Effects of cyclosporin, phenytoin, and nifedipine on the synthesis and degradation of gingival collagen in tufted capuchin monkeys (Cebus apella): Histochemical and MMP-1 and -2 and collagen I gene expression analyses

Background: The purpose of this experimental study was to evaluate the collagen fiber distribution histologically after phenytoin, cyclosporin, or nifedipine therapy and to correlate it with collagen I and matrix metalloproteinase (MMP)-1 and -2 gene expression levels.Methods: Gingival samples from the canine area were obtained from 12 male monkeys (Cebus apella). The mesial part of each sample was assessed by reverse transcription-polymerase chain reaction, whereas the distal part was processed histologically for picrosirius red and hematoxylin and eosin stainings, as well as for collagen IV immunostaining. One week after the first biopsy, the animals were assigned to three groups that received daily oral dosages of cyclosporin, phenytoin, or nifedipine for 120 days. Additional gingival samples were obtained on days 52 and 120 of treatment from two animals from each group on the opposite sides from the first biopsies.Results: Picrosirius red staining showed a predominance of mature collagen fibers in the control group. Conversely, there was an enlargement of areas occupied by immature collagen fibers in all groups at days 52 and 120, which was not uniform over each section. There was a general trend to lower levels of MMP-1 gene expression on day 52 and increased levels on day 120. Phenytoin led to increased levels of MMP-2 and collagen I gene expression on day 120, whereas the opposite was observed in the nifedipine group.Conclusion: Cyclosporin, phenytoin, and nifedipine led to phased and drug-related gene expression patterns, resulting in impaired collagen metabolism, despite the lack of prominent clinical signs.

ESTUDO COMPARATIVO DUPLO-CEGO DA EFICACIA E SEGURANCA DO CILAZAPRIL COMPARADAS A NIFEDIPINE 'RETARD' NO TRATAMENTO DA HIPERTENSAO ARTERIAL LEVE E MODERADA

Purpose: To evaluate the antihypertensive efficacy and safety of cilazapril compared to nifedipine retard in mild to moderate hypertension. Methods: Forty randomized out-patients with mild moderate hypertension, diastolic pressure (DP) between 95 and 115 mmg/Hg, with placebo for 15 days were randomized and allocated for treatment, double-blind, once daily with cilazapril 2.5 mg (n = 20) or nifedipine retard 20 mg (20 = n) for four weeks. The non-responders (DP > 90 mmHg) had the dosage increased twice, b.i.d., while responders were maintained up to 10 weeks. Clinical visits were performed before, at baseline and every two weeks and the laboratory test was performed after placebo run-in, 4th and 10th weeks of treatment. Results: The blood pressure (BP) were similar between groups at the end of the placebo (cilazapril 151 ± 14/103 ± 5 - nifedipine 157 ± 17/108 ± 7 mmHg, p > 0.05). DP decreased already at second weeks (cilazapril 95 ± 9 - nifedipine 96 ± 11 mmHg, p < 0.05, compared to week 0) in both groups at the end of study with no differences inter groups. BP normalization was obtained in 58% of the patients with cilazapril and in 61% in the nifedipine group. Adverse biochemical effects were not observed in any group. Six (16%) patients of the cilazapril and 15 (39%) of nifedipine related collateral events, although no difference were observed between groups. Conclusion: Cilazapril 2.5 to 5 mg normalized BP in 58% of mild and moderate hypertension patients, and this efficacy was similar to sustained-release nifedipine 20 to 40 mg. Cilazapril had no adverse effects on the biochemical parameters with low incidence of collateral effects.

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. © Blackwell Munksgaard, 2002.

Combined effects of cyclosporin and nifedipine on gingival overgrowth in rats is not age dependent

Background: Cyclosporin A and nifedipine cause gingival overgrowth in rat, and the combined use of these drugs increases the overgrowth severity. Objective: The purpose of this study was to compare gingival overgrowth of rats of differents ages treated with cyclosporin A and nifedipine alone or given concurrently. Materials and methods: Rats 15, 30, 60 and 90 d old were treated with 10 mg/kg body weight of cyclosporin A and/or 50 mg/kg body weight of nifedipine in the chow. Results: Young rats showed evident gingival overgrowth with nifedipine, cyclosporin A, and cyclosporin A and nifedipine given concurrently. Adult rats did not show significant gingival alterations when treated with cyclosporin A and nifedipine alone. Nevertheless evident gingival overgrowth with alterations of the epithelium and connective tissue were observed when treated simultaneously with cyclosporin A and nifedipine. Conclusion: These results suggest that the combined effects of cyclosporin A and nifedipine on gingival overgrowth in rat is not age dependent.

Influence of age on combined effects of cyclosporin and nifedipine on rat alveolar bone

Background: There is some evidence showing that cyclosporin A (CsA) and nifedipine (NIF) affect bone metabolism. The purpose of this work was to study the effects of CsA and NIF, given alone or concurrently, on alveolar bone of rats of different ages. Methods: Rats 15, 30, 60, and 90 days old were treated daily with 10 mg/kg body weight of CsA subcutaneously injected and/or 50 mg/kg body weight of NIF/day given orally for 60 days. Alveolar bone of the first lower molars was morphologically and stereologically evaluated in serial 5 μm bucco-lingual paraffin sections, stained with hematoxylin and eosin. Serum calcium and alkaline phosphatase levels were measured in all animals at the end of the experimental period. Results: Rats treated with CsA or NIF alone or CsA and NIF concurrently showed decreased alveolar bone density. CsA was more effective than NIF. A significant decrease in serum calcium was found only in animals treated with CsA or CsA/NIF. The results were similar regardless of age. Conclusions: These results indicate that the decrease in the alveolar bone volume in rats caused by CsA and NIF alone or concurrently is not age dependent. Furthermore, NIF (50 mg/kg) did not further increase the loss of alveolar bone volume induced by CsA (10 mg/kg).

Central nifedipine-induced alterations in salivary flow and compounds: Role of nitric oxide

The aim of this study was to examine the role of nifedipine and Nitric Oxide (NO) on salivary flow and compounds (salivary amylase, saliva total proteins, saliva calcium, sodium and potassium). Male Holtzman rats weighting 200-250 g were anesthetized with zoletil 50 mg kg -1 (tiletamine chloridrate 125.0 mg and zolazepan chloridrate 125.0 mg) into quadriceps muscle and stainless steel cannulas were implanted into their lateral ventricle of the brain (LV). Animals in divided group were injected with nifedipine (50 μg μL -1) alone and in combination with 7-nitroindazol (7-NIT) (40 μg μL -1), neuronal NO Sinthase Inhibitor (nNOSI) and Sodium Nitroprussate (SNP) (30 μg μL -1) NO donor agent. As a secretory stimuli, pilocarpine dissolved in isotonic was administered intraperitoneally (ip) at a dosage of 10 mg kg -1 body weight. Saliva was collected for 7 min with four cotton balls weighing approximately 20 mg each, two of which were placed on either side of the oral cavity, with the other two placed under the tongue. Nifedipine treatment induced a reduction in saliva secretion rate and concentration of amylase, total protein and calcium without changes in sodium and potassium concentration in comparison with controls. Co-treatment of animals with nifedipine and SNP retained flow rate and concentration of amylase, total protein and calcium in normal levels. Co-treatment of animals with nifedipine and 7-NIT potentiated the effect of nifedipine on the reduction of saliva secretion and concentrations of amylase, total protein and calcium. Nifedipine (dihydroperidine) calcium-channel blocker widely in use is associated with salivary dysfunction acting in the central nervous system structures. NO might be the mechanism for protective effect against the nifedipine-induce salivary dysfunction, acting in the CNS. © 2006 Asian Network for Scientific Information.

Clinical assessment of nifedipine-induced gingival overgrowth in a group of brazilian patients

Although it has been established that nifedipine is associated with gingival overgrowth (GO), there is little information on the prevalence and severity of this condition in the Brazilian population. The aim of this study was to assess the occurrence of nifedipine-induced GO in Brazilian patients and the risk factors associated using a Clinical Index for Drug Induced Gingival Overgrowth (Clinical Index DIGO). The study was carried out on 35 patients under treatment with nifedipine (test group) and 35 patients without treatment (control group). Variables such as demographic (age, gender), pharmacological (dose, time of use), periodontal (plaque index, gingival index, probing depth, clinical insertion level, and bleeding on probing), and GO were assessed. Statistical analysis showed no association between GO and demographic or pharmacological variables. However, there was an association between GO and periodontal variables, except for plaque index. According to our study, the Clinical Index DIGO can be used as a parameter to evaluate GO. Therefore, we conclude that the presence of gingival inflammation was the main risk factor for the occurrence of nifedipine-induced GO.

Anti-hypertensive drugs have different effects on ventricular hypertrophy regression

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Safety Assessment of Potentially Inappropriate Medications (PIM) use in Older People and the Factors Associated with Hospital Admission

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Functional Aesthetic Treatment of Patient With Phenytoin-Induced Gingival Overgrowth

Gingival overgrowth (GO) may be related to the frequent use of certain medications, such as cyclosporin, phenytoin (PHT), and nifedipine, and is therefore denominated drug-induced GO. This article reports a case of a patient who with chronic periodontitis made use of PHT and presented generalized GO. A 30-year-old man with GO was referred to the clinic of the Universidade Estadual Paulista, Brazil. The complaint was poor aesthetics because of the GO. The patient had a medical history of a controlled epileptic state, and PHT was administered as an anticonvulsant medication. The clinical examination showed generalized edematous gingival tissues and presence of bacterial plaque and calculus on the surfaces of the teeth. The diagnosis was GO associated with PHT because no other risk factors were identified. Treatment consisted of meticulous oral hygiene instruction, scaling, root surface instrumentation, prophylaxis, and daily chlorhexidine mouth rinses. After this stage, periodontal surgery was performed, and histopathologic evaluation was made. The patient has been under control for 3 years after the periodontal surgery, and up to the present time, there has been no recurrence. It can be concluded that PHT associated with the presence of irritants favored gingival growth and that the association of nonsurgical and surgical periodontal therapies was effective in the treatment of GO. Besides, motivating the patient to maintain oral hygiene is a prerequisite for the maintenance of periodontal health.

L-Type calcium channels mediate water intake induced by angiotensin injection into median preoptic nucleus

Calcium ions are widely accepted as critically important in responses of neurons to a stimulus. We have show previously the central involvement of angiotensin II (ANGII) in water intake. This study determined whether voltage-dependent calcium channels are involved in ANGII-induced behavioral drinking implicating nitrergic mechanism. The antidipsogenic actions of L-type calcium channel antagonists nifedipine, on ANGII-induced drinking behavior were studied when it is injected into the median preoptic nucleus (MnPO). The influence of nitric oxide (NO) on nifedipine antidipsogenic action was also studied by utilizing the N-W-nitro-L-arginine methyl ester (L-NAME) a constitutive nitric oxide synthase inhibitor constitutive (cNOSI) and 7-nitroindazol (7-NIT) a specific neuronal nitric oxide synthase inhibitor (nNOSI) and L-arginine a NO donor. Rats 200-250 g, with cannulae implanted into MnPO, pre-treated into MnPO with either nifedipine, followed by ANGII, drank significantly less water than controls during the first 15 min after injection. However, L-NAME potentiated the dipsogenic effect of ANGII that is blocked by prior injection of nifedipine and L-arginine. 7-NIT injected prior to ANGII into MnPO also potentiated the dipsogenic effect of ANGII but with a less intensity than L-NAME that it is also blocked by prior injection of nifedipine. The results described in this paper provide evidence that calcium channels play important roles in the ANGII-induced behavioral water intake. The structures containing NO in the brain such as MnPO include both endothelial cells and neurons might be responsible for the influence of nifedipine on dipsogenic effect of ANGII. These data shows the correlation between L-type calcium channel and a free radical gas NO produced endogenously from amino acids L-arginine by endothelial and neuronal NO synthase in the control of ANGII-dipsogenic effect. This suggests that an L-type calcium channel participates in both short- and longer-term neuronal actions of ANGII by nitrergic way. (c) 2006 Elsevier B.V. All rights reserved.

Subfornical organ mediates pressor effect of angiotensin: Influence of nitric oxide synthase inhibitors, AT(1) and AT(2) angiotensin antagonist's receptors

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Nitric oxide and L-type calcium channel influences the changes in arterial blood pressure and heart rate induced by central angiotesin II

We study the voltage dependent calcium channels and nitric oxide involvement in angiotensin II-induced pressor effect. The antipressor action of L-Type calcium channel antagonist, nifedipine, has been studied when it was injected into the third ventricle prior to angiotensin II. The influence of nitric oxide on nifedipine antipressor action has also been studied by utilizing N(W)-nitro-L-arginine methyl ester (LNAME) (40 mu g/0.2 mu l) a nitric oxide synthase inhibitor and L-arginine ( 20 mu g/0.2 mu l), a nitric oxide donor agent. Adult male Holtzman rats weighting 200-250 g, with cannulae implanted into the third ventricle were injected with angiotensin II. Angiotensin II produced an elevation in mean arterial pressure and a decreased in heart rate. Such effects were potentiated by the prior injection of LNAME. L-arginine and nifedipine blocked the effects of angiotensin II. These data showed the involvement of L-Type calcium channel and a free radical gas nitric oxide in the central control of angiotensin II-induced pressor effect. This suggested that L-Type calcium channel of the circunventricular structures of central nervous system participated in both short and long term neuronal actions of ANG II with the influence of nitrergic system.