Bryophyllum pinnatum enhances the inhibitory effect of atosiban and nifedipine on human myometrial contractility: an in vitro study.

BACKGROUND: The herbal medicine Bryophyllum pinnatum has been used as a tocolytic agent in anthroposophic medicine and, recently, in conventional settings alone or as an add-on medication with tocolytic agents such as atosiban or nifedipine. We wanted to compare the inhibitory effect of atosiban and nifedipine on human myometrial contractility in vitro in the absence and in the presence of B. pinnatum press juice (BPJ). METHODS: Myometrium biopsies were collected during elective Caesarean sections. Myometrial strips were placed under tension into an organ bath and allowed to contract spontaneously. Test substances alone and at concentrations known to moderately affect contractility in this setup, or in combination, were added to the organ bath, and contractility was recorded throughout the experiments. Changes in the strength (measured as area under the curve (AUC) and amplitude) and frequency of contractions after the addition of all test substances were determined. Cell viability assays were performed with the human myometrium hTERT-C3 and PHM1-41 cell lines. RESULTS: BPJ (2.5 µg/mL), atosiban (0.27 µg/mL), and nifedipine (3 ng/mL), moderately reduced the strength of spontaneous myometrium contractions. When BPJ was added together with atosiban or nifedipine, inhibition of contraction strength was significantly higher than with the tocolytics alone (p = 0.03 and p < 0.001, respectively). In the case of AUC, BPJ plus atosiban promoted a decrease to 48.8 ± 6.3% of initial, whereas BPJ and atosiban alone lowered it to 70.9 ± 4.7% and to 80.9 ± 4.1% of initial, respectively. Also in the case of AUC, BPJ plus nifedipine promoted a decrease to 39.9 ± 4.6% of initial, at the same time that BPJ and nifedipine alone lowered it to 78.9 ± 3.8% and 71.0 ± 3.4% of initial. Amplitude data supported those AUC data. The inhibitory effects of BPJ plus atosiban and of BPJ plus nifedipine on contractions strength were concentration-dependent. None of the test substances, alone or in combination, decreased myometrial cell viability. CONCLUSIONS: BPJ enhances the inhibitory effect of atosiban and nifedipine on the strength of myometrial contractions, without affecting myometrium tissue or cell viability. The combination treatment of BPJ with atosiban or nifedipine has therapeutic potential.

Effects of licochalcone A on the bioavailability and pharmacokinetics of nifedipine in rats: possible role of intestinal CYP3A4 and P-gp inhibition by licochalcone A.

The purpose of this study was to investigate the possible effects of licochalcone A (a herbal medicine) on the pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats. The pharmacokinetic parameters of nifedipine and/or dehydronifedipine were determined after oral and intravenous administration of nifedipine to rats in the absence (control) and presence of licochalcone A (0.4, 2.0 and 10 mg/kg). The effect of licochalcone A on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity was also evaluated. Nifedipine was mainly metabolized by CYP3A4. Licochalcone A inhibited CYP3A4 enzyme activity in a concentration-dependent manner with a 50% inhibition concentration (IC50 ) of 5.9 µm. In addition, licochalcone A significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. The area under the plasma concentration-time curve from time 0 to infinity (AUC) and the peak plasma concentration (Cmax ) of oral nifedipine were significantly greater and higher, respectively, with licochalcone A. The metabolite (dehydronifedipine)-parent AUC ratio (MR) in the presence of licochalcone A was significantly smaller compared with the control group. The above data could be due to an inhibition of intestinal CYP3A4 and P-gp by licochalcone A. The AUCs of intravenous nifedipine were comparable without and with licochalcone A, suggesting that inhibition of hepatic CYP3A4 and P-gp was almost negligible.

The effects of serotonin biosynthesis inhibition on nicotine and nifedipine-induced analgesia in rats.

UNLABELLED: The calcium channel blocker nifedipine has analgesic properties that are enhanced by nicotine. Although it is not known how this analgesic state might affect the awareness of anginal pain and impending myocardial infraction, recent studies have shown an increased mortality associated with the use of large doses of nifedipine. Because both nifedipine- and nicotine-induced analgesia involve serotonergic mechanisms, we studied the effects of the serotonin biosynthesis inhibitor parachlorophenylalanine (pCPA) on nifedipine- and nicotine-induced analgesia. Nociception was assessed by tail-flick method. Rats pretreated with pCPA (300 mg/kg intraperitoneally [IP]) followed by either nifedipine (15 mg/kg IP) or nicotine (1 mg/kg subcutaneously) had a increase in tail-flick latency of 41% (P = 0.09) and 50% (P = 0.05), respectively, compared with animals that did not receive pCPA. Additionally, rats pretreated with pCPA followed by a combination of nicotine and nifedipine doubled their tail-flick latency (P = 0.0001) compared with animals that were not treated with pCPA. These data further support the involvement of the serotonergic system in both nifedipine- and nicotine-induced analgesia and suggest that drugs that affect serotonin levels, including tricyclic antidepressants and serotonin-specific reuptake inhibitors, may also affect the analgesia induced by nifedipine and nicotine. IMPLICATIONS: This study examines the effect of serotonin depletion on nicotine- and nifedipine-induced analgesia. Nifidipine is a calcium channel blocker used to treat high blood pressure. It also has pain-relieving properties that are enhanced by nicotine. Because both nifedipine- and nicotine-induced analgesia involve the neurotransmitter serotonin, it is important to know how changes in serotonin concentration might affect both nicotine- and nifedipine-induced analgesia. This study not only supports the involvement of the serotonergic system in both nifidipine- and nicotine-induced analgesia, but also suggests that drugs that affect serotonin levels may also affect analgesia induced by nifidipine and nicotine.

[Methodologic approaches to evaluation of interaction of anti-anginal agents in their combined use in patients with exercise-induced angina]. / Metodicheskie podkhody k otsenke vzaimodeistviia antianginalnykh preparatov pri ikh kombinirovannom primenenii u bolnykh so stenokardiei napriazheniia.

The paper shows methodological approaches to assessing the interaction (antagonism and synergism) of antianginal agents in their combination used in 15 patients with stable angina. Each patient underwent paired bicycle ergometry with placebo, isosorbide dinitrate, 10 mg (ID), nifedipine, 20 mg (N), propranolol, 40 mg (P), and a combination of the drugs: ID, 10 mg, +P, 40 mg; N, 20 mg, +P, 40 mg; ID, 10 mg+N, 20 mg. The results were processed by two-dimensional dispersion analysis. Based on the findings, it was concluded that the interaction of drugs in all combinations was statistically insignificant in patients. At the same time the developed individual criteria for assessing the interaction allowed patients both with synergic and antagonistic interaction of antianginal drugs to be revealed.

Avanços terapêuticos em cardiologia: parte 1 - Antagonistas do cálcio: estado atual em cardiologia / Therapeutic advances in cardiology: part 1 - Calcium antagonists: up-to-date state in cardiology

O cálcio representa a base celular para a excitaçäo e contraçäo da musculatura cardiovascular. Os bloqueadores do cálcio têm estruturas moleculares diferentes, com efeitos comuns, e repercussöes cardiovasculares com potências desiguais. Aumentam o fluxo coronário, diminuem a pós-carga, o consumo de oxigênio e o espasmo coronário. Têm múltiplas indicaçöes clínicas, representando um marco na estratégia terapêutica em cardiologia

Counteraction of nifedipine-induced hyperglycaemia by metformin.

Nifedipine-induced hyperglycaemia in rats was counteracted by concurrent administration of metformin (500 mg/kg p.o.). However, glibenclamide (5 mg/kg p.o.) did not change the hyperglycaemic effect of nifedipine. It is suggested that nifedipine-induced hyperglycaemia was not related to pancreatic effect and might be attributed to extra pancreatic mechanism by preventing the action of insulin in the tissues. Therefore, counteraction of nifedipine-induced hyperglycaemia by metformin, may play a role in diabetic patients treated with nifedipine.