Doses Of Nifedipine Research Articles

Comparison of the Effect of Oral Dydrogesterone with Oral Nifedipine on the Treatment of Threatened Preterm Labor: A Randomized Controlled Trial

Background: Determining the most effective treatment for women at risk of preterm labor is crucial in reducing potential complications and neonatal mortality. This study aimed to compare the effects of two oral medications, Dydrogesterone and nifedipine, on managing preterm labor in pregnant women admitted with threatened preterm labor. Objectives: The trial aimed to compare the efficacy of Dydrogesterone versus nifedipine in preventing preterm labor. Methods: In this randomized controlled clinical trial, 54 pregnant women aged 18 to 45 years, with a gestational age of 26 to 34 weeks and at risk of preterm labor, were randomly assigned to receive either 40 mg oral Dydrogesterone or a standard dose of nifedipine (10 mg for the first dose) as a tocolytic. Key maternal and neonatal outcomes, including the interval between intervention and delivery, delivery type, neonatal intensive care unit (NICU) admission, NICU stay duration, and Bishop scores, were evaluated and compared between the two study groups. Results: The mean age of participants was 27.78 ± 2.53 years in the nifedipine group and 27.67 ± 2.53 years in the Dydrogesterone group. There were no significant differences (P > 0.05) between the two groups in baseline characteristics. The mean NICU stay in the Dydrogesterone group (2.3 ± 0.5 days) was significantly shorter than in the nifedipine group (4.6 ± 0.5 days) (P = 0.001). Although the frequency of gestational age at delivery, NICU admission, the interval between intervention and delivery, and repeated preterm labor were lower in the Dydrogesterone group, the differences between the groups were not statistically significant (P > 0.05). Conclusions: The findings suggest that Dydrogesterone is effective in treating preterm labor. Both drugs prevented preterm labor; however, nifedipine, despite being a standard treatment, has potential side effects and may not be suitable for all patients. These results indicate that Dydrogesterone, with fewer side effects, could be an alternative for patients who cannot use nifedipine. Further studies with larger sample sizes are needed to confirm or refute this finding.

The Alzheimer’s disease risk gene BIN1 regulates activity-dependent gene expression in human-induced glutamatergic neurons

Bridging Integrator 1 (BIN1) is the second most important Alzheimer’s disease (AD) risk gene, but its physiological roles in neurons and its contribution to brain pathology remain largely elusive. In this work, we show that BIN1 plays a critical role in the regulation of calcium homeostasis, electrical activity, and gene expression of glutamatergic neurons. Using single-cell RNA-sequencing on cerebral organoids generated from isogenic BIN1 wild type (WT), heterozygous (HET) and homozygous knockout (KO) human-induced pluripotent stem cells (hiPSCs), we show that BIN1 is mainly expressed by oligodendrocytes and glutamatergic neurons, like in the human brain. Both BIN1 HET and KO cerebral organoids show specific transcriptional alterations, mainly associated with ion transport and synapses in glutamatergic neurons. We then demonstrate that BIN1 cell-autonomously regulates gene expression in glutamatergic neurons by using a novel protocol to generate pure culture of hiPSC-derived induced neurons (hiNs). Using this system, we also show that BIN1 plays a key role in the regulation of neuronal calcium transients and electrical activity via its interaction with the L-type voltage-gated calcium channel Cav1.2. BIN1 KO hiNs show reduced activity-dependent internalization and higher Cav1.2 expression compared to WT hiNs. Pharmacological blocking of this channel with clinically relevant doses of nifedipine, a calcium channel blocker, partly rescues electrical and gene expression alterations in BIN1 KO glutamatergic neurons. Further, we show that transcriptional alterations in BIN1 KO hiNs that affect biological processes related to calcium homeostasis are also present in glutamatergic neurons of the human brain at late stages of AD pathology. Together, these findings suggest that BIN1-dependent alterations in neuronal properties could contribute to AD pathophysiology and that treatment with low doses of clinically approved calcium blockers should be considered as an option to slow disease-onset and progression.

Vasorelaxant and hypotensive effects of an ethanolic extract of Nymphaea pubescens and its main compound quercetin 3-methyl ether 3'-O-β-xylopyranoside.

Aim: Nymphaea plants were traditionally used to treat diseases associated with endothelial dysfunction. The present study investigated the effects of an ethanolic extract of Nymphaea pubescens Willd. (commonly named water lily, WL) and its main compound 1 (quercetin 3-methyl ether 3'-O-β-xylopyranoside) on vascular function in rats. Materials and methods: The vasorelaxant effects of the WL extract and its main compound 1 and their underlying mechanisms of action were evaluated on isolated mesenteric arteries from Wistar rats. Blood pressure and heart rate were measured in anesthetized rats after infusion (i.v) of vehicle, WL extract, and compound 1 (at 0.01, 0.025, 0.05, 0.1, 0.5, and 1mg/kg). Nifedipine was used as a positive control. Results: Both WL extract and compound 1 induced vasorelaxant effects (with EC50 of 0.08 ± 0.01mg/mL and 42.8 ± 6.3 µM, respectively) that were reduced by endothelium removal. A significant decrease in these relaxations was observed with L-NAME but not with apamin-charybdotoxin or indomethacin. In the endothelium-denuded condition, WL extract-induced relaxation was enhanced by 4-aminopyridine and glibenclamide, while iberiotoxin and ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one) had no effect. In contrast, compound 1-induced relaxation was not changed by any of these inhibitors. Both WL extract and compound 1 enhanced sodium nitroprusside-induced relaxation and inhibited receptor-operated Ca2+ channels. Only the WL extract was able to reduce PE-induced contraction (p < 0.001). As compared to the vehicle, the infusion of WL extract and compound 1 lowered systolic and diastolic blood pressure. Interestingly, the hypotensive effect of the compound was similar to that of nifedipine. The rebound tachycardia found at the highest dose of nifedipine was not observed with the WL extract or compound 1 (p < 0.05). Conclusion and discussion: Our study demonstrated a vasorelaxant effect of the WL extract and its main compound quercetin 3-methyl ether 3'-O-β-xylopyranoside, relying on the potentiation of the NO-cGMP pathway and calcium inhibitory effects. These vasorelaxant effects were associated with a potent hypotensive effect, providing pharmacological evidence for the traditional use of this plant.

In vitro inhibition of uterine contractions using electrospun nanofibers loaded with nifedipine and ML7.

To formulate a nanofiber-based controlled drug delivery system that could be effective in preventing uterine contractions and can be used for the treatment of preterm labor. We utilized uterine tissue samples obtained from ten pregnant women who underwent cesarean section at term to investigate the effect of nanofibers on spontaneous and induced myometrial contractions. We prepared nifedipine and ML7-loaded nanofibers using the electrospinning method with Poly(D,L-lactide-co-glycolide) (PLGA) polymer, resulted in seven groups of nanofibers, including a control group. Group I served as the control, Group II was non-drug loaded nanofiber, Group III was nifedipine (10-5 M) loaded nanofiber, Group IV was ML7 (3x10-5 M) loaded nanofiber, Group V was ML7 (3x10-5 M) and nifedipine (10-5 M) nanofiber, Group VI was ML7 (3x10-5 M) and nifedipine (3x10-5 M) nanofiber, and Group VII was ML7 (3x10-5 M) and nifedipine (10-4 M) nanofiber. To evaluate the contractile response, the nanofibers loaded with different doses of ML7 and nifedipine were applied onto the tissue strips, and in vitro organ bath experiments were performed. Full-thickness uterine samples were cleared of the serosa and surrounding tissues, and eight strips (3x10 mm) were prepared from each sample. The seven different nanofiber formulations were gently placed and sutured onto the strips, with one strip always kept as the time control. We recorded spontaneous, KCl-induced, and stimulated cumulative oxytocin-induced contractions from all samples in all groups. After completing all experiments, the viability of the strips was checked, and weight measurement was recorded. The administration of drug-loaded polymers resulted in a significant decrease in both the frequency and intensity of spontaneous and induced contractions in all groups (p<0.01). No significant difference was observed between the control group and the non-drug-loaded nanofiber group in post hoc analysis (p=0.704). In terms of amplitude and frequency of contractions, the most significant decrease was observed in group VII at cumulative oxytocin doses compared to the control and non-drug-loaded nanofiber groups (p<0.05). Moreover, group VI also showed a significant decrease in contraction intensity and frequency compared to the control and non-drug-loaded nanofiber groups (p<0.05). While the use of nifedipine and/or ML7-loaded nanofibers decreased both intensity and frequency of contraction, this attenuation was not significant compared to the control and empty polymer groups. However, a more significant inhibition was observed when ML7 was used with nifedipine at doses of 3x10-5 M and 10-4 M. The results indicate that human uterine contractions can be inhibited using calcium channel blocker (nifedipine) and myosin light chain kinase inhibitor (ML7) loaded nanofibers in uterine tissue strips. These results strongly suggested the potential for the development of locally effective and safe controlled drug release systems to prevent premature birth.

Use of Tocolytic Agents in Preterm Labor: A Cross‐Sectional Analysis from a Chinese Real‐World Study from 2016 to 2021

What Is Known and Objective. Tocolytic agents are used to prolong gestational age and prevent immediate preterm birth (PTB). This study aims to provide an overview of the use of tocolytics among patients with PTB in China through retrospectively analyzing trends in application, influencing factors, and inappropriate prescriptions. Methods. The prescription data of five tocolytic agents from 2016 to 2021 were extracted from the database of the Hospital Prescription Analysis Cooperation Project. Drug consumption was expressed as number of prescriptions, cost of prescriptions, and DDDs (defined daily doses). Pearson correlation analysis was used to examine the association between DDDs and DDC (defined daily cost). The appropriateness of prescriptions was analyzed in terms of drug dosage form, administration, clinical diagnosis, and combined medication. Results. The total number of tocolytic prescriptions and the total cost of tocolytic agents increased by 6.12% and 387.58%, respectively, over the six‐year duration of the study. From 2016 to 2021, the ranking of the number of prescriptions and DDDs of tocolytic agents was magnesium sulfate &gt; ritodrine &gt; nifedipine &gt; indomethacin &gt; atosiban. During the study period, the cost of tocolytic agents increased significantly, which was mainly related to the increased costs of magnesium sulfate in 2017 and atosiban in 2018 and 2019. The ranking of DDCs was atosiban &gt; ritodrine &gt; magnesium sulfate &gt; nifedipine = indomethacin from 2016 to 2021. For atosiban, the DDC was negatively correlated with the DDDs. Inappropriate prescription, which accounted for 14.84% of all prescriptions, was mainly manifested in the inappropriate selection of nifedipine dosage form, low frequency of nifedipine and indomethacin, and overdosing of ritodrine. Furthermore, 22.87% of tocolytic prescriptions remained active after 34 weeks of gestation, and 7.24% of the prescriptions authorized the use of combination drugs, with magnesium sulfate and nifedipine being the most commonly prescribed combination. What Is New and Conclusion. Magnesium sulfate, ritodrine, and nifedipine were the top three tocolytic agents. As the inappropriate use of tocolytic agents continues to persist, it is important to intensify efforts to ensure the safety and the appropriateness of maternal medication.

Effect of Omeprazole Administration on the Pharmacokinetics of Oral Extended-Release Nifedipine in Healthy Subjects.

Oral extended-release (ER) dosage forms have been used to sustain blood drug levels, reduce adverse events, and improve patient compliance. We investigated potential effects of comedication on pharmacokinetic exposure of nifedipine ER products with different formulation designs and manufacturing processes. A clinical study compared a generic version of nifedipine ER tablet with pH-dependent dissolution behavior with an osmotic pump product with pH independent drug release under fasting condition. In this study, two nifedipine tablet products were tested with or without short-term omeprazole comedication in healthy subjects. Seven-day administration of omeprazole before nifedipine dosing significantly increased the gastric pH, and subsequently increased the geometric least square (LS) means of area under the concentration-time curve from time zero to the last measurable timepoint (AUC0-t ) and maximum plasma concentration (Cmax ) of nifedipine to 132.6% (90% confidence interval (CI): 120.6-145.7%) and 112.8% (90% CI: 100.8-126.3%) for pH-dependent ER tablets, and 120.6% (90% CI: 109.7-132.5%) and 122.5% (90% CI: 113.7-131.9%) for the pH-independent ER tablets, respectively. Similar extent of increase in AUC0-t and Cmax was confirmed in the subpopulations whose gastric pH was ≥ 4 or ≤ 3 in subjects with or without omeprazole administration. Given that similar increases in drug exposures were observed for both pH-dependent and pH-independent nifedipine formulations and the geometric LS mean ratios were between 112% and 133% with and without short-term omeprazole comedication, the gastric pH may have limited effects on omeprazole-induced nifedipine PK changes on the tested formulations. The inhibition of cytochrome P450 3A4 activity may play a significant role causing nifedipine exposure changes for both formulations, which would warrant additional assessment.

Differential Effects of Ca2+ Channel Blockers Nifedipine and Cilnidipine on Arterial Elasticity in the Aortic and Femoral Arterial Segments of Anesthetized Rabbits.

Ca2+ channel blockers have potent vasodilatory effects and excellent efficacy in preserving organ blood flow. These hemodynamic actions may be partly controlled by the functional stiffness of conduit arteries. In this study, we assessed the effects of the L-type Ca2+ channel blocker nifedipine on aortic and femoral arterial stiffness (referred to as aortic β and femoral β, respectively) in anesthetized rabbits. To further clarify the involvement of the autonomic nervous system, we compared the effects of nifedipine with those of the L/N-type Ca2+ channel blocker cilnidipine. Further, the effect of the α-adrenergic receptor blocker doxazosin on the effects of nifedipine on arterial elasticity was examined. An antihypertensive dose of nifedipine (300 µg/kg, administered intravenously) was found to increase the aortic β but hardly affected the femoral β. An antihypertensive dose of cilnidipine (30 µg/kg, administered intravenously) increased the aortic β but decreased the femoral β. Interestingly, nifedipine decreased the femoral β in the presence of the α-adrenoceptor blocker doxazosin (1 mg/kg, administered intravenously). These effects suggest that L-type Ca2+ channel blockers essentially increase vascular elasticity via the decrement in arterial stiffness in the femoral artery segment, which is modified by the presence or absence of the inhibitory effect of each drug on reflex sympathetic nerve activity, while decreasing vascular elasticity via the increment in arterial stiffness in the aortic segment independently of sympathetic nerve activity.

Comparison of Efficacy and Safety of Magnesium Sulphate Versus oral Nifedipine in Acute Tocolysis of Preterm Labour

Aim: To compare the efficacy and safety of magnesium sulphate and oral nifedipine in acute tocolysis of preterm labor. Study design: Randomized controlled trial. Place and duration of study: Department of Obstetrics &amp; Gynecology, DHQ Hospital, Mirpur from 19th October 2019 to 18th April 2020. Methodology: This study included 178 pregnant women with singletons (18 to 40 years of age) assessed through ultrasonography and presented preterm labor. Pregnant women having fetal growth restriction, fetal death, severe preeclampsia, fetal distress, hyperthyroidism,any maternal contraindication for the use of tocolytic drugs, cardiovascular disease, abruptio placentae or placenta-previa were placed in the seclusion criteria of the study. In the group A, oral loading dose of nifedipine 20mg was given. While in group B, magnesium sulphate was injected intravenously with a loading dose of 4 grams over 15 minutes followed by maintenance dose of 2-3 grams/hr. All patients in both groups were evaluated by the researcher herself for prolongation of pregnancy at 48 hours after the start of treatment and efficacy and safety was noted. Results: Efficacy was seen in 80 (89.89%) in group A (Oral nifedipine) and 67 (75.28%) in group B (magnesium sulfate) with p0.019. Safety was seen in 72 (80.90%) in group B (magnesium sulfate) and 83 (93.26%) in group A (oral nifedipine) with p 0.014. Practical Implication: The administration of corticosteroids and also assist in reducing mortality and morbidity related with preterm labor events. Conclusion: This study concluded that oral nifedipine is efficacious and safe than magnesium sulphate for acute tocolysis of preterm labour. Keywords: Tocolytic Agents, Preterm Birth, Magnesium Sulphate.

Nifedipine attenuates alveolar bone destruction and improves trabecular microarchitectures in mice with experimental periodontitis.

Studies have shown that nifedipine exerts anti-inflammatory and immunosuppressive actions in addition to being a calcium channel blocker. The present study was performed to explore the influence of nifedipine on alveolar bone destruction in mice with experimental periodontitis by evaluating morphological information acquired from micro-computed tomography analysis. BALB/c mice were randomly assigned into four groups: control (C) group; experimental periodontitis (E) group; experimental periodontitis + 10mg/kg dose of nifedipine (EN10) group; and experimental periodontitis + 50mg/kg dose of nifedipine (EN50) group. Periodontitis was induced by oral inoculation with Porphyromonas gingivalis over a 3-week time period. Nifedipine significantly mitigated the loss of alveolar bone height as well as increase of root surface exposure induced by experimental periodontitis. Additionally, the reduction in the bone volume fraction associated with P. gingivalis infection was significantly recovered upon nifedipine treatment. Further, nifedipine attenuated P. gingivalis-induced deteriorations in the trabeculae-associated parameters. Significant difference was evident between Groups EN10 and EN50 in both the extent of alveolar bone loss and microstructural parameters assessed, except trabecular separation and trabecular number. Nifedipine appeared to have good performance in ameliorating bone loss in mice with induced periodontitis. Nifedipine may be utilized in the clinical management of periodontitis, though further research is indicated to verify the therapeutic effect.

Daily Versus Twice-Daily Dosing of Nifedipine for Blood Pressure Control in Pregnancy and Postpartum [ID: 1375881

INTRODUCTION: Hypertensive disorders of pregnancy (HDP) may be managed with oral antihypertensives; however, pregnancy-induced changes in the hormonal milieu and volume of distribution make it difficult to determine optimal dosing regimens. Nifedipine is a first-line therapy for treatment of HDP. The purpose of this study is to compare 60 mg daily (QD) of extended released (XR) nifedipine to 30 mg twice daily (BID) for blood pressure (BP) control antepartum and postpartum. METHODS: This was a retrospective chart review conducted in Mount Sinai Health System. Patients admitted from January 1, 2015 to April 30, 2021, who were diagnosed with a HDP and received nifedipine XR 30 mg BID or 60 mg QD for intrapartum or postpartum BP control were included. The primary outcome was need for dose adjustment of nifedipine or addition of another antihypertensive agent. Patients were excluded if they had preexisting renal disease or were already taking oral antihypertensives. RESULTS: Two hundred thirty-seven patients were included, 139 (59%) received 30 mg BID and 98 (41%) 60 mg QD. There was no statistically significant difference in the need for increase in nifedipine dose or addition of another oral antihypertensive between those receiving 30 mg BID versus 60 mg QD (33.8% versus 35.7%, adjusted odds ratio [95% CI], 0.90 [0.50, 1.60]; P=.71). Additionally, there was no difference in need for emergency hypertensive treatment after reaching study dose (P=.19) or readmission for BP control between the two groups (P&gt;.99). CONCLUSION: These findings suggest that BID versus QD dosing of nifedipine XR does not improve blood pressure control in the antepartum or postpartum periods; thus, daily dosing is reasonable and may be preferable for patient convenience and compliance.

Effect of zolmitriptan on blood pressure-relevant cardiovascular biomarkers in rats with experimentally induced hypertension

Background and objective: Zolmitriptan is among widely used medicines for the management of migraine attach, zolmitriptan is acting through stimulating serotonin (5-HT1B/1D) receptors that will cause cranial vasoconstriction. This study was aimed to compare and evaluate the impact of zolmitriptan on the relevant cardiovascular and renal biomarkers during hypertension in rats with experimentally induced hypertension. Methods: Twenty-four Wister albino male rats were randomly divided into four groups of six rats each. The first group (Group I) of rats served as the control group. To induce hypertension, the rats in the second (Group II), third (Group III) and fourth (Group IV) groups have received an intraperitoneal injection of cadmium chloride CdCl2 a dose of 1.5 mg/kg/day for 14 days. The rats in Group II were considered as the positive control. Whereas, rats in Group III received zolmitriptan orally (2 mg/kg/day), and Group IV rats received nifedipine dose of 10mg/kg for two weeks concurrently with CdCl2. Results: Inducing hypertension with CdCl2 injection significantly increased the systolic, diastolic, and mean blood pressure in Group II compared with Group I, respectively. The systolic, diastolic, and mean blood pressure in rats that received zolmitriptan did not exhibit any statistically significant differences from the rats in Group II, whereas nifedipine has significantly reduced blood pressure in group IV rats. Intraperitoneal injection of CdCl2 increased the concentrations of endothelin and nitric oxide as well as renin activity level in hypertensive Group II rats compared to control rats. Zolmitriptan administration did not produce any significant change in the endothelin and nitric oxide levels. Inducing hypertension in rats significantly reduced the corticosterone level. In contrast, administering medications in Group III and VI rats did not produce any statistically significant change in the serum concentration of corticosterone. Conclusion: Zolmitriptan administration (2 mg/kg/day, p.o) showed no statistically significant effects on the systolic, diastolic, and mean blood pressure in rats with experimentally induced hypertension. Zolmitriptan has also failed to produce any statistically significant change in the levels of endothelin-1, renin, nitric oxide, corticosterone, and serum creatinine in rats with hypertension.

Effectiveness of nifedipine, labetalol, and hydralazine as emergency antihypertension in severe preeclampsia

Background: Preeclampsia is a highly prevalent disease among pregnant women. In the event of hypertensive emergency, nifedipine, labetalol, and hydralazine are assigned as first-line therapies in preeclampsia. Further studies are needed to compare the effectiveness of these drugs to find the most cost-effective drug with minimal side effects. This study aimed to compare the effectiveness of these drugs in lowering blood pressure during hypertensive emergencies in severe preeclampsia. Methods: 60 pregnant women with severe preeclampsia were recruited in this multiple centre double-blind randomized clinical trial from May 2021 to April 2022 in Indonesia. The patients were divided equally into three groups and treated with three doses of nifedipine, labetalol, and hydralazine, respectively within one hour with 20 minutes interval. The effectiveness was measured based on systolic and diastolic blood pressures, and mean arterial pressure (MAP). The observation was carried out until five hours post-third dose administration. Results: The blood pressure was reduced significantly after the administration of the first to the third dose of each antihypertensive (p&lt;0.05). A single dose administration, four, one, and three patients had 20% MAP reduction in nifedipine, labetalol, and hydralazine group. Three, seven, and one patient had a failure of reaching 20% MAP reduction even after receiving the third dose. The effectiveness of the drugs to achieve 20% reduction of MAP could be ranked as follows: nifedipine&gt;labetalol&gt;hydralazine (57.49%, 42.13%, and 40.87%, respectively) for single dose and hydralazine&gt;nifedipine&gt;labetalol (111.3%, 85.12%, and 90.04%, respectively) for triple dose. Conclusions: Nifedipine is the most effective drug to reduce the blood pressure when single dose administration is used, but requires more doses to further reduce the blood pressure. Hydralazine is the most effective when the drug administration is maxed up to three doses within 60 minutes with 20 minutes interval. Thai Clinical Trials Registry (TCTR): TCTR20221014007 (14/10/2022)

Population Pharmacokinetic Modelling for Nifedipine to Evaluate the Effect of Parathyroid Hormone on CYP3A in Patients with Chronic Kidney Disease.

PurposeParathyroid hormone (PTH) can induce the downregulation of CYP3A in chronic kidney disease (CKD). Nevertheless, the effect of PTH on CYP3A-mediated clearance pathways from a clinical perspective remains unclear.MethodsThis study employed population pharmacokinetic (PopPK) modeling to delineate potential changes in CYP3A activity in patients with CKD. Pharmacokinetic data for nifedipine, a typical CYP3A substrate, as well as covariate information, were prospectively collected from 157 patients with a total of 612 concentrations. PopPK data analysis was performed using a nonlinear mixed-effects model.ResultsThe pharmacokinetics of nifedipine were optimally described according to a one-compartment model with zero-order absorption and first-order elimination. The estimated population parameters (and interindividual variability) were apparent clearance (CL/F) 49.61 L/h (58.33%) and apparent volume of distribution (V/F) 2300.26 L (45.62%), and the PTH level negatively correlated with CL/F. In comparison with the reference level, it was observed that the dosage of nifedipine should be reduced with the maximum boundary value of PTH, after a Monte Carlo simulation.ConclusionThis study provides insight into the effects of PTH on CYP3A-mediated clearance pathways. Moreover, PTH could be used as a guide for the appropriate administration of CYP3A eliminated drugs in patients with CKD.

Autonomic Dysreflexia with Concurrent Orthostatic Hypotension: A Clinical Approach Dilemma

Background and aim: Autonomic dysreflexia (AD) commonly occurs in high cervical spinal cord injury (SCI) patients. However, concurrent orthostatic hypotension (OH) makes the management of this condition more difficult. This case report highlighted the complicated condition that creates a dilemma for clinicians to prioritise the management. Methods: A 26-year-old man presented with traumatic cervical SCI C4 ASIA B secondary to C3 – C5 vertebral body fracture underwent anterior corpectomy and fusion. He had frequent episodes of AD in the rehabilitation clinic, presenting with sweating, headache, and high blood pressure (BP) while he was in a wheelchair. No other precipitating factors were identified except for his chronic sacral and ischial wounds. These AD episodes also happened multiple times daily at home with intermittent presyncope attacks. He was given stat doses of Nifedipine during the clinic visits but was never prescribed antihypertensive as no proper BP monitoring was done at home. Nonpharmacological measures for OH were already established. The rehabilitation team educated him on a side-lying position to alleviate his AD symptoms and preventive strategies such as optimal pressure relief with wheelchair cushions and using the reclining function on his motorised wheelchair. Results: He had difficulty achieving independent mobility because he could not tolerate upright sitting without having AD and intermittent OH. Conclusion: OH as a precipitating factor for AD should be considered. The lowest possible dose of antispastic medications for optimum spasm control and consideration of mineralocorticoid drugs for OH management may be helpful. Antihypertensives are commonly used for prophylaxis of chronic recurrent AD. However, its usage may be limited in patients with OH. Prazosin may be an option as studies have shown that it did not excessively lower baseline BP. Pressure mapping and surgical intervention to facilitate chronic non-healing wound closure also should be considered. Chronic recurrent AD with intermittent OH remains a challenging condition in high SCI.

Dual effect of nifedipine on pregnant human myometrium contractility: Implication of TRPC1.

Nifedipine, an L‐type voltage‐gated Ca2+ channel (L‐VGCC) blocker, is one of the most used tocolytics to treat preterm labor. In clinical practice, nifedipine efficiently decreases uterine contractions, but its efficacy is limited over time, and repeated or maintained nifedipine‐based tocolysis appears to be ineffective in preventing preterm birth. We aimed to understand why nifedipine has short‐lasting efficiency for the inhibition of uterine contractions. We used ex vivo term pregnant human myometrial strips treated with cumulative doses of nifedipine. We observed that nifedipine inhibited spontaneous myometrial contractions in tissues with high and regular spontaneous contractions. By contrast, nifedipine appeared to increase contractions in tissues with low and/or irregular spontaneous contractions. To investigate the molecular mechanisms activated by nifedipine in myometrial cells, we used the pregnant human myometrial cell line PHM1‐41 that does not express L‐VGCC. The in vitro measurement of intracellular Ca2+ showed that high doses of nifedipine induced an important intracellular Ca2+ entry in myometrial cells. The inhibition or downregulation of the genes encoding for store‐operated Ca2+ entry channels from the Orai and transient receptor potential‐canonical (TRPC) families in PHM1‐41 cells highlighted the implication of TRPC1 in nifedipine‐induced Ca2+ entry. In addition, the use of 2‐APB in combination with nifedipine on human myometrial strips tends to confirm that the pro‐contractile effect induced by nifedipine on myometrial tissues may involve the activation of TRPC channels.

Effects of nifedipine on fetal pulmonary blood flow in preterm labor

Objective To determine the effect of nifedipine on the fetal pulmonary system by acceleration/ejection time ratio of the fetal main pulmonary artery Doppler waveform. Methods This prospective study was conducted in a high-risk pregnancy clinic with pregnant women who required nifedipine treatment to prevent preterm labor between 24 and 34 weeks of gestation. An ultrasound examination that included measurements of the acceleration time (AT), ejection time (ET), and AT/ET ratio (PATET) were performed before and 48 h after the first nifedipine dose. Results Forty-three pregnant women were included in this study. AT and PATET found higher in the after nifedipine group when compared with before nifedipine group. When the ET parameters were compared, no differences were detected between the groups. Conclusion Nifedipine increases fetal pulmonary blood flow which appears to increase AT and PATET on Doppler parameters in pregnant women with preterm labor after 48h treatment.

Effects of Nifedipine on Renal and Cardiovascular Responses to Neuropeptide Y in Anesthetized Rats.

Neuropeptide Y (NPY) acts via multiple receptor subtypes termed Y1, Y2 and Y5. While Y1 receptor-mediated effects, e.g., in the vasculature, are often sensitive to inhibitors of L-type Ca2+ channels such as nifedipine, little is known about the role of such channels in Y5-mediated effects such as diuresis and natriuresis. Therefore, we explored whether nifedipine affects NPY-induced diuresis and natriuresis. After pre-treatment with nifedipine or vehicle, anesthetized rats received infusions or bolus injections of NPY. Infusion NPY (1 µg/kg/min) increased diuresis and natriuresis, and this was attenuated by intraperitoneal injection of nifedipine (3 µg/kg). Concomitant decreases in heart rate and reductions of renal blood flow were not attenuated by nifedipine. Bolus injections of NPY (0.3, 1, 3, 10 and 30 μg/kg) dose-dependently increased mean arterial pressure and renovascular vascular resistance; only the higher dose of nifedipine (100 μg/kg/min i.v.) moderately inhibited these effects. We conclude that Y5-mediated diuresis and natriuresis are more sensitive to inhibition by nifedipine than Y1-mediated renovascular effects. Whether this reflects a general sensitivity of Y5 receptor-mediated responses or is specific for diuresis and natriuresis remains to be investigated.

Dual role played by Ca 2+ in the cytotoxicity of human metastatic breast cancer cells

Introduction Cancer cells exhibit enhanced potential to metastasize via increased acto-myosin cross bridges formation which requires increased Ca2+ influx via cell surface voltage-gated Ca2+ channels (VGCC) leading to activation of myosin light chain kinase (MLCK). The MLCK then phosphorylates myosin and forms acto-myosin cross-bridges. The role of MLCK, and calcium channel in cancer cell growth has not been extensively tested. Objective In this study, we tested the individual effects of blocking VGCC and MLCK on MCF-7 cell (human metastatic breast cancer cell) survival. We also treated the cells with high KCl to induce increased Ca2+ influx and test if the effects of KCl will be opposite to that of VGCC blocker. Methods The experimental design of this study is primarily focused on the administration of specific inhibitors to MCF-7 cells with an interest in the dose-dependent response of the cells to varying concentrations of the treatments as well as a thorough comparison of the cell morphology, viability, and proliferation to the effects of the 1% BME control. The three drugs that have been investigated so far are Nifedipine, a voltage-gated calcium blocker, Nifedipine in the presence of KCl [in order to artificially depolarize the cell membrane to open the VGCC], and ML-7, a myosin light chain kinase inhibitor. The cell viability was then assessed through an MTT colorimetric assay at 562 nm in order to visually and quantitatively assess the results. Additionally, transfection studies are planned to be carried out to substantiate pharmacological findings of inhibitors. Results & Conclusion Nifedipine dose-dependently inhibited MCF-7 cell viability. Following were the % absorbance values with increasing doses of nifedipine. All values are relative to control without nifediine considered as 100%; [0.625 um Nif – 43.05%, 1.25 um Nif – 42.19%, 2.5 um Nif – 40.15%, 5 um Nif -39.53%, 10 um Nif – 38.19%, 20 um Nif – 25.1%, 40 um Nif – 22.96%, 1% BME –39.26%]. The 1% BME (bitter melon extract) is the positive control in our studies as our lab have found BME to be toxic to MCF-7 cells. ML-7 also dose-dependently inhibited MCF-7 cell viability. Following were the % absorbance values with increasing doses of ML-7. All values are relative to control without ML-7 considered as 100%; (0.5 um ML7- 70.01%, 1 um ML7 – 65.74%, 2 um ML7 – 57.71%, 4 um ML7 – 49.36%, 8 um ML7 – 48.28%, 16 um ML7 – 34.13%, 1% BME – 36.17%]. When we stimulated cells with increasing doses of KCl, increasing toxicity was seen as reflected by the decreasing absorbance values. We tested the effects of KCl in the presence or absence of nifedipine. Following were the % absorbance values with increasing doses of KCl and/or nifedipine. All values are relative to control (neither KCl nor nifedipine) considered as 100%; [40 mm KCl – 29.55%, 20 mm KCl – 44.024%, 10 mm KCl –56.51%, 40 um Nif – 22.81%, 40 mm KCl + 40 um Nif – 13.69%, 20 mm KCl + 40 um Nif –15.87%, 10 mm KCl + 40 um Nif – 30.91%, EtOH – 86.85%, 1% BME – 35.27%.]. Thus, either inhibiting Ca2+ influx with nifedipine or opening VGCC with high KCl both exerted cytotoxic effects on MCF-7 cells. This suggests that Ca2+ is critical for the viability of these cells but at the same time too much Ca2+ is toxic to the cells.

Design and characterisation of an amorphous formulation of nifedipine for the treatment of autonomic dysreflexia.

Current treatment for autonomic dysreflexia (AD) involves rupturing a liquid-filled soft capsule of nifedipine to aid rapid drug release and absorption, however, this application is not covered under the manufacturer's license. The objective of the current work was to design a rapidly dissolving solid dosage formulation for the treatment of AD as an alternative to the off-license "bite and swallow" use of currently available commercial products. Amorphous solid dispersions (ASDs) of nifedipine were prepared by spray-drying using three different polymers: hydroxypropyl methyl cellulose (HPMC), polyvinyl pyrrolidone (PVP) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (Soluplus), at a 15% w/w drug loading and were formulated and compressed into tablets. Dissolution testing was performed in the paddle dissolution apparatus using either a monophasic or biphasic medium. The PVP-nifedipine ASD tablets exhibited rapid dissolution, with 35% of the total nifedipine dose dissolving within 15 min in the monophasic dissolution medium. The HPMC-nifedipine ASD exhibited a very slow dissolution, while the Solupus-nifedipine system exhibited no nifedipine release over 120 min. When tested in the biphasic dissolution medium, the PVP-nifedipine ASD tablets exhibited a release profile comparable to that of the pre-split/ruptured nifedipine soft capsule product. This study demonstrates that a nifedipine-PVP ASD is a promising formulation strategy in the treatment of AD.

395 Dual effect of nifedipine on term pregnant human myometrium contractility

Nifedipine, L-type voltage-gated Ca2+ channels (L-VGCC) blocker, is one of the most used tocolytics to treat preterm labor. In clinical practice, nifedipine efficiently decreases uterine contractions but its efficacy is limited overtime (48h). The aim of this study was to understand why nifedipine has short-lasting efficiency for inhibition of uterine contractions. Term pregnant human myometrial strips with different ex vivo contractile capacities [either regular (n=6) or irregular (n=5) spontaneous contractions] were mounted in an organ bath, and treated with cumulative doses of nifedipine. Tissue contractility in response to nifedipine was analyzed. Then, to investigate the molecular mechanisms activated by nifedipine in myometrial cells with irregular contractile capacity, we used the pregnant human myometrial cell line PHM1-41 that does express L-VGCC. Cells were transfected with siRNA for ORAI1, a non-voltage gated Ca2+ channel, and STIM1, the ORAI1 regulator. Both transfected and non-transfected cells were treated with different doses of nifedipine. Evolution of intracellular Ca2+ level was monitored with a Ca2+ indicator dye. Treatment of myometrial strips with cumulative doses of nifedipine inhibited spontaneous myometrial contraction in tissues with high contractility, even at low doses. On the contrary, nifedipine treatment appeared to increase contractions in tissues with low contractility (Fig1). In vitro, high doses of nifedipine (>10-6M) induced an important intracellular Ca2+ entry in myometrial cells (Fig2). Nifedipine-induced Ca2+ influx was not affected by knock-down of ORAI1 and STIM1 neither individually, nor together This study highlighted existence of a dual action of nifedipine. In addition to inhibit contraction in contracting myometrial tissue, we showed that nifedipine had an opposite pro-contractile effect in weak-contracting muscle. This effect could involve an activation of Ca2+ entry into myometrial cells, but this process does not seem to involve neither STIM1 nor ORAI1 Ca2+ channel.View Large Image Figure ViewerDownload Hi-res image Download (PPT)