Ana Micov

Background and Purpose: Chronic migraine (CM) is a highly disabling condition that remains suboptimally treated. Metabolic disturbances may trigger migraine chronification, whereas impaired endogenous pain inhibition contributes to CM development. Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), used for type 2 diabetes and obesity, show efficacy in chronic pain models. We evaluated the prophylactic effects of liraglutide, semaglutide and dulaglutide compared with propranolol (reference drug), potential opioidergic/endocannabinoid involvement and sex differences in a CM model. Experimental Approach: Chronic migraine‐like hypersensitivity was induced by repeated nitroglycerin administration in male and female mice. The prophylactic effects of GLP‐1RAs and propranolol were examined using von Frey, acetone and orofacial glutamate tests. Body weight and glucose tolerance were monitored to evaluate metabolic safety. Potential opioidergic/endocannabinoid involvement in semaglutide‐induced antinociception (selected GLP‐1RA class representative) was assessed by pharmacological blockade and/or quantitative polymerase chain reaction (qPCR) analysis of pain‐related neurobiomarker mRNA expression in brainstem and trigeminal ganglia. Key Results: Liraglutide, semaglutide and dulaglutide dose‐dependently attenuated CM‐like hypersensitivity in both sexes, with efficacy comparable to propranolol. GLP‐1RAs did not affect metabolic parameters, whereas propranolol induced male‐specific hyperglycaemia. Semaglutide‐induced antinociception was partially sensitive to naloxone and was associated with sex‐dimorphic, brainstem‐specific transcriptional changes in opioid‐ and endocannabinoid‐related pathways. Semaglutide increased Glp1r, Cnr1 , Pomc, Pcsk1 and Pcsk2 mRNA expression in males, whereas it up‐regulated Glp1r and down‐regulated Faah and Mgll in females. Conclusions and Implications: GLP‐1RAs exert class‐wide antinociceptive effects in a preclinical CM model, with semaglutide‐based analyses suggesting sex‐specific modulation of central opioid‐ and endocannabinoid‐related pathways. These findings support further investigation of GLP‐1RAs as prophylactic strategies for migraine, particularly in individuals with metabolic comorbidities.

Hormonal therapy has an important role in preserving and improving women's health across the lifespan. Its use extends beyond contraception and hormone replacement therapy to the management of menstrual disorders, acne, hirsutism, polycystic ovary syndrome (PCOS), endometriosis, and osteoporosis. The development of new hormonal products, together with ongoing appraisal of evidence on the efficacy and safety of existing therapies, supports rational hormone use tailored to each woman. In adolescence, hormones are most commonly used for emergency contraception, management of menstrual disorders, acne, and PCOS. The combination of estetrol, a natural estrogen of fetal origin, and drospirenone provided good cycle control and acceptable tolerability in girls aged 12-17 years, expanding the available combined hormonal options for this population. During the reproductive age, a personalized approach is essential, with particular attention to thromboembolic risk, estrogen-sensitive malignancies, and comorbidities when selecting contraceptives or treatments for gynecological disorders. In this regard, the expanding range of progestogen-only contraceptives, including drospirenone-only products, allows more individualized treatment selection. Recent observational data also suggest a small association between levonorgestrel-releasing intrauterine system use and breast cancer risk. The most remarkable novelties in hormonal therapy concern menopause. The US Food and Drug Administration has eased warnings in the labeling of menopausal hormone therapy products regarding cardiovascular disease, breast cancer, and dementia. Local hormonal therapy remains a rational treatment option for genitourinary syndrome. Preserving and improving women's health requires pharmacists to keep up with advances in rational hormone use and translate them into clear, safe, and personalized therapeutic interventions.

Chronic migraine (CM) is a disabling disorder characterised by pain and cognitive impairment. Current preventive therapies show limited efficacy. GLP-1 receptor agonists (GLP-1RAs) exhibit antinociceptive and procognitive properties, yet the effects of the long-acting GLP-1RA dulaglutide remain unexamined. We assessed whether dulaglutide attenuates mechanical hypersensitivity and improves cognitive performance in a nitroglycerin-induced CM model, with focus on sex differences. CM was induced by repeated nitroglycerin injections (10 mg/kg, i.p., every other day over 9 days) in C57BL/6 mice of both sexes. Dulaglutide (30, 150 and 300 µg/kg/every 3 days, s.c.) and propranolol (20 mg/kg/day, i.p.; positive control) were administered throughout the protocol. Mechanical hypersensitivity was assessed by the von Frey test (VFT) and cognition by the novel object recognition test (NORT). Nitroglycerin induced basal and acute hypersensitivity, as well as cognitive deficits in both sexes (p < 0.05). In the VFT, dulaglutide reduced pain hypersensitivity (p < 0.05), comparably to propranolol. Sex differences appeared at the lowest and highest doses (p = 0.003, p = 0.013; respectively), with greater effects in females. In the NORT, dulaglutide (150 and 300 µg/kg) improved performance in both sexes (p < 0.05). Further analysis of the discrimination index revealed no significant sex differences (p > 0.05). Locomotor activity was unaffected. Taken together, dulaglutide reduced mechanical pain hypersensitivity and improved cognitive function without affecting locomotion in a CM model, supporting further investigation of dulaglutide in migraine prevention and associated cognitive disorders.

Medication overuse headache (MOH) is a chronic secondary headache disorder caused by excessive use of analgesics for acute headache treatment, predominantly affecting women. It is associated with reduced quality of life and cognitive deficits. The drugs most strongly linked to the development of MOH are triptans and opioids. Although opioid use is discouraged in headache treatment, codeine, as a component of combined analgesic preparations (in Serbia and the surrounding region), is used relatively often. We aimed to establish a codeine-induced MOH model in female and male mice, and to assess pain-related behaviour, general well-being/motivation, and cognitive performance. MOH was induced by administering codeine (15 mg/kg/day p.o. for 10 days) to female and male C57BL/6 mice. Periorbital allodynia was assessed using von Frey test. Cognitive performance was evaluated using the novel object recognition test, and general well-being using the burrowing test. After 12 days of codeine withdrawal, we assessed the recurrence of periorbital allodynia induced by a low dose of glyceryl trinitrate (latent sensitisation phenomenon). Codeine caused a comparable level of periorbital allodynia in both sexes. After discontinuation of codeine, mechanical hypersensitivity gradually resolved in both males and females. Codeine reduced cognitive performance in both sexes, whereas burrowing activity was reduced only in codeine-treated females compared to the vehicle control group. Glyceryl trinitrate induced a recurrence of periorbital allodynia in both sexes, with a more pronounced effect in females. Codeine induced cutaneous allodynia and cognitive impairment in both sexes, whereas decreased motivation/general well-being and latent sensitisation were more pronounced in females.

Background: The incorporation of polymers into drug delivery vehicles has been shown to be an effective strategy to prolong the residence time of active ingredients in the precorneal tear film and to increase ocular bioavailability. Objectives: The aim of this study was to develop novel, viscous eye drops containing olopatadine (OCH) as the active ingredient, polysaccharides hydroxypropyl guar gum (HPG), and sodium hyaluronate (SH), individually, and in combination as functional polymers. Methods: Viscous eye drops containing 0.1% OCH in combination with HPG (0.25%) and SH (0.4%), were prepared and evaluated for their physicochemical properties, rheological behavior, mucoadhesion, and preliminary stability. A novel rheological method was used to evaluate the resistance of the eye drops under simulated blinking conditions. In vivo efficacy was evaluated using an ocular itch test in mice to compare the formulations with a commercial product. Results: The formulations remained stable and transparent, with physicochemical parameters within acceptable ranges. Rheological studies confirmed pseudoplastic flow, with the HPG-SH combination exhibiting enhanced viscosity and shear-thinning properties for prolonged retention in the eye. Mucoadhesion was highest in SH-HPG formulations. During simulated blinking cycles, eye drops containing a combination of SH and HPG polymers fully regained their initial viscosity during the resting periods. Preliminary stability studies indicate that the formulated eye drops exhibit satisfactory physicochemical stability under various storage conditions. In vivo, OCH-SH and OCH-HPG-SH drops provided prolonged antipruritic and analgesic effects compared to the reference product. Conclusions: Polysaccharide-based innovative formulations improve OCH retention, enhancing therapeutic efficacy and patient compliance in the treatment of allergic conjunctivitis.

Background and Purpose: Vortioxetine, a multimodal‐acting antidepressant, has recently shown analgesic properties. We aimed to investigate its prophylactic effect in the osteoarthritis (OA) model and gain insights into the underlying molecular mechanisms. Duloxetine was studied as a reference.Experimental Approach: In the monoiodoacetate (MIA)‐induced rat model of knee OA, pain‐related behaviour was assessed in weight‐bearing and Von Frey tests. Antidepressants were administered orally once daily for 28 days. Gene expression of pain‐related mediators (Ngf, Il‐1β, Tnf‐α, Bdnf, and Tac1 encoding substance P) and oxidative stress parameters were determined after completion of the treatment/behavioural testing protocol.Key Results: Vortioxetine and duloxetine dose dependently reduced weight‐bearing asymmetry and mechanical hyperalgesia of the paw ipsilateral to the MIA‐injected knee. Vortioxetine reduced the increased Ngf mRNA expression in the MIA‐injected knees to the level in sham‐injected counterparts. It reduced oxidative stress parameters in the affected knees, more effectively in females than males. Duloxetine showed no effect on Ngf mRNA expression and oxidative stress. Both antidepressants decreased mRNA expression of pain‐related mediators in the lumbar L3–L5 ipsilateral DRGs and spinal cords, which were up‐regulated in MIA‐injected rats. This effect was male‐specific.Conclusion and Implications: Vortioxetine may be effective against the development of chronic pain in OA. Its antihyperalgesic effect may be mediated, at least in part, by normalization of NGF expression in the affected joint. Decrease of localized oxidative stress and of expression of pain‐related mediators that contribute to central sensitization are also involved in vortioxetine's antihyperalgesic effect, in a sex‐specific pattern.

Obesity is a chronic, progressive, and recurring disease. The prevalence of obesity has reached pandemic proportions, along with overweight-related conditions like diabetes, cardiovascular diseases, and certain cancers. Reducing residual morbidity is the main goal of obesity treatment. Pharmacotherapy is intended for patients who have not responded to lifestyle interventions. There are currently six anti-obesity medications (orlistat, phentermine/topiramate, naltrexone/bupropion, liraglutide, semaglutide, and tirzepatide) approved for long-term obesity management. Most of them, except orlistat, predominantly act centrally by increasing satiety, as well as reducing appetite and food reward. The most effective anti-obesity drugs are semaglutide and tirzepatide, which might provide weight loss of more than 10% of the initial weight. Although all anti-obesity medications have been demonstrated to improve cardiometabolic risk factors, only liraglutide and semaglutide lower the risk of major cardiovascular events in patients with or without established cardiovascular disease. A personalized approach, considering both drug (weight-reducing capacity and drug safety) and patient (comorbidities, age, and the patient's preferences) features, guarantees the best results. In this article, we will critically appraise the efficacy and safety of currently approved anti-obesity medications and those in the pipeline.