[Anxiolytics: Appropriate Use of Benzodiazepine Receptor Agonists].

Anxiolytics are a class of drugs that include benzodiazepine receptor agonists and serotonin 1A receptor partial agonists. Although benzodiazepine receptor agonists have anxiolytic, sedative-hypnotic, muscle relaxant, and anticonvulsant effects, their use should be carefully monitored due to their potential for paradoxical reactions, withdrawal symptoms, and dependence. On the other hand, serotonin 1A receptor partial agonists have a slower onset, and their use also presents challenges. In clinical practice, having a thorough understanding of the various types of anxiolytics and their unique features is crucial.

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.

Efficacy of ubrogepant based on prior exposure and response to triptans: A post hoc analysis.

OBJECTIVE: To determine the potential efficacy of ubrogepant for acute treatment of migraine based on historical experience with triptans. BACKGROUND: Although triptans have improved migraine treatment, their efficacy and tolerability may limit their utility in some individuals. Ubrogepant is a small-molecule, oral calcitonin gene-related peptide receptor antagonist approved by the Food and Drug Administration for acute treatment of migraine in adults. METHODS: This post hoc analysis of pooled data from the pivotal trials ACHIEVE I and II, identically designed, randomized, double-blind, phase 3, single-attack trials of ubrogepant in adults with a history of migraine with/without aura, examined the efficacy and tolerability of ubrogepant 50 mg versus placebo based on participants' historical experience with triptans: triptan responder, triptan-insufficient responder, and triptan naïve. Co-primary efficacy endpoints were pain freedom and absence of most bothersome migraine-associated symptom (MBS) 2 h post initial dose. Adverse events (AEs) within historical triptan experience subgroups were evaluated. RESULTS: In the pooled analysis population (n = 1799), 682 (placebo, n = 350; ubrogepant 50 mg, n = 332), 451 (placebo, n = 223; ubrogepant, n = 228), and 666 (placebo, n = 339; ubrogepant, n = 327) participants were triptan responders, triptan-insufficient responders, and triptan-naïve, respectively. Response rates on co-primary efficacy endpoints were higher for ubrogepant versus placebo across all groups. Treatment-by-subgroup interaction p values based on odds ratios for pain freedom (p = 0.290) and absence of MBS (p = 0.705) indicated no significant impact of historical triptan experience on ubrogepant efficacy. AE incidence for ubrogepant did not differ appreciably across historical triptan experience subgroups. CONCLUSIONS: Ubrogepant efficacy and tolerability did not differ for the acute treatment of migraine in participants classified as triptan responders, triptan-insufficient responders, and triptan-naïve based on their historical experience with triptans.

Targeting the 5-HT1B/1D and 5-HT1F receptors for acute migraine treatment.

Migraine is a common and highly disabling headache disorder associated with a substantial socioeconomic burden. Migraine treatments can be categorized as preventive treatment, aimed at reducing the frequency and severity of migraine attacks, and acute therapy, intended to abort attacks. Traditionally, acute treatment can be classified as specific (ergot derivatives and triptans) or nonspecific (analgesics and nonsteroidal anti-inflammatory drugs). Triptans, a class of 5-HT1B/1D receptor agonists with some affinity for the 5-HT1F receptor subtype, have been proven to be efficacious for acute treatment of moderate to severe migraine and have been deemed the gold standard. The availability of triptans in non-oral formulations, such as subcutaneous (SC) and intranasal forms, can be beneficial for patients who suffer from prominent nausea or vomiting, have a suboptimal response to oral agents, and/or seek a more rapid onset of treatment effects. However, triptans are contraindicated in patients with preexisting cardiovascular and/or cerebrovascular diseases due to their 5-HT1B-mediated vasoconstrictive action. For this reason, studies have focused on the development of ditans, a group of antimigraine drugs targeting 5-HT1D and 5-HT1F receptors. Unfortunately, 5-HT1D receptor agonists have been shown to be ineffective in the acute treatment of migraine. Several ditans targeting the 5-HT1F receptor have been developed and have shown no vasoconstrictive effect in preclinical studies, but only two of them, lasmiditan and LY334370, have been tested in clinical trials for migraine, and only lasmiditan has reached to Phase III clinical trials. These Phase III trials have demonstrated the efficacy and safety of lasmiditan, a selective 5-HT1F receptor agonist, in acute migraine treatment. Lasmiditan might offer an alternative migraine therapy without cardiovascular risks. This review will summarize the development of agents targeting the 5-HT1B/1D and 5-HT1F receptors and the clinical evidence supporting the use of these agents for acute migraine treatment.

The effectiveness and value of novel acute treatments for migraine.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, America's Health Insurance Plans, Anthem, Allergan, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, and United Healthcare. Agboola, Borrelli, Rind, and Pearson are employed by ICER. Touchette, through the University of Illinois at Chicago, received funding from ICER for development of the economic model described in this publication. Atlas has nothing to disclose.

Aripiprazole for prevention of delirium in the neurosurgical intensive care unit: a double-blind, randomized, placebo-controlled study.

PURPOSE: Delirium is reported in over 50% of critically ill ICU patients, and is associated with increased mortality and long-term cognitive consequences. Prevention and early management of delirium are essential components of ICU care. However, pharmacological interventions have not been effective in delirium prevention. This study investigated the effect of aripiprazole in the prevention of delirium in a neurosurgical intensive care unit. METHODS: In this prospective, randomized placebo-controlled small clinical trial, 53 patients, 18 to 80 years old, were randomized to receive enteric aripiprazole (15 mg) or placebo for up to 7 days. Delirium, detected by the Confusion Assessment Method-ICU, ICU events, laboratory studies, aripiprazole safety, time to delirium onset, delirium-free days, delirium prevalence during follow-up and ICU length of stay were recorded. RESULTS: Forty patients with similar baseline characteristics, including age, sex, neurosurgery types and APACHE II scores, completed the study. Delirium incidence and the mean days to its onset were 20% vs. 55% (p = 0.022) and 2.17 ± 0.41 vs. 2.09 ± 0.30 (p = 0.076) in the aripiprazole and placebo groups, respectively. The mean number of delirium-free days were: 5.6 (95%CI, 4.6-6.5) and 4.3 (95%CI, 3.2-5.4), in aripiprazole and placebo groups, respectively (p = 0.111). The prevalence of delirium during the follow-up was significantly lower in the aripiprazole group (p = 0.018). Serious aripiprazole adverse reactions were not observed. CONCLUSIONS: Aripiprazole can reduce the incidence of delirium in the neurosurgical ICU. Studies with larger sample size in diverse ICU settings and longer follow-up are needed to confirm our findings.

The Headache Pipeline: Excitement and Uncertainty.

There are many new treatment options available for migraine and more are coming. Three calcitonin gene-related peptide (CGRP) antagonist monoclonal antibodies have been approved and a 4th is due in early 2020. Small molecule CGRP receptor-blocking oral compounds, both for acute care and prevention, are also coming. Four neurostimulators are available, with others on the way. New acute treatments coming soon include the 5HT1F agonist lasmiditan, a zolmitriptan intradermal micro-needle patch, and a nasal mist sumatriptan with a permeability enhancer. Farther out, three novel dihydroergotamine delivery systems, and a liquid-filled capsule of celecoxib show early promise. A new, safer form of methysergide is in the works, as is a longer-duration onabotulinumtoxinA. As always with new products, questions regarding safety, tolerability, cost, and insurance coverage will need to be addressed. Despite these concerns and uncertainties, a robust headache treatment pipeline is good for patients who are not satisfied with the results of their treatment and/or cannot tolerate existing treatments.

Review of antidepressants in clinic and active ingredients of traditional Chinese medicine targeting 5-HT1A receptors.

Serotonin, which also named as 5-hydroxytryptamine (5-HT), is a neurotransmitter, which plays significant roles in a wide range of physiological and pathological processes. Depression is a complex disease that involves numerous factors, increasing evidences have showed that the level of 5-HT was lower in depressed patients and the administration of some selective serotonin re-uptake inhibitors exhibited antidepressant effects. The 5-HT1A receptor is a key protein in the brain serotonin system, modulating the release of 5-HT and other neurotransmitters. Behavioral and molecular biological studies have demonstrated that the differences of 5-HT1A receptor regulation was connected with depression and the responses to antidepressants. In this review, the authors will introduce the structure and function of 5-HT1A receptor and summarize some antidepressants targeting 5-HT1A receptor, including 5-HT1A receptor agonists and antagonists in a clinic, active ingredients of traditional Chinese medicine. And we found the major of drugs by targeting 5-HT1A receptor on the market or in clinical trials mostly have the similar functional groups, such as piperazine, piperidine, and pyrimidine. There are also some literatures found that these functional groups may be the site produce activity. So, we hope that it may provide basis and references for the research of the clinical drugs for depression.

Targeting CGRP and 5-HT1F Receptors for the Acute Therapy of Migraine: A Literature Review.

OBJECTIVE: To review and highlight current literature on emerging acute migraine treatments, focusing on CGRP receptor antagonists, gepants, and 5-HT1F receptor agonists (ditans). BACKGROUND: Current acute migraine therapy consists of nonspecific analgesia and triptans. Limitations to these medicines, including lack of efficacy in many patients, side effects and the contraindication of triptans in patients with cardiovascular disease, suggest that there is an unmet need for new treatments. Studies of serotonin pharmacology led to the development of triptans, 5-HT1B/1D receptor agonists, some of which have actions at the 5-HT1F receptor. Exploration of the role of calcitonin gene-related peptide (CGRP) has resulted in the development of CGRP receptor antagonists. METHOD: The authors performed a literature search of Pubmed and Cochrane databases as well as reviewed abstracts presented at meetings: American Headache Society, American Academy of Neurology, European Headache Federation and the Migraine Trust International Symposium, as well as on-line sources. The authors briefly detail the relevant migraine pathophysiology pertaining to 5-HT1F receptor and the CGRP pathway relevant to acute therapies. Recent clinical trials of acute therapies in which 5-HT1F receptor agonists or CGRP receptor antagonists were studied are summarized. RESULTS: Two 5-HT1F receptor agonists have reached phase II clinical trials. One, lasmiditan, has completed 2 phase III clinical trials, demonstrating a significant effect for pain freedom and most bothersome symptom at 2 hours. Among the 6 gepants tested for the acute treatment of migraine to date, after issues for some of hepatic safety or efficacy, 2 CGRP receptor antagonists, rimegepant and ubrogepant, have completed phase III trials showing efficacy and safety. CONCLUSION: Current available therapies have either been nonspecific or had important limitations, including in patients with cardiovascular risk factors. Phase III clinical trials of lasmiditan, rimegepant and ubrogepant all met their primary endpoints, so the options for migraine-targeted acute therapy will likely soon increase.

Traditional and Novel Migraine Therapy in the Aging Population.

Migraine is a common disabling disorder that affects 36 million Americans. The clinical features of migraine are less typical in the people above age 60, making the diagnosis and treatment difficult in this group. In this review, we will discuss migraine-specific drugs and their use in populations about age 60 who suffer from migraine. This discussion will include an overview of traditional treatments for the acute and preventive treatment of migraine, and considerations for their use in patient populations above age 60. In addition, we will discuss newer agents that show a more promising safety profile.

Diagnosis and treatment of migraine in the patient with depression.

BACKGROUND AND PURPOSE: Migraine headache is an enormous health care burden resulting in billions of dollars in workforce revenue lost and millions of lost workdays per year. Migraine headaches and depression are common comorbidities and require expertise in treatment and prevention. METHODS: The aim of this article is to update the nurse practitioner (NP) on best clinical practices for managing the patient with migraine and previously diagnosed depression. This will include an overview of the pathophysiology of migraine, as well as criteria for diagnosis, treatment, prevention, and patient teaching. CONCLUSIONS: Migraine and depression are commonly linked and require expertise in treatment to achieve the best patient outcomes. IMPLICATIONS FOR PRACTICE: Patients with migraine are more likely to have depression than the general population. Both conditions require optimal treatment and patient education to reduce overall disease burden. A better understanding of the relationship between depression and migraine will enable the NP to better manage patients with migraine and comorbid depression.

Migraine in children: presentation, disability and response to treatment.

PURPOSE OF REVIEW: The current review presents findings from investigations of migraine in children. The presentation of pediatric migraine, related consequences, and medication treatments are reviewed. RECENT FINDINGS: A number of advancements have been made in the study of the presentation, disability, and treatments for migraine in children. However, recent research suggests that not all approaches are equally effective in the treatment of migraine in children. Specifically, a recent study comparing pharmacological interventions found that preventive medications were not statistically more effective than placebo in children. Consistent findings showing clinically meaningful placebo response rates, shorter duration of headaches and other characteristic features (e.g. frontal, bilateral location) have been barriers to the design of randomized clinical trials in children and adolescents with migraine. Better understanding of treatment mechanisms for medication interventions is needed. SUMMARY: Several migraine treatments have determined to be effective for use in children but few controlled studies have evaluated the effectiveness of medication treatments. Recent research suggests that preventive medications may not be more effective than placebo. Additional research is needed to evaluate the effectiveness of medication treatment in migraine headache care.

Serotonin-1A receptor dependent modulation of pain and reward for improving therapy of chronic pain.

Chronic pain conditions such as low back pain and osteoarthritis are the most prominent causes of disability worldwide. Morphine and other opioid drugs are the gold standard treatment for severe pain, including surgical pain, but the use of these drugs for chronic pain is limited largely because long term use of these drugs is associated with drug abuse and hyperalgesia which produces a negative impact on the treatment. Non-addictive treatments for chronic pain are, therefore, highly needed. Commonly used opioid drugs activate mu opioid receptors, resulting in an inhibition of tonic activity of nociceptive neurons. The rewarding effects of opioid drugs are also mediated via activation of mu opioid receptors and inhibition of GABA mediated control of the activity of dopamineregic neurons. Enhanced glutamate release and greater activity of NMDA glutamate receptors is linked to the hyperalgesic effects of opioid drugs. Evidence suggests that activation of serotonin (5-hydroxytryptamine; 5-HT)-1 A receptors modulates dopamine neurotransmission to inhibit rewarding effects of drugs of abuse. Activation of these receptors inhibits glutamate release from the sensory neurons to reduce pain transmission. To help develop strategies for improving therapeutics in chronic pain, and draw research interest in the synthesis of non-addictive opioid drugs which do not predispose to hyperalgesia, the present article concerns the potential mechanism involved in 5-HT-1 A receptor mediated inhibition of pain and reward.

DFN-02 (Sumatriptan 10 mg With a Permeation Enhancer) Nasal Spray vs Placebo in the Acute Treatment of Migraine: A Double-Blind, Placebo-Controlled Study.

OBJECTIVE: The objective of this study was to evaluate the efficacy, safety, and tolerability of DFN-02 - a nasal spray comprising sumatriptan 10 mg and a permeation-enhancing excipient (0.2% 1-O-n-Dodecyl-ß-D-Maltopyranoside [DDM]) - for the acute treatment of migraine with or without aura in adults. BACKGROUND: Prior work has shown that DFN-02, which contains only half the recommended adult dose of sumatriptan found in the original formulation (10 mg vs 20 mg), is more rapidly absorbed than commercial nasal spray of sumatriptan, with favorable pharmacokinetic and safety profiles. The efficacy of DFN-02 in the acute treatment of migraine has not been previously assessed. METHODS: This was a multicenter, randomized, 2-period, double-blind, placebo-controlled efficacy, safety, and tolerability phase 2 study of DFN-02. Subjects with at least a 12 month history of episodic migraine, who averaged 2-8 attacks per month, with no more than 14 headache days per month and a minimum of 48 headache-free hours between attacks, were randomized (1:1) to receive DFN-02 or a matching placebo. Subjects were instructed to treat a single migraine attack of moderate to severe pain intensity. The primary efficacy endpoint, the proportion of subjects who were pain-free at 2 hours postdose in the first double-blind treatment period, was assessed with 2 protocol prespecified primary analyses: last observation carried forward (LOCF) and observed cases (OC). Secondary efficacy endpoints at 2 hours included pain relief; absence of the most bothersome symptom (MBS) among nausea, photophobia, and phonophobia; freedom from nausea, photophobia, and phonophobia. Sustained pain freedom from 2 through 24 hours postdose was also assessed. RESULTS: Of 107 subjects randomized, 86.9% (N = 93 [DFN-02, n = 50; placebo, n = 43]) had data in the first double-blind treatment period. The study met its primary endpoint; the proportion of subjects who were free from headache pain at 2 hours postdose, was statistically significantly higher in the DFN-02 group than in the placebo group in both prespecified primary analyses: LOCF (DFN-02, n = 21/48; placebo, n = 9/40; 43.8% vs 22.5%, P = .044) and OC (DFN-02, n = 21/48; placebo, n = 8/39; 43.8% vs 20.5%, P = .025). For secondary efficacy endpoints, at 2 hours postdose, DFN-02 was also statistically significantly superior to placebo for the proportion of subjects who had pain relief (83.3% vs 55.0%, P = .005); who were free of their MBS (70.7% vs 39.5%, P = .007); and who were free of nausea (78.3% vs 42.1%, P = .026), photophobia (71.8% vs 38.9%, P = .005), and phonophobia (78.1% vs 40.0%, P = .004). Compared with placebo, statistically significantly greater proportions of subjects who were treated with DFN-02 had sustained pain freedom from 2 through 24 hours postdose (38.9% vs 13.8%, P = .029). In total, 9.7% (9/93) of subjects reported a treatment-emergent adverse event during the study: 10.0% (5/50) of DFN-02 subjects in the first double-blind treatment period and 13.5% (5/37) of DFN-02 subjects in the second double-blind treatment period. The most common treatment-emergent adverse event with DFN-02 was dysgeusia (3/37 subjects in the second double-blind treatment period). CONCLUSIONS: DFN-02 was shown to be effective, well tolerated, and safe in the acute treatment of episodic migraine. Additional studies are needed to confirm these preliminary results. (ClinicalTrials.gov Identifier: NCT02856802).

Pharmacokinetics and Skin Tolerability of Intracutaneous Zolmitriptan Delivery in Swine Using Adhesive Dermally Applied Microarray.

Adhesive Dermally Applied Microarray (ADAM) is a new drug-delivery system that uses microprojections (340-µm long) for intracutaneous drug self-administration. We formulated zolmitriptan, a well-accepted and commonly used migraine medication, for administration using ADAM. In vivo studies were conducted in female prepubescent Yorkshire pigs using ADAM 1.9-mg zolmitriptan applied to the inner thigh and left in place for 1 h. Pharmacokinetic studies showed that the ADAM 1.9-mg zolmitriptan was delivered with high efficiency (85%) and high absolute bioavailability (77%). Furthermore, in vivo evaluation showed a rapid systemic absorption with a median Tmax of 15 min. Skin biopsies of the treatment sites showed a mean depth of microprojection penetration of 105.4 ± 3.6 µm. Mass spectrometry imaging showed that the zolmitriptan after 1 h of patch wear time was predominantly localized to the dermis. ADAM zolmitriptan was well tolerated with a transient mild-to-moderate erythema response. The findings in these studies, particularly the rapid zolmitriptan absorption profile after intracutaneous administration, provided validation to advance ADAM zolmitriptan development.

A review of clinical safety data for sumatriptan nasal powder administered by a breath powered exhalation delivery system in the acute treatment of migraine.

INTRODUCTION: AVP-825 (sumatriptan nasal powder) is an FDA-approved intranasal medication delivery system containing low-dose sumatriptan powder for acute treatment of migraine with or without aura in adults. AVP-825 utilizes unique nasal anatomy features to avoid limitations of other intranasal delivery methods. Areas covered: Literature search terms: 'AVP-825', 'sumatriptan nasal powder', 'intranasal sumatriptan', 'sumatriptan safety', 'sumatriptan acute migraine'. Pharmacokinetic, Phase 2/3 studies, reviews (AVP-825) and metanalyses/reviews (sumatriptan) were evaluated. Expert opinion: AVP-825 provides a more efficient sumatriptan delivery method versus other formulations. Pharmacokinetics showed that a single dose of AVP-825 (22 mg) delivers 15-16 mg sumatriptan and produces significantly lower exposure than oral or injectable formulations, which may translate into a better safety/tolerability profile. AVP-825 was well tolerated in controlled trials, with the most common adverse events localized at the administration-site (abnormal taste, nasal discomfort); these were mostly mild, leading to only one discontinuation. Compared to 100 mg oral sumatriptan, AVP-825 had a significantly lower rate of atypical sensations across multiple attacks. AVP-825 has the advantage of early efficacy onset associated with faster absorption at a lower delivered dose than liquid nasal spray or oral formulations. AVP-825 provided earlier efficacy (within 30 min) vs. 100 mg oral sumatriptan and similar sustained efficacy. AVP-825 offers the benefits of a non-oral, low-dose, tolerable acute migraine medication.

Effects of Flibanserin on the Pharmacokinetics of a Combined Ethinylestradiol/Levonorgestrel Oral Contraceptive in Healthy Premenopausal Women: A Randomized Crossover Study.

PURPOSE: This study aimed to investigate the effect of steady-state exposure to flibanserin, a 5-HT1A agonist/5-HT2A antagonist approved for the treatment of hypoactive sexual desire disorder in premenopausal women, on the single-dose pharmacokinetics of the contraceptive steroids ethinylestradiol and levonorgestrel in healthy premenopausal women. METHODS: Healthy female volunteers (N = 24) received 2 single doses of a combined oral contraceptive containing ethinylestradiol 30 µg and levonorgestrel 150 µg, either alone (reference) or preceded by treatment with flibanserin 100 mg once daily for 14 days (test). The 2 treatments were given in randomized order, with a 4-week washout period following the last administration of the first treatment. Plasma concentrations of ethinylestradiol and levonorgestrel were measured over 48 hours after dosing for the determination of pharmacokinetic parameters; the primary end points were Cmax and AUC0-∞ of ethinylestradiol and levonorgestrel. FINDINGS: Of the 24 women enrolled (mean age, 38.0 years), 23 completed the study. Mean (SD) Cmax and AUC0-∞ values of ethinylestradiol were 66.7 (16.3) pg/mL and 693 (268) pg · h/mL, respectively, following the oral contraceptive alone, and 72.7 (25.5) pg/mL and 740 (235) pg · h/mL, respectively, when the oral contraceptive was preceded by flibanserin. In both cases, the 90% CIs of the reference/test ratios of Cmax and AUC0-∞ were within the range of 80% to 125%, indicating that flibanserin had no significant effect on the pharmacokinetic properties of ethinylestradiol. Similarly, the mean (SD) Cmax and AUC0-∞ values of levonorgestrel were 5.0 (1.6) ng/mL and 52.2 (18.7) ng · h/mL, respectively, with the oral contraceptive alone, and 5.0 (1.6) ng/mL and 53.3 (20.4) ng · h/mL, respectively, following flibanserin; again, in both cases, the 90% CIs of the reference/test ratios were within the range of 80% to 125%, indicating that flibanserin had no significant effect on the pharmacokinetic properties of levonorgestrel. All adverse events were mild to moderate in intensity (incidence: 12.5% and 70.8% with ethinylestradiol/levonorgestrel treatment alone and following administration of flibanserin, respectively). IMPLICATIONS: Pretreatment with flibanserin 100 mg once daily for 2 weeks did not produce a clinically relevant change in oral contraceptive drug exposure following single-dose administration of ethinylestradiol/levonorgestrel. This finding is relevant to women with hypoactive sexual desire disorder who might prefer oral contraceptives to other forms of birth control. EudraCT No: 2006-006960-46.

Adjunctive azapirone for schizophrenia: A meta-analysis of randomized, double-blind, placebo-controlled trials.

Azapirones, which are serotonin1A (5-HT1A) receptor partial agonists, have been used as an adjunctive treatment for schizophrenia with mixed results. This is a meta-analysis of the efficacy and tolerability of azapirones for schizophrenia based on randomized, double-blind, placebo-controlled trials (RCTs). English and Chinese databases were systematically and independently searched by two investigators. Data were extracted and analyzed using the RevMan software (version 5.3). Seven RCTs (n = 368) of azapirones (buspirone in 6 RCTs and tandospirone in 1 RCT) were identified and analyzed. Only adjunctive buspirone outperformed placebo regarding total psychopathology [standardized mean difference: -1.03 (95% confidence interval (CI): -1.91, -0.15), P = 0.02; I2 = 92%], but the significance disappeared in sensitivity analysis after removing two outlying studies, and in 10 of the 12 subgroup analyses. In 5 RCTs examining neurocognitive function of azapirones, only 2 RCTs found the superiority of buspirone in improving attention/speeded motor performance, verbal and performance intelligence. Adjunctive buspirone outperformed placebo regarding extrapyramidal symptoms [SMD:-0.51, (95%CI: -0.99, -0.02), P = 0.04; I2 = 0%]. Similar rates of discontinuation [risk ratio:1.06 (95%CI:0.54, 2.07), P = 0.86, I2 = 0%] and adverse drug reactions were found between both groups. Adjunctive buspirone and tandospirone failed to show efficacy for psychotic symptoms, but adjunctive buspirone may be associated with improvement in extrapyramidal symptoms and cognitive deficits in schizophrenia. Due to the preliminary nature of this meta-analysis, larger sample size and higher quality RCTs are needed to confirm these finding.

Drug-induced Myopia and Bilateral Angle Closure Secondary to Zolmitriptan.

PURPOSE: To describe a unique case of drug-induced transient myopia with angle-closure glaucoma in a patient being treated with zolmitriptan for migraines. METHODS: A 42-year-old woman who had been using increasing amounts of zolmitriptan over the previous 12 months presented with an acute myopic shift and raised intraocular pressures (IOP) with anterior chamber shallowing. Clinical examination findings at presentation and at follow-up visits were reviewed. RESULTS: Initial examination revealed unaided visual acuities of 20/100 in the right eye and 20/125 in the left, with IOP measuring 34 mm Hg bilaterally. Zolmitriptan was ceased and the patient was commenced on topical antiglaucoma medication. Within 2 weeks, IOP had normalized, with deepening of the anterior chambers and complete resolution of her myopia. Her final recorded unaided visual acuities were 20/12.5 in the right eye and 20/16 in the left. When topical antiglaucoma medication was ceased the patient developed pressure-related headaches and selective laser trabeculoplasty was performed to minimize the need for long-term topical medication use. CONCLUSION: Idiosyncratic drug reactions resulting in ciliochoroidal effusion, secondary angle closure, and transient myopia are well described, but they have not been previously reported with zolmitriptan use. An awareness of the various potential causative agents is important, as findings are generally reversible if recognized early and if the offending drug is discontinued.