Aims The local concentration of extracellular Ca.sup.2+ (Ca.sup.2+ .sub.o) in bone microenvironment is accumulated during bone remodeling. In the present study we investigated whether elevating ...Ca.sup.2+ .sub.o induced store-operated calcium entry (SOCE) in primary rat calvarial osteoblasts and further examined the contribution of elevating Ca.sup.2+ .sub.o to osteoblastic proliferation. Methods Cytosolic Ca.sup.2+ concentration (Ca.sup.2+ .sub.c) of primary cultured rat osteoblasts was detected by fluorescence imaging using calcium-sensitive probe fura-2/AM. Osteoblastic proliferation was estimated by cell counting, MTS assay and ATP assay. Agonists and antagonists of calcium-sensing receptors (CaSR) as well as inhibitors of phospholipase C (PLC), SOCE and voltage-gated calcium (Cav) channels were applied to study the mechanism in detail. Results Our data showed that elevating Ca.sup.2+ .sub.o evoked a sustained increase of Ca.sup.2+ .sub.c in a dose-dependent manner. This Ca.sup.2+ .sub.c increase was blocked by TMB-8 (Ca.sup.2+ release inhibitor), 2-APB and BTP-2 (both SOCE blockers), respectively, whereas not affected by Cav channels blockers nifedipine and verapamil. Furthermore, NPS2143 (a CaSR antagonist) or U73122 (a PLC inhibitor) strongly reduced the Ca.sup.2+ .sub.o -induced Ca.sup.2+ .sub.c increase. The similar responses were observed when cells were stimulated with CaSR agonist spermine. These data indicated that elevating Ca.sup.2+ .sub.o resulted in SOCE depending on the activation of CaSR and PLC in osteoblasts. In addition, high Ca.sup.2+ .sub.o significantly promoted osteoblastic proliferation, which was notably reversed by BAPTA-AM (an intracellular calcium chelator), 2-APB, BTP-2, TMB-8, NPS2143 and U73122, respectively, but not affected by Cav channels antagonists. Conclusions Elevating Ca.sup.2+ .sub.o induced SOCE by triggering the activation of CaSR and PLC. This process was involved in osteoblastic proliferation induced by high level of extracellular Ca.sup.2+ concentration.
Background Apamin is commonly used as a small-conductance Ca.sup.2+ -activated K.sup.+ (SK) current inhibitor. However, the specificity of apamin in cardiac tissues remains unclear. Objective To test ...the hypothesis that apamin does not inhibit any major cardiac ion currents. Methods We studied human embryonic kidney (HEK) 293 cells that expressed human voltage-gated Na.sup.+, K.sup.+ and Ca.sup.2+ currents and isolated rabbit ventricular myocytes. Whole-cell patch clamp techniques were used to determine ionic current densities before and after apamin administration. Results Ca.sup.2+ currents (CACNA1c+CACNB2b) were not affected by apamin (500 nM) (data are presented as median 25.sup.th percentile;75.sup.th percentile (from -16 -20;-10 to -17 -19;-13 pA/pF, P = NS), but were reduced by nifedipine to -1.6 -3.2;-1.3 pA/pF (p = 0.008). Na.sup.+ currents (SCN5A) were not affected by apamin (from -261 -282;-145 to -268 -379;-132 pA/pF, P = NS), but were reduced by flecainide to -57 -70;-47 pA/pF (p = 0.018). None of the major K.sup.+ currents (I.sub.Ks, I.sub.Kr, I.sub.K1 and I.sub.to) were inhibited by 500 nM of apamin (KCNQ1+KCNE1, from 28 20; 37 to 23 18; 32 pA/pF; KCNH2+KCNE2, from 28 24; 30 to 27 24; 29 pA/pF; KCNJ2, from -46 -48;-40 to -46 -51;-35 pA/pF; KCND3, from 608 505;748 to 606 454;684). Apamin did not inhibit the I.sub.Na or I.sub.CaL in isolated rabbit ventricular myocytes (I.sub.Na, from -67 -75;-59 to -68 -71;-59 pA/pF; I.sub.CaL, from -16 -17;-14 to -14 -15;-13 pA/pF, P = NS for both). Conclusions Apamin does not inhibit human cardiac Na.sup.+ currents, L-type Ca.sup.2+ currents or other major K.sup.+ currents. These findings indicate that apamin is a specific SK current inhibitor in hearts as well as in other organs.
Severe fever with thrombocytopenia syndrome (SFTS), an emerging tick-borne infectious disease caused by a novel phlebovirus (SFTS virus, SFTSV), was listed among the top 10 priority infectious ...diseases by the World Health Organization due to its high fatality of 12%-50% and possibility of pandemic transmission. Currently, effective anti-SFTSV intervention remains unavailable. Here, by screening a library of FDA-approved drugs, we found that benidipine hydrochloride, a calcium channel blocker (CCB), inhibited SFTSV replication in vitro. Benidipine hydrochloride was revealed to inhibit virus infection through impairing virus internalization and genome replication. Further experiments showed that a broad panel of CCBs, including nifedipine, inhibited SFTSV infection. The anti-SFTSV effect of these two CCBs was further analyzed in a humanized mouse model in which CCB treatment resulted in reduced viral load and decreased fatality rate. Importantly, by performing a retrospective clinical investigation on a large cohort of 2087 SFTS patients, we revealed that nifedipine administration enhanced virus clearance, improved clinical recovery, and remarkably reduced the case fatality rate by >5-fold. These findings are highly valuable for developing potential host-oriented therapeutics for SFTS and other lethal acute viral infections known to be inhibited by CCBs in vitro.
Patients with hypertensive disorders of pregnancy have a high rate of postpartum readmission.
This study aimed to evaluate whether the type of antihypertensive medication prescribed at discharge was ...associated with postpartum readmission after a hypertensive disorder of pregnancy.
This was a retrospective cohort study of 57,254 pregnancies complicated by hypertensive disorders of pregnancy between 2012 and 2018 in the electronic obstetrical database of Kaiser Permanente Northern California. Postpartum readmissions occurred within 6 weeks after discharge from delivery hospitalization. Cox regression models were used to evaluate the association between the type of antihypertensive medication prescription at discharge (none, labetalol only, nifedipine only, or 2 or more antihypertensive medications) and postpartum readmission, adjusted for type of hypertensive disorder of pregnancy, final inpatient systolic and diastolic blood pressures, age, body mass index, mode of delivery, insurance status, race and ethnicity, delivery facility, comorbidity score, smoking, preterm delivery, parity, and Neighborhood Deprivation Index.
Among eligible patients with a hypertensive disorder of pregnancy, 1696 (3.0%) were readmitted within 6 weeks. Approximately 86% of patients were discharged without a prescription for antihypertensive medication; among those discharged with a prescription for antihypertensive medication, most were prescribed either labetalol only (54%) or nifedipine only (30%). The unadjusted readmission risk was the highest for patients discharged with a prescription for labetalol only (7.6%), lower for those discharged with a prescription for nifedipine only (3.6%) or 2 or more antihypertensive medications (3.2%), and the lowest for those discharged without a prescription for antihypertensive medication (2.5%). In the adjusted models, compared with discharge without a prescription for antihypertensive medication, discharge with a prescription for labetalol only was associated with a 63% (hazard ratio, 1.63; 95% confidence interval, 1.41–1.88) greater incidence of postpartum readmission, and discharge with a prescription for nifedipine only and discharge with a prescription for 2 or more antihypertensive medications were associated with 26% (hazard ratio, 0.74; 95% confidence interval, 0.59–0.93) and 47% (hazard ratio, 0.53; 95% confidence interval, 0.38–0.74) lower incidence of postpartum readmission, respectively. There was no strong evidence to suggest that the effect of the type of antihypertensive medication at discharge on the incidence of readmission varied by race and ethnicity (interaction P=.88). The results indicating an elevated risk associated with labetalol use were consistent in models that excluded patients with prepregnancy hypertension.
Discharge with a prescription for nifedipine alone or multiple antihypertensive medications (vs no medication) was associated with a lower incidence of readmission, whereas discharge with a prescription for labetalol alone was associated with an elevated readmission incidence. A large-scale, prospective research to compare the effectiveness of commonly prescribed hypertension medications at discharge is warranted.
This research study utilized a light-sensitive drug, nifedipine (NFD), to understand the impact of processing parameters and formulation composition on drug degradation, crystallinity, and quality ...attributes (dimensions, hardness, disintegration time) of selective laser sintering (SLS)-based three-dimensional (3D)-printed dosage forms. Visible lasers with a wavelength around 455 nm are one of the laser sources used for selective laser sintering (SLS) processes, and some drugs such as nifedipine tend to absorb radiation at varying intensities around this wavelength. This phenomenon may lead to chemical degradation and solid-state transformation, which was assessed for nifedipine in formulations with varying amounts of vinyl pyrrolidone–vinyl acetate copolymer (Kollidon VA 64) and potassium aluminum silicate-based pearlescent pigment (Candurin) processed under different SLS conditions in the presented work. After preliminary screening, Candurin, surface temperature (ST), and laser speed (LS) were identified as the significant independent variables. Further, using the identified independent variables, a 17-run, randomized, Box–Behnken design was developed to understand the correlation trends and quantify the impact on degradation (%), crystallinity, and quality attributes (dimensions, hardness, disintegration time) employing qualitative and quantitative analytical tools. The design of experiments (DoEs) and statistical analysis observed that LS and Candurin (wt %) had a strong negative correlation on drug degradation, hardness, and weight, whereas ST had a strong positive correlation with drug degradation, amorphous conversion, and hardness of the 3D-printed dosage form. From this study, it can be concluded that formulation and processing parameters have a critical impact on stability and performance; hence, these parameters should be evaluated and optimized before exposing light-sensitive drugs to the SLS processes.
The aim of this study was to evaluate the bioequivalence of generic nifedipine controlled-release tablet compared to branded product under fasting and fed conditions. A randomized, single-dose, ...2-period, crossover study with a 7-day washout period was performed in 84 healthy Chinese volunteers (fasting cohort, n = 42; fed cohort, n = 42). In each study period, volunteers were assigned to receive a single oral dose of the generic or reference product (30 mg). Blood samples were collected before dosing and up to 72 hours after administration. The plasma concentration of nifedipine was determined by a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were obtained using a noncompartmental model and log-transformed pharmacokinetic parameters (maximum plasma concentration, area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration, AUC from time 0 to infinity) were used to evaluate bioequivalence. The results showed that the 90% confidence interval for the geometric mean ratio of pharmacokinetic parameters of the test and reference products ranged from 80.0% to 125.0% in both the fasting and fed cohorts, meeting the criteria for bioequivalence. No serious adverse events were reported throughout the study and no adverse events led to withdrawal from the study. Food effects were found in both the test and reference products, with mean maximum plasma concentration, AUC from time 0 to the last measurable concentration, and AUC from time 0 to infinity increased by 23.7%, 20.7%, and 20.5%, respectively, for the test product and 35.2%, 13.4%, and 14.7% for the reference product after a high-fat and high-calorie breakfast.
Background
Oral nifedipine is recommended along with labetalol and hydralazine for treatment of severe hypertension during pregnancy by most authorities. Although nifedipine is cheap and easily ...administered, the usage pattern among health care providers suggests a strong preference for labetalol despite lack of evidence for the same.
Objectives
To determine the efficacy and safety of oral nifedipine for treatment of severe hypertension of pregnancy compared with intravenous labetalol.
Search strategy
We systematically searched for articles comparing oral nifedipine with intravenous labetalol for the treatment of severe hypertension during pregnancy in any language, over Medline, Cochrane Central Register of Clinical Trials and Google Scholar from inception till February 2014.
Selection criteria
We included all RCTs that compared intravenous labetalol with oral nifedipine for treatment of severe hypertension during pregnancy, addressing relevant efficacy and safety outcomes.
Data collection and analysis
Eligible studies were reviewed, and data were extracted onto a standard form. We used Cochrane review manager software for quantitative analysis. Data were analysed using a fixed effect model.
Main results
The pooled analysis of seven trials (four from developing countries) consisting of 363 woman–infant pairs showed that oral nifedipine was associated with less risk of persistent hypertension (RR 0.42, 95% CI 0.18–0.96) and reported maternal side effects (RR 0.57, 95% CI 0.35–0.94). However, on sensitivity analysis the outcome ‘persistent hypertension’ was no longer significant. Other outcomes did not reach statistical significance.
Conclusion
Oral nifedipine is as efficacious and safe as intravenous labetalol and may have an edge in low resource settings.
Tweetable
Although studies to date are few in number and small, nifedipine shows promise for severe hypertension in pregnancy.
Tweetable
Although studies to date are few in number and small, nifedipine shows promise for severe hypertension in pregnancy.
Quantitative prediction of food effects (FE) upon drug pharmacokinetics, including population variability, in advance of human trials may help with trial design by optimising the number of subjects ...and sampling times when a clinical study is warranted or by negating the need for conduct of clinical studies. Classification and rule-based systems such as the BCS and BDDCS and statistical QSARs are widely used to anticipate the nature of FE in early drug development. However, their qualitative rather than quantitative nature makes them less appropriate for assessing the magnitude of FE. Moreover, these approaches are based upon drug properties alone and are not appropriate for estimating potential formulation-specific FE on modified or controlled release products. In contrast, physiologically-based mechanistic models can consider the scope and interplay of a range of physiological changes after food intake and, in combination with appropriate in vitro drug- and formulation-specific data, can make quantitative predictions of formulation-specific FE including the inter-individual variability of such effects. Herein the Advanced Dissolution, Absorption and Metabolism (ADAM) model is applied to the prediction of formulation-specific FE for BCS/BDDCS Class II drug and CYP3A4 substrate nifedipine using as far as possible only in vitro data. Predicted plasma concentration profiles of all three studied formulations under fasted and fed states are within 2-fold of clinically observed profiles. The % prediction error (%PE) in fed-to-fasted ratio of Cmax and AUC were less than 5% for all formulations except for the Cmax of Nifedicron (%PE=−29.6%). This successful case study should help to improve confidence in the use of mechanistic physiologically-based models coupled with in vitro data for the anticipation of FE in advance of in vivo studies. However, it is acknowledged that further studies with drugs/formulations exhibiting a wide range of properties are required to further validate this methodology.
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