Anti-Calcitonin Gene-Related Peptide Monoclonal Antibodies in Migraine: Focus on Drug Interactions.

Calcitonin gene-related peptide neurotransmission was the target for recent development of monoclonal antibodies that effectively prevent attacks of both episodic and chronic migraine. The aim of this narrative review was to offer deeper insight into drug-drug, drug-food and drug-disease interactions of monoclonal antibodies approved for prevention of migraine attacks. For this narrative review, relevant literature was searched for in MEDLINE and Google Scholar databases, covering the 1966-2023 and 2006-2023 periods, respectively. The ClinicalTrials.gov database was also searched for relevant clinical studies whose results had not been published previously in medical journals, covering 2000-2023. Monoclonal antibodies (erenumab, fremanezumab, galcanezumab and eptinezumab) augment prophylactic action of gepants and onabotulinumtoxin A and somewhat increase efficacy of triptans used to abort migraine attacks; however, their adverse reactions may also be augmented. Pharmacokinetic interactions and interactions in general with drugs used for other indications except migraine are negligible, as are drug-food interactions. However, monoclonal antibodies may worsen diseases with already weakened CGRP neurotransmission, Raynaud phenomenon and constipation. Monoclonal antibodies used for prevention of migraine do not engage in significant pharmacokinetic interactions with other drugs; however, they do engage in pharmacodynamic interactions with other anti-migraine drugs, additively augmenting their prophylactic action, but also increasing frequency and severity of adverse reactions, which are a consequence of the CGRP neurotransmission interruption.

Anti-calcitonin Gene-Related Peptide Monoclonal Antibodies in Migraine: Focus on Clinical Pharmacokinetics.

The calcitonin gene-related peptide transmission was the target for recent development of drugs that effectively prevent attacks of both episodic and chronic migraine. The aim of this narrative review was to offer deeper insight into pharmacokinetics of monoclonal antibodies approved for prevention of migraine attacks. For this narrative review, relevant literature was searched for in MEDLINE and Google Scholar databases, covering periods 1966-2023 and 2006-2023, respectively. The ClinicalTrials.gov database was also searched for relevant clinical studies whose results had not been published previously in medical journals, covering the period 2000-2023. The monoclonal antibodies from this group are distributed mainly in the plasma and part of the extracellular space; they are neither metabolized in the liver nor excreted via the kidneys. The elimination of galcanezumab, eptinezumab and fremanezumab takes place only by a non-specific linear process via the reticuloendothelial system in the liver, while erenumab is eliminated by a non-specific process and by a specific, saturable process because of binding to receptors located on the cell membrane. Since the elimination processes do not have a large capacity, the half-life is about 2 weeks for erenumab and about 4 weeks for other monoclonal antibodies. Variability in the pharmacokinetics of these monoclonal antibodies is small in different subpopulations, and body weight is the only parameter to consider when choosing the dose of these drugs.

Investigational new drugs for the treatment of Dravet syndrome: an update.

INTRODUCTION: While there are already approved anticonvulsants for treatment of children with Dravet syndrome, disease modifying therapy is at its beginning. AREAS COVERED: This narrative review is updating the latest information about efficacy and safety of both anticonvulsant and disease modifying investigational drugs for Dravet syndrome. Relevant publications were searched for in MEDLINE, GOOGLE SCHOLAR, SCINDEKS, and CLINICALTRIALS.GOV databases, from the dates of their foundation till January 2023. EXPERT OPINION: The main advancements were made in the treatment of Dravet syndrome with confirmed haploinsufficiency of SCN1A gene. The application of antisense oligonucleotides has so far proven to be the most successful within disease-modifying therapy, but it also requires further refinement of the methodology of application and delivery to target cells, as well as additional testing of the effectiveness of antisense oligonucleotides outside of TANGO technology. Also, the full potential of gene therapy has yet to be explored, given that high capacity adenoviral vectors that can incorporate the SCN1A gene have recently been prepared.

Clinical Pharmacokinetics and Pharmacodynamics of Esaxerenone, a Novel Mineralocorticoid Receptor Antagonist: A Review.

Esaxerenone is a selective, nonsteroidal, high-affinity mineralocorticoid receptor antagonist recently approved in Japan for the treatment of hypertension. It has high oral biovailability, a large volume of distribution, and is primarly metabolized in liver and excreted in bile. Esaxerenone is an efficient antihypertensive, whether given alone or as add-on therapy. The antihypertensive effect is accompanied by renoprotective action, which is being further investigated in current clinical trials. Due to its relatively long half-life and high affinity for the mineralocorticoid receptor, esaxerenone is administered once daily and in low absolute doses. The safety of esaxerenone is considerable, since hyperkalemia is not frequent and, when it does appear, not sustained. Endocrine adverse events, which frequently occur with steroidal mineralocorticoid receptor antagonists, are extremely rare with esaxerenone. Although the risk of clinically significant drug-drug interactions is not high, esaxerenone treatment should start with low doses, with subsequent titration to achieve the optimal clinical effect, all while monitoring serum potassium and paying attention to concomitant therapy with drugs that may induce or inhibit esaxerenone metabolism. This review article offers comprehensive information about the pharmacodynamics and pharmacokinetics of esaxerenone in humans, which should help clinicians to more precisely tailor esaxerenone dosing regimens to their patients.

Experimental GABA A Receptor Agonists and Allosteric Modulators for the Treatment of Focal Epilepsy.

GABA A receptors are ubiquitous in the central nervous system and there is a huge diversity of receptor subtypes in almost all regions of the brain. However, the expression of GABA A receptor subtypes is altered in both the gray and white matter of patients with focal epilepsy. Although there is a number of anticonvulsants with marketing authorization for the treatment of focal epilepsy which act through GABA A receptors, potentiating the inhibitory effects of GABA, it is necessary to develop more potent and more specific GABAergic anticonvulsants that are effective in drug-resistant patients with focal epilepsy. There are three orthosteric and at least seven allosteric agonist binding sites at the GABA A receptor. In experimental and clinical studies, full agonists of GABA A receptors showed a tendency to cause desensitization of the receptors, tolerance, and physical dependence; therefore, partial orthosteric agonists and positive allosteric modulators of GABA A receptors were further developed. Preclinical studies demonstrated the anticonvulsant efficacy of positive allosteric modulators with selective action on GABA A receptors with α2/α3 subunits, but only a handful of them were further tested in clinical trials. The best results were obtained for clobazam (already marketed), ganaxolone (in phase III trials), CVL-865 (in phase II trials), and padsevonil (in phase III trials). Several compounds with more selective action on GABA A receptors, perhaps only in certain brain regions, have the potential to become effective drugs against specific subtypes of focal-onset epilepsy. However, their development needs time, and in the near future we can expect only one or two new GABA A agonists to obtain marketing authorization for focal epilepsy, an advance that would be of use for just a fraction of patients with drug-resistant epilepsy.

Lessons learned from the discovery of sodium valproate and what has this meant to future drug discovery efforts?

INTRODUCTION: The discovery of the anticonvulsant properties of valproic acid and the development of valproic acid/valproate to market authorization for specific epilepsy types and syndromes, as well as their repurposing for other indications, are illustrative examples of both the strengths and weaknesses of drug development strategies. AREAS COVERED: This review summarizes and interprets the development and repurposing history of valproic acid/valproate. The article is based on articles, including original studies and systematic reviews obtained from PubMed, Scopus, EBSCO, SCIndeks and Google Scholar databases. EXPERT OPINION: Random screening and careful observation of the experimental effects of tested substances were crucial for discovering the anticonvulsant effects of valproic acid, while rational drug design and clinical observation strategies led to repurposing valproic acid and valproate for bipolar disorder maintenance treatmentand prevention of migraine attacks. Early planning and feasibility studies of future clinical trials are essential for obtaining marketing authorization of new substances or new indications of old anticonvulsants. Significant progress has been made recently toward understanding, treatment and prevention of hepatotoxicity caused by valproic acid/valproate, making its long-term administration safer. There are ongoing efforts to repurpose valproic acid/valproate for augmentation with antipsychotic drugs for the treatment of schizophrenia.

Effects of selective serotonin reuptake inhibitors on motility of isolated fallopian tube.

Selective serotonin reuptake inhibitors (SSRIs) affect the smooth muscle cells acting on voltage-dependent channels for Na+ , K+ and Ca2+ , but their action is tissue and species specific. The aim of our study was to investigate effects of selective serotonin reuptake inhibitors on motility of the isolated fallopian tubes. Isolated preparations of isthmus and ampoule were taken from fallopian tubes of 20 women during hysterectomy due to uterine fibroids and then tested for reactivity on increasing concentrations of selective serotonin reuptake inhibitors. Escitalopram (from 0.9 × 10-9  M/L to 1.4 × 10-6  M/L) produced concentration-dependent increase of spontaneous contractions of the isolated ampulla (EC50 = 1.20 ± 1.06 × 10-8  M/L, r = 0.580, P < 0.05) (F = 2.980, df1  = 6, df2  = 28, P < 0.05). Paroxetine (from 1.2 × 10-9  M/L to 5.1 × 10-5  M/L) produced concentration-dependent increase of spontaneous contractions of the isolated isthmus (EC50 = 7.01 ± 3.50 × 10-8  M/L, r = 0.500, P < 0.05) (F = 2.350, df1  = 9, df2  = 40, P < 0.05). The SSRIs differ among themselves in regard to their potential to affect motility of the fallopian tubes. Escitalopram and paroxetine have clear stimulating effect which may interfere with functioning of the fallopian tubes, and potentially impair fertility if taken by women in reproductive period of life. The other SSRIs tested in the study did not produce significant effect throughout the concentration range used in the experiments.

Angiotensin Receptor Blocker Losartan Inhibits Spontaneous Motility of Isolated Human Ureter.

BACKGROUND AND OBJECTIVES: Ureteral motility is essential for elimination of intraluminal stones, and it may be adversely affected by cardiovascular drugs that a patient is taking chronically. The aim of our study was to test whether ACE inhibitors and an angiotensin receptor blocker may influence spontaneous contractions of isolated human ureter. METHODS: Both phasic and tonic contractions of the isolated ureteral segments taken from 10 patients were measured as changes of the longitudinal tension or pressure recordings. Captopril, enalapril and losartan were separately added to the organ baths cumulatively. RESULTS: While enalapril (2.7 × 10-7-3.9 × 10-4 M) and captopril (6.1 × 10-7-2.7 × 10-3 M) did not affect either spontaneous activity or tone of isolated ureteral segments, losartan (2.9 × 10-7-4.2 × 10-4 M) caused concentration-dependent inhibition of spontaneous contractions of the segments (50 % effective concentration (EC50) = 13.46 ± 1.80 × 10-6 M; F = 10.72, r = 0.79, p < 0.001). CONCLUSIONS: Due to differences in molecular mechanism of action, angiotensin receptor blocker losartan does and ACE inhibitors captopril and enalapril do not inhibit spontaneous contractions of isolated human ureter.

Calcitonin Gene-Related Peptide Receptor Blocker Inhibits Spontaneous Activity of Human Ureter.

Calcitonin gene-related peptide (CGRP) is present in nerve fibers that innervate the human ureter and may have important influence on the motility of this organ. The aim of our study was to investigate whether CGRP could affect the motility of an isolated human ureter. The tension and intraluminal pressure of the isolated ureteral segments were recorded and registered on a personal computer. Both phasic and tonic contractions of the isolated preparations were measured as area under the tension or pressure recordings. CGRP and CGRP fragment 8-37 were separately added to the organ baths in a cumulative way, thereby gradually increasing their concentration in the baths' solution. Alpha-CGRP did not affect either phasic, spontaneous activity or tone of isolated ureteral segments, as measured by both tension and intraluminal pressure. On the other hand, CGRP 8-37 caused concentration-dependent inhibition of spontaneous contractions of the isolated ureteral segments.

Effects of aurothiomalate and gold(III) complexes on spontaneous motility of isolated human oviduct.

Organic gold complexes have different biological activity, depending on their potential for interactions with key functional molecules.The aim of this study was to investigate potential of several newly synthesized organic gold complexes to influence spontaneous motility of the Fallopian tubes.The effects of [Au(bipy)Cl(2)](+) (dichloride(2,2'-bipyridyl)aurate(III)-ion), aurothiomalate, [Au(DMSO)(2)Cl(2)]Cl and DMSO on spontaneous motility of Fallopian tubes were tested on the isolated tube segments in vitro. Aurothiomalate (from 2.9 × 10(-9) to 4.9 × 10(-4) M/l), [Au(bipy)Cl(2)]Cl (from 3.3 × 10(-9) to 4.2 × 10(-5) M/l) and DMSO (from 1.9 × 10(-8) to 1.0 × 10(-5) M/l) did not affect spontaneous contractions of the isolated Fallopian tube ampulla, while [Au(DMSO)(2)Cl(2)]Cl (from 2.9 × 10(-9) to 4.2 × 10(-5) M/l) showed concentration-dependent increase (stimulation) of spontaneous contractions of the isolated Fallopian tube isthmus, and remained without effect on the isolated ampulla.The drugs designed as organic gold complexes with weaker bonds between the gold itself and organic part of a molecule could adversely affect motility of the Fallopian tubes, and theoretically fertility of women taking such drugs in their reproductive age.

Contractile effects of endothelins on isolated ampullar segment of human oviduct in luteal phase of menstrual cycle.

Endothelin-1 induces contractions of human oviduct ampullar segment in follicular phase of menstrual cycle, acting on ET(A) receptors. The aim of our study was to investigate effects of endothelin-1, endothelin-2 and endothelin-3 on isolated ampullar segment of human oviducts, taken from the patients in luteal phase of menstrual cycle. Fallopian tubes were taken from 20 female patients (one tube from each patient) during abdominal hysterectomy with adnexectomy, due to extensive uterine fibroids. The oviduct ampulla was mounted in an organ bath longitudinally, and the tension of the isolated preparation was recorded with the isometric transducer. Endothelin-1 produced concentration-dependent tonic contraction of the isolated ampullar segment (EC(50)=6.80 +/- 1.2 x 10(-10)M), and concentration-dependent inhibition of its rhythmic contractions (EC(50)=7.86 +/- 2.3 x 10(-10)M). Endothelin-2 produced concentration-dependent tonic contraction of the isolated ampullar segment (EC(50)=4.56 +/- 0.3 x 10(-10)M), without affecting its rhythmic contractions. Endothelin-3 did not affect either tone or rhythmic contractions of the isolated preparations. Selective antagonist for ET(A) receptor subtype, BQ 123, produced inhibition of endothelin-1 effects on both tone (pA(2)=9.50) and spontaneous rhythmic contractions (pA(2)=10.73), while selective antagonist for ET(B) receptor subtype, BQ 788, produced only inhibition of endothelin-1 effects on tone (pA(2)=9.61), while the effect of endothelin-1 on spontaneous rhythmic contractions remained unaffected. The results of our study suggest that in the luteal phase both ET(A) and ET(B) receptors regulate tone, and only ET(A) receptors regulate rhythmic activity of human oviduct's ampullar segment.

Effects of exogenous glutamate and kainate on electric field-stimulated contractions of isolated human ureter.

OBJECTIVES: A neurotransmitter role for glutamate in the autonomous nervous system was recently demonstrated in the gastrointestinal tract, and its stimulatory effect on spontaneous motility of human ureter was shown. The aim of our study was to investigate the effects of glutamate on the release of neurotransmitters from intramural nerves of the human ureter. METHODS: The effects of exogenous glutamate were tested on electric field-stimulated contractions of isolated human ureter, taken from 16 adult patients after nephrectomy. The longitudinal tension and intraluminal pressure of the isolated ureter were recorded simultaneously. The electric field stimulation was done with square wave pulses (20 V through electrodes, 400 mA, duration 1 ms, frequency 16 Hz). The pulse trains lasted for 30 s, a with 30-s pause. RESULTS: Glutamate (7.9 x 10(-6) M/L to 10.6 x 10(-3) M/L) and kainic acid (6.3 x 10(-8) M/L to 2.2 x 10(-5) M/L) produced a concentration-dependent decrease in the electric field-stimulated activity of the isolated preparations. However, N-methyl-D-aspartic acid (9.1 x 10(-8) M/L to 3.1 x 10(-5) M/L), (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (7.2 x 10(-8) M/L to 3.2 x 10(-6) M/L) and (+/-)-1-Aminocyclopentane-trans-1,3-dicarboxylic acid (7.7 x 10(-8) M/L to 6.5 x 10(-5) M/L) were ineffective. The electric field-stimulated contractions of isolated ureter were also inhibited by lidocaine (3.70 x 10(-4)M/L) and atropine (1.00 x 10(-6)M/L). CONCLUSIONS: The results of our study suggest that glutamate inhibits electric field-stimulated release of acetylcholine in the human ureter through activation of kainate ionotropic receptors, located on the intramural nerve fibers.

Effects of cisplatin and other Pt(II) complexes on spontaneous motility of isolated human oviduct.

The toxicity of platinum(II) ion could be significantly modified by coordination with some organic compounds. In our study, the cytotoxicity and the influence of platinum(II) complexes, such as cisplatin, cis-[PtCl(2)(NH(3))(2)], [PtCl(2)(SMC)] and [PtCl(2)(DMSO)(2)] (where SMC is S-methyl-l-cysteine and DMSO is dimethyl sulphoxide) on spontaneous motility of isolated human fallopian tubes were investigated. Cisplatin showed potent pro-apoptotic effects on peripheral blood mononuclear cells (PBMC). However, peripheral blood mononuclear cells were substantially less sensitive to [PtCl(2)(SMC)] and [PtCl(2)(DMSO)], and these compounds showed no toxic effect on PBMC in all concentrations examined. Cisplatin showed concentration-dependent inhibition of spontaneous contractions of the isolated ampulla. (EC(50)=1.14+/-0.03 x 10(-6)M/l, r=0.714, p<0.05) while [PtCl(2)(SMC)] and [PtCl(2)(DMSO)(2)] did not affect spontaneous contractions of isolated fallopian tube ampulla.

Inverse correlation of valproic acid serum concentrations and quality of life in adolescents with epilepsy.

BACKGROUND: Correlation between steady-state serum concentrations of antiepileptic drugs and both seizure control and adverse drug reactions frequency (two major determinants of quality of life in patients with epilepsy) is still matter of controversy. OBJECTIVE: The aim of our study was to investigate whether a correlation exists between steady-state serum concentration of valproic acid and quality of life in adolescent patients with epilepsy. METHOD: Twenty-one adolescent patients with epilepsy, treated with valproic acid for more than 6 months entered the study. On two occasions, 3 months apart, both through and 2-h-after-the-dose serum concentrations of valproic acid were measured, as well as quality of life, using QOLIE-AD-48 for adolescents. Adverse drug reactions and seizure control were also recorded. RESULTS: Significant inverse correlation between through serum concentrations of valproic acid and total QOLIE-AD-48 scores was observed, together with correlation between through serum concentrations and adverse drug reactions frequency. The scores of memory/concentration and physical functioning QOLIEAD-48 domains were significantly and inversely correlated with through serum concentrations. CONCLUSION: Our study suggests that therapeutic monitoring of valproic acid serum concentrations could be useful predictor and marker of the most important epilepsy treatment outcome--quality of life.

Effect of exogenous glutamate and N-Methyl-D-aspartic acid on spontaneous activity of isolated human ureter.

OBJECTIVES: While the neurotransmitter role of glutamate in the gastrointestinal tract has been shown, its effects on smooth muscle of the human ureter have not previously been investigated. In our study we have investigated the effects of exogenous glutamate on the spontaneous activity of isolated human ureter, taken from 14 adult patients after nephrectomy. METHODS: The segment of ureter, excised 3 cm distal from the pyeloureteral junction, was isolated in an organ bath. Both longitudinal tension and intraluminal pressure of the segment were recorded simultaneously. RESULTS: Glutamate administered in the lumen of the isolated ureteral segments (7.8 x 10(-7) M/L-3.5 x 10(-2) M/L) was ineffective. When added to the isolated organ bath from the serous side of the ureteral segment, glutamate (7.9 x 10(-6) M/L-10.6 x 10(-3) M/L) and N-Methyl-D-aspartic acid (NMDA) (9.1 x 10(-8) M/L-3.1 x 10(-5) M/L) produced a concentration-dependent increase in spontaneous activity of the isolated preparations, while kainic acid (6.3 x 10(-8) M/L-10.5 x 10(-5) M/L) and (+/-)-trans-1-Aminocyclopentane-trans-1,3-dicarboxylic acid (ACPD) (7.7 x 10(-8) M/L -6.5 x 10(-5) M/L) were ineffective. CONCLUSIONS: The results of our study suggest that an excitatory neurotransmitter glutamate stimulates spontaneous activity of the human ureter through activation of NMDA ionotropic receptors, located on smooth muscle cells or intramural nerve fibers.

Inhibitory effects of selected antiepileptics on spontaneous motility of isolated human oviducts.

OBJECTIVE: Spontaneous motility of the human oviduct is an important factor in the regulation of fertility that can be influenced by a variety of substances. In this study we examined the effects of several antiepileptic drugs on spontaneous contractions of isolated human oviducts. METHODS: The isolated ampullar and isthmic segments of Fallopian tubes, taken from 34 patients with extensive uterine fibroids, were exposed to carbamazepine, lamotrigine, valproic acid, phenobarbital, diazepam and lorazepam. RESULTS: Carbamazepine and lamotrigine produced concentration-dependent inhibition of spontaneous contractions of both ampullar and isthmic isolated preparations, while the other investigated substances did not exhibit any effect. The effective concentrations of carbamazepine and lamotrigine fall within the range of their therapeutic serum concentrations. CONCLUSION: When choosing antiepileptics for women of reproductive age, the effects of the drug on motility of the Fallopian tubes should also be considered.

Effect of the exogenous glutamate and the NMDA on electric field-stimulated contractions of isolated rat ileum.

While neurotransmitter role of glutamate in gastrointestinal intrinsic nervous system was shown, its effects in various segments of gastrointestinal tract were not yet understood completely. In our study, we have investigated effects of exogenous glutamate on electric field-stimulated contractions of isolated rat ileum. The ilea from forty Wistar rats of both sexes were isolated in an organ bath, according to the Magnus mounting method, and exposed to field stimulation with square wave pulses (20 V over the electrodes, 400 mA, 1 ms duration, frequency 16 Hz, pulse trains for 30 s with 30 s pause). The stimulation produced tonic contractions and relaxations recorded with an isometric system. Atropine (2.3 x 10(-6) M/l) completely abolished contractions of isolated rat ileum produced by the field stimulation, while relaxations remained unaffected. Glutamate (from 7.8 x 10(-6) to 3.5 x 10(-3) M/l) and N-Methyl-D-aspartic acid (NMDA) (from 9.1 x 10(-9) to 1.3 x 10(-5) M/l) caused concentration-dependent inhibition of the field-stimulated contractions of isolated rat ileum (EC50 was 90.17 +/- 1.81 x 10(-5) and 53.51 +/- 3.68 x 10(-9) M/l, respectively) while not affecting the field-stimulated relaxations. On the other hand, (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (from 6.0 x 10(-9) to 9.3 x 10(-6) M/l), kainic acid (from 5.8 x 10(-9) to 8.3 x 10(-6) M/l) and (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid ((+/-)-trans-ACPD) (from 7.0 x 10(-9) to 1.1 x 10(-5) M/l) did not influence both the field-stimulated contractions and the field-stimulated relaxations of isolated rat ileum. The results of our study suggest inhibitory effect of glutamate on acetylcholine release from intrinsic neurons of rat ileum, mediated through NMDA receptors.