The aim of this work is to highlight the influence of UV light on the hydrolysis reaction of nifedipine (NIF) in the presence of alkaline solutions. In this context, the photodegradation of NIF in the absence of alkaline solutions caused (a) a change in the ratio between the absorbances of three bands in the UV-VIS spectra localized at 224-240 nm, 272-276 nm and 310-340 nm, assigned to the electronic transitions of -COOCH3 groups, -NO2 groups and a heterocycle with six atoms; (b) a red-shift of the photoluminescence (PL) band from 458 nm to 477 nm, simultaneous with an increase in its intensity; (c) a decrease in the ratio of the Raman line intensities, which peaked at 1224 cm-1 and 1649 cm-1, associated with the vibrational modes of -C-C-O in the ester group and C=C stretching; and (d) a decrease in the ratio between the absorbances of the IR bands, which peaked at 1493 cm-1 and 1223 cm-1, associated with the vibrational modes of the -NO2 group and C-N stretching. These changes were explained considering the NIF photodegradation reaction, which leads to the generation of the compound 4-(2-nitrosophenyl)-2.6-dimethyl-3.5-dimethoxy carbonyl pyridine. The interaction of NIF with NaOH in the absence of UV light was demonstrated to induce changes in the vibrational mode of the -C-C-O bond in the ester group. The photodegradation of NIF after its reaction with NaOH induces significant changes highlighted in its (a) UV-VIS spectra, by the shift of the absorption band at 238 nm; (b) PL spectra, by the supraunitary value of the ratio between the emission band intensities at 394-396 nm and 450 nm; (c) Raman spectra, by the change in the ratio between the intensities of the lines that peaked at 1224 cm-1 and 1649 cm-1 from 0.61 to 0.49; and (d) FTIR spectra, by the lowered absorbance of the IR band at 1493 cm-1 assigned to the vibrational mode of the -NO2 group as a result of the generation of the nitroso compound. These changes were explained considering the hydrolysis reaction products of NIF, as the nitroso compound is converted to a lactam-type compound. The photodegradation reaction rate constants of NIF and NIF after interaction with NaOH were also reported. The decrease in thermal stability of NIF samples after interaction with NaOH, as well as of NIF after exposure to UV light compared to NIF prior to exposure to UV light, was demonstrated by thermogravimetry, and the key fragments were confirmed by mass spectrometry.

The traditional Chinese herbal formula Shenmai-Yin (SY) and nifedipine have both been used to treat patients with cardiovascular disorders. Nifedipine is primarily oxidized by cytochrome P450 (CYP) 3A. The oxidation and pharmacokinetics of nifedipine were studied in rats in vitro and in vivo to illustrate the interaction of SY with nifedipine. Schisandrol A, schisandrin A and schisandrin B were identified as the main lignans in SY. In the study in vitro, the ethanolic extract of SY was used due to the solubility and the extract inhibited nifedipine oxidation (NFO) activity in a time-dependent manner. Among lignans, schisandrin B caused the most potent inhibition. According to the time-dependent inhibition behavior, rats were treated with SY 1 h before nifedipine administration. After oral treatment with 1.9 g/kg SY, nifedipine clearance decreased by 34% and half-life increased by 142%. SY treatment decreased hepatic NFO activity by 49%. Compared to the change caused by ketoconazole, the SY-mediated reduction of nifedipine clearance was moderate. These findings demonstrate that SY causes a time-dependent inhibition of NFO and schisandrin B contributes to the inhibition. The decreased nifedipine clearance by SY in rats warrants further human study to examine the clinical impact of this decrease.

Nifedipine, an effective hypotensive drug in severe hypertension, was investigated by invasive methods in 15 hypertensive patients while they were supine, erect, and exercising moderately. The effects of oral nifedipine 20 mg examined 45 minutes after the dose showed a reduced systemic arterial blood pressure via a reduction in peripheral resistance. Nifedipine reduced pulmonary arterial pressure and pulmonary wedge pressures (PWP) during exercise in patients with abnormally high values but did not alter them in patients with normal values. Heart rate and cardiac output increased by a reflex mechanism. The decreases in arterial blood pressure and PWP correlated with the initial values while the increases in heart rate and cardiac output did not correlate with the extent of blood pressure reduction. Since nifedipine decreases arterial blood pressure, pulmonary arterial pressure, and PWP in proportion to the pretreatment values, it is a useful drug in severe hypertension with and without elevated pulmonary pressures.

Glycyrrhizic acid, or glycyrrhizin (GA), a major active component of licorice root, has been widely used in traditional Chinese and Japanese medicine since ancient times. However, only in the last decades has a novel and unusual property of the GA been discovered to form water-soluble, supramolecular complexes with a variety of lipophilic drugs. These complexes show significant advantages over other known delivery systems, in particular, due to strong pH sensitivity, the properties of GA self-associates. In the present study, a supramolecular complex formation of the hypotensive and antiarrhythmic drug nifedipine with GA has been studied at different pH values, corresponding to the different degrees of GA dissociation, including a fully dissociated state of GA. Both NMR experiments and molecular dynamics simulations demonstrate the existence of the nifedipine complex with GA at all dissociation states of GA. However, optical absorption experiments show the decrease of complex stability and solubility at pH > 6 when the GA molecule is fully deprotonated. It means the higher release rate of the drug in a neutral and basic environment compared with acid media. These results could form the basis of follow-up studies of GA self-associates as pH-controlled drug delivery systems.

Lipid accumulation in renal cells has been implicated in the pathogenesis of obesity-related kidney disease, and lipotoxicity in the kidney can be a surrogate marker for renal failure or renal fibrosis. Fatty acid oxidation provides energy to renal tubular cells. Ca2+ is required for mitochondrial ATP production and to decrease reactive oxygen species (ROS). However, how nifedipine (a calcium channel blocker) affects lipogenesis is unknown. We utilized rat NRK52E cells pre-treated with varying concentrations of nifedipine to examine the activity of lipogenesis enzymes and lipotoxicity. A positive control exposed to oleic acid was used for comparison. Nifedipine was found to activate acetyl Coenzyme A (CoA) synthetase, acetyl CoA carboxylase, long chain fatty acyl CoA elongase, ATP-citrate lyase, and 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase, suggesting elevated production of cholesterol and phospholipids. Nifedipine exposure induced a vast accumulation of cytosolic free fatty acids (FFA) and stimulated the production of reactive oxygen species, upregulated CD36 and KIM-1 (kidney injury molecule-1) expression, inhibited p-AMPK activity, and triggered the expression of SREBP-1/2 and lipin-1, underscoring the potential of nifedipine to induce lipotoxicity with renal damage. To our knowledge, this is the first report demonstrating nifedipine-induced lipid accumulation in the kidney.

To clarify the possible pathophysiological role of medullasin, a neutrophil elastase-like proteinase, in nifedipine (NF)-induced gingival overgrowth, a rat model of gingival overgrowth was first established using a diet containing NF. The relation between histopathological changes and the distribution of the proteinase was then investigated. Thirty-two, specific pathogen-free 20 day-old, male, Fisher 344 rats were fed a diet containing NF and killed at 2, 8, 16 and 32 weeks. Control rats (n = 32) were fed the same diet but without the drug. The mandible of each rat was resected and sectioned at 4-microm thickness buccolingually between the first and second molars. Computer image analysis was used to evaluate the extent of overgrowth in the approximal gingiva of each sample. To examine medullasin activity, the mean percentage of medullasin-positive cells per total cells counted in the pocket epithelium and the connective tissue adjacent to the epithelium of approximal gingiva was determined immunohistochemically. The height of the mid-portion and the area in NF-treated group increased significantly with time (with the exception of area at 2 weeks) compared with the corresponding regions in the control group. A marked inflammatory-cell infiltration and elongated rete pegs, especially in the mid-portion of approximal gingiva, were seen in the NF-treated group. The mean percentages of medullasin-positive cells in the NF-treated group at 8, 16 and 32 weeks were significantly higher than those of the control. Although medullasin-positive cells were mainly neutrophils, in several samples of the NF-treated group they were recognized as macrophage-like. These findings suggest that medullasin may be involved in host defence and immunoregulation in a NF-induced rat model of gingival overgrowth.

Inflammatory gingival enlargement is a common observation in routine dental practice. Drugs like nifedipine, used for hypertension and Porphyromonas gingivalis infection-induced gingival enlargement is of a major concern. The current study aims to identify the inflammatory response of the gingival enlargement by measuring the major inflammatory markers fibrinogen and C-reactive protein (CRP).

Proliposomes were used to improve the solubility and oral bioavailability of nifedipine. Nifedipine proliposomes were prepared by methanol injection-spray drying method. The response surface method was used to optimize formulation to enhance the encapsulation efficiency (EE%) of nifedipine. The particle size of nifedipine proliposomes after rehydration was 114 nm. Surface morphology of nifedipine proliposomes was observed by a scanning electron microscope (SEM) and interaction of formulation ingredients was assessed by differential scanning calorimetry (DSC). The solubility of nifedipine is improved 24.8 times after forming proliposomes. In vitro release experiment, nifedipine proliposomes had a control release effect, especially in simulated gastric fluid. In vivo, nifedipine proliposomes significantly improved the bioavailability of nifedipine. The area under the concentration-time curve (AUC0-∞) of nifedipine proliposomes was about 10 times than nifedipine after oral administration. The elimination half-life (T1/2β) of nifedipine was increased from 1.6 h to 6.6 h. In conclusion, proliposomes was a promising system to deliver nifedipine through oral route and warranted further investigation.

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.

1. We have shown previously that exposing the rat or rabbit microcirculation to nifedipine increases the permeability of the post-capillary venule, the segment of microcirculation that is known to control inflammatory oedema. 2. In the present study modulation by the inotropes isoprenaline, dopexamine and dobutamine of nifedipine-induced oedema was examined in the rabbit skin microcirculation by measuring the localised leakage of 125I-radiolabelled albumin after the i.d. injection of agents. 3. Coinjection of isoprenaline (10(-11) moles per site), dopexamine (10(-10) moles per site) or dobutamine (10(-10) moles per site) suppressed significantly (P < 0.05) the oedema response to nifedipine (10(-7.2) moles per site) in the rabbit dorsal skin microcirculation. 4. To confirm the oedema suppresser effect of the inotropes, dopexamine or dobutamine were also coinjected with histamine 10(-8) + PGE2 10(-10) moles per site, or bradykinin 10(-10) + PGE2 10(-10) moles per site. Both inotropes at 10(-10) moles per site reduced significantly (P < 0.05) the leakage of albumin caused by bradykinin + PGE2 and histamine + PGE2. 5. When measured by laser Doppler, basal local skin blood flow increased at 30 min by 57 +/- 14% with nifedipine 10(-7.2) moles per site and 15 +/- 11% with isoprenaline 10(-11) moles per site. Isoprenaline did not suppress the blood flow response to nifedipine, the response to coinjection being 68 +/- 11%. 6. Oedema caused by nifedipine can be suppressed by low concentrations of beta-adrenergic agonists that do not suppress the blood flow response to nifedipine. This suggests that cardiac inotropes can influence non-inflammatory changes in microvascular permeability.

Nifedipine is widely used as a calcium channel blocker (CCB) to treat angina and hypertension,but it is controversial with respect the risk of stimulation of cancers. In this study, we demonstrated that nifedipine promoted the proliferation and migration of breast cancer cells both invivo and invitro. However, verapamil, another calcium channel blocker, didn't exert the similar effects. Nifedipine and high concentration KCl failed to alter the [Ca2+]i in MDA-MB-231 cells, suggesting that such nifedipine effect was not related with calcium channel. Moreover, nifedipine decreased miRNA-524-5p, resulting in the up-regulation of brain protein I3 (BRI3). Erk pathway was consequently activated and led to the proliferation and migration of breast cancer cells. Silencing BRI3 reversed the promoting effect of nifedipine on the breast cancer. In a summary, nifedipine stimulated the proliferation and migration of breast cancer cells via the axis of miRNA-524-5p-BRI3-Erk pathway independently of its calcium channel-blocking activity. Our findings highlight that nifedipine but not verapamil is conducive for breast cancer growth and metastasis, urging that the caution should be taken in clinic to prescribe nifedipine to women who suffering both hypertension and breast cancer, and hypertension with a tendency in breast cancers.

Preterm birth is the most common cause of neonatal morbidity and mortality. Tocolytics are considered a standard treatment for women with threatened preterm delivery to allow time for maternal steroid administration and transfer to referral centers with neonatal intensive care units. However, there is controversy about the best tocolytic therapy to be considered as the first choice. The aim of this study is to compare the tocolytic effectiveness and tolerability of combination therapy with nifedipine and indomethacin versus nifedipine monotherapy among Sudanese women with preterm labor (PTL) as well as to compare the possible neonatal outcomes associated with each drug.

A calcium antagonist, nifedipine, causes gingival overgrowth as a side effect. It has been confirmed that the Japanese traditional medicine, Saireito, inhibits the nifedipine-induced proliferation of gingival fibroblasts in vitro. We performed an in vivo experiment to determine whether Saireito has a therapeutic use in the treatment of nifedipine-induced gingival overgrowth.

Understanding the solvation and desolvation of pharmaceutical materials is an important part of materials discovery and development. In situ structural data are vital to understand the changes to crystal form that may occur in the system. In this study, the isolation and characterization of seven solvates of the L-type calcium channel antagonist, nifedipine, is described using variable-temperature powder X-ray diffraction so that the structural evolution as a function of temperature can be followed. The solvates reported herein can be split into those that are structurally similar to the previously reported dimethyl sulfoxide (DMSO) and dioxane solvates and those that have a novel packing arrangement. Of particular note is the solvate with tetrahydrofuran (THF) which has a hydrogen-bonding motif between the nifedipine molecules very similar to that of metastable β-nifedipine. In addition to variable-temperature X-ray diffraction, the stability of the solid forms was assessed using differential scanning calorimetry and thermogravimetric analysis and indicates that in all cases desolvation results in the thermodynamically stable α-polymorph of nifedipine even with the THF solvate. From the diffraction data the pathway of desolvation during heating of the DMF solvate showed conversion to another likely 1:1 polymorph before desolvation to α-nifedipine. The desolvation of this material indicated a two-stage process; first the initial loss of 90% of the solvent before the last 10% is lost on melting. The methanol solvate shows interesting negative thermal expansion on heating, which is rarely reported in organic materials, but this behaviour can be linked back to the winerack-type hydrogen-bonding pattern of the nifedipine molecules.

Calcium ion participates in the regulation of neural transmission and the presynaptic release of neurotransmitters. It is also involved in epileptic events, cardiac arrhythmias and abnormal conduction of stimuli. The purpose of the present study was to evaluate the effects of nifedipine, a calcium channel blocker, on epileptic seizures and on reperfusion arrhythmias in rats prone to audiogenic epileptic seizures (Wistar audiogenic rats, WAR) and in normal Wistar rats (N = 6/group). The seizure severity index was applied after an intraperitoneal injection of 20 or 40 mg/kg nifedipine (N20 and N40 groups, respectively). The Langendorff technique was used to analyze cardiac function, as well as the incidence and severity of the reperfusion arrhythmias after ligature and release of the left coronary artery in rats treated or not with nifedipine. We found that nifedipine treatment decreased seizure severity (0.94 ± 0.02 for WAR; 0.70 ± 0.10 for WAR + N20; 0.47 ± 0.08 for WAR + N40) and increased the latent period (13 ± 2 s for WAR; 35 ± 10 s for WAR + N20; 48 ± 7 s for WAR + N40) for the development of seizures in WAR. Furthermore, the incidence and severity of the reperfusion arrhythmias were lower in WAR and normal Wistar rats injected with nifedipine. In WAR, these effects were mediated, at least in part, by a decrease in heart rate. Thus, our results indicate that nifedipine may be considered to be a potential adjuvant drug for epilepsy treatment, especially in those cases associated with cardiac rhythm abnormalities.

The calcium channel blocker nifedipine induces cellular iron export, thereby limiting the availability of the essential nutrient iron for intracellular pathogens, resulting in bacteriostatic activity. To study if nifedipine may exert a synergistic anti-microbial activity when combined with antibiotics, we used the mouse macrophage cell line RAW267.4, infected with the intracellular bacterium Salmonella Typhimurium, and exposed the cells to varying concentrations of nifedipine and/or ampicillin, azithromycin and ceftriaxone. We observed a significant additive effect of nifedipine in combination with various antibiotics, which was not observed when using Salmonella, with defects in iron uptake. Of interest, increasing intracellular iron levels increased the bacterial resistance to treatment with antibiotics or nifedipine or their combination. We further showed that nifedipine increases the expression of the siderophore-binding peptide lipocalin-2 and promotes iron storage within ferritin, where the metal is less accessible for bacteria. Our data provide evidence for an additive effect of nifedipine with conventional antibiotics against Salmonella, which is partly linked to reduced bacterial access to iron.

Chagas disease is a neglected tropical disease. About 6 to 8 million people are chronically infected and 10% to 15% develop irreversible gastrointestinal disorders, including megaesophagus. Treatment focuses on improving symptoms, and isosorbide and nifedipine may be used for this purpose.

No abstract available

Rapidly activating Kv4 voltage-gated ion channels are found in heart, brain, and diverse other tissues including colon and uterus. Kv4.3 can co-assemble with KChIP ancillary subunits, which modify kinetic behavior. We examined the affinity and use dependence of nifedipine block on Kv4.3 and its modulation by KChIP2b. Nifedipine (150 microM) reduced peak Kv4.3 current approximately 50%, but Kv4.3/KChIP2b current only approximately 27%. Nifedipine produced a very rapid component of open channel block in both Kv4.3 and Kv4.3/KChIP2b. However, recovery from the blocked/inactivated state was strongly sensitive to KChIP2b. Kv4.3 Thalf,recovery was slowed significantly by nifedipine (120.0+/-12.4 ms vs. 213.1+/-18.2 ms), whereas KChIP2b eliminated nifedipine's effect on recovery: Kv4.3/KChIP2b Thalf,recovery was 45.3+/-7.2 ms (control) and 47.8+/-8.2 ms (nifedipine). Consequently, Kv4.3 exhibited use-dependent nifedipine block in response to a series of depolarizing pulses which was abolished by KChIP2b. KChIPs alter drug affinity and use dependence of Kv4.3.

Spontaneous preterm birth is the leading cause of perinatal morbidity and mortality. Tocolytics are drugs used in cases of imminent preterm birth to inhibit uterine contractions. Nifedipine is a calcium channel blocking agent used to delay threatened spontaneous preterm birth, however, has limited efficacy and lacks preclinical data regarding mechanisms of action. It is unknown if nifedipine affects the pro-inflammatory environment associated with preterm labour pathophysiology and we hypothesise nifedipine only targets myometrial contraction rather than also mitigating inflammation. We assessed anti-inflammatory and anti-contractile effects of nifedipine on human myometrium using in vitro and ex vivo techniques, and a mouse model of preterm birth. We show that nifedipine treatment inhibited contractions in myometrial in vitro contraction assays (P = 0.004 vs. vehicle control) and potently blocked spontaneous and oxytocin-induced contractions in ex vivo myometrial tissue in muscle myography studies (P = 0.01 vs. baseline). Nifedipine treatment did not reduce gene expression or protein secretion of pro-inflammatory cytokines in either cultured myometrial cells or ex vivo tissues. Although nifedipine could delay preterm birth in some mice, this was not consistent in all dams and was overall not statistically significant. Our data suggests nifedipine does not modulate preterm birth via inflammatory pathways in the myometrium, and this may account for its limited clinical efficacy.