety data on incretin-based therapies currently available (exenatide, liraglutide, sitagliptin, vildagliptin) for the treatment of type 2 diabetes mellitus in Asian population. Methods We conducted Medline search of all relevant randomized clinical trials of incretin-based therapies for type 2 diabetes mellitus in Asian populations. Data pertinent to the effi cacy and safety of GLP-1 mimetics and DPP-4 inhibitors were extracted and used. Results We found 14 randomized controlled trials of incretin based-therapy which included 3567 type 2 diabetes mellitus in Asian population (Japanese, Chinese, Korean, Indian). It was shown that incretin-based therapies improved HbA1c at higher extent (up to -1.42% in exenatide 10 mcg bid, -1.85% for liraglutide 0.9 mg qd, -1.4% for sitagliptin 100 mg and -1.4% for vildagliptin 50 mg bid) compared to the effects observed in studies with Caucasian population, with comparable safety profi le. Conclusion The effi cacy of incretin-based therapies in Asian patients improved glycemic parameters in a higher magnitude on some glycemic parameters compared with those in Caucasian population. These results indicate that incretin-based therapies may be more effective in Asian population than in Caucasian.

A survey on the appropriateness of drug therapy in patients with renal dysfunction at the Internal Medicine Ward FMUI/Dr. Cipto Mangunkusumo Hospital.

Aim Dose adjusment and drug selection is important in patient with renal dysfuction.This study was aimed to assess the accuracy of dose adjustment and drug selection for renal dysfunction patient at the Internal Medicine Ward FMUI/Dr. Cipto Mangunkusumo Hospital, Jakarta Methods Patients ≥ 18 years old with estimated creatinine clearance < 60 mL/minute based on Cockroft-Gault formula were included in this study. The drugs assessed were those excreted by the kidney or having nephrotoxic effect. The appropriateness of drug selection is assessed based on the preserce or not contraindication or potential of drug-drug interaction. The accuracy of dose adjustment were assessed based on information available in various textbooks, literatures, and drug brochures. Data were collected between May to July 2007. Results Data obtained from 43 patients met the inclusion criterias demonstrated that 164 out of 385 drug prescriptions were mainly eliminated by the kidney or have nephrotoxic characteristic. Out of 164 drug prescriptions, 142 (86.5%) were appropriately adjusted, while the other 22 (13.5%) were inappropriately adjusted for the dose. There was only one contraindication for the usage of the drug and 15.1% potentially drug interaction. Conclusion Dose adjustment and drug selections in patients with renal dysfunction at the Internal Medicine Ward FMUI/Dr. Cipto Mangunkusumo Hospital are conducted appropriately.