Buspirone and Zolmitriptan Combination for Dyskinesia: A Randomized, Controlled, Crossover Study.

BACKGROUND: Preclinical evidence suggests that co-administration of the 5-HT1A agonist buspirone and the 5-HT1B/1D agonist zolmitriptan act synergistically to reduce dyskinesia to a greater extent than that achieved by either drug alone. OBJECTIVES: Assess the therapeutic potential of a fixed-dose buspirone and zolmitriptan combination in Parkinson's disease (PD) patients with levodopa-induced dyskinesia. METHODS: Single-center, randomized, placebo-controlled, two-way crossover study (NCT02439203) of a fixed-dose buspirone/zolmitriptan regimen (10/1.25 mg three times a day) in 30 patients with PD experiencing at least moderately disabling peak-effect dyskinesia. RESULTS: Seven days of treatment with buspirone/zolmitriptan added to levodopa significantly reduced dyskinesia as assessed by Abnormal Involuntary Movement Scale scores versus placebo (mean treatment effect vs. placebo: -4.2 [-6.1, -2.3]) without significantly worsening Unified Parkinson's Disease Rating Scale (UPDRS) Part III (ON) scores (mean treatment effect vs. placebo: 0.6 [-0.1, 1.3]). No serious adverse events were reported. CONCLUSIONS: In this proof-of-concept study, addition of buspirone/zolmitriptan to the patients' PD medication regimen significantly reduced dyskinesia severity without worsening motor function. © 2024 International Parkinson and Movement Disorder Society.

Beneficial effect of 5-HT1b/1d agonist on Parkinson's disease by modulating glutamate and reducing deposition of α-synuclein.

The given investigation examined the neuroprotection role of 5-HT1b/1d agonist in reserpine induced Parkinson's disease (PD) in male Wistar rats. PD was induced in rats by reserpine at 5 mg/kg ip for 3 days and thereafter the rats were provided with the following treatments for 4 days, zolmitriptan (ZLM) group (30 mg/kg ip); STD group (levodopa + carbidopa, 200 + 5 mg/kg ip); ZLM + GA group (zolmitriptan, 30 mg/kg ip and glutamic acid, 1.5 mg/kg); ZLM + DX group (zolmitriptan, 30 mg/kg ip and dextromethorphan, 20 mg/kg ip). All the groups were then assessed for cognitive and motor functions at the end of the protocol. Moreover, oxidative stress parameters and histopathological changes were observed in rats of all treatment groups. Deposition of α-synuclein in the brain tissue was observed by silver staining. Data of this investigation revealed that motor and cognitive functions were improved in the ZLM-treated group compared with the negative control group, which was observed to be reversed in ZLM + GA group. Treatment with ZLM ameliorated oxidative stress and histopathological changes in the brain tissue of PD rats. Further, ZLM reduced the deposition of α-synuclein in PD rats, which reversed in ZLM + GA-treated group. This study concludes by stating that 5-HT1b/1d agonist can prevent neurodegeneration and reduce oxidative stress in PD rats. The probable underlying mechanism of such an effect of 5-HT1b/1d agonist could be by regulating the deposition of α-synuclein and reducing the expression of NMDA receptor.

A multicenter, randomized, double-blind, placebo-controlled, crossover trial to evaluate the efficacy and safety of zolmitriptan nasal spray for the acute treatment of migraine in patients aged 6 to 11 years, with an open-label extension.

OBJECTIVE: To evaluate the efficacy and safety of zolmitriptan nasal spray (ZNS) in the acute treatment of migraine headache in patients aged 6 to 11 years. BACKGROUND: Triptans have demonstrated efficacy in adults, but pediatric studies of these agents have largely failed and there are few triptan options for these patients. Because lack of response to 1 triptan does not necessarily preclude response to an alternate triptan, additional triptan options for pediatric patients are desirable. METHODS: This Phase 3, randomized, double-blind, placebo-controlled, multicenter crossover trial with an open-label extension enrolled patients aged 6 to 11 years with a diagnosis of migraine for ≥6 months and ≥16 headache-free days/month (N = 373). After a run-in period to eliminate placebo responders, 186 patients were randomized within their body weight stratum to ZNS followed by matching placebo, or placebo followed by matching ZNS. Patients <50 kg who were randomly allocated to ZNS were randomized to 5:1 to ZNS 2.5 or 1.0 mg; those ≥50 kg were randomized 5:1 to ZNS 5.0 or 2.5 mg. Patients had 6 weeks to treat 1 moderate to severe migraine headache and then crossed over to the alternate arm, during which they had 6 weeks to treat a second migraine attack. Patients could participate in a subsequent 6-month outpatient open-label extension. The primary efficacy endpoint was pain-free status at 2 h in patients treated with the high dose from each stratum. RESULTS: The trial was terminated early due to slow enrollment. Three hundred patients (mean age, 9 years) entered the placebo run-in period and 186 entered the double-blind period. Pain-free status at 2 h postdose was achieved by 45/133 (33.8%) and 30/128 (23.4%) of patients who received high-dose ZNS and placebo, respectively (p = 0.0777; odds ratio [OR] 1.51; 95% confidence interval [CI] 0.96, 2.38). Several secondary endpoints achieved statistical significance. There were few treatment-related adverse events and none led to discontinuation. ZNS retained efficacy and demonstrated a consistent safety profile throughout the 6-month open-label extension. CONCLUSION: The effect of high-dose ZNS on the primary endpoint of pain-free status at 2 h did not achieve statistical significance. ZNS was safe and well tolerated in this pediatric population.

Two spectroscopic methods for estimation of anti-migraine medications: Sumatriptan and Zolmitriptan based on nucleophilic substitution reaction.

Sensitive and selective spectrophotometric and spectrofluorimetric methods have been developed for the estimation of two anti-migraine drugs, namely sumatriptan succinate (SUM) and zolmitriptan (ZOL). These methods depend on producing a yellow-coloured product after the reaction of the two drugs with 7-chloro-4-nitrobenz-2-oxa-1,3-diazole (NBD-Cl). The reaction products exhibited maximum absorbance at 481 nm in borate buffer of pH 9 and fluorescence emission peak at 540 nm after excitation at 470 nm for the two drugs. The linear ranges were 5-60 µg/ml for SUM and 5-50 µg/ml for ZOL in the spectrophotometric method (Method I), whereas this was 0.4-4 µg/ml for SUM and 0.5-5 µg/ml for ZOL in the spectrofluorimetric method (Method II). The method validity was assessed according to International Council for Harmonisation (ICH) guidelines. Statistical analysis of the results obtained from the proposed and comparison methods confirmed that the proposed methods were highly accurate and precise. The suggested methods could be used for the determination of the mentioned drugs in both pure form and in tablets.

Metabolic activation of zolmitriptan mediated by CYP2D6.

Zolmitriptan (ZOL), a member of triptans, has been used for the treatment of migraine with definite therapeutic effects. However, several cases of liver injury associated with ZOL have been reported and the underlying mechanisms remain unclear.The present study aimed to investigate the metabolic activation of ZOL in vitro and in vivo. ZOL-derived glutathione (GSH) and N-acetyl cysteine (NAC) conjugates were detected in rat liver microsomal incubations. In addition, the GSH and NAC conjugates were also found in bile and urine of rats given ZOL, respectively.ZOL-derived GSH conjugate M1 was also observed in ZOL-treated rat primary hepatocytes, and the formation of M1 was inhibited by pre-cultured with quinidine (a selective inhibitor of CYP2D6). Combining with recombinant P450 enzymes incubations, we found that CYP2D6 was the predominant enzyme responsible for the metabolic activation of ZOL.ZOL can be metabolized to an α,ß-unsaturated imine intermediate by CYP2D6. Pre-treatment of primary hepatocytes with quinidine was able to reverse ZOL-induced cytotoxicity. The finding facilitates the understanding of the mechanisms involved in ZOL-associated liver adverse reactions.

Efficacy of ADAM Zolmitriptan for the Acute Treatment of Difficult-to-Treat Migraine Headaches.

OBJECTIVE: To understand the efficacy of zolmitriptan applied with Adhesive Dermally Applied Microarray (ADAM) in treating types of migraine (those with severe headache pain, the presence of nausea, treatment ≥2 hours after migraine onset, or migraine present upon awakening) that are historically considered to be less responsive to oral medications. BACKGROUND: ADAM is an investigational system for intracutaneous drug administration. In a pivotal Phase 2b/3 study (ZOTRIP, N = 321 in the modified intention-to-treat population), ADAM zolmitriptan 3.8 mg provided superior pain freedom and freedom from patients' usual most bothersome associated symptom (MBS), compared with placebo at 2 hours post-dose. We undertook a post hoc analysis of data from the ZOTRIP trial to examine these same outcomes in subsets of patients whose migraine characteristics have been associated with poorer outcomes when treated with oral medications. METHODS: The ZOTRIP trial was a multicenter, randomized, double-blind, placebo-controlled, parallel group Phase 2b/3 study conducted at 36 sites in the United States. Presented here are post hoc subgroup analyses of patients with nausea (n = 110) or severe pain (n = 72) at baseline, those whose treatment was delayed 2 or more hours after onset (n = 75), and those who awoke with migraine (n = 80). The Cochran-Mantel-Haenszel test was used to assess whether patients in the ADAM zolmitriptan 3.8 mg group had superior treatment outcomes compared with placebo. RESULTS: In patients with nausea, 2-hour pain freedom was achieved in 44% (26/59) in the ADAM zolmitriptan 3.8 mg group and 14% (7/51) in the placebo group (P = .005) (odds ratio = 5.11, 95% CI: 1.96-13.30), and 2-hour MBS freedom was achieved in 68% (40/59) in the active treatment group and 45% (23/51) of those receiving placebo (P = .009) (odds ratio = 2.86, 95% CI: 1.28-6.43). For those with severe pain, corresponding pain-free values were 26% (10/39) and 15% (5/33) (P = .249) (odds ratio = 2.14, 95% CI: 0.60-7.62), and MBS-free values were 64% (25/39) and 42% (14/33) (P = .038) (odds ratio = 2.86, 95% CI: 1.05-7.79). Among participants who awoke with migraine, 44% (16/36) and 16% (7/44) were pain-free in the ADAM zolmitriptan 3.8 mg and placebo groups, respectively (P = .006) (odds ratio = 4.29, 95% CI: 1.50-12.31), and 72% (26/36) vs 39% (17/44) were MBS-free, respectively (P = .003) (odds ratio = 4.40, 95% CI: 1.61-12.05). In those whose treatment was delayed ≥2 hours, pain freedom in the active treatment group and placebo group were 33% (12/36) and 10% (4/39), respectively (P = .017) (odds ratio = 4.33, 95% CI: 1.24-15.10), and MBS freedom was achieved in 69% (25/36) and 41% (16/39), respectively, in the delayed treatment group (P = .014) (odds ratio = 3.37, 95% CI: 1.27-8.95). No significant effects (overall interaction P = .353) were observed in logistical regression models of treatment by subgroup interaction. CONCLUSION: Severe pain, delayed treatment, awakening with a headache, and the presence of nausea are factors that predict a poorer response to acute migraine treatment. In these post hoc analyses of subgroups of patients with each of these characteristics in the ZOTRIP trial, participants receiving ADAM zolmitriptan 3.8 mg displayed nearly uniformly better headache responses (2-hour headache freedom and 2-hour MBS freedom) compared with those who received placebo.

Preparation and evaluation of optimized zolmitriptan niosomal emulgel.

Objective: Novel niosomal formulation may be successfully applied to treat a systemic disease such as migraine through transdermal drug delivery system (TDDS), moreover, the treatment of topical diseases such as mycotic infections by targeting and localizing the drug to the stratum corneum. The current study aims to formulate zolmitriptan (Zt) in niosomal vesicles to potentiate its transdermal effect. Significance: The development of a promising niosomal formulation will push the scaling up of pharmaceutical industry in this field. Methods: Design- Expert 10 was used to design twelve formulations using Box-Behnken. Zt loaded niosomes were prepared by the thin film hydration method using Span 60(S 60), Span 80(S 80) along with cholesterol(Ch) at three different levels. The optimized formulation (F11) was formulated in Emulgel (1:1 emulsion/gel ratio). Results: The vesicles revealed vesicle size (VS) ranging from 133.1 to 851.3 nm, zeta potential (ZP) -43.8 to -82.8 mV, entrapment efficiency (EE%) from 66.7 to 88.7%, and Zt release after 4 h up to 67%. Optimized niosomal formulation (F11) depicted the smallest VS (133.1 nm), highest EE (88.7%), high ZP (-80.6 mV) and satisfactory release after 4 h (61.5%). There was a significant difference (p <.05) in drug permeation after 8 h for niosomal F11(460.98 ug/cm2) and niosomal F11 loaded Emulgel (336.92 ug/cm2) compared to plain Zt loaded emulgel (160.83 ug/cm2). Niosomal F11 loaded emulgel showed thixotropic behavior of rapid recovery, significant bioavailability and pharmacokinetic parameters as compared to the plain Zt-loaded Emulgel. Conclusion: Optimized F11 represents a promising formulation for transdermal drug delivery system to treat both topical and systemic diseases.

Investigation of Effect of Isopropyl Palmitate on Drug Release from Transdermal Patch and Molecular Dynamics Study.

Chemical penetration enhancers are widely used in transdermal drug delivery system. However, few studies have focused on changes of concentration in chemical penetration enhancers. In this study, the effect of concentrations of enhancers on drug release and its mechanism were investigated. Zolmitriptan (ZOL) was used as a model drug and isopropyl palmitate (IPP) was used as a model enhancer to investigate drug release behaviors in pressure-sensitive adhesives (PSAs). The IPP concentrations were 2, 5, 10, 12, and 15%. Drug release percents increased by 4.8, 11.5, 16, 15.1, and 14.8%, respectively. Interestingly, the linear relationship between concentrations of IPP and release percents was improved in the 0-10% and remained unchanged in the 10-15%. Moreover, thermal and rheology studies were performed to investigate changes of the fluidity of PSAs. FT-IR and molecular dynamics simulation were conducted to confirm the interaction strength among ZOL, IPP, and PSAs. The results elucidated that IPP increased fluidity of PSAs and vied for drug from PSAs. As a result, the interaction among three components played a major role in changing release behaviors of ZOL, but the increased fluidity only worked in the concentration of less than 10%.

Randomized, double-blind, placebo-controlled, parallel-group, multi-center study of the safety and efficacy of ADAM zolmitriptan for the acute treatment of migraine.

Objective To determine the efficacy, tolerability, and safety of ascending doses of Adhesive Dermally-Applied Microarray (ADAM) zolmitriptan versus placebo for acute migraine treatment. Background ADAM is a novel patient-administered system for intracutaneous drug administration. In a phase 1 pharmacokinetic study, zolmitriptan administered using ADAM had much faster absorption than oral administration with higher exposure in the first two hours. Methods This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase 2b/3 study evaluating ADAM zolmitriptan 1 mg, 1.9 mg, and 3.8 mg versus placebo. Co-primary endpoints were pain freedom and freedom from most bothersome other migraine-associated symptom 2 hours post-dose. Results Of patients treated with ADAM zolmitriptan 3.8 mg or placebo, 41.5% and 14.2%, respectively were pain-free 2 hours post-dose ( p = 0.0001) and 68.3% and 42.9% were free from their most bothersome other symptom ( p = 0.0009). Due to the fixed sequential testing methodology, formal statistical significance was not established for secondary endpoints. However, the proportion of patients who were photophobia-free, phonophobia-free, and nausea-free at 2 hours post-dose was higher in the ADAM zolmitriptan 3.8 mg group compared with placebo, as were the percentages of patients who were pain-free, and who experienced pain relief up to 48 hours post-dose. Systemic adverse events were consistent with previous triptan trials, and included dizziness, paresthesia, muscle tightness, and nausea, all of which occurred in < 5% of patients in any group. Application site reactions were generally mild and resolved within 48 hours, although erythema and bruising persisted for longer periods in some patients. Conclusion ADAM zolmitriptan 3.8 mg provides effective relief of migraine headache and associated most bothersome symptoms compared with placebo, and is well-tolerated. ClinicalTrials.gov NCT02745392.

Use of Most Bothersome Symptom as a Coprimary Endpoint in Migraine Clinical Trials: A Post-Hoc Analysis of the Pivotal ZOTRIP Randomized, Controlled Trial.

OBJECTIVE: To better understand the utility of using pain freedom and most bothersome headache-associated symptom (MBS) freedom as co-primary endpoints in clinical trials of acute migraine interventions. BACKGROUND: Adhesive dermally applied microarray (ADAM) is an investigational system for intracutaneous drug administration. The recently completed pivotal Phase 2b/3 study (ZOTRIP), evaluating ADAM zolmitriptan for the treatment of acute moderate to severe migraine, was one of the first large studies to incorporate MBS freedom and pain freedom as co-primary endpoints per recently issued guidance by the US Food and Drug Administration. In this trial, the proportion of patients treated with ADAM zolmitriptan 3.8 mg, who were pain-free and MBS-free at 2 hours post-dose, was significantly higher than for placebo. METHODS: We undertook a post-hoc analysis of data from the ZOTRIP trial to examine how the outcomes from this trial compare to what might have been achieved using the conventional co-primary endpoints of pain relief, nausea, photophobia, and phonophobia. RESULTS: Of the 159 patients treated with ADAM zolmitriptan 3.8 mg or placebo, prospectively designated MBS were photophobia (n = 79), phonophobia (n = 43), and nausea (n = 37). Two-hour pain free rates in those with photophobia as the MBS were 36% for ADAM zolmitriptan 3.8 mg and 14% for placebo (P = .02). Corresponding rates for those with phonophobia as the MBS were 14% and 41% (P = .05). For those whose MBS was nausea, corresponding values were 56% and 16%, respectively (P = .01). Two-hour freedom from the MBS for active drug vs placebo were 67% vs 35% (P < .01) for photophobia, 55% vs 43% (P = .45) for phonophobia, and 89% vs 58% for nausea (P = .04). MBS freedom but not pain freedom was achieved in 28%. Only 1 patient (1%) achieved pain freedom, but not MBS freedom. The proportion with both pain and MBS freedom was highest (56%) among those whose MBS was nausea. CONCLUSION: In this study, the use of MBS was feasible and seemed to compare favorably to the previously required 4 co-primary endpoints.

Development of zolmitriptan transfersomes by Box-Behnken design for nasal delivery: in vitro and in vivo evaluation.

The aim was to prepare an optimized zolmitriptan (ZT)-loaded transfersome formulation using Box-Behnken design for improving the bioavailability by nasal route for quick relief of migraine and further to compare with a marketed nasal spray. Here, three factors were evaluated at three levels. Independent variables include: amount of soya lecithin (X1), amount of drug (X2) and amount of tween 80 (X3). The dependent responses were vesicle size (Y1), flexibility index (Y2) and regression coefficient of drug release kinetics (Y3). Prepared formulations were evaluated for physical characters and an optimal system was identified. Further, in vivo pharmacokinetic study was performed in male wistar rats to compare the amount of drug in systemic circulation after intranasal administration. Optimized ZT-transfersome formulation containing 82.74 mg of lecithin (X1), 98.37 mg of zolmitriptan (X2) and 32.2 mg of Tween 80 (X3) and had vesicle size of 93.3 nm, flexibility index of 20.25 and drug release regression coefficient of 0.992. SEM picture analysis revealed that the vesicles were spherical in morphology and had a size more than 1 µm. The formulations were found to be physically stable upon storage at room temperature up to 2 months period, as there were no significant changes noticed in size and ZP. The nasal bioavailability of optimized transfersome formulation was found to be increased by 1.72 times than that of marketed nasal spray (Zolmist®). The design and development of zolmitriptan as transfersome provided improved nasal delivery over a conventional nasal spray for a better therapeutic effect.

Bursting deep dorsal horn neurons: the pharmacological target for the antispastic effects of zolmitriptan?

In a recent publication, Thaweerattanasinp et al. (J Neurophysiol 116: 1644-1653, 2016) investigated spinal cord injury and firing properties of deep dorsal horn neurons during NMDA or zolmitriptan application by employing electrophysiology in an in vitro spinal cord preparation. Deep dorsal horn neurons were classified into bursting, simple, or tonic firing groups,with bursting neurons showing NMDA and zolmitriptan sensitivity. We discuss the findings in a methodological framework and propose future experiments of importance for translating the results into physiological settings.

Preclinical Evidence That 5-HT1B Receptor Agonists Show Promise as Medications for Psychostimulant Use Disorders.

Background: 5-HT1B receptor agonists enhance cocaine intake during daily self-administration sessions but decrease cocaine intake when tested after prolonged abstinence. We examined if 5-HT1B receptor agonists produce similar abstinence-dependent effects on methamphetamine intake. Methods: Male rats were trained to self-administer methamphetamine (0.1 mg/kg, i.v.) on low (fixed ratio 5 and variable ratio 5) and high (progressive ratio) effort schedules of reinforcement until intake was stable. Rats were then tested for the effects of the selective 5-HT1B receptor agonist, CP 94,253 (5.6 or 10 mg/kg), or the less selective but clinically available 5-HT1B/1D receptor agonist, zolmitriptan (10 mg/kg), on methamphetamine self-administration both before and after a 21-day forced abstinence period during which the rats remained in their home cages. Results: The inverted U-shaped, methamphetamine dose-response function for intake on the fixed ratio 5 schedule was shifted downward by CP 94,253 both before and after abstinence. The CP 94,253-induced decrease in methamphetamine intake was replicated in rats tested on a variable ratio 5 schedule, and the 5-HT1B receptor antagonist SB 224,289 (10 mg/kg) reversed this effect. CP 94,253 also attenuated methamphetamine intake on a progressive ratio schedule both pre- and postabstinence. Similarly, zolmitriptan attenuated methamphetamine intake on a variable ratio 5 schedule both pre- and postabstinence, and the latter effect was sustained after each of 2 more treatments given every 2 to 3 days prior to daily sessions. Conclusions: Unlike the abstinence-dependent effect of 5-HT1B receptor agonists on cocaine intake reported previously, both CP 94,253 and zolmitriptan decreased methamphetamine intake regardless of abstinence. These findings suggest that 5-HT1B receptor agonists may have clinical efficacy for psychostimulant use disorders.

Microneedle-assisted transdermal delivery of Zolmitriptan: effect of microneedle geometry, in vitro permeation experiments, scaling analyses and numerical simulations.

OBJECTIVE: The present study was aimed to investigate the effect of salient microneedle (MN) geometry parameters like length, density, shape and type on transdermal permeation enhancement of Zolmitriptan (ZMT). METHODS: Two types of MN devices viz. AdminPatch® arrays (ADM) (0.6, 0.9, 1.2 and 1.5 mm lengths) and laboratory fabricated polymeric MNs (PM) of 0.6 mm length were employed. In the case of PMs, arrays were applied thrice at different places within a 1.77 cm2 skin area (PM-3) to maintain the MN density closer to 0.6 mm ADM. Scaling analyses was done using dimensionless parameters like concentration of ZMT (Ct/Cs), thickness (h/L) and surface area of the skin (Sa/L2). RESULTS: Micro-injection molding technique was employed to fabricate PM. Histological studies revealed that the PM, owing to their geometry/design, formed wider and deeper microconduits when compared to ADM of similar length. Approximately 3.17- and 3.65-fold increase in ZMT flux values were observed with 1.5 mm ADM and PM-3 applications when compared to the passive studies. Good correlations were observed between different dimensionless parameters with scaling analyses. Numerical simulations, using MATLAB and COMSOL software, based on experimental data and histological images provided information regarding the ZMT skin distribution after MN application. DISCUSSION: Both from experimental studies and simulations, it was inferred that PM were more effective in enhancing the transdermal delivery of ZMT when compared to ADM. CONCLUSIONS: The study suggests that MN application enhances the ZMT transdermal permeation and the geometrical parameters of MNs play an important role in the degree of such enhancement.

Intranasal Eutectic Powder of Zolmitriptan with Enhanced Bioavailability in the Rat Brain.

Intranasal administration can potentially deliver drugs to the brain because of the proximity of the delivery site to the olfactory lobe. We prepared triturates of micronized or crystalline zolmitriptan with a GRAS substance, nicotinamide, to form a eutectic. We characterized the formulation using differential scanning calorimetry, powder X-ray diffraction, and FTIR spectroscopy to confirm its eutectic nature and generated a phase diagram. The eutectic formulation was aerosolized using an in-house insufflator into the nares of rats. Groups of rats received zolmitriptan intravenously or intranasally, or intranasal eutectic formulation. Zolmitriptan was estimated in the olfactory lobe, cerebral cortex, cerebellum, and blood plasma at different time-points by LC-MS. Pharmacokinetics in these tissues indicated the superiority of the intranasal eutectic formulation for brain targeting when compared with results of IV solution and intranasal pure zolmitriptan powder. Enhancement of nose-to-brain transport is likely to have resulted from more rapid dissolution of the eutectic as compared to pure drug.

Efficacy and tolerability of zolmitriptan nasal spray for the treatment of acute migraine in adolescents: Results of a randomized, double-blind, multi-center, parallel-group study (TEENZ).

OBJECTIVE: The primary objective of the TEENZ Study (NCT01211145) was to assess the efficacy of zolmitriptan nasal spray in the acute treatment of adolescent migraine patients (ages 12 to 17 years), as measured by the primary outcome variable of pain-free status at 2 hours post-treatment. METHODS: This randomized, double-blind, placebo-controlled, four-arm parallel group study compared zolmitriptan nasal spray with placebo in the treatment of a single episode of adolescent migraine. Patients completed a 30-day run-in period to treat a single migraine attack with single-blind placebo nasal spray. Eligible patients, who had not responded to placebo, were randomized to one of three zolmitriptan nasal spray doses (5, 2.5, or 0.5 mg) or placebo in a ratio of 5:3:3:5 according to a computer-generated randomization scheme. Patients completed diaries for 24 hours after treatment, recording headache pain scores, adverse events (AEs), and medications taken. RESULTS: In an interim futility analysis, zolmitriptan nasal spray doses of 0.5 and 2.5 mg were declared futile relative to placebo and further randomization to these treatment arms was discontinued. Of 1653 patients enrolled into the study, 855 patients failed to meet study eligibility criteria and were considered screen failures. The most common reason for screen failure was response to placebo challenge (325 patients [38.0%]). Of the 798 patients who were randomized to treatment, 721 (90.4%) completed the study period. Of these, 657 (82.3%) treated a migraine within the study period and contributed data for analysis. Zolmitriptan nasal spray 5 mg was significantly more effective than placebo in achieving pain-free status at 2 hours after treatment (P < .001), with 30% of patients achieving pain-free status at 2 hours vs 17% of placebo-treated patients (OR 2.18; 95% CI 1.40, 3.39). Zolmitriptan nasal spray 5 mg was also more effective than placebo in achieving pain-free status at 3 and 4 hours post-treatment (45 vs 24%, and 56 vs 39%; both P < .001). Zolmitriptan nasal spray 5 mg was also more effective than placebo in achieving headache response at 2, 3, and 4 hours after treatment (51 vs 39%, 61 vs 48%, and 69 vs 57%, respectively; all P ≤ .011). Zolmitriptan nasal spray was well-tolerated at all doses. Dysgeusia was the most frequently reported AE, with greater frequencies reported in active treatment groups versus placebo. No serious AEs or AEs leading to discontinuation were reported. Most AEs were mild or moderate in severity, and consistent with the known profile of zolmitriptan in adult and adolescent populations. CONCLUSION: Zolmitriptan nasal spray was well-tolerated in the acute treatment of adolescent (ages 12 to 17 years) migraine. Zolmitriptan 5 mg nasal spray demonstrated superior efficacy compared with placebo for the primary efficacy endpoint of pain-free status 2 hours after treatment and the efficacy of the 5 mg dose was supported by the majority of secondary efficacy endpoints.

Systematic evaluation of matrix effect and cross-talk-free method for simultaneous determination of zolmitriptan and N-desmethyl zolmitriptan in human plasma: a sensitive LC-MS/MS method validation and its application to a clinical pharmacokinetic study.

The objective of the present work was to carry out systematic evaluation to eliminate matrix effect owing to plasma phospholipids as observed during sample preparation and to develop a cross-talk-free sensitive, selective and rapid bioanalytical method for the simultaneous determination of zolmitriptan (ZT) and N-desmethyl zolmitriptan (DZT) in human plasma by liquid chromatography-tandem mass spectrometry using naratriptan as internal standard (IS). The analytes and IS were quantitatively extracted from 200 µL human plasma by solid phase extraction. No cross-talk was found between ZT and DZT having identical product ions. Quantitation was performed on a triple quadrupole mass spectrometer employing electrospray ionization technique, operating in multiple reaction monitoring and positive ion mode. The total chromatographic run time was 2.5 min. The method was fully validated for sensitivity, selectivity, specificity, linearity, accuracy, precision, recovery, matrix effect, dilution integrity and stability studies. The method was validated over a dynamic concentration range of 0.1-15 ng/mL for ZT and DZT. The method was successfully applied to a bioequivalence study of 2.5 mg ZT tablet formulation in 18 healthy Indian male subjects under fasting conditions. Assay reproducibility was assessed by reanalysis of 62 incurred samples.

Poloxamer 407-based intranasal thermoreversible gel of zolmitriptan-loaded nanoethosomes: formulation, optimization, evaluation and permeation studies.

Zolmitriptan is the drug of choice for migraine, but low oral bioavailability (<50%) and recurrence of migraine lead to frequent dosing and increase in associated side effects. Increase in the residence time of drug at the site of drug absorption along with direct nose to brain targeting of zolmitriptan can be a solution to the existing problems. Hence, in the present investigation, thermoreversible intranasal gel of zolmitriptan-loaded nanoethosomes was formulated by using mucoadhesive polymers to increase the residence of the drug into the nasal cavity. The preparation of ethosomes was optimized by using 3(2) factorial design for percent drug entrapment efficiency, vesicle size, zeta potential, and polydispersity index. Optimized formulation E6 showed the vesicle size (171.67 nm) and entrapment efficiency (66%) when compared with the other formulations. Thermoreversible gels prepared by using poloxamer 407 showed the phase transition temperature at 32-33 °C which was in line with the nasal physiological temperature. The optimized ethosomes were loaded into the thermoreversible mucoadhesive gel optimized by varying concentrations of poloxamer 407, carbopol 934, HPMC K100, and evaluated for gel strength, gelation temperature, mucoadhesive strength, in vitro drug release, and ex vivo drug permeation, where G3 and G6 were found to be optimized formulations. In vitro drug release was studied by different kinetic models suggested that G3 (n = 0.582) and G6 (n = 0.648) showed Korsemeyer-Peppas (KKP) model indicating non-Fickian release profiles. A permeation coefficient of 5.92 and 5.9 µg/cm(2) for G3 and G6, respectively, revealed very little difference in release rate after 24 h between both the formulations. Non-toxic nature of the gels on columnar epithelial cells was confirmed by histopathological evaluation.

99mTc-zolmitriptan: radiolabeling, molecular modeling, biodistribution and gamma scintigraphy as a hopeful radiopharmaceutical for lung nuclear imaging.

Lung imaging radiopharmaceuticals are helpful agents for measuring pulmonary blood flow and allow detection of pulmonary embolism and lung cancer. The goal of this study was to develop a novel potential radiopharmaceutical for lung imaging. Zolmitriptan (a selective serotonin receptor agonist) was successfully labeled with 99mTc via direct labeling method under reductive conditions studying different factors affecting the labeling efficiency. 99mTc-zolmitriptan was obtained with a maximum labeling yield of 92.5 ± 0.61 % and in vitro stability up to 24 h. Molecular modeling was done to predict the structure of 99mTc-zolmitriptan and ensure that radiolabeling did not affect binding ability of zolmitriptan to its receptor. Biodistribution studies showed that maximum lung uptake of 99mTc-zolmitriptan was 23.89 ± 1.2 % injected dose/g tissue at 15 min post-injection and retention in lungs remained high up to 1 h, whereas the clearance from mice appeared to proceed mainly via the renal pathway. Scintigraphic images confirmed the biodistribution results showing a high resolution lung image with low accumulation of radioactivity in other organs except kidneys and urinary bladder. 99mTc-zolmitriptan is not a blood product and so it is more safe than the currently available 99mTc-MAA, and its lung uptake is higher than that of the recently discovered 123I-IPMPD, 99mTc(CO)5I and 99mTc-DHPM. So, 99mTc-zolmitriptan could be used as a hopeful radiopharmaceutical for lung scintigraphic imaging.

Analytical Quality by Design in pharmaceutical quality assurance: Development of a capillary electrophoresis method for the analysis of zolmitriptan and its impurities.

A fast and selective CE method for the determination of zolmitriptan (ZOL) and its five potential impurities has been developed applying the analytical Quality by Design principles. Voltage, temperature, buffer concentration, and pH were investigated as critical process parameters that can influence the critical quality attributes, represented by critical resolution values between peak pairs, analysis time, and peak efficiency of ZOL-dimer. A symmetric screening matrix was employed for investigating the knowledge space, and a Box-Behnken design was used to evaluate the main, interaction, and quadratic effects of the critical process parameters on the critical quality attributes. Contour plots were drawn highlighting important interactions between buffer concentration and pH, and the gained information was merged into the sweet spot plots. Design space (DS) was established by the combined use of response surface methodology and Monte Carlo simulations, introducing a probability concept and thus allowing the quality of the analytical performances to be assured in a defined domain. The working conditions (with the interval defining the DS) were as follows: BGE, 138 mM (115-150 mM) phosphate buffer pH 2.74 (2.54-2.94); temperature, 25°C (24-25°C); voltage, 30 kV. A control strategy was planned based on method robustness and system suitability criteria. The main advantages of applying the Quality by Design concept consisted of a great increase of knowledge of the analytical system, obtained throughout multivariate techniques, and of the achievement of analytical assurance of quality, derived by probability-based definition of DS. The developed method was finally validated and applied to the analysis of ZOL tablets.