Clinical evaluation of valsartan and metoprolol tartrate in treatment of diabetic nephropathy with positive β1-adrenergic and anti-angiotensin Ⅱ type 1 receptor antibody

Background Studies have confirmed that angiotensin II receptor blocker （ARB） and angiotensin converting enzyme inhibitors （ACEI） in the treatment of diabetic nephropathy （DN） has special advantages. We observed the effects of valsartan and metoprolol tartrate hydrchloride in treatment of DN patients with positive β1-adrenergic and anti-angiotensin II type 1 （AT1） receptor antibody. Methods The epitopes of the second extracellular loop of β1 receptor （197-222） and AT1 receptor （165-191）, were synthesized and used respectively to screen serum autoantibodies from patients with DN （n=371, group A）, diabetes mellitus （DM） without renal failure （n=107, group B） and healthy blood donors （n=47, control, group C） by enzyme-linked immunosorbent assay （ELISA）. Metoprolol tartrate 25-50 mg, three times per day, valsartan 160 mg, once a day, aspirin 100 rag, once a day, and nitrendipine 10-20 mg, three times per day, were given to DN patients with positive or negative autoantibodies. The cystatin C level and 24-hour urinary protein were measured before and after treatment. Results In DN patients, the positive rate of the autoantibodies against β1 receptors and AT1 receptor was 47.7% and 51.5%, respectively, which were significantly higher than those in DM patients and healthy controls （all P 〈0.01）. Patients with anormalous cystatin C had higher positive rates of the autoantibodies than patients with normal cystatin C. Valsartan and metoprolol tartrate reduced proteinuria significantly （P 〈0.01） in DN patients with positive autoantibodies. Conclusions The findings suggest that these autoantibodies against β1 and ATl-receptor may play important roles in the pathogenesis of DN. Valsartan and metoDrolol tartrate are effective and safe in the treatment of DN.

Quantitative analysis of 3-isopropylamino-1,2-propanediol as a degradation product of metoprolol in pharmaceutical dosage forms by HILIC-CAD

Aryloxypropanolamine is an essential structural scaffold for a variety of b-adrenergic receptor antagonists such as metoprolol.Molecules with such a structural motif tend to degrade into α,β ehydroxypropanolamine impurities via a radicaleinitiated oxidation pathway.These impurities are typically polar and nonchromophoric,and are thus often overlooked using traditional reversed phase chromatography and UV detection.In this work,stress testing of metoprolol confirmed the generation of 3-isopropylamino-1,2-propanediol as a degradation product,which is a specified impurity of metoprolol in the European Pharmacopoeia(impurity N).To ensure the safety and quality of metoprolol drug products,hydrophilic interaction chromatography(HILIC)methods using Halo Penta HILIC column(150mm×4.6 mm,5 μm)coupled with charged aerosol detection(CAD)were developed and optimized for the separation and quantitation of metoprolol impurity N in metoprolol drug products including metoprolol tartrate injection,metoprolol tartrate tablets,and metoprolol succinate extended-release tablets.These HILIC-CAD methods were validated per USP validation guidelines with respect to specificity,linearity,accuracy,and precision,and have been successfully applied to determine impurity N in metoprolol drug products.