A Systematic Review on Drug Safety for Molsidomine, Nicorandil and Trimetazidine

BACKGROUND: Ischemic heart disease is the most common type of heart disease and an important cause of death in Korea. Among marketed anti-anginal medications, molsidomine, nicorandil, and trimetazidine are approved in Korea with unique mechanism of actions. As these drugs are not approved by the US Food and Drug Administration, the access to the up-to-dated and comprehensive safety-related information has been less than optimal from drug information resources used by Korean pharmacists. METHODS: A systematic review was conducted using Embase and Korean manuscripts to compile safety updates for these medications. Out of 418 articles from keyword searches, 52 studies were reviewed in full to compare adverse effects (AEs) with the approved package inserts (PI). RESULTS: Molsidomine related adverse effects were mostly mild or moderate, but anxiety, palpitation, epigastric pain, and sexual potency reduction were additional AEs found from the review not listed in PI. Although PI has included ulceration in oral cavity and gastrointestinal tracts including anus by nicorandil, the Korea FDA recently recommended adding corneal, genital, and skin ulcers to the approved PI. Trimetazidine induced Parkinsonism, worsening of the symptoms for patients diagnosed with Parkinson's disease, gastrointestinal burning, and muscle cramps were additionally identified AEs not listed in PI for trimetazidine. CONCLUSION: Continuous evaluations of the safety profile of these agents are needed to balance the risks and benefits to provide evidence-based safety counseling to the patients. In addition, more focused efforts on spontaneous reporting are warranted by healthcare professionals to safeguard patients against AEs.

Improvement of the Determination Method of Content and Related Substances of Molsidomine Tablet / 中国药房

OBJECTIVE:To improve the method for the determination of content and related substances of Molsidomine tablet. METHODS:HPLC was adopted to determine the content and related substances,HPLC-MS was adopted for the qualitative degra-dation impurities in destruction test. The column was Waters Symmetry-C18 with mobile phase of 0.05% formic acid- methanol (gradient elution) at a flow rate 1.0 ml/min and 0.2 ml/min (respectively for content and related substances determination,mass spectrometry),the detection wavelength was 210 nm,column temperature was 30℃,the injection volume was 20μl and 5μl(re-spectively for content and related substances determination,mass spectrometry). RESULTS:Each component was well separated un-der chromatographic conditions;degradation impurities were confirmed;the linear range of molsidomine was 4. 0-28.0 μg/ml(r=0.9997);RSDs of precision,stability and reproducibility tests were lower than 1%;recovery was 97.74%-100.70%(RSD=0.49%,n=9). CONCLUSIONS:The method is simple,accurate with good specific and high precision,and can improve the quali-ty control of Molsidomine tablet.

Nitric oxide-induced immune switching in experimental inflammatory autoimmune diseases

BACKGROUND: Nitric oxide (NO) production has been described as a double-edged sword eliciting both pro-and anti-inflammatory effect s in different immune reactions. This work was undertaken to investigate the immunoregulatory role of NO in experimental allergic encephalomyelitis (EAE) and experimental allergic uveitis (EAU). MEHHOD: We examined whether molsidomine (MSDM), a NO donor, administration to the myelin basic protein (MBP)-or interphotoreceptor retinoid binding protein (IRBP)-immunized rat s could suppress EAE development by shifting toward the Th2 cytokine response. In the EAE experiment s, the rat s were treated orally with MSDM (10 mg/kg/day) at the early stage (-1-4 days) or throughout the experimental period (-1-15 days). RESULTS: This resulted in significant amelioration of the disease and mild clinical symptoms, while MBP-immunization without MSDM administration showed severe EAE development . A marked reduction in inflammation was also observed in the spinal cord, indicating the crucial role of NO in the pathogenesis of EAE in in vivo. In the EAU experiments, a 24 h pre-treatment with MSDM prior to IRBP immunization resulted in significant inhibition of the disease. Furthermore, MSDM administration for 2 1 days completely reduced the incidence and severity of EAU. To investigate whether MSDM could modulate cytokine switching from Th 1 to Th2, culture supernatants of MBP-or IRBP-stimulated inguinal lymphocytes were analyzed. MSDM treatment enhanced IL-10 secretion but decreased IFN-gamma. IL-4 was undetectable in all groups. In contrast, the MBP-or IRBP-immunized rat s without MSDM secreted high concentrations of IFN-gamma, but low concentrations of IL-10. CONCLUSION: In conclusion, NO administation suppresses EAE and EAU by modulating the Th 1/Th2 balance during inflammatory immune responses. This work further suggest s that NO may be useful in the therapeutic control of autoimmune disease.

Role of nitric oxide and molsidomine in the management of pulmonary hypertension in Takayasu's arteritis / 결핵

We report three patients with pulmonary hypertension in Takayasu's arteritis, who showed long-term favorable response, clinically and hemodynamically, to the nitric oxide donor, molsidomine. In these patients, the inhaled nitric oxide was effective in reducing pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) as was shown in the acute vasodilator response test using the invasive hemodynamic monitoring. Molsidomine (single oral dose of 4 mg) was also effective in reducing PAP and PVR in the acute test, but nifedipine was not. With 4 mg of molsidomine three times daily, their dyspnea, exercise capacity and hemodynamic parameters were improved. These favorable responses have lasted during the 1st and 3rd month follow-up in all patients.

The Effects of Oral Nitric Oxide Donor (Molsidomine) in Patients with Variant Angina Unresponsive to Conventional Anti-Anginal Drugs

BACKGROUND: We observed the changes of clinical characteristics after oral Molsidomine, a nitric oxide donor, in patients who have documented coronary artery spasm by ergonovine coronary angiogram and refractory to conventional anti-anginal therapy. METHOD: Molsidomine, oral nitric oxide donor, was administrated over 12 weeks in 20 patients (6 male, 14 female, 54+/-11.5 years) in order to observe the clinical effects in patients with coronary artery spasm unresponsive to nitrate and calcium channel blockers. Changes in the frequency of pain and sublingual nitroglycerin use, blood pressure, heart rate, side effects, electrocardiogram, and laboratory findings were evaluated before and after Molsidomine therapy. RESULTS: The frequencies of pain and sublingual nitroglycerin use were 3.9+/-0.9/week before treatment and decreased to 2.9+/-0.9/week at 4th week after the additional Molsidomine treatment (pre-treatment vs. 4th week; p<0.001), to 1.0+/-0.8/week at 8th week (4th week vs. 8th week; p<0.001), and to 0.7+/-0.8/week at 12th week. Systolic blood pressure decreased after treatment, but there were no significant changes in diastolic blood pressure, heart rate, resting electrocardiogram and laboratory findings. Molsidomine was discontinued in one patient because of headache. CONCLUSIONS: Molsidomine is an effective and well tolerated anti-ischemic agent in patients with variant angina refractory to conventional anti-anginal therapy.