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.

Migraine headaches are usually intolerable, and a quick-relief treatment remains an unmet medical need. Almotriptan malate is a serotonin (5-HT1B/1D) receptor agonist approved for the treatment of acute migraine in adults. It is currently available in an oral tablet dosage form and has a Tmax of 1-3 h, and therefore, there is a medical need to develop a non-invasive rapidly acting formulation. We have developed an intranasal formulation of almotriptan malate using the quality-by-design (QbD) approach. A 2-factor 3-level full factorial design was selected to build up the experimental setting. The developed formulation was characterized for pH, viscosity, in vitro permeation, ex vivo permeation, and histopathological tolerance. To assess the potential of the developed formulation to produce a rapid onset of action following intranasal delivery, a pharmacokinetic study was performed in the Sprague-Dawley rat model and compared to the currently available marketed oral tablet formulation. For this, the LC-MS/MS bioanalytical method was developed and used for the determination of plasma almotriptan malate concentrations. Results of a pharmacokinetic study revealed that intranasal administration of optimized almotriptan malate formulation enabled an almost five-fold reduction in Tmax and about seven-fold increase in bioavailability in comparison to the currently available oral tablet formulation, suggesting the potential of developed almotriptan malate intranasal formulation in producing a rapid onset of action as well as enhanced bioavailability.

Almotriptan is a medication used in the management and treatment of acute migraines. It is in the triptan 5-HT class of drugs. This activity reviews the indications, action, and contraindications for almotriptan as a valuable agent in treating and managing acute migraines. This activity will highlight the mechanism of action, adverse effects, and other vital factors such as dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions pertinent for interprofessional team members in the treatment and care of patients with acute migraines and related conditions.

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.

Here we report the direct conversion of strong, aliphatic C(sp3)-H bonds into the corresponding alkyl sulfinic acids via decatungstate photocatalysis. This transformation has been applied to a diverse range of C(sp3)-rich scaffolds, including natural products and approved pharmaceuticals, providing efficient access to complex sulfur-containing products. To demonstrate the broad potential of this methodology for the divergent synthesis of pharmaceutically relevant molecules, procedures for the diversification of the sulfinic acid products into a range of medicinally relevant functional groups have been developed.

There is minimal published experience with almotriptan during breastfeeding, although the dose in milk appears to be low. If almotriptan 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.

Introduction: Nearly 80% of children with epilepsy have one or more chronic comorbidities that require specific drug treatments in several cases. Drug-drug interactions (DDIs) between antiseizure medications (ASMs) and all other drugs (NON-ASMs) used to treat comorbid diseases may have serious consequences.Areas covered: All potential DDIs between 27 ASMs and all NON-ASMs used for oral chronic treatment of those disorders most often comorbid with epilepsy in children were searched for drug compendia. Clinical evidence of the identified DDIs was also searched in the literature. Forty-eight drugs have been identified as potential DDIs with at least one ASM. Most important DDIs are between some ASMs and omeprazole and pantoprazole (drugs for gastrointestinal disorders), ibuprofen and cyclobenzaprine (drugs for musculoskeletal disorders), loratidine, lumacaftor/ivacaftor, montelukast, and theophylline (drugs for respiratory system), levothyroxine, liothyronine and several corticosteroids (systemic hormonal preparations), almotriptan, dihydroergotamine, ergotamine, and several antipsychotics, antidepressants and anxiolytics (drugs for nervous diseases). Clinical evidence of the predicted DDIs was found in a minority of cases.Expert opinion: Treatment of children with epilepsy should be decided considering treatment of both seizures and comorbid diseases and aimed at minimizing the risk of DDIs between ASMs and NON-ASMs.

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.

Migraine in pediatric is a common neurological disease, and its prevalence is varying widely. The medication for the acute attack of pediatric migraine is various. we take advantage of network meta-analysis to address the efficacy and rank of these medications. Database including Pubmed and Cochrane Library were queried using a specific searching strategy. The quality of trials enrolled was assessed according to the Cochrane collaboration'tool for assessing risk of bias. The data analysis was conducted by using the core software for Cochrane reviews (Rev Man 5.3) and the Aggregate Data Drug Information System (Addis v1.16.8). The outcomes were pain-free and pain relief at 2 hours post-dose. Totally, twenty trials with high quality including 6029 migraineurs with 6912 attacks randomly assigned to 14 different drugs. The data of ketorolac and prochlorperazine were missing. We found that sumatriptan nasal spray and zolmitriptan nasal spray were superior to placebo in the two efficacy outcomes, whereas almotriptan, rizatriptan, sumatriptan with naproxen sodium, ibuprofen and ibuprofen suspension were superior to placebo only in one of the efficacy outcomes. And in network meta-analysis, we found the best 3 treatments were ibuprofen, sumatriptan with naproxen sodium and ibuprofen suspension in achieving pain-free. Meanwhile, the best 3 treatments were ibuprofen suspension, ibuprofen, and rizatriptan in achieving pain relief. In conclusion, in acute treatments of pediatric migraine, most triptans and NSAIDS were effective to achieve pain-free or pain-relief. And the most effective treatment to achieve pain-free is sumatriptan with naproxen sodium. Ibuprofen and ibuprofen suspension were the most effective treatments to achieve pain-relief.

Oral Almotriptan maleate (ALM) is used in the treatment of migraine; however, due to its extreme aqueous solubility, shows poor penetration and lesser concentration in the brain thus requiring frequent oral dosing. Being flexible and lipophilic in nature, nanostructured lipid carriers (NLCs) represent a promising tool in delivering therapeutic substances to the brain. This investigation is meant to explore the capability of mucoadhesive chitosan-coated NLCs to efficiently deliver ALM to the brain through the nasal route as a non-invasive alternative route for targeting the central nervous system (CNS). D-optimal design was adopted and thirteen different formulae were prepared using hot homogenization and ultrasonication technique; where an accurate amount of the almotriptan was added to the molten lipid mixture followed by the addition of the heated aqueous phase under stirring, then the mixture was subjected to homogenization and ultrasonication. The prepared systems were then assessed for their particle size, PDI (polydispersity index), zeta potential (ZP), and entrapment efficiency (EE). The optimized selected formula; F1; composed of 50/50 Compritol/Labrafil and a co-mixture of 2:1 tween 80: Lauroglycol all coated in chitosan, showed a PS of 255 nm, PDI 0.27, ZP 34.1 mV, and 80% EE. A bi-phasic in vitro drug release pattern was obtained, enhanced mucoadhesive property and ex-vivo permeability through sheep nasal mucosa were attained. The In vivo studies performed on albino rabbits showed significantly higher Cmax results in plasma of the optimized ALM-NLC (1.54 μg/mL) compared to those of IN ALM solution (0.25 μg/mL) and ALM oral tablet market product (0.58 μg/mL). Brain Cmax were found to be 3.64 μg/mL, 0.5 μg/mL and 0.48 μg/mL for IN ALM-NLC, oral ALM market product and, IN ALM solution, respectively. Histopathological examination marked the formula as safe.

Administration of almotriptan as an oral therapy is largely limited because of poor aqueous solubility and rather low bioavailability. The aim of present investigation was to formulate oral mucoadhesive film of almotriptan to improve the drug delivery and desired therapeutic effects. Placebo films (F1-F8) were prepared by varying the concentrations of Proloc 15 (7.5-15% w/v) and Eudragit RL 100/RS 100 (15-30% w/v) polymers. Physicomechanical and pharmaceutical characteristics of drug loaded films (FA1-FA4) were examined. Selected FA4 film was evaluated in vivo by assessing the pharmacokinetic profile and compared with oral therapy in rabbits. FA1-FA4 films exhibited excellent physicomechanical properties and rapid hydration. A biphasic and considerably greater drug release (p < 0.05) was observed in FA3 and FA4 films contain higher amount of hydrophilic polymer. The rate of permeation of almotriptan was found to be significantly higher in FA4 than FA3 film (p < 0.005). Fourier transform infrared spectral scan indicates no incompatibility exists between the drug and polymers used. Differential scanning calorimetry thermogram represents the evidence of almotriptan amorphization and molecular dispersion of it in the film. Scanning electron microscopy images shows that FA4 possess good morphological features and hence suitable for use in the buccal application. In vivo data demonstrated rapid and efficient absorption (p < 0.005) of almotriptan with greater AUC0-12 (>2 folds, p < 0.0001) by FA4 film as compared to oral (control). In general, the data established the potential of FA4 film to improve the therapeutic delivery of almotriptan and offers a promising option in migraine therapy.

Triptans are 5-hydroxytryptamine 1B/1D receptor agonists used in moderate to severe migraine attacks as first line when non-specific, symptomatic, nonsteroidal anti-inflammatory drugs are not effective. To gain insight in the treatment of migraine in the regional context, this retrospective (from January to August of the years 2017 and 2018) study aimed at monitoring the use of triptans approved by the regional health authority in Calabria. The data demonstrate that the overall treatment of migraine with triptans in the different provinces of Calabria falls in the average regional prescription/dispensation. Interestingly, Crotone showed a trend to an increased amount of defined daily dose/1000 inhabitants per day. The present analysis might stand for homogeneity of treatment of migraineurs in Calabria and highlights the need for better understanding the apparent differences in the local pattern of almotriptan use to improve the appropriateness.

The introduction of the second generation triptans in clinical and experimental practice was a major progress in the pharmacotherapy of migraine. Frovatriptan is a second generation triptan with strong 5-HT1B/1D serotonergic agonism and low 5-HT1A/7 receptor affinity, while almotriptan possesses not only the typical 5-HT1B/1D receptor agonist activity, but shows an affinity to the 5-HT1F receptor. The aim of our study was to assess the impact of frovatriptan and almotriptan on hemodynamics in male and female rats. We used a non-invasive "tail-cuff" method to measure the arterial blood pressure. Female and male Wistar rats were treated separately with high and low dosages of frovatriptan and almotriptan. Male and female rats showed reduction in all hemodynamic parameters, but only male rats showed an increase in the heart rate. In general, we could say that both almotriptan and frovatriptan potentiate cardiovascular safety.

Introduction: Almotriptan (ALT), a serotonin 5-HT1B/1D agonist has been used in the acute treatment of migraine with or without aura for 20 years, accumulating data on more than 15,000 patients in studies and from an estimated >150 million treated migraine attacks in daily clinical practice. The last major review of ALT was written almost 10 years ago. The current narrative review provides an overview of the experience gained with almotriptan over that time, and highlights data published in the last decade. Areas covered: Randomized clinical trials, observational studies, postmarketing studies and meta-analyses involving ALT for the treatment of acute migraine identified through a systematic literature search. Expert opinion: Triptans are a mainstay of anti-migraine treatment. Findings with ALT over the last 10 years have reinforced the positive efficacy and tolerability results that were reported during the first 10 years following its introduction. In particular, more recent clinical results have confirmed its efficacy in women with menstrual migraine, the usefulness of early intervention, long-term benefit in adults, and also its efficacy and safety in adolescents. Overall, ALT can be considered an optimal choice for managing acute migraine resistant to first-line drugs.

Migraine is increasingly recognized as an extremely burdensome and disabling disorder in both children and adolescents. A proper treatment plan is needed to improve the quality of life of both children and families as well as to minimize the risk of disease progression.

This work aimed at designing efficient safe delivery system for intranasal (IN) brain targeting of the water soluble anti- migraine drug Almotriptan malate (ALM). Solid lipid nanoparticles (SLNs) were prepared by w/o/w double emulsion-solvent evaporation method. Selection of the optimized SLNs formula was based on evaluating particle size (PS), poly dispersity index (PDI) and entrapment efficiency (%EE). Optimized formula exhibited acceptable ranges; PS of 207.9 nm, PDI of 0.41 and %EE of 50.81%. Poloxamer 407 (Plx) at different concentrations (16%, 18%, 20% w/v), with different mucoadhesive polymers (Carbopol-974P, Na alginate, Na-CMC) were evaluated for gelling time and temperature, pH and mucoadhesion. The chosen mucoadhesive in-situ gel formula; 18% Plx 407 based-0.75%w/v Na-CMC, showed acceptable results, so that the optimized SLNs formula was further dispersed in it and evaluated for in vitro release, stability, in vivo and pharmacokinetics studies. Biomarkers' evaluation and histopathological examination were also investigated. Results revealed rapid ALM brain delivery of the optimized formula; Brain/blood ratios at 10 min. for NF (SLNs based IN in-situ gel), ND (Free ALM IN in situ gel) and ALM i.v. (ALM IV solution) were 0.89, 0.19 and 0.31, respectively. Toxicological results confirmed the safety of NF for nasal administration. The achieved out comings are encouraging for further clinical trials of the developed system in humans in future research.

A practical palladium-mediated cascade Tsuji-Trost reaction/Heck coupling of N-Ts o-bromoanilines with 4-acetoxy-2-butenonic acid derivatives using a Pd(OAc)2/P(o-tol)3/DIPEA system is described for a straightforward synthesis of indole-3-acetic acid derivatives. This methodology was successfully applied to synthesize various substituted indole/azaindole-3-acetic acid derivatives and Almotriptan, which is a drug for the acute treatment of migraines. Moreover, a plausible cyclization mechanism has been proposed.

Almotriptan maleate (ALMT), a highly selective 5-hydroxy tryptamine 1B/1D (5-HT1B/1D) receptor agonist used in the treatment of migraine headache was subjected to various ICH (Q1A (R2)) specified guidelines. The drug underwent significant degradation under hydrolytic (acid, base and neutral), oxidative and photolytic stress conditions, while it was stable under thermal stress condition. A total of seven significant degradation products (DPs) were obtained. A simple, selective and reliable UPLC method has been developed for the separation of ALMT and its DPs using Acquity UPLC HSS Cyano (100 × 2.1 mm, 1.8 μm) column with mobile phase consisting of ammonium acetate (10 mM, pH 4.4) buffer and acetonitrile in gradient elution mode. Chromatographic analysis was performed at a flow rate of 0.3 mL/min using a PDA detector at a wavelength of 230 nm. All the DPs (DP-1 to DP-7) were characterized using UHPLC-ESI-QTOF based on mass fragmentation pattern and accurate m/z values. The developed UPLC method was validated in terms of specificity, linearity, precision and accuracy. The developed stability-indicating method helps in quantification of drug in the presence of DPs.

Migraine is a common neurovascular disorder, affecting millions of people worldwide. Current guidelines recommend triptans as first-line treatment for moderate-to-severe migraine attacks. Frovatriptan is a second-generation triptan with a longer terminal elimination half-life in blood than other triptans (~26 hours). Three double-blind, randomized crossover preference studies have been recently conducted, assessing efficacy and safety of frovatriptan versus rizatriptan, zolmitriptan, and almotriptan, respectively. Frovatriptan showed favorable tolerability and sustained effect, with a significantly lower rate of relapse over 48 hours versus the other triptans. These findings were confirmed in a series of analyses of patient subsets from the three studies, including patients with menstrually related and oral contraceptive-induced migraine, hypertension, obesity, weekend migraine, as well as patients with migraine with aura. In all patient subsets analyzed, lower headache recurrence rates were observed versus the comparator triptans, indicating a more sustained pain-relieving effect on migraine symptoms. A further randomized, double-blind study demonstrated that frovatriptan given in combination with the fast-acting cyclooxygenase inhibitor dexketoprofen provided improved migraine pain-free activity at 2 hours, and gave more sustained pain-free activity at 24 hours, versus frovatriptan alone. These benefits were observed both when the combination was administered early (<1 hour after symptom onset) or late (>1 hour after onset). Different pharmacokinetic, but synergistic, properties between frovatriptan and dexketoprofen may make the combination of these agents particularly effective in migraine treatment, with rapid onset of action and sustained effect over 48 hours. These benefits, together with potential cost-effectiveness advantages versus other triptans could drive selection of the most appropriate treatment for acute migraine attacks.