A narrative review of the importance of pharmacokinetics and drug-drug interactions of preventive therapies in migraine management.

OBJECTIVE: To review the pharmacokinetics of major classes of migraine preventives and the clinical implications of drug-drug interactions (DDIs) with the use of these therapies in migraine management. BACKGROUND: Preventive treatments for migraine are recommended for a large proportion of patients with frequent migraine attacks. These patients often exhibit a number of comorbidities, which may lead to the introduction of multiple concomitant therapies. Potential DDIs must be considered when using polytherapy to avoid increased risk of adverse events (AEs) or inadequate treatment of comorbid conditions. METHODS: A literature search was performed to identify pharmacokinetic properties and potential DDIs of beta-blockers, antiepileptic drugs, antidepressants, calcium channel blockers, gepants, and monoclonal antibody therapies targeting the calcitonin gene-related peptide pathway with medications that may be used for comorbid conditions. RESULTS: Most DDIs occur through alterations in cytochrome P450 isoenzyme activity and may be complicated by genetic polymorphism for metabolic enzymes. Additionally, drug metabolism may be altered by grapefruit juice ingestion and smoking. The use of migraine preventive therapies may exacerbate symptoms of comorbid conditions or increase the risk of AEs associated with comorbid conditions as a result of DDIs. CONCLUSIONS: DDIs are important to consider in patients with migraine who use multiple medications. The development of migraine-specific evidence-based preventive treatments allows for tailored clinical management that reduces the risk of DDIs and associated AEs in patients with comorbidities.

In Silico, Ex Vivo and In Vivo Studies of Roflumilast as a Potential Antidiarrheal and Antispasmodic agent: Inhibition of the PDE-4 Enzyme and Voltage-gated Ca++ ion Channels.

The aim of the present study was to evaluate the possible gut inhibitory role of the phosphodiesterase (PDE) inhibitor roflumilast. Increasing doses of roflumilast were tested against castor oil-induced diarrhea in mice, whereas the pharmacodynamics of the same effect was determined in isolated rabbit jejunum tissues. For in silico analysis, the identified PDE protein was docked with roflumilast and papaverine using the Autodock vina program from the PyRx virtual screening tool. Roflumilast protected against diarrhea significantly at 0.5 and 1.5 mg/kg doses, with 40% and 80% protection. Ex vivo findings from jejunum tissues show that roflumilast possesses an antispasmodic effect by inhibiting spontaneous contractions in a concentration-dependent manner. Roflumilast reversed carbachol (CCh, 1 µM)-mediated and potassium (K+, 80 mM)-mediated contractile responses with comparable efficacies but different potencies. The observed potency against K+ was significantly higher in comparison to CCh, similar to verapamil. Experiments were extended to further confirm the inhibitory effect on Ca++ channels. Interestingly, roflumilast deflected Ca++ concentration-response curves (CRCs) to the right with suppression of the maximum peak at both tested doses (0.001-0.003 mg/mL), similar to verapamil. The PDE-inhibitory effect was authenticated when pre-incubation of jejunum tissues with roflumilast (0.03-0.1 mg/mL) produced a leftward deflection of isoprenaline-mediated inhibitory CRCs and increased the tissue level of cAMP, similar to papaverine. This idea was further strengthened by molecular docking studies, where roflumilast exhibited a better binding affinity (-9.4 kcal/mol) with the PDE protein than the standard papaverine (-8.3 kcal/mol). In conclusion, inhibition of Ca++ channels and the PDE-4 enzyme explains the pharmacodynamics of the gut inhibitory effect of roflumilast.

Moringa oleifera leaf extract induces vasorelaxation via endothelium-dependent hyperpolarization and calcium channel blockade in mesenteric arterial beds isolated from L-NAME hypertensive rats.

BACKGROUND: An aqueous extract of Moringa oleifera leaves (MOE) is known to cause relaxation of mesenteric resistance arteries of rats in which hypertension has been induced by the administration of L-NAME, but the mechanism(s) of action of MOE remains unclear. The purpose of this study was to investigate these mechanisms in mesenteric arterial beds isolated from L-NAME induced hypertensive rats. Methods: An investigation of vascular reactivity was conducted on isolated mesenteric arterial beds by measuring the changes in perfusion pressure using an in vitro system. RESULTS: MOE (0.001-3 mg in 0.1 ml injection volume) caused a dose-dependent relaxation in methoxamine (5 µM) pre-contracted arterial beds, which was partially abolished by endothelium removal. The endothelium-dependent component of vasorelaxation was insensitive to both L-NAME (100 µM) and indomethacin (10 µM), while completely inhibited in high KCl (45 mM)-induced contraction. MOE (1 and 3 mg/ml) showed a dose-dependent inhibitory effect on CaCl2-induced contractions of denuded preparations in Ca2+-free medium containing a high KCl (60 mM) or methoxamine (10 µM). In Ca2+-free medium, MOE (3 mg/ml) also inhibited phenylephrine-induced contractions of denuded preparations. Conclusion: These findings suggest that MOE relaxes mesenteric arterial beds of L-NAME hypertensive rats via both endothelium-dependent and endothelium-independent mechanisms. The endothelium-dependent action occurred via endothelium-derived hyperpolarizing factor-mediated hyperpolarization. The endothelium-independent action was related to blocking the entry of extracellular Ca2+ via voltage-operated and receptor-operated Ca2+ channels, and inhibiting mobilization of sarcolemmal Ca2+ via inositol trisphosphate receptor Ca2+ channels. MOE may be potentially useful as a natural vasodilator against hypertension.

Comparative pharmacokinetics of verapamil and norverapamil in normal and ulcerative colitis rats after oral administration of low and high dose verapamil by UPLC-MS/MS.

In this study, UC rat model was established by administration of 5% (w/v) dextran sulfate sodium, and the pharmacokinetics of verapamil and norverapamil were evaluated in normal and UC rats using UPLC-MS/MS after oral administration of 5 mg/kg and 50 mg/kg verapamil.The peak concentration (Cmax) and the area under plasma concentration-time curves (AUC) of verapamil in UC rats after oral administration of 5 mg/kg were significantly greater (2.5 times and 2 times, respectively) than those in normal rats, but the clearance rate (Cl) was significantly lower (by 50%). For norverapamil, Cmax and AUC were significantly greater (2.8 times and 2.5 times, respectively), and Cl was significantly lower (by 45%). But, pharmacokinetic parameters of verapamil and norverapamil after oral administration of 50 mg/kg were no significant differences between UC and normal rats.The better absorption and poor excretion for low-dose verapamil may be attributed to down-regulation of P-gp expression in the intestine and kidney. No significant differences of pharmacokinetic parameters for high-dose verapamil may be explained as the saturation of an efflux mechanism.The findings of this study suggested that in UC patients, doses of verapamil should be decreased when low-dose verapamil was orally administrated.

Effects of Danshen tablets on pharmacokinetics of amlodipine in rats.

CONTEXT: Danshen tablets (DST), an effective traditional Chinese multi-herbal formula, are often combined with amlodipine (ALDP) for treating coronary heart disease. OBJECTIVE: This study investigated the effects of DST on the pharmacokinetics of ALDP and the potential mechanism. MATERIALS AND METHODS: The pharmacokinetics of ALDP (1 mg/kg) in male Sprague-Dawley rats (n = 6), with or without pretreatment of DST (100 mg/kg for 7 d), were investigated using LC-MS/MS. The effects of DST on the metabolic stability of ALDP were also investigated using rat liver microsomes (RLM). RESULTS: The results indicated that Cmax (16.25 ± 2.65 vs. 22.79 ± 2.35 ng/ml), AUC(0-t) (222.87 ± 59.95 vs. 468.32 ± 69.87 n gh/ml), and t1/2 (10.60 ± 1.05 vs. 14.15 ± 1.59 h) decreased significantly when DST and ALDP were co-administered, which suggested that DST might influence the pharmacokinetic behaviour of ALDP when they are co-administered. The metabolic stability of ALDP was also decreased (23.6 ± 4.7 vs. 38.9 ± 5.2) with the pretreatment of DST. DISCUSSION AND CONCLUSIONS: This study indicated that DST could accelerate the metabolism of ALDP in RLM and change the pharmacokinetic behaviours of ALDP. Accordingly, these results showed that the herb-drug interaction between DST and ALDP might occur when they were co-administered. Therefore, the clinical dose of ALDP should be increased when DST and ALDP are co-administered.

First-in-human phase I study of SOR-C13, a TRPV6 calcium channel inhibitor, in patients with advanced solid tumors.

Introduction This was an open-label, dose escalation (3 + 3 design), Phase I study of SOR-C13 in patients with advanced tumors of epithelial origin. Primary objectives were to assess safety/tolerability and pharmacokinetics. Secondary goals were to assess pharmacodynamics and efficacy of SOR-C13. Methods SOR-C13 was administered IV QD on days 1-3 and 8-10 of a 21-day cycle. Doses were 2.75 and 5.5 mg/kg (20-min infusion) and 1.375, 2.75, 4.13 and 6.2 mg/kg (90-min infusion). Toxicity was assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Dose limiting toxicity (DLT) was assessed within the first treatment cycle. Tumors were evaluated, using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, after two cycles. Results Twenty-three patients were treated. No drug-related serious adverse events occurred. DLTs occurred in six patients: asymptomatic, drug-related, transient Grade 2 hypocalcemia (4 patients), and unrelated Grade 3 anemia and Grade 3 atrial fibrillation, 1 patient each. Calcium and vitamin D supplementation eliminated further Grade 2 hypocalcemia. One Grade 3 treatment emergent adverse event, urticaria, was definitely related to SOR-C13. Four possibly drug-related, Grade 3 events (alanine aminotransferase and aspartate aminotransferase elevation, headache, and hypokalemia) were observed. Of 22 evaluable patients, 54.5% showed stable disease ranging from 2.8 to 12.5 months. The best response was a 27% reduction in a pancreatic tumor with a 55% reduction in CA19-9 levels at 6.2 mg/kg. Conclusion SOR-C13 was safe and tolerated up to 6.2 mg/kg. The Maximal Tolerated Dose (MTD) was not established. Stable disease suggested antitumor activity.

Efecto espasmolítico de Jasonia glutinosa en intestino de roedores / Spasmolytic effect of Jasonia glutinosa on rodent intestine

Antecedentes: Jasonia glutinosa es una planta utilizada en la Península Ibérica y en el sur de Francia por su efecto espasmolítico, pero sin evidencia científica sobre ello. Objetivo: examinar el efecto espasmolítico de un extracto de té de roca. Métodos: estudiamos el efecto de dicho extracto sobre las contracciones espontáneas en duodeno de rata in vitro y sobre el tránsito gastrointestinal en el ratón in vivo. Resultados: el extracto de té de roca redujo las contracciones espontáneas en el músculo liso longitudinal del duodeno de rata, inhibió las contracciones inducidas por KCl, bloqueó la contracción causada por la entrada de Ca2+ extracelular y la contracción inducida por el Bay K8644, agonista de los canales de Ca2+ tipo L. El efecto inhibitorio del extracto de té de roca fue similar al del verapamilo, inhibidor de los canales de Ca2+ tipo L. El té de roca no modificó el tránsito gastrointestinal total en ratones sanos. Sin embargo, tras el tratamiento con dextrano sulfato de sodio, un inductor de colitis, el extracto de té de roca revirtió el aumento del tránsito gastrointestinal asociado a dicho tratamiento. Conclusión: el extracto de té de roca relajó el músculo liso duodenal a través de canales de Ca2+ tipo L y normalizó el tránsito gastrointestinal en un modelo de colitis. Estos resultados validan el uso tradicional de Jasonia glutinosa en alteraciones digestivas. Así, el té de roca podría ser utilizado como espasmolítico en el tratamiento de diversas patologías gastrointestinales (AU)

Introduction: Jasonia glutinosa is an endemic plant species of the Iberian Peninsula and Southern France traditionally used in infusions as a spasmolytic; this plant is also known as "té de roca" (rock tea) but there is no scientific evidence about the effects of this plant. Aim: To evaluate the spasmolytic effect of rock tea. Methods: We have studied the in vitro effect of a rock tea extract on rat duodenum spontaneous contractions and the in vivo effect on mice gastrointestinal transit. Results: Rock tea extract reduced the spontaneous contractions of rat duodenal smooth muscle, inhibited KCl-induced contractions and blocked the contractions invoked by both extracellular Ca2+ and the agonist of L-type calcium channels Bay K8644. This inhibitory effect was similar to the one observed after the addition of the antagonist of L-type calcium channels verapamil. Rock tea did not modify gastrointestinal transit in healthy mice. However, after the treatment with dextran sulfate sodium, an inducer of colitis, rock tea extract reverted the increase in the gastrointestinal transit associated with this treatment. Conclusion: Rock tea extract relaxed duodenal smooth muscle via L-type calcium channels and normalized gastrointestinal transit in a model of colitis. These results may validate the traditional use of Jasonia glutinosa in patients with gastrointestinal alterations. Thus, rock tea may be used as a spasmolytic agent to treat gastrointestinal disorders (AU)

Coffee-Antihypertensive Drug Interaction: A Hemodynamic and Pharmacokinetic Study With Felodipine.

OBJECTIVES: A period of abstinence from coffee to permit caffeine elimination appears to enable increased blood pressure on subsequent exposure. We hypothesized that this would offset the antihypertensive effect of the dihydropyridine calcium channel blocker felodipine. METHODS: A randomized, single-dose, crossover study assessed hemodynamic and pharmacokinetic effects following 2 days without coffee and caffeine-containing foods. Consistently brewed black coffee (2×300ml), felodipine maximum recommended dose (10mg), and coffee plus felodipine were tested in middle-aged normotensive subjects. RESULTS: Pretreatment plasma caffeine concentrations were unquantifiable. After coffee, blood pressure changes (mm Hg) averaged over study hours 1-4 were increased for brachial systolic (7.6, P < 0.001) and diastolic (4.9, P < 0.001) and aortic systolic (7.4, P < 0.001), pulse (3.0, P < 0.05) and augmentation (1.4, P < 0.05) relative to baseline. After coffee plus felodipine, they were higher for brachial systolic (4.0, P < 0.05) and diastolic (3.9, P < 0.001) and aortic systolic (4.6, P < 0.05) compared to felodipine alone. The pressor effects of coffee and its modulation by felodipine were variable among individuals. Coffee containing caffeine (127mg) caused maximum pressor effect. Caffeine and felodipine pharmacokinetics were similar for coffee and felodipine given alone or in combination indicating an interaction having a pharmacodynamic basis. Plasma felodipine concentration-diastolic blood pressure reduction relationship shifted with coffee such that doubling the felodipine concentration would eliminate the pressor effect. However, this may increase the risk of adverse drug events particularly during the timeframe without coffee. CONCLUSION: Intermittent coffee ingestion might complicate hypertension diagnosis and management for many individuals.

A novel vesicular transdermal delivery of nifedipine - preparation, characterization and in vitro/in-vivo evaluation.

Nifedipine is a calcium channel blocker extensively used in the treatment of anginal and hypertension. On oral administration it undergoes extensive first pass metabolism, which outweighs its absorbance through gastrointestinal tract (GIT) and bioavailability of the drug in systemic circulation. As an alternative to oral route transdermal route of drug delivery was developed. In the present investigation, proniosomes are prepared by varying the ratio of span-40, lecithin, aqueous phase and polymer. Formulation containing span-40, lecithin, isopropyl alcohol, 0.1% glycerol (5:5:4) and HPMC (2%) showed smaller vesicle size, high entrapment efficiency. The niosomal formation after hydration and their surface morphology of optimized formulation was studied by Motic and transmission electron microscopy. FTIR and differential scanning calorimetry studies were performed to unravel and understand the solid state properties of the drug and chemical interaction with formulation excipients. The ex-vivo Franz-diffusion studies were carried out in pH 6.8 using rat skin and the results showed better permeability of niosomes with good steady state flux and enhancement ratio suggesting the potential of proniosomal carriers for improved transdermal delivery of nifedipine. Skin irritation studies for 7 days, showed that the drug when formulated as proniosomes to be non-irritant with no erythemia development compared to pure drug. From the bio-distribution studies, the vesicles prepared with hydroxy propyl methyl cellulose with span-40 was found to be ideal batch as the concentration of drug at target site was higher.

Late sodium current block for drug-induced long QT syndrome: Results from a prospective clinical trial.

Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market. At the same time, the current regulatory paradigm for screening new drugs causing long QT syndrome is preventing drugs from reaching the market, sometimes inappropriately. In this study, we report the results of a first-of-a-kind clinical trial studying late sodium (mexiletine and lidocaine) and calcium (diltiazem) current blocking drugs to counteract the effects of hERG potassium channel blocking drugs (dofetilide and moxifloxacin). We demonstrate that both mexiletine and lidocaine substantially reduce heart-rate corrected QT (QTc) prolongation from dofetilide by 20 ms. Furthermore, all QTc shortening occurs in the heart-rate corrected J-Tpeak (J-Tpeak c) interval, the biomarker we identified as a sign of late sodium current block. This clinical trial demonstrates that late sodium blocking drugs can substantially reduce QTc prolongation from hERG potassium channel block and assessment of J-Tpeak c may add value beyond only assessing QTc.

Effect of Ginkgo Leaf Tablets on the Pharmacokinetics of Amlodipine in Rats.

BACKGROUND AND OBJECTIVE: Ginkgo leaf tablet (GLT) is an effective traditional Chinese multi-herbal formula, which is often combined with amlodipine for treating senile hypertension in clinic. The aim of this study was to study the pharmacokinetics of amlodipine after oral administration of amlodipine and GLT and to investigate the potential for pharmacokinetic herb-drug interactions between GLT and amlodipine in rats. METHODS: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method was developed for quantification of amlodipine in rat plasma. The accuracy, precision, linearity, selectivity and recovery were all within an acceptable range. Male Sprague-Dawley rats were randomly assigned to two groups: amlodipine group and amlodipine + GLT group. Plasma concentrations of amlodipine were determined at the designated time points after oral administration by using the developed LC-MS/MS method, and the main pharmacokinetic parameters were calculated and compared. As ginkgolides A, ginkgolides B, bilobalide, quercetin and kaempferol were the main components of GLT, the effects of these ingredients in GLT on metabolism of amlodipine were further investigated in rat liver microsomes. RESULTS: The pharmacokinetic parameters, maximum plasma concentration (C max), time to reach C max (T max), area under the concentration-time curve (AUC), area under the first moment plasma concentration-time curve (AUMC) and elimination half-life (t 1/2), of amlodipine were significantly increased in amlodipine + GLT group, which suggested that GLT may influence the pharmacokinetic behavior after oral co-administration with amlodipine. Amlodipine is metabolized by cytochrome P450 (CYP) 3A4, so it was speculated that GLT may change the pharmacokinetic parameters of amlodipine through modulating the metabolism of CYP3A4 enzymes. When ginkgolides B, bilobalide, or quercetin and amlodipine were co-incubated in the rat liver microsomes, the metabolic rate of amlodipine was prolonged to 533.1, 216.1 and 407.6 min, respectively, from 73.7 min. CONCLUSIONS: These results suggested that these components in GLT inhibit the metabolism of amlodipine. So it can be speculated that the herb-drug interactions between GLT and amlodipine resulted from inhibiting the metabolism of amlodipine by GLT when they were co-administered.

Rock Tea extract (Jasonia glutinosa) relaxes rat aortic smooth muscle by inhibition of L-type Ca2+ channels

In traditional herbal medicine, Rock Tea (Jasonia glutinosa) is known for its prophylactic and therapeutic value in various disorders including arterial hypertension. However, the mechanism by which Rock Tea exerts blood pressure-lowering actions has not been elucidated yet. Our aim was to demonstrate vasorelaxing effects of Rock Tea extract and to reveal its possible action mechanism. Isometric myography was conducted on high-K+-precontracted rings from rat thoracic aorta and tested extracts at concentrations of 0.5-5 mg/ml. Whole-cell patch-clamp experiments were performed in rat aortic vascular smooth muscle cells (line A7r5) to determine blocking effects on L-type Ca2+ channels. Rock Tea extract relaxed the aorta contracted by high [K+] concentration dependently with an EC50 of ≈2.4 mg/ml and produced ≈75 % relaxation at the highest concentration tested. The L-type Ca2+ channel blocker, verapamil (10−6 M), had similar effects. Rock Tea extract had no effect in nominally Ca2+-free high-K+ buffer but significantly inhibited contractions to re-addition of Ca2+. Rock Tea extract inhibited the contractions induced by the L-type Ca2+ channel activator Bay K 8644 (10−5 M) and by phenylephrine (10−6 M). Rock Tea extract and Y-27632 (10−6 M), Rho-kinase inhibitor, had similar effects and the respective effects were not additive. Patch-clamp experiments demonstrated that Rock Tea extract (2.5 mg/ml) virtually abolished L-type Ca2+ currents in A7r5. We conclude that Rock Tea extract produced vasorelaxation of rat aorta and that this relaxant effect is mediated by inhibition of L-type Ca2+ channels. Rock Tea extracts may be of phytomedicinal value for prevention and adjuvant treatment of hypertension and other cardiovascular diseases

Practical Radiosynthesis and Preclinical Neuroimaging of [11C]isradipine, a Calcium Channel Antagonist.

In the interest of developing in vivo positron emission tomography (PET) probes for neuroimaging of calcium channels, we have prepared a carbon-11 isotopologue of a dihydropyridine Ca2+-channel antagonist, isradipine. Desmethyl isradipine (4-(benzo[c][1,2,5]oxadiazol-4-yl)-5-(isopropoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine -3-carboxylic acid) was reacted with [11C]CH3I in the presence of tetrabutylammonium hydroxide in DMF in an HPLC injector loop to produce the radiotracer in a good yield (6 ± 3% uncorrected radiochemical yield) and high specific activity (143 ± 90 GBq·µmol-1 at end-of-synthesis). PET imaging of normal rats revealed rapid brain uptake at baseline (0.37 ± 0.08% ID/cc (percent of injected dose per cubic centimeter) at peak, 15-60 s), which was followed by fast washout. After pretreatment with isradipine (2 mg·kg-1, i.p.), whole brain radioactivity uptake was diminished by 25%-40%. This preliminary study confirms that [11C]isradipine can be synthesized routinely for research studies and is brain penetrating. Further work on Ca2+-channel radiotracer development is planned.

The anti-addiction drug ibogaine and the heart: a delicate relation.

The plant indole alkaloid ibogaine has shown promising anti-addictive properties in animal studies. Ibogaine is also anti-addictive in humans as the drug alleviates drug craving and impedes relapse of drug use. Although not licensed as therapeutic drug and despite safety concerns, ibogaine is currently used as an anti-addiction medication in alternative medicine in dozens of clinics worldwide. In recent years, alarming reports of life-threatening complications and sudden death cases, temporally associated with the administration of ibogaine, have been accumulating. These adverse reactions were hypothesised to be associated with ibogaine's propensity to induce cardiac arrhythmias. The aim of this review is to recapitulate the current knowledge about ibogaine's effects on the heart and the cardiovascular system, and to assess the cardiac risks associated with the use of this drug in anti- addiction therapy. The actions of 18-methoxycoronaridine (18-MC), a less toxic ibogaine congener with anti-addictive properties, are also considered.

Discovery of 7-azaindole derivatives as potent Orai inhibitors showing efficacy in a preclinical model of asthma.

Synthesis and SAR of a series of 7-azaindoles as Orai channel inhibitors showing good potency inhibiting IL-2 production in Jurkat cells is described. Compound 14d displaying best pharmacokinetic properties was further characterized in a model of allergen induced asthma showing inhibition in the number of eosinophils in BALF. High lipophilicity remains as one of the main challenges for this class of compounds.

Breastfeeding and migraine drugs.

PURPOSE: Breastfeeding women may suffer from migraine. While we have many drugs for its treatment and prophylaxis, the majority are poorly studied in breastfeeding women. We conducted a review of the most common anti-migraine drugs (AMDs) and we determined their lactation risk. METHODS: For each AMD, we collected all retrievable data from Hale's Medications and Mother Milk (2012), from the LactMed database (2014) of the National Library of Medicine, and from a MedLine Search of relevant studies published in the last 10 years. RESULTS: According to our review, AMDs safe during breastfeeding are as follows: low-dose acetylsalicylic acid (ASA), ibuprofen, sumatriptan, metoprolol, propranolol, verapamil, amitriptyline, escitalopram, paroxetine, sertraline, acetaminophen, caffeine, and metoclopramide. AMDs compatible with breastfeeding but warranting caution are as follows: diclofenac, ketoprofen, naproxen, most new triptans, topiramate, valproate, venlafaxine, and cyproheptadine. Finally, high-dose ASA, atenolol, nadolol, cinnarizine, flunarizine, ergotamine, methysergide, and pizotifen are contraindicated. CONCLUSIONS: According to our review, the majority of the revised AMDs were assessed to be compatible with breastfeeding.

A peripherally acting, selective T-type calcium channel blocker, ABT-639, effectively reduces nociceptive and neuropathic pain in rats.

Activation of T-type Ca²âº channels contributes to nociceptive signaling by facilitating action potential bursting and modulation of membrane potentials during periods of neuronal hyperexcitability. The role of T-type Ca²âº channels in chronic pain is supported by gene knockdown studies showing that decreased Ca(v)3.2 channel expression results in the loss of low voltage-activated (LVA) currents in dorsal root ganglion (DRG) neurons and attenuation of neuropathic pain in the chronic constriction injury (CCI) model. ABT-639 is a novel, peripherally acting, selective T-type Ca²âº channel blocker. ABT-639 blocks recombinant human T-type (Ca(v)3.2) Ca²âº channels in a voltage-dependent fashion (IC50 = 2 µM) and attenuates LVA currents in rat DRG neurons (IC50 = 8 µM). ABT-639 was significantly less active at other Ca²âº channels (e.g. Ca(v)1.2 and Ca(v)2.2) (IC50 > 30 µM). ABT-639 has high oral bioavailability (%F = 73), low protein binding (88.9%) and a low brain:plasma ratio (0.05:1) in rodents. Following oral administration ABT-639 produced dose-dependent antinociception in a rat model of knee joint pain (ED50 = 2 mg/kg, p.o.). ABT-639 (10-100 mg/kg, p.o.) also increased tactile allodynia thresholds in multiple models of neuropathic pain (e.g. spinal nerve ligation, CCI, and vincristine-induced). [corrected]. ABT-639 did not attenuate hyperalgesia in inflammatory pain models induced by complete Freund's adjuvant or carrageenan. At higher doses (e.g. 100-300 mg/kg) ABT-639 did not significantly alter hemodynamic or psychomotor function. The antinociceptive profile of ABT-639 provides novel insights into the role of peripheral T-type (Ca(v)3.2) channels in chronic pain states.

Design and evaluation of polysaccharide-based transdermal films for the controlled delivery of nifedipine.

It was aimed to develop the matrix type polysaccharide-based transdermal films of nifedipine (NFD) to provide its long term plasma concentration. The mechanical tests were carried out on gel formulations which were utilised in the fabrication of transdermal films to determine the type of polymer (pectin, sodium alginate) and plasticizer (propylene glycol, glycerine) as well as their concentrations. The mechanical strength, elasticity, bioadhesiveness and the drug release characteristics of optimised films containing NFD were evaluated. Permeation of NFD from the films with/without adding an enhancer (nerolidol) was followed through excised rat skin using Franz diffusion cells. Results showed that the gels composed of either pectin or sodium alginate were appropriate for the fabrication of transdermal films of NFD, and the addition of propylene glycol improved mechanical strength, flexibility, and bioadhesiveness of the films. Permeation data showed that nerolidol was an effective permeation enhancer for the polysaccharide-based transdermal films of NFD.

Inefficacy of a highly selective T-type calcium channel blocker in preventing atrial fibrillation related remodeling.

BACKGROUND: The T-type Ca(2+) channel (I(CaT)) blocker mibefradil prevents AF-promoting remodeling occurring with atrial tachycardia, an action that has been attributed to I(CaT) inhibition. However, mibefradil has other effects, including ability to inhibit L-type Ca(2+) channels, Na(+) channels and cytochromes. Thus, the relationship between I(CaT) inhibition and remodeling protection in AF is still unknown. OBJECTIVE: To assess the effects of a novel highly selective Cav3 (I(CaT)) blocker, AZ9112, on atrial remodeling induced by 1-week atrial tachypacing (AT-P) in dogs. METHODS: Mongrel dogs were subjected to AT-P at 400 bpm for 7 days, with atrioventricular-node ablation and right-ventricular demand pacing (80 bpm) to control ventricular rate. Four groups of dogs were studied in investigator-blinded fashion: (1) a sham group, instrumented but without tachypacing or drug therapy (n = 5); (2) a placebo group, tachypaced but receiving placebo (n = 6); (3) a positive control tachypacing group receiving mibefradil (n = 6); and (4) a test drug group, subjected to tachypacing during oral treatment with AZ9112 (n = 8). RESULTS: One-week AT-P decreased atrial effective refractory period (ERP) at 6 of 8 sites and diminished rate-dependent atrial ERP abbreviation. Mibefradil eliminated AT-P-induced ERP-abbreviation at 4 of these 6 sites, while AZ9112 failed to affect ERP at any. Neither drug significantly affected AF vulnerability or AF duration. CONCLUSIONS: I(CaT) blockade with the highly selective compound AZ9112 failed to prevent rate-related atrial remodeling. Thus, prevention of atrial electrophysiological remodeling by mibefradil cannot be attributed exclusively to I(CaT) blockade. These results indicate that I(CaT) inhibition is not likely to be a useful approach for AF therapy.