CGRP Receptor Antagonists and 5-HT1F Receptor Agonist in the Treatment of Migraine.

Discovering that calcitonin-related peptide (CGRP) plays a key role in the complex pathophysiology of migraine has allowed us to make great strides in the development of new approaches for acute and preventive treatment. This evidence has led to the development of small molecules antagonist molecules of the CGRP receptor ("gepants") and of a new class of medications called "Ditans". This review presents the data from clinical trials reporting the efficacy, safety, and tolerability of the new drugs used in the treatment of migraines. Evidences show that therapeutic approaches targeted to CGRP have the potential to transform the clinical management of migraine, even though its appropriate place has yet to be determined with accuracy.

Psychotropic Drugs Levels in Seminal Fluid: A New Therapeutic Drug Monitoring Analysis?

The aim of this observational study was to develop a new quantitative liquid chromatography-mass spectrometry (LC-MS/MS) method for Therapeutic-Drug-Monitoring (TDM) of psychotropic drugs in seminal fluid to investigate potential gonadotoxic effects in patients with reduced fertility. After the validation of the LC-MS/MS method for psychotropics' levels determination in seminal fluid, we included 20 male partners of infertile couples with idiopathic and/or unexplained male infertility, treated with psychotropic medications for more than 3 months and 10 untreated fertile controls. General and andrological clinical examination, semen analysis and seminal drugs, and metabolites levels determination were performed for each subject. Of the 20 patients included, 6 were treated with antidepressants; 4 with benzodiazepines and 10 with antipsychotics. Seminal drugs and metabolites levels were detectable in all samples. In particular, alprazolam, olanzapine, and levetiracetam showed seminal and serum similar concentrations, while fluoxetine, quetiapine, and aripiprazole were detectable, but seminal levels were significantly lower than the serum therapeutic range. Sperm progressive motility was significantly reduced in subjects treated with psychotropic drugs compared to the untreated controls (p = 0.03). Sperm concentration and progressive motility were significantly reduced in subjects treated with antipsychotics compared to the untreated controls and to the other classes of psychotropics (p < 0.05). In conclusion, this study reports a validated LC-MS/MS method for the detection of seminal psychotropic levels and preliminary data suggesting a potential correlation of seminal psychotropics with alterations of sperm concentration and motility. Pending larger studies, semen TDM might represent a new pivotal tool in the clinical management of reduced fertility in males treated with psychotropic medications.

Polyamines serum levels in episodic and chronic migraine.

Background: Previous studies focused on food as the trigger of a migraine attack did not consider polyamines as possible activators and sensitizers of the trigeminal-vascular system through their interaction with NMDA glutamate receptors. Therefore, this study aimed to assess serum levels of nine polyamines and to evaluate their role as possible triggers and crisis maintainers in episodic and chronic migraine patients. Materials and methods: The study included 50 patients with episodic migraine (EM), 50 patients with chronic migraine (CM) and 50 healthy controls (HC). Serum levels of nine polyamines have been determined by Liquid Chromatography tandem Mass Spectrometry. Specifically, agmatine, spermidine, spermine, putrescine, cadaverine, arginine, ornithine, citrulline and lysine levels were studied. Results: Agmatine serum levels resulted reduced in EC patients with respect to CM and HC. Compared to HC subjects, serum levels of spermine and spermidine were statistically significantly increased both in CM and EM patients. Conclusions: The authors suggest that alterations of polyamines levels might contribute to the understanding of migraine external activation and help to clarify the potential role of NMDA receptor polyamines site antagonists in migraine treatment.

Ubrogepant for the treatment of migraine.

INTRODUCTION: Migraine is a neurovascular disorder involving neurogenic inflammation and transmission of trigeminovascular nociceptive pathways mediated by Calcitonin Gene-Related Peptide (CGRP). Several small molecules antagonizing the CGRP receptor have been developed as migraine-specific acute medications. The CGRP receptor antagonist ubrogepant, also known as MK-1602, has been recently evaluated in phase III clinical trials for clinical efficacy and long-term safety as an abortive migraine treatment. AREAS COVERED: This paper discusses the pharmacodynamics, pharmacokinetics, clinical efficacy, safety, and tolerability profile of ubrogepant for the acute treatment of migraine with or without aura. EXPERT OPINION: Ubrogepant, a selective CGRP antagonist belonging to the gepants family, has been evaluated in large short- and long-term Phases 2 and 3 clinical trials aimed to assess clinical efficacy and safety as acute migraine medication. It did not significantly affect liver function and was not associated with other serious adverse events. Long-term non-serious adverse events were similar between placebo and ubrogepant. The efficacy was evaluated in large placebo-controlled studies and ubrogepant 50 mg and 100 mg was superior, even if the therapeutic gain seems to be low. Nevertheless, the favorable safety profile compared to other abortive drugs makes ubrogepant a promising option for the acute treatment of migraine.

Profiling lasmiditan as a treatment option for migraine.

Introduction: In recent years, research into acute migraine treatment has aimed to develop molecules capable of inhibiting trigeminal pathways, mediated by agonism to 5-HT1F receptors in order to avoid the vasoconstrictive action due to the stimulation of 5-HT 1B/1D receptors. A novel migraine drug class, called 'neurally acting anti-migraine agents', has been developed for the management of acute migraine attacks. Lasmiditan is the only compound of this drug class that has been evaluated in Phase III clinical trials.Areas covered: This review discusses lasmiditan including its pharmacokinetics, pharmacodynamics, efficacy and safety profile. Original research and review articles, relative to the period 2010-2019, were included in the reviewed literature.Expert opinion: The most recent phase III trials have demonstrated the efficacy of lasmiditan for acute migraine treatment, even if compared only with placebo. Nevertheless, the low rate of cardiovascular side effects with lasmiditan might offer a potential therapeutic option for migraine patients with cardiovascular disorders. With the lack of data on lasmiditan's pharmacokinetic features, several phase I clinical trials are still ongoing in order to evaluate half-life, metabolism, excretion and the potential production of active metabolites. Possible pharmacodynamic interaction with drugs acting on central nervous system should be evaluated in future studies.

Fremanezumab for the preventive treatment of migraine in adults.

Introduction: The Calcitonin Gene-Related Peptide (CGRP) has been implicated in migraine pathophysiology due to its role in neurogenic inflammation and transmission of trigeminovascular nociceptive signal. New molecules targeting CGRP and its receptor have been developed as migraine-specific preventative treatments. Fremanezumab (or TEV-48,125, LBR-101), a human monoclonal antibody against CGRP, has been recently approved for clinical use by FDA and EMA. Areas covered: This paper briefly discusses the calcitonin family of neurotransmitters and resultant activation pathways and in-depth the chemical properties, pharmacodynamics, pharmacokinetics, clinical efficacy and safety of Fremanezumab for the prophylactic treatment of migraine. Expert opinion: Fremanezumab, a migraine-specific drug, is effective and safe as a prophylactic treatment of chronic and episodic migraine. As a monoclonal antibody, it was not associated to liver toxicity and is not expected to interact with other drugs. The long half-life might improve patients' compliance. Long-term effects of CGRP block in cardiovascular, grastrointestinal and bone functions should be evaluated in ongoing trials, since CGRP is involved in multiple biological activities in the human body. Nevertheless, targeting CGRP itself allows the receptor binding with other ligands involved in several physiological functions. Thus, the long-term treatment with Fremanezumab is expected to be associated with a lower risk of severe adverse effects.

Pharmacogenetic considerations for migraine therapies.

INTRODUCTION: Migraine is a common neurological disorder with a complex pathophysiology. It has been estimated that incidence between adults of current headache disorder is about 50%. Different studies show that this condition has an important and complex genetic component in response to drug therapy. Areas covered: This review shows and summarizes the importance of the polymorphisms associated with the major antimigraine drug metabolizing enzymes. The research of bibliographic databases has involved only published peer-reviewed articles from indexed journals. Expert opinion: Pharmacogenetics is based on the identification of polymorphism and promises personalized therapy with efficacy and reduction of adverse events. The association between genotype and an altered metabolizer status could guide clinical decision to evade concomitant treatments and adverse events. The introduction of routine genetic testing could help to choose the efficacy drug on the individual and genetic profile.

Single nucleotide polymorphism of GSTP1 and pathological complete response in locally advanced rectal cancer patients treated with neoadjuvant concomitant radiochemotherapy.

PURPOSE: Standard treatment for locally advanced rectal cancer consists of neoadjuvant radiochemotherapy with concomitant fluoropyrimidine or oxaliplatin and surgery with curative intent. Pathological complete response has shown to be predictive for better outcome and survival; nevertheless there are no biological or genetic factors predictive for response to treatment. We explored the correlation between the single nucleotide polymorphisms (SNPs) GSTP1 (A313G) and XRCC1 (G28152A), and the pathological complete response and survival after neoadjuvant radiochemotherapy in locally advanced rectal cancer patients. MATERIALS AND METHODS: Genotypes GSTP1 (A313G) and XRCC1 (G28152A) were determined by pyrosequencing technology in 80 patients affected by locally advanced rectal cancer. RESULTS: The overall rate of pathological complete response in our study population was 18.75%. Patients homozygous AA for GSTP1 (A313G) presented a rate of pathological complete response of 26.6% as compared to 8.5% of the AG+GG population (p = 0.04). The heterozygous comparison (AA vs. AG) showed a significant difference in the rate of pathological complete response (26.6% vs. 6.8%; p = 0.034). GSTP1 AA+AG patients presented a 5- and 8-year cancer-specific survival longer than GSTP1 GG patients (87.7% and 83.3% vs. 44.4% and 44.4%, respectively) (p = 0.014). Overall survival showed only a trend toward significance in favor of the haplotypes GSTP1 AA+AG. No significant correlations were found for XRCC1 (G28152A). CONCLUSION: Our results suggest that GSTP1 (A313G) may predict a higher rate of pathological complete response after neoadjuvant radiochemotherapy and a better outcome, and should be considered in a more extensive analysis with the aim of personalization of radiation treatment.

Short-term one-lung ventilation does not influence local inflammatory cytokine response after lung resection.

BACKGROUND: One-lung ventilation (OLV) is a ventilation procedure used for pulmonary resection which may results in lung injury. The aim of this study was to evaluate the local inflammatory cytokine response from the dependent lung after OLV and its correlation to VT. The secondary aim was to evaluate the clinical outcome of each patient. METHODS: Twenty-eight consecutive patients were enrolled. Ventilation was delivered in volume-controlled mode with a VT based on predicted body weight (PBW). 5 cmH2O positive end-expiratory pressure (PEEP) and FiO2 0.5 were applied. Bronchoalveolar lavage (BAL) was performed in the dependent lung before and after OLV. The levels of pro-inflammatory interleukins (IL-1α, IL-1ß, IL-6, IL-8), tumor necrosis factor alpha (TNFα), vascular endothelial growth factor (VEGF), endothelial growth factor (EGF), monocyte chemoattractant protein-1 (MCP-1) and anti-inflammatory cytokines, such as interleukins (IL-2, IL-4, IL-10) and interferon (IFN-γ), were evaluated. Subgroup analysis: to analyze the VT setting during OLV, all patients were ventilated within a range of 5-10 mL/kg. Thirteen patients, classified as a conventional ventilation (CV) subgroup, received 8-10 mL/kg, while 15 patients, classified as a protective ventilation (PV) subgroup, received 5-7 mL/kg. RESULTS: Cytokine BAL levels after surgery showed no significant increase after OLV, and no significant differences were recorded between the two subgroups. The mean duration of OLV was 64.44±21.68 minutes. No postoperative respiratory complications were recorded. The mean length of stay was for 4.00±1.41 days in the PV subgroup and 4.45±2.07 days in the CV group; no statistically significant differences were recorded between the two subgroups (P=0.511). CONCLUSIONS: Localized inflammatory cytokine response after OLV was not influenced by the use of different VT. Potentially, the application of PEEP in both ventilation strategies and the short duration of OLV could prevent postoperative complications.

Lasmiditan for the treatment of migraine.

INTRODUCTION: Migraine is one of the most common diseases in the world, with high economical and subjective burden. Migraine acute therapy is nowadays based on specific and non-specific drugs but up to 40% of episodic migraineurs still have unmet treatment needs and over 35% do not benefit from triptans administration. Serotonin-1F receptors have been identified in trigeminal system and became an ideal target for anti-migraine drug development as potential trigeminal neural inhibitors. Lasmiditan, a novel serotonin1F receptor agonist, showed specific affinity in vitro for the receptor without any vasoconstrictive action and inhibited markers associated with electrical stimulation of trigeminal ganglion in migraine animal models. Areas covered: This article reviews both preclinical and clinical studies on lasmiditan as a potential acute therapy for migraine, as well as pharmacokinetic and pharmacodynamic features. It also summarizes safety and tolerability data gathered in the various human studies. Expert opinion: The absence of vasoconstrictive effects makes lasmiditan a promising novel migraine acute therapy. Although preclinical and Phase I and II studies established a significant efficacy, the limited knowledge about pharmacokinetics and metabolism, the high rate of non-serious central nervous system side effects and the lack of larger studies remain still a matter of concern that should be addressed in future studies.

Acute, transitional and long-term cluster headache treatment: pharmacokinetic issues.

INTRODUCTION: The cornerstones of cluster headache therapy are based on the tripod of acute, transitional and preventative treatments that respectively aim to the control of the bouts, the transitional suppression of the relapse and the prevention of the entire cluster period. Particularly in chronic cluster headache, where a long-term preventative therapy is necessary, multiple drug regimens increase the risk of drug-drug interactions leading to variability in the clinical efficacy and to potentially harmful adverse effects. AREAS COVERED: We focused on how clinically significant pharmacokinetic drug-drug and food-drug interactions can be carefully managed both in cluster headache patients with a progressive frequency of bouts and in chronic cluster headache sufferers. In fact, in these cases a long-term preventive therapy is indicated, increasing the possibility of interactions both with other transitional and acute cluster headache medications and with other foods or xenobiotics. EXPERT OPINION: Pharmacokinetic interactions for both preventive, transitional and acute drugs are significant with a number of xenobiotics and other medications. Therefore, the pharmacokinetic issues knowledge is advisable for a safe and effective cluster headache management.

Choosing the safest acute therapy during chronic migraine prophylactic treatment: pharmacokinetic and pharmacodynamic considerations.

INTRODUCTION: Drugs used in the treatment of migraine have been reported to be highly associated with the occurrence of clinically significant drug-drug interactions (DDIs). Multiple drug therapy regimens are used for migraine treatment, particularly for chronic migraine. In fact, additional pharmacological agents are usually administered during an acute migraine attack in patients chronically treated with the prophylactic therapy. The variety of drugs available for migraine prophylactic and acute treatment, and consequently their pharmacological interactions, might complicate the choice of a safe combination therapy. AREAS COVERED: This study discusses the prophylactic-acute DDIs from a pharmacokinetic and pharmacodynamic perspective, particularly interactions between antiepileptic drugs, tricyclic antidepressants, ß-blockers, calcium channel blockers, triptans, nonsteroidal anti-inflammatory drugs and ergot derivatives. The available online tools have been used to evaluate the clinically significant DDIs. EXPERT OPINION: The interactions between different drugs might be accurately predicted by the huge and detailed knowledge about the molecular pathways involved in pharmacodynamics and pharmacokinetics. Pharmacogenomic research has shed further light onto the mechanisms involved in the inter-individual variation in drug response and DDIs. Based on this knowledge, this paper will provide suggestions to improve the appropriateness of the drug choice in the prescription of preventative and acute migraine medications.