Multidrug and toxin extrusion protein (MATE/SLC47A) secretes metabolites and xenobiotics into the urine in the proximal tubules of the kidney. Uptake assays have been commonly used for evaluating MATE-mediated transport of new chemical entities in drug development. The purpose of this study was to examine the relationship between in vitro uptake activities by MATEs and the impact of MATE-mediated transport in in vivo renal secretion. In vitro uptake in mouse Mate1- (mMate1) expressing HEK293 cells and several in vivo parameters from mMate1 knockout and wild type mice were compared using nine cationic compounds (almotriptan, naratriptan, talinolol, sumatriptan, alogliptin, sitagliptin, rivaroxaban, saxagliptin, and vildagliptin). Compounds that showed statistically significant decrease in secretory clearances with respect to kidney concentrations (CLR, kidney) in mMate1 knockout mice were categorized as in vivo substrates in this study. A good correlation (R2 =0.637) was observed between the in vitro uptake ratio and the in vivo ratio of CLR, kidneyof mMate1 knockout mice and wild type mice. This study supported the rationale of using an uptake assay to determine whether investigational compounds are the substrate of MATEs and to predict DDI risk via renal secretion by MATE from the viewpoint of drug development in pharmaceutical companies. Significance Statement We revealed that substrates judged in vitro experiments using mMate1-expressing cells were excreted in urine via mMate1 in vivo, and a good correlation (R2 =0.637) was observed between the mice in vitro UR and in vivo ratio of secretory clearance with respect to the kidney concentrations (CLR, kidney) of mMate1 knockout mice and wild type mice. This study supported the rationale of using an uptake assay to predict potential human MATE1-mediated DDI as a victim in drug development.

Drug information can be obtained from various drug information sources that were available as government (National Formulary of India [NFI]; Central Drugs Standard Control Organization [CDSCO]), as well as commercial documents (Current Index of Medical Specialties [CIMS] and Monthly Index of Medical Specialties [MIMS]). Irrational drug usage may happen due to wide variation in the information available in these sources. In this study, we tried to assess these variations in a sample of drugs for the acute-specific management of migraine with ergot and Triptans antimigraine drugs in drug information sources such as NFI, CIMS, MIMS, and CDSCO. Scoring was done for various drug information based on the completeness of information about drugs used in acute-specific management of migraine. The scores for the completeness of drug information about the selected antimigraine drugs are 18.37% for CIMS (Ergotamine, Sumatriptan, Rizatriptan, and Zolmitriptan), 21.1% for NFI (Dihydroergotamine, Sumatriptan), 72.79% for MIMS (Ergotamine tartrate, Sumatriptan, Rizatriptan, Naratriptan, zolmitriptan, Almotriptan) and 21.77% for CDSCO (Ergotamine tartrate, Sumatriptan, Rizatriptan, Naratriptan, Zolmitriptan, eletriptan and almotriptan). The information for the antimigraine drugs available from various sources found to so much deficient. Necessary steps need to be taken in case of government public or hard documents to streamline drug information available with them as well the commercial documents as to provide reliable drug information uniformly for promoting rational use of the drug.

The hydrosulfamoylation of diverse aryl olefins provides facile access to alkylsulfonamides. Here we report a novel protocol utilizing radical-mediated addition and a thiol-assisted strategy to achieve the hydrosulfamoylation of diverse styrenes in modest to excellent yields under mild and economic reaction conditions. The methodology was found to provide an efficient and convenient approach for the synthesis of the anti-migraine drug naratriptan and it also can be used for the late-stage functionalization of natural products or medicines.

The current outbreak of COVID-19 is leading an unprecedented scientific effort focusing on targeting SARS-CoV-2 proteins critical for its viral replication. Herein, we performed high-throughput virtual screening of more than eleven thousand FDA-approved drugs using backpropagation-based artificial neural networks (q2LOO = 0.60, r2 = 0.80 and r2pred = 0.91), partial-least-square (PLS) regression (q2LOO = 0.83, r2 = 0.62 and r2pred = 0.70) and sequential minimal optimization (SMO) regression (q2LOO = 0.70, r2 = 0.80 and r2pred = 0.89). We simulated the stability of Acarbose-derived hexasaccharide, Naratriptan, Peramivir, Dihydrostreptomycin, Enviomycin, Rolitetracycline, Viomycin, Angiotensin II, Angiotensin 1-7, Angiotensinamide, Fenoterol, Zanamivir, Laninamivir and Laninamivir octanoate with 3CLpro by 100 ns and calculated binding free energy using molecular mechanics combined with Poisson-Boltzmann surface area (MM-PBSA). Our QSAR models and molecular dynamics data suggest that seven repurposed-drug candidates such as Acarbose-derived Hexasaccharide, Angiotensinamide, Dihydrostreptomycin, Enviomycin, Fenoterol, Naratriptan and Viomycin are potential SARS-CoV-2 main protease inhibitors. In addition, our QSAR models and molecular dynamics simulations revealed that His41, Asn142, Cys145, Glu166 and Gln189 are potential pharmacophoric centers for 3CLpro inhibitors. Glu166 is a potential pharmacophore for drug design and inhibitors that interact with this residue may be critical to avoid dimerization of 3CLpro. Our results will contribute to future investigations of novel chemical scaffolds and the discovery of novel hits in high-throughput screening as potential anti-SARS-CoV-2 properties.Communicated by Ramaswamy H. Sarma.

There is minimal published experience with naratriptan during breastfeeding. If naratriptan is required by the mother of an older infant, it is not a reason to discontinue breastfeeding, but until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.

Clinical data on the transfer of triptans into human breast milk remain scarce. In a lactation study including 19 breastfeeding women with migraine, we examined the excretion of six different triptans into milk. Following intake of a single dose, each participant collected seven breast milk samples at predefined intervals up to 24 hours after dose. Triptan concentrations in milk were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Infant drug exposure was estimated by calculating the relative infant dose (RID). Twenty-two breast milk sample sets were obtained for sumatriptan (n = 8), rizatriptan (n = 5), zolmitriptan (n = 4), eletriptan (n = 3), almotriptan (n = 1) and naratriptan (n = 1). Based on the average concentration in milk throughout the day, estimated mean RIDs (with range in parenthesis) were as follows: eletriptan 0.6% (0.3%-0.8%), sumatriptan 0.7% (0.2%-1.8%), rizatriptan 0.9% (0.3%-1.4%), almotriptan 1.8% (-), zolmitriptan 2.1% (0.7%-5.3%) and naratriptan 5.0% (-). Infant drug exposure through breastfeeding appears to be low and indicates that use of the triptans in this study is compatible with breastfeeding. Naratriptan may not be first choice in breastfeeding mothers initiating triptans during the neonatal period.

The efficacy of triptans as the main acute treatment strategy for migraine headache at the population-wide level needs to be understood to inform clinical decision-making. We summarise key trends in triptan use using more than 25 years of Danish nationwide data.

The synthesis of functionalized α,β-unsaturated sulfonamides by means of cross-metathesis of vinyl sulfonamides and olefins has been developed. The reaction proceeds smoothly in the presence of Hoveyda-Grubbs catalyst and its nitro analogue, providing a wide range of substituted products. The usefulness of this methodology has been proven in the preparation of new derivatives of biologically active ingredients, moxifloxacin and naratriptan.

Status migrainosus is a condition with limited epidemiological knowledge, and no evidence-based treatment guideline or rational-driven assessment of successful treatment outcome. To fill this gap, we performed a prospective observational study in which we documented effectiveness of treatment approaches commonly used in a tertiary headache clinic.

A sensitive, precise, accurate, and specific isocratic reversed-phase high-performance liquid chromatographic (RP-HPLC) method for the simultaneous separation and determination of zolmitriptan, naratriptan, dihydroergotamine, ketotifen, and pizotifen in pharmaceutical formulations has been developed and validated. An experimental design was applied for the optimization of the chromatographic parameters. A two-level full factorial 2 k was used for studying the interaction between the variables to be optimized: the percentage of acetonitrile in the mobile phase, mobile-phase pH, nature of the buffer, and column oven temperature. The most significant parameters are the percentage of acetonitrile and the mobile-phase pH. These significant parameters were optimized using the Doehlert matrix. The optimum separation was achieved by means of a Waters XBridge C18 column (250 mm × 4.6 mm, 5 μm) with a mobile phase consisting of acetonitrile and a 10 mM sodium perchlorate buffer (38 : 62, v/v) at a flow rate of 1.0 mL·min-1 and UV detection at 220 nm. The selectivity, method linearity, accuracy, and precision were examined as part of the method validation. The described method shows excellent linearity over a range of 30 to 70 μg·mL-1 for all compounds with correlation coefficients higher than 0.995. The standard deviations of the intraday and interday precision were between 0.75 and 1.94%. The validated method was successfully applied to perform routine analysis of these compounds in different pharmaceutical products such as syrups and tablets. In the presence of some preservatives, it was found that there were no peaks at the related peak locations.

In randomised controlled trials (RCTs) of oral drug treatment of migraine attacks, efficacy is evaluated after 2 hours. The effect of oral naratriptan 2.5 mg with a maximum blood concentration (Tmax) at 2 hours increases from 2 to 4 hours in RCTs. To check whether such a delayed effect is also present for other oral antimigraine drugs, we hand-searched the literature for publications on RCTs reporting efficacy. Two triptans, 3 nonsteroidal anti-inflammatory drugs (NSAIDs), a triptan combined with an NSAID and a calcitonin gene-related peptide receptor antagonist were evaluated for their therapeutic gain with determination of time to maximum effect (Emax). Emax was compared with known Tmax from pharmacokinetic studies to estimate the delay to pain-free. The delay in therapeutic gain varied from 1-2 hours for zolmitriptan 5 mg to 7 hours for naproxen 500 mg. An increase in effect from 2 to 4 hours was observed after eletriptan 40 mg, frovatriptan 2.5 mg and lasmiditan 200 mg, and after rizatriptan 10 mg (Tmax = 1 h) from 1 to 2 hours. This strongly indicates a general delay of effect in oral antimigraine drugs. A review of 5 possible effects of triptans on the trigemino-vascular system did not yield a simple explanation for the delay. In addition, Emax for triptans probably depends partly on the rise in plasma levels and not only on its maximum. The most likely explanation for the delay in effect is that a complex antimigraine system with more than 1 site of action is involved.

Petadolex®, a defined butterbur extract has clinically proven efficacy against migraine attacks. However, spontaneous reports indicate cases of herbal induced liver injury (HILI). While most HILI patients presented mild serum biochemistry changes (<3 ULN, dose range 50 to 225 mg/day; treatment duration 4-730 days) nine developed severe HILI (average time-to-onset 103 days, ALT-range 3-153; AST 2-104-fold ULN). HILI cases resolved after medication withdrawal though two patients required liver transplantation. Liver biopsies revealed an inconsistent injury pattern, i.e. necrosis, macrovesicular steatosis, inflammation, cholestasis, and bile duct proliferation. Causality assessment rated 3 cases likely, 13 possible, 8 unlikely and 24 as unclassifiable/unclassified. Note, 22 patients reported hepatotoxic co-medications especially during periods of pain. A no-observable-adverse-effect-level at 15-fold of the maximal clinical dose (3 mg/kg/day MCD) was established for rats. At >45 and 90-fold MCD bile duct hyperplasia was observed but could not be confirmed in an explorative minipig study at 218-fold MCD. Human hepatocyte studies at 49-fold Cmax serum petasins (=active ingredient) and therapeutic Ibuprofen, Paracetamol and Naratriptan concentrations evidenced liver transaminase and CYP-monooxygenase changes. Collectively, Petadolex® HILI cases are rare, idiosyncratic and frequently confounded by co-medications. A physician-supervised self-medication plan with herbs and pain relief medication is needed to minimize risk for HILI.

Experimental and clinical studies suggest that the low-affinity N-methyl-d-aspartate (NMDA) receptor open-channel blockers Mg2+ and memantine are effective in reducing trigeminal nociceptive activation. The aim of this study was to investigate the apparent effectiveness of these channel blockers using a model of trigeminal activation in vivo. Rats were anaesthetized before electrically stimulating the dura mater adjacent the middle meningeal artery. Neurons responding to stimulation were recorded extracellularly using electrophysiological methods. l-Glutamate or NMDA, and Mg2+ , memantine, or sodium controls were applied locally using microiontophoresis. Microiontophoretic application of Mg2+ or memantine into the trigeminocervical complex inhibited mechanically and electrically stimulated craniovascular afferents, and l-glutamate or NMDA-evoked neuronal activity at the second-order trigeminal synapse of craniovascular afferents. By contrast, intravenous administration of MgSO4 (100 mg/kg) or memantine (10 mg/kg) did not significantly affect electrically stimulated afferent-evoked activity within the trigeminocervical complex. The Mg2+ and memantine concentrations achieved after systemic administration may not effectively inhibit activation of the trigeminocervical complex, perhaps providing an explanation for the relatively poor efficacy of these NMDA receptor open-channel blockers for headache treatment in clinical studies. Nevertheless, the present results suggest blocking of NMDA-receptor open channels inhibits nociceptive activation of the trigeminocervical complex. Further exploration of such channel blockers as a therapeutic strategy for primary head pain is warranted.

During the production process, an editorial error occurred where the typesetter placed the ± symbol on the right side of the values in Table IV, whereas the symbol should be placed on the left side. The original article has been corrected.

Optimization of a lyophilized fast-disintegrating tablet (LFDT) formulation containing naratriptan hydrochloride, an antimigraine drug, was the foremost objective of the study, aiming in achieving fast headache pain relief. The Design-Expert® v10 software was used to generate formulations using D-optimal mixture design with four components: gelatin (X1), hydrolyzed gelatin (X2), glycine (X3), and mannitol (X4) of total solid material (TSM) w/w. The effect of the relative proportion of each component was determined on friability (Y1), hardness (Y2), and in vitro disintegration time (Y3), which was then applied for formulation optimization. In addition, their effect on tablet porosity was determined via scanning electron microscopy (SEM). Drug-excipient interaction was evaluated using differential scanning calorimetry (DSC). A comparative dissolution study against the conventional tablets was studied. Accelerated stability study was carried out in (Al/Al) and (Al/PVC) blister packs. An in vivo pharmacokinetic study was carried out to compare the optimized formulation and the conventional tablets. The optimized formulation's responses were 0.30%, 3.4 kg, and 6.12 s for Y1, Y2, and Y3, respectively. No drug-excipient interaction was specified via DSC. The optimized formulation exhibited porous structure as determined via SEM. Dissolution study demonstrated complete dissolution within 1.5 min. Study indicated stability for 78 months in (Al/Al) blister packs. In vivo pharmacokinetic study demonstrated that Cmax, AUClast, and AUCinf were significantly higher for the developed formulation. As well, the Tmax was 1 h earlier than that of convenient tablet. An LFDT would achieve a faster onset of action for naratriptan compared to other formulations.

Naratriptan, active pharmaceutical ingredient with antimigraine activity was electrochemically detected in untreated screen-printed carbon electrodes (SPCEs). Cyclic voltammetry and differential pulse voltammetry were used to carry out quantitative analysis of this molecule (in a Britton-Robinson buffer solution at pH 3.0) through its irreversible oxidation (diffusion controlled) at a potential of +0.75V (vs. Ag pseudoreference electrode). Naratriptan oxidation product is an indole based dimer with a yellowish colour (maximum absorption at 320nm) so UV-VIS spectroelectrochemistry technique was used for the very first time as an in situ characterization and quantification technique for this molecule. A reflection configuration approach allowed its measurement over the untreated carbon based electrode. Finally, time resolved Raman Spectroelectrochemistry is used as a powerful technique to carry out qualitative and quantitative analysis of Naratriptan. Electrochemically treated silver screen-printed electrodes are shown as easy to use and cost-effective SERS substrates for the analysis of Naratriptan.

Objective Naratriptan has been reported to reduce the frequency of cluster headache. The purpose of this study was to determine whether naratriptan is effective as a prophylactic treatment for cluster headache in Japan. Methods We retrospectively reviewed all 43 patients with cluster headache who received preventive treatment with naratriptan from April 2009 to April 2015. The International Classification of Headache Disorders, 3rd Edition (beta version) (ICHD-3 beta) was used to diagnose cluster headache. This study was conducted at 3 centers (Department of Neurology, Saitama Medical University; Saitama Neuropsychiatric Institute; Saitama Medical University International Medical Center). Patients were recruited from these specialized headache outpatient centers. Naratriptan was taken before the patient went to bed. Results The study population included 30 men (69.8%) and 13 women (30.2%). Twenty-two cases received other preventive treatments (51.2%), while 21 cases only received naratriptan (48.8%). Among the 43 cases, 37 patients (86.0%) achieved an improvement of cluster headache on naratriptan. Conclusion Naratriptan has been suggested as a preventive medicine for cluster headache because of the longer the biological half-life in comparison to other triptans. The internal use of naratriptan 2 hours before attacks appears to achieve a good response in patients with cluster headache.

Naratriptan is second-generation triptan class of antimigraine drug which selectively bind with 5-HT(1B/1D) receptor. It is widely used to treat the migraine attack due to its better tolerability and lower recurrence rate as compared to other triptans. Despite of the applicability, Naratriptan also have several drawback like slow onset of action and fist pass metabolism which reduce its efficacy. In order to increase the efficacy of naratriptan fast dissolving film is prepared.