Morphological evaluation of combined effects of cyclosporin and nifedipine on gingival overgrowth in rats

It has previously been shown that, while cyclosporin A (CsA) and nifedipine both cause gingival overgrowth in the rat, the combined use of these drugs increases the severity of overgrowth. The aim of this study was to describe the histometry and densities of fibroblasts, collagen fibers and vessels in the gingival tissue of rats that were treated with CsA and nifedipine, either alone or in combination. Rats were treated for 60 days with a daily subcutaneous injection of 10 mg/kg body weight of CsA and/or with 50 mg/kg body weight of nifedipine added to the chow. The results confirmed that CsA causes a more severe overgrowth than nifedipine, and that the combined use of these drugs increases the overgrowth severity. All the rat groups that were studied showed that, as the severity of overgrowth increased, there was a parallel increase in fibroblasts and collagen, and a decrease in vessel content. Therefore, independently of whether the gingival overgrowth was caused by CsA alone, nifedipine alone, or both treatments in combination, the fibroblast and collagen density increased in parallel with the severity of the overgrowth.     

氨氯地平及硝苯地平控释片引起老年患者严重水肿

1例82岁男性患者,因患冠心病、高血压多年住院治疗。给予氨氯地平5mg,1次/d口服。服药1周后出现下肢水肿,15d后发展为全身水肿,检查见胸腔、心包积液。怀疑患者心功能不全,氨氯地平加量至5mg,2次/d口服,次日水肿急剧加重。停用氨氯地平,改用硝苯地平控释片30mg,1次/d,呋塞米20mg,2次/d口服,2d后水肿逐渐减轻,1个月后水肿完全消退出院。5个月后因血压高(180～170/120～100mmHg)再次入院。硝苯地平控释片加量为30mg,2次/d,20d后见眼睑、下肢水肿,超声心动图(UCG)检查示心包少量积液,硝苯地平控释片减量为30mg,1次/d,加用呋塞米20mg,2次/d口服,3d后水肿逐渐消退,3周后痊愈出院。     

Effects of the calcium antagonist, isradipine, and nifedipine on resting and exercise haemodynamics and the neurohumoral system in patients with stable chronic angina

In a randomized double-blind study, the haemodynamic and anti-ischaemic effects of the new dihydropyridine calcium channel blocker isradipine (5 mg and 10 mg thrice daily (t.i.d.) were investigated over 1 week in nine patients with coronary artery disease and chronic effort angina and compared with nifedipine (20 mg t.i.d.) and placebo. In standardized exercise stress tests and exercise radionuclide ventriculography, haemodynamics improved under medication compared with placebo: resting end-diastolic and end-systolic volume index decreased on isradipine 5 mg, 10 mg and on nifedipine, and ejection fraction at rest increased with all medications. Resting mean arterial pressure was reduced compared with placebo accompanied by a decrease in systemic vascular resistance (P less than 0.05) and systolic wall tension (P less than 0.05). Cumulative ST-segment depression was significantly reduced by all three medications (-48%, -23%, -36%), while the increase in work capacity was insignificant. No significant change was found for either heart rate, double product, cardiac index, or stroke work index. Resting plasma levels of noradrenaline, adrenaline and renin activity increased with all three medications (except adrenaline at isradipine 5 mg). Isradipine has favourable effects comparable with those of nifedipine in patients with chronic stable angina and can be safely administered in these patients.     

Clinical assessment of gingival hyperplasia in patients treated with nifedipine

Abstract Gingival hyperplasia caused by the use of nifedipine has been extensively reported. In this paper, the gingiva of 18 patients suffering from cardiopathy and treated with nifedipine were compared with those of 10 patients with cardiac disorders who had not been treated with calcium antagonists and with a no-treatment group of 12 patients. Nifedipine produced gingival hyperplasia although patients who had not been treated with calcium antagonists also had mild hyperplasia. Hyperplasia first appeared in the interproximal areas, an observation which may be important for early detection. There was a direct correlation between the degree of hyperplasia and the bacterial plaque score. When we studied the influence of administration time and dose of nifedipine with the degree of hyperplasia, no statistically significant differences were found.     

尼群地平(NT)和硝苯吡啶(NF)对离体豚鼠工作心脏的作用

连续记录的豚鼠离体工作心脏100min,50min内各项指标(AF、CF、LVP、dp/dtmax、ASP和HR等)值较稳定和可靠。其后有自然衰竭趋势,-dp/dtmax最先减慢,提示心脏的自然衰竭与心室舒张功能受损有关。0.1-100nMN T和0.001—10nM有负性肌力和降低心泵的作用,且呈剂量依赖关系。NT和NF抑制AF的ID_(50),分别为15.2nM和1.03nM;+dp/dtmax的ID_(50),分别为52.4nM和3.3nM;-dp/dtmax的ID_(50),分别为56.3nM和1.6nM,两者相差15倍以上,差异显著,提示NT对心脏的抑制作用比NF弱得多。     

Site-specific variations in metabolism by human fibroblasts exposed to nifedipine in vitro

Nifedipine induces overgrowth of gingival tissues in some patients. However, other collagenous tissues in their body do not overgrow. The purpose of this study was to compare effects of serial dilutions of nifedipine on the in vitro metabolism of fibroblasts derived from normal gingiva. nifedipine-induced hyper-plastic gingiva. knee capsular ligament, and dermis. The data suggested that nifedipine affects the metabolism of fibroblasts derived not only from gingiva. but also from other connective tissues. Thus, nifedipine-responder cells are present in tissues other than gingiva. There was an inverse relationship between in vivo tissue levels of IL-1-beta and in vitro responsiveness to nifedipine of fibroblasts derived from that tissue. Nifedipine-induced overgrowth of connective tissues, other than gingiva, probably does not occur either because of the relatively slow rate of collagenous protein synthesis by resident fibroblasts or because of alterations in collagen deposition/resorption within susceptible tissues produced by nifedipine on collagenase synthesis.     

Controversies concerning calcium antagonists

Summary The paper discusses the controversial attitude regarding the safety of calcium channel blockers (CCBs), especially of the dihydropyridine nifedipine, induced through several meta-analyses of studies with CCBs by Dr. Furberg et al.; as a result, a detrimental effect of CCBs, especially during acute myocardial infarction, has been claimed. Several independent re-analyses of the 16 studies, all performed in the 1980s and mainly using the short-acting nifedipine capsule, did not confirm Furberg's results and showed an insignificant mortality difference between patients on CCBs versus those on control. Nevertheless, new safety studies applying long-acting CCBs (half-lives of 1 or more days) combined with efficacy assessments are necessary, both in hypertension as well as coronary artery disease, to finally clear up this important question.     

Administration of slow-release nifedipine does not affect lactate threshold,hormone release during exercise,and quality of life in normal subjects

Summary In a double-blind crossover study of 10 normal healthy subjects, we examined the effects of slow-release nifedipine (nifedipine-SR, 10 mg b.i.d) administration on exercise capacity, hormone levels during exercise, and quality of life (QOL) after a 2-week treatment. Two exercise tests, a progressive exercise test and a constant work-rate exercise test, were performed. Maximal oxygen uptake (\.VO₂max) and blood lactate concentration were measured during the progressive exercise test and the exercise intensity corresponding to half lactate threshold (LT), LT, and 4 mmol/l of lactate concentration was determined. Subjects underwent 20 minutes of constant work-rate exercise at each work load, and blood lactate, plasma epinephrine, plasma norepinephrine, plasma renin activity, plasma aldosterone, atrial natriuretic peptide, plasma β-endorphin, and met-enkephalin were measured. Taking nifedipine-SR had no effect on the responses of blood pressure, heart rate, VO₂max, maximal work load, and LT compared to taking placebo. Blood lactate, plasma catecholamine, plasma renin activity, aldosterone, atrial natriuretic peptide, and β-endorphin levels increased during exercise, and there was no difference between nifedipine-SR and placebo. Met-enkephalin did not increase with either treatment. In the QOL questionnaires, no differences were noted between the two treatments. These findings suggest nifedipine-SR to be a potentially useful drug in view of the lack of effect on exercise capacity, hormone release, and QOL.