A novel intranasal breath-powered delivery system for sumatriptan: a review of technology and clinical application of the investigational product AVP-825 in the treatment of migraine

Introduction: AVP-825, formerly ‘OptiNose Sumatriptan,’ is an investigational Breath-Powered^TM Bi-Directional^TM intranasal delivery system containing low-dose sumatriptan (22 mg intranasal powder) that avoids limitations of other types of intranasal administration by taking advantage of unique features of nasal anatomy and physiology.

Areas covered: This review summarizes intranasal drug delivery for migraine, how the breath-powered technology works, and AVP-825 pharmacokinetic, efficacy and safety/tolerability findings. To identify AVP-825 clinical studies, a PubMed/MEDLINE database search was conducted with the terms AVP-825, OptiNose, OptiNose Sumatriptan, Breath-Powered Nasal Delivery or sumatriptan powder. Of 20 articles, 5 clinical studies were identified, including the head-to-head comparative COMPASS trial (AVP-825 vs oral sumatriptan) and two placebo-controlled studies.

Expert opinion: AVP-825 has faster sumatriptan absorption versus oral tablets or traditional liquid nasal spray. In Phase II/III randomized, double-blind, placebo-controlled trials, AVP-825 produced early and sustained efficacy with minimal triptan-related adverse effects. In COMPASS, AVP-825 produced earlier reduction of migraine pain intensity and migraine-associated symptoms than 100 mg oral sumatriptan, and higher early rates of pain relief and pain freedom, similar sustained efficacy, and fewer atypical sensations. AVP-825 has the potential to provide migraine patients with improved intranasal administration of sumatriptan that may enhance efficacy and tolerability.     

AVP-786 for the treatment of agitation in dementia of the Alzheimer’s type

Introduction: Agitation is common and distressing in patients with Alzheimer-type dementia, but safe, effective treatments remain elusive. Psychological treatments are first-line options, but they have limited efficacy. Off-label psychotropic medications are frequently used, but they also have limited effectiveness, and their use may have harmful side effects, including death.

Areas covered: This review discusses the history leading to the conception of AVP-786 (deuterated (d6)-dextromethorphan/quinidine), its pharmacokinetic and pharmacodynamic profiles and safety issues, together with an overview of recent clinical trials. Data were found in the medical literature, in US and EU clinical trial registries and in information provided by the manufacturer.

Expert opinion: AVP-786 is one of six investigational compounds in recent phase III clinical development for agitation in Alzheimer disease (AD). Quinidine and deuteration appear to prolong dextromethorphan’s plasma half-life and facilitate brain penetration. The FDA granted fast-track designation to AVP-786 and allowed use of data generated on dextromethorphan-quinidine (AVP-923, Nuedexta®) for regulatory filings. AVP-923 reduced agitation in AD and was well tolerated in a phase II RCT that included more than 200 patients. A phase III clinical development program of AVP-786 for AD agitation was recently initiated. This program is expected to start generating results in July 2018.     

Olopatadine hydrochloride ophthalmic solution for the treatment of allergic conjunctivitis

Introduction: Olopatadine hydrochloride is an antihistamine and mast cell stabilizer available as oral, intranasal and ocular preparations. Most of the practical applications of olopatadine therapy focus on the treatment of allergic rhinoconjunctivitis via intranasal and ocular routes.

Areas covered: This article was created from a comprehensive literature search with information taken from meta-analyses, systematic reviews, and clinical trials of children and adults. The articles that have been selected, evaluate the use of intranasal and ocular antihistamines and their role in allergic rhinoconjunctivitis.

Expert opinion: Olopatadine is significantly more effective than placebos in relieving the symptoms of allergic rhinoconjunctivitis. It can function both as a viable alternative or addition to first line therapies such as intranasal steroids and oral antihistamines.     

AVP-825: a novel intranasal delivery system for low-dose sumatriptan powder in the treatment of acute migraine

Introduction: Migraine is a common, disabling disorder, and many patients remain dissatisfied with existing treatments. AVP-825 (ONZETRA® Xsail®) is a Breath Powered® exhalation delivery system for low-dose sumatriptan nasal powder (22 mg) that has been recently approved for use in the treatment of acute migraine with or without aura in adults. AVP-825 takes advantage of unique features of nasal anatomy and physiology to avoid limitations typically seen with other types of intranasal medication delivery.

Areas covered: This review provides a summary of the pharmacology, clinical efficacy and tolerability of AVP-825 in clinical studies to date and also provides an overview of the unique aspects of the delivery system.

Expert commentary: AVP-825 represents an improvement in nasal delivery of sumatriptan for migraine. PK studies indicate a distinct advantage of AVP-825 over traditional liquid nasal sprays in terms of absorption time, which may underlie the early efficacy observed with AVP-825. It offers the benefits of non-oral medications at a comparatively low sumatriptan dose, without the limitations associated with more invasive approaches. AVP-825 is suitable for use across multiple phases of a migraine attack from use as an early intervention to use in a more advanced migraine with nausea, given the non-oral application.     

Mulberry leaves and their potential effects against cardiometabolic risks: a review of chemical compositions,biological properties and clinical efficacy

Context: Cardiometabolic risks are regarded as the crucial factors associated with type 2 diabetes (T2DM) and cardiovascular diseases (CVD). Regarding an increased attention to medicinal plants in the current healthcare system, the effects of mulberry (Morus spp., Moraceae) leaves on cardiometabolic risks have been consecutively considered in scientific research.

Objective: The present review compiles and summarizes the chemical compositions, biological properties and clinical efficacy of mulberry leaves that are related to the amelioration of cardiometabolic risks.

Methods: Published English literature from the PubMed, Science Direct and Google Scholar databases was searched by using ‘mulberry leaves’ ‘Morus spp.’, ‘hyperglycemia’, ‘hyperlipidemia’, ‘obesity’, ‘hypertension’, ‘oxidative stress’, ‘atherosclerosis’ and ‘cardiovascular diseases’ as the keywords. The relevant articles published over the past two decades were identified and reviewed.

Results: Mulberry leaves contain numerous chemical constituents. 1-Deoxynojirimycin (DNJ), phenolics and flavonoids are the prominent functional compounds. Preclinical and clinical studies showed that mulberry leaves possessed various beneficial effects against cardiometabolic risks, including antihyperglycaemic, antihyperlipidaemic, antiobesity, antihypertensive, antioxidative, anti-inflammatory, anti-atherosclerotic and cardioprotective effects.

Conclusions: Mulberry leaves could be a promising therapeutic option for modulating cardiometabolic risks. However, further investigations should be performed to substantiate the potential of mulberry leaves in practical uses.     

The therapeutic potential of novel anti-migraine acute therapies

Introduction: Migraine is a highly disabling neurovascular disorder. ‘The complex and multifactorial properties of migraine pathogenesis provide the opportunity to identify new therapeutic targets from a wide range of receptors.

Areas covered: In this editorial, the authors focus on future pharmacological interventions for acute migraine including: 5-HT receptors and their agonists, calcitonin gene-related peptide receptors and their antagonists, PAC1 receptors and their antagonists, glutamate receptors and some of their antagonists as well as transient receptor potential channels and their antagonists. The authors also discuss preventative treatments for migraine that are currently in development.

Expert opinion: Future pharmaceutical research that looks at the well-known mechanisms involved in the pathophysiology of migraine should aim to overcome the existing limitations of each pharmacological class and their side effects. There has lately been particular interest in the role of glutamate receptors, particularly metabotropic glutamate receptors, in the pathophysiology of migraine. These receptors may be potentially viable drug targets for migraine in the future.     

Needle-free cutaneous delivery of living human cells by Er:YAG fractional laser ablation

Background: Dermatological diseases, including most skin cancers and rare genetic conditions frequently originate in the epidermis. Targeted, topical cell-based therapy is a promising therapeutic strategy. Here, we present the first report demonstrating that fractional laser ablation enables local ‘needle-free’ intraepidermal delivery of living human cells.

Methods: The cells penetrated porcine ear skin via microchannels created by Er:YAG fractional laser ablation; cell delivery was quantified using a haemocytometer. Cutaneous distribution was confirmed visually by laser scanning confocal microscopy and histological analysis.

Results: Total cell delivery (sum of amounts permeated and deposited) after 24 h increased from 5.7 ± 0.1 x10⁵ to 9.6 ± 1.6 x10⁵ cells/cm² when increasing pore density from 300 to 600 pores/cm², – corresponding to 19- and 32-fold increases over the control. At 600 pores/cm², cell deposition was 136-fold greater than cell permeation – the latter most likely due to transport from micropores into appendageal pathways. Production of GFP post-delivery confirmed cell remained viability.

Conclusion: The results demonstrate the feasibility of using controlled laser microporation to achieve local ‘needle-free’ cutaneous delivery of living human cells to the epidermis and dermis. This raises the possibility of using this technique for targeted new approaches for dermatological therapy in these regions.     

Suspected adverse drug reaction reports with oral anticoagulants in Portugal: a pharmacovigilance study

Objective: In this pharmacovigilance study, we aimed to determine the incidence of spontaneously reported suspected adverse drug reactions (ADRs) related to oral anticoagulants: non-vitamin K antagonist oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban, rivaroxaban) and vitamin K antagonists (VKA)

Research design and methods: In this retrospective observational study, we extracted all the individual case safety reports related to oral anticoagulants recorded in the Portuguese Pharmacovigilance Database (January 2010 to April 2015). The annual incidence of suspected ADRs was estimated using drug exposure data. Disproportionality of reporting ADR was addressed through reporting odds ratio (ROR) and 99% confidence intervals.

Results: We appraised 794 suspected ADR (78% related to NOACs). The annual number of ADRs increased overtime with 9 ADRs/million Defined Daily Dose (DDD) at the end of 2014. The incidence of NOACs ADRs decreased from 2012 onwards. VKA showed a disproportion in ‘Investigation’ (ROR 0.10, 99%CI 0.05–0.22) and ‘Injury, poisoning and procedural complications’ (ROR 0.36, 99%CI 0.19–0.69) ADRs compared with NOACs. NOACs had a higher significant disproportion of ‘Nervous system disorders’ related ADRs (ROR 3.98, 99%CI 1.50–10.53).

Conclusions: Reporting of ADRs associated with oral anticoagulants (mainly NOACs), is increasing. Exploratory disproportion analyses showed an increase of reports of nervous system ADRs with NOACs, and INR-related ADRs with VKA.     

New and incremental FDA black box warnings from 2008 to 2015

Background: The boxed warning (also known as ‘black box warning [BBW]’) is one of the strongest drug safety actions that the U.S. Food & Drug Administration (FDA) can implement, and often warns of serious risks. The objective of this study was to comprehensively characterize BBWs issued for drugs after FDA approval.

Methods: We identified all post-marketing BBWs from January 2008 through June 2015 listed on FDA’s MedWatch and Drug Safety Communications websites. We used each drug’s prescribing information to classify its BBW as new, major update to a preexisting BBW, or minor update. We then characterized these BBWs with respect to pre-specified BBW-specific and drug-specific features.

Results: There were 111 BBWs issued to drugs on the US market, of which 29% (n = 32) were new BBWs, 32% (n = 35) were major updates, and 40% (n = 44) were minor updates. New BBWs and major updates were most commonly issued for death (51%) and cardiovascular risk (27%). The new BBWs and major updates impacted 200 drug formulations over the study period, of which 64% were expected to be used chronically and 58% had available alternatives without a BBW.

Conclusions: New BBWs and incremental updates to existing BBWs are frequently added to drug labels after regulatory approval.     

Serotonin receptor targeted therapy for migraine treatment: an overview of drugs in phase I and II clinical development

Introduction: Research has focused on serotonin (5-HT) 5-HT_1D and 5-HT_1F receptors to develop drugs acting through non-vasoconstrictive mechanisms for treating acute migraine and those targeting 5-HT_2B and 5-HT₇ receptors for preventing migraine.

Areas covered: This paper reviews antimigraine drugs targeting 5-HT receptors in one phase I trial (sumatriptan iontophoretic transdermal system, TDS) and five phase II clinical trials (PNU-142633, LY334370, lasmiditan, NOX-188).

Expert opinion: Data from our overview on investigational drugs in phase I and II clinical trials using the 5-HT_1B/1D receptor agonist (sumatriptan TDS), 5-HT_1D receptor agonist (PNU-142633), 5-HT_1F receptor agonists (LY334370, lasmiditan) and a combined 5-HT_1B/1D receptor agonist with nNOS inhibition (NOX-188) provided encouraging data for sumatriptan TDS and lasmiditan, disappointing results for PNU-142633, and promising findings for NOX-188. The 5-HT_1F receptor agonist lasmiditan, a drug acting through non-vasoconstrictive mechanisms, represents a promising safe, effective and tolerated acute migraine therapy also for patients at cardiovascular risk. Upcoming phase III trials should clarify the optimal lasmiditan dose and eventual clinical advantages over triptans. The negative results for the PNU-142633 trial prompt further studies using specific compounds more precisely targeting 5-HT_1D receptors. Antagonism at 5-HT_2B and 5-TH₇ receptors, a promising strategy to prevent migraine, is still limited to experimental migraine models.     

The influence of excipients on physical and pharmaceutical properties of oral lyophilisates containing a pregabalin-acetaminophen combination

Objectives: The purpose of the study was to investigate and characterize the oral lyophilisates containing the pregabalin-acetaminophen drug combination and as xcipients mannitol with microcrystalline cellulose or hydroxypropyl methylcellulose, in order to conclude upon drug-excipient interactions and their stability implications, impact of excipients on drug release and on the physicochemical and mechanical properties of the pharmaceutical formulations.

Methods: The oral tablets were made by using a Christ freeze-dryer alpha 2–4-LSC lyophilizer, and evaluated for stability, drug-excipient compatibility and homogeneity of the prepared pharmaceutical formulations. The formulations were evaluated for in vivo absorption in rabbits by histopathological exams.

Results: FTIR and thermogravimetric analyses, DLS technique, SEM and NIR-CI studies confirmed the compatibility between compounds. From the determined physical and biochemical parameters of the formulations it was established that they are stable, homogeneous, and meet the conditions for orally disintegrating tablets.

Conclusion: In the case of the investigated pharmaceutical formulations the study evidenced the assembling through physical bonds between the excipients and the ‘codrug’ complex, which do not affect the release of the bioactive compounds.     

The anti-inflammatory activity of licorice,a widely used Chinese herb

Context: Increasing incidence and impact of inflammatory diseases have encouraged the search of new pharmacological strategies to face them. Licorice has been used to treat inflammatory diseases since ancient times in China.

Objective: To summarize the current knowledge on anti-inflammatory properties and mechanisms of compounds isolated from licorice, to introduce the traditional use, modern clinical trials and officially approved drugs, to evaluate the safety and to obtain new insights for further research of licorice.

Methods: PubMed, Web of Science, Science Direct and ResearchGate were information sources for the search terms ‘licorice’, ‘licorice metabolites’, ‘anti-inflammatory’, ‘triterpenoids’, ‘flavonoids’ and their combinations, mainly from year 2010 to 2016 without language restriction. Studies were selected from Science Citation Index journals, in vitro studies with Jadad score less than 2 points and in vivo and clinical studies with experimental flaws were excluded.

Results: Two hundred and ninety-five papers were searched and 93 papers were reviewed. Licorice extract, 3 triterpenes and 13 flavonoids exhibit evident anti-inflammatory properties mainly by decreasing TNF, MMPs, PGE2 and free radicals, which also explained its traditional applications in stimulating digestive system functions, eliminating phlegm, relieving coughing, nourishing qi and alleviating pain in TCM. Five hundred and fifty-four drugs containing licorice have been approved by CFDA. The side effect may due to the cortical hormone like action.

Conclusion: Licorice and its natural compounds have demonstrated anti-inflammatory activities. More pharmacokinetic studies using different models with different dosages should be carried out, and the maximum tolerated dose is also critical for clinical use of licorice extract and purified compounds.     

Fevipiprant in the treatment of asthma

Introduction: Asthma is common and in many, particularly those with more severe disease, there remains a substantial unmet need. Success with biologics targeting eosinophilic inflammation underscore the value of treating inflammation in asthma beyond corticosteroids. Fevipiprant (QAW039) is an oral treatment for asthma. It competitively and reversibly antagonises the prostaglandin D2 receptor 2 (DP2) expressed on inflammatory and structural cells.

Areas covered: We reviewed fevipiprant’s mode of action and efficacy against other current and emerging pharmacological interventions for moderate-to-severe asthma. We undertook a literature review using the PubMed/Medline database, the U.S. National Library of Medicine’s Clinical Trials website and from manufacturers’ press releases with the search terms: ‘QAW039’, ‘Fevipiprant’, ‘CRTH2 antagonists’, ‘DP2’, ‘DP1’, ‘monoclonal antibody’, ‘eosinophil’ with ‘asthma’ plus the names of individual drugs. Three Phase 2 trials have been conducted and three Phase 3 trials (NCT02563067, NCT03052517, NCT02555683) are in progress. To date Fevipiprant’s greatest success has been in targeting severe eosinophilic asthma.

Expert opinion: Fevipiprant presents the possibility of a new orally active therapy for asthma. If successful in phase 3 trials it will have an enormous impact on the treatment paradigm for asthma and will potentially widen access for pre-biologic treatment to a larger population.     

Use of traditional herbal medicine as an alternative in dental treatment in Mexican dentistry: a review

Context: Herbal therapies are used worldwide to treat health conditions. In Mexico, generations have used them to treat gingivitis, periodontitis, mouth infections, and discoloured teeth. However, few studies have collected scientific evidence on their effects.

Objective: This study aimed at searching and compiling scientific evidence of alternative oral and dental treatments using medicinal herbs from Mexico.

Methods: We collected various Mexican medicinal plants used in the dental treatment from the database of the Institute of Biology at the National Autonomous University of Mexico. To correlate with existing scientific evidence, we used the PubMed database with the key term ‘(scientific name) and (oral or dental)’.

Results: Mexico has various medical herbs with antibacterial and antimicrobial properties, according to ancestral medicinal books and healers. Despite a paucity of experimental research demonstrating the antibacterial, antimicrobial, and antiplaque effects of these Mexican plants, they could still be useful as an alternative treatment of several periodontal diseases or as anticariogenic agents. However, the number of studies supporting their uses and effects remains insufficient.

Discussion and conclusion: It is important for the health of consumers to scientifically demonstrate the real effects of natural medicine, as well as clarify and establish their possible therapeutic applications. Through this bibliographical revision, we found papers that testify or refute their ancestral uses, and conclude that the use of plants to treat oral conditions or to add to the dental pharmacological arsenal should be based on experimental studies verifying their suitability for dental treatments.     

Glutamate receptor antagonists with the potential for migraine treatment

Introduction: Preclinical, clinical, and other (e.g., genetic) evidence support the concept that migraine susceptibility may at least partially result from a glutamatergic system disorder. Therefore, the receptors of the glutamatergic system are considered relatively new targets for investigational drugs to treat migraine. Investigational and established glutamate receptor antagonists (GluRAs) have been shown to possess antinociceptive properties in preclinical models of trigeminovascular nociception and have been evaluated in clinical trials. This review focuses on preclinical and clinical studies of GluRAs for the treatment of migraine.

Areas covered: A PubMed database search (from 1987 to December 2016) and a review of published studies on GluRAs in migraine were conducted.

Expert opinion: All published clinical trials of investigational GluRAs have been unsuccessful in establishing benefit for acute migraine treatment. Clinical trial results contrast with the preclinical data, suggesting that glutamate (Glu) does not play a decisive role after the attack has already been triggered. These antagonists may instead be useful for migraine prophylaxis.

Improving patient care requires further investigating and critically analyzing the role of Glu in migraine, designing experimental models to study more receptors and their corresponding antagonists, and identifying biomarkers to facilitate trials designed to target specific subgroups of migraine patients.     

Investigational new drugs for allergic rhinitis

Introduction: Allergic rhinitis (AR) is a multifactorial disease characterized by paroxysmal symptoms of sneezing, rhinorrhea, postnasal drip and nasal congestion. For over a century, subcutaneous allergen immunotherapy (SCIT) has been recognized as the most effective therapy to date that may modify the underlying disease course and provide long-term benefits for individuals refractory to pharmacotherapy. However, over the past 25 years, there has been substantial growth in developing alternative therapies to traditional SCIT.

Areas covered: This article will review the most current literature focusing on advancements of AR therapies. Novel AR therapies that are currently under investigation include: the addition of omalizumab, an anti-immunoglobulin E (IgE) monoclonal antibody (mAb), to SCIT; altering the method of delivery of allergen immunotherapy (AIT) including sublingual (SLIT), epicutaneous (EIT), intralymphatic (ILIT), intranasal (INIT) and oral mucosal immunotherapy (OMIT); use of capsaicin spray; novel H3 and H4 antihistamines; activation of the innate immune system through Toll-like receptor agonists; and the use of chemically altered allergens, allergoids, recombinant allergens and relevant T-cell epitope peptides to improve the efficacy and safety of AIT.

Expert opinion: These promising novel therapies may offer more effective and/or safer treatment options for AR patients, and in some instances, induce immunologic tolerance.     

Advances in the treatment options for vitiligo: activated low-dose cytokines-based therapy

Introduction: Vitiligo is a skin disorder characterized by a progressive depigmentation, which is caused by the loss of melanocytes at the cutaneous level. A shift of the immune system with a prevalence of T helper (Th)1/Th17 response instead of a Tregs/Th2 one and may be part of etiology of 10 vitiligo.

Areas covered: This review describes the major points of vitiligo onset and shows the cutting-edge results in the field of low-dose medicine in the treatment of dermatologic diseases and, in particular. in vitiligo. In this review on advances in vitiligo pharmacotherapy, the most pertinent recent publications are reported. Electronic databases such as PubMed were searched for terms ‘low-dose medicine’ or ‘low dose and vitiligo’ or ‘low dose and psoriasis.’

Expert opinion: The availability of a systemic treatment for vitiligo, based on the oral administration of low-dose activated signaling molecules represents an opportunity for the dermatologists to overcome some specific pitfalls of currently available therapeutic protocols.     

Meta-analysis of the efficacy of the fentanyl iontophoretic transdermal system versus intravenous patient-controlled analgesia in postoperative pain management

Objective: This meta-analysis was conducted to analyze and compare the efficacy outcomes associated with the fentanyl iontophoretic transdermal system (ITS) and morphine intravenous (IV) patient-controlled analgesia (PCA) in the management of postoperative pain.

Research design and methods: This meta-analysis assessed the efficacy of the fentanyl ITS versus morphine IV PCA using data from four randomized, active-controlled trials (n = 1271 fentanyl ITS and 1298 morphine IV PCA patients). Main outcome measures were patient global assessment (PGA) of the method of pain control at 24 h.

Results: Fentanyl ITS and morphine IV PCA did not significantly differ regarding ‘good’ and ‘excellent’ ratings on the PGA of the method of pain control at 24 h (odds ratio = 0.95, p = 0.66), however, fentanyl ITS was superior in terms of ‘excellent’ PGA ratings at that time point (odds ratio = 1.53, p < 0.0001). No significant differences were found in weighted mean pain intensity scores at 24, 48 and 72 h.

Conclusions: In this meta-analysis, fentanyl ITS was as efficacious as morphine IV PCA and may offer additional benefits as demonstrated by its ‘excellent’ PGA ratings.     

Primary and secondary nonresponse to infliximab: mechanisms and countermeasures

Introduction: Primary and secondary non-response to infliximab are common in patients with inflammatory bowel disease and remain a management challenge in clinical practice.

Areas covered: This article describes the epidemiology, mechanisms and risk factors for primary and secondary nonresponse to infliximab in patients with inflammatory bowel disease. Data on proactive and reactive therapeutic drug monitoring are examined in this review. An algorithm for evaluation and management of non-response to infliximab is provided. Preventative measures are also discussed. Relevant articles were identified after a literature search using PubMed. Search terms included ‘infliximab’, ‘loss of response’, ‘immunogenicity’, and ‘drug monitoring’. References of identified articles were also reviewed to identify additional references.

Expert opinion: A common cause for primary and secondary non-response include inadequate dosing of infliximab; inadequate dosing can be identified through assessment of drug and anti-drug antibody levels. Therapeutic drug monitoring should be done in patients losing response to infliximab. Use of drug monitoring proactively is still under debate.