The diuretic and natriuretic responses to structurally distinct classes of Ca2+ channel blockers have been compared, to determine whether any agent provoked K+-sparing natriuresis, and to assess the relation of such responses with drug effects on blood pressure. Conscious normotensive Sprague-Dawley rats received vehicle or one of the following drugs in an oral saline load (40 mL kg-1) nifedipine, nimodipine, nitrendipine, prenylamine, cinnarizine, flunarizine, diltiazem, verapamil, hydrochlorothiazide, amiloride, or hydralazine, at doses from 0.316 to 100 mg kg-1. Urine was collected for 6h. Blood pressure was monitored directly in parallel studies. Diltiazem (31.6, 100 mg kg-1) and flunarizine (100 mg.kg-1) enhanced urine and electrolyte excretion in spite of marked hypotension; diltiazem was the only drug to produce dose-related renal responses. In contrast, equihypotensive doses of hydralazine and nifedipine produced overt urine and electrolyte retention. Nitrendipine and prenylamine (0.316 mg kg-1 each) produced slight diuresis or natriuresis without altering blood pressure; higher doses had no effect. The 31.6 mg kg-1 doses of verapamil, nitrendipine, and nimodipine markedly reduced blood pressure, but neither enhanced nor limited urine and electrolyte excretion. Cinnarizine failed to produce any cardiovascular or renal effects. Diuretic responses evoked by the Ca2+ channel blockers were not class-specific, showed no tendency towards sparing K+, were generally weaker than those produced by low doses of amiloride or hydrochlorothiazide, and were dissociable from drug-induced changes in blood pressure.
2‐[(cyclohexylmethylene)hydrazino]adenosine (MRE‐0470) is an A2A‐adenosine receptor agonist that is a potent and selective coronary vasodilator. As part of a preclinical program, the pharmacology and toxicology of MRE‐0470 have been studied in the rat. In isolated vas deferens, MRE‐0470 activated A2A receptors (EC50 = 6.3 nM) and at higher concentrations activated A2B receptors (EC50 = 13 μM). In atrial tissues, MRE‐0470 produced negative inotropic and chronotropic actions through activation of A1 receptors (EC50 ˜ 9 μM). MRE‐0470 produced no positive inotropic or chronotropic actions in atrial or ventricular tissues. In anesthetized, reflex‐blocked rats, MRE‐0470 produced a decrease in hindquarter perfusion pressure (A2: ED50 = 0.31 μg) and a decrease in heart rate (A1: ED50 = 620 μg). In conscious rats, MRE‐0470 (0.04–117 μg/kg bolus or 0.03–150 μg/kg/min infusion) produced dose‐dependent hypotension and reflex tachycardia. MRE‐0470 was rapidly eliminated from rat plasma with an elimination half‐life of 10 min. In toxicology studies, once per day 10‐minute i.v. infusions of 3, 30, or 150 μg/kg/min MRE‐0470 for 14 consecutive days resulted in no deaths and no changes in blood chemistry, but resulted in decreased motor activity and dose‐related cardiomyopathy. Cardiomyopathy did not occur following single doses of MRE‐0470. The incidence of this lesion is related to the duration of the repeated reflex tachycardia. These studies show that MRE‐0470 is a potent and selective A2A receptor agonist in the rat. The observed toxicology of MRE‐0470 is consistent with the exaggerated pharmacology due to high‐dose drug administration. Drug Dev. Res. 42:76–85, 1997. © 1997 Wiley‐Liss, Inc.
Standard drug monographs (SDMs) have been described as deficient in providing information in a manner simplified enough for patient reading. The aim of this study was to design patient information leaflets for hydrochlorothiazide, nifedipine and enalapril with content indicated by patients as relevant and to evaluate them against the SDM. Patient information leaflet (PIL) for each drug was designed to contain information on name, use of drug, how it works, how it is to be taken, common side effects, storage, missed dose action, things to avoid and when to contact the physician. Appropriateness was assessed by 10 practising pharmacists. For each drug, 40 patients were recruited, of which 20 were given SDM and 20 PIL. The knowledge of each participant was examined before and after exposure to SDM or PIL, as well as opinion on ease of reading and attractiveness using Pearson's Chi-square analysis. The results showed that both SDM and PIL improved knowledge of common side effects when compared with responses before exposure (χ 2 = 24.26 for SDM and 27.64 for PIL, p < 0.001) with no difference between the groups. Respondents receiving PILs were better able to recall "things to avoid" after exposure to PIL (χ 2 =10.85, p < 0.001). After exposure to SDM or PIL, the respondents who received PIL were more aware of when to contact the physician, compared to the SDM group (χ 2 = 8.41, p < 0.01). When compared with SDM, respondents receiving PIL were more likely to indicate that PIL was easy to read (χ 2 = 20.00, p < 0.001), attractive (χ 2 = 12.45, p < 0.001) and they were more likely to recommend distribution of their reading material to other patients (χ 2 = 22.11, p < 0.001). We conclude that there is benefit in designing information leaflets that simplify language and medication information contained in SDMs, including better understanding of precautions to take while on medication and when to consult physicians. Palabras claves: antihipertensivos, prospecto de información al paciente, monografía estandarizada del medicamento West Indian Med J 2011; 60 (3): 272
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