escitalopram + clonazepam (Citapure Forte)

Minthostachys verticillata aqueous extract ameliorates intestinal and systemic alterations induced by a model of acute stress.

Rodríguez-Basso Angeles Gloria AG, Carranza María Andrea MA, Bach Hernan H, Prado Hector Juan HJ et al.

Minthostachys verticillata (Griseb.) Epling (Lamiaceae), popularly known as Peperina (Mv), is a native plant widely used in traditional medicine as a digestive, sedative, antispasmodic, antidiarrheal, antiemetic, and carminative agent. However, its potential beneficial effects on intestinal and systemic changes induced by acute stress have not been fully elucidated. To assess the effects of its aqueous extract on the gastrointestinal system in a rat model of acute restraint stress related to inflammatory intestinal pathologies. Animals were treated for four consecutive days (n=6 per group) with Mv extract (250 and 500 mg/Kg p.o), clonazepam (1 mg/Kg p.o) or water. The acute stress model was induced by restraint for 6 hours in plastic cones adapted to the animal one hour after the last dose of the treatments. Control animals were not subjected to stress. Following the restraint period, animals were removed from the plastic cone and weighed. Glycemia and corticosterone were determined in plasma. Histological analysis and inflammatory and permeability markers were measured in colon and ileum samples. Stressed animals exhibited elevated corticosterone levels and intestinal damage, including villous rupture, goblet cell depletion, and increased biogenic amines levels. Treatment with Mv extract prevented these alterations in the ileum and colon and improved short-chain fatty acid profiles, especially butyrate and acetate in the colon. Stress also increased the glutathione redox ratio, upregulated inflammatory markers (TNFα, IL-1β, IL-6, TGFβ) and PI3K/AKT pathway proteins in the colon, effects that were attenuated by the extract. Furthermore, markers associated with cytoskeletal uncoupling (pVASP) and extracellular matrix remodeling (MMP-2) were reduced by Mv, suggesting a protective effect against stress-induced mucosal structural and molecular alterations. No changes were observed in myeloperoxidase activity, indicating that neutrophils were likely not involved in the observed inflammatory response. This study demonstrates, for the first time, the ability of Mv to reduce the imbalance induced by acute restraint stress. Mitigation of inflammatory cascades, preservation of goblet cell lineage, attenuation of markers associated with cytoskeletal uncoupling (pVASP) and extracellular matrix remodeling (MMP-2) markers, and maintenance of colonic short-chain fatty acids represent key protective mechanisms. These findings suggest that Mv could exert beneficial effects in stress-related intestinal disorders.

Reversible Cerebral Vasoconstriction Syndrome Secondary to Dermatologic Cream: A Case Report.

Wilhelm Mark Edward ME, Sessions Andrew Joseph AJ, Das Gitanjali G, Sederholm Benson H BH et al.

Imiquimod is an FDA-approved prescription topical medication used in the treatment of skin lesions and neoplasms, such as actinic keratosis, superficial basal cell carcinoma, and external genital and perianal warts. The etiology of rare CNS effects, including headache and stroke, is not completely understood. Headache is a commonly reported adverse reaction, while stroke has been identified through postmarketing pharmacovigilance reports without a definitively established causal relationship. A 60-year-old female with mild depression and basal cell carcinoma, and an absence of traditional vascular risk factors, presented with a 2-week history of new recurrent thunderclap headaches. CT angiogram showed 40-50% narrowing of the proximal right A1. Conventional angiography demonstrated multiple regions of vasoconstriction which improved with intra-arterial verapamil, supporting the diagnosis of reversible cerebral vasoconstrictive syndrome (RCVS) diagnosis. Oral verapamil was up-titrated to 40 mg every 3 h for vasospasm and headache control. At 4-week follow-up, there was only residual A1 stenosis. Pre-RCVS, the patient had been diagnosed with basal cell carcinoma and was prescribed imiquimod 5% cream, with instructions to apply one 0.25-g prefilled packet topically once daily, which she used for 8.5 weeks prior to symptom onset. The patient had been on a stable low dose (2.5 mg daily) of escitalopram, a selective serotonin reuptake inhibitor and recognized potential trigger of RCVS, for several years without prior neurological symptoms. Discontinuation after the first headache did not prevent subsequent episodes, making it less likely to be the sole precipitant, though a contributory role cannot be excluded. In the absence of other vasoactive substances or identifiable etiologies for vasculitis, we suspect that topical imiquimod was responsible for RCVS in this case. Imiquimod is an immune modulating agent that acts as a toll-like receptor (TLR) 7 agonist, causing cytokine induction, inflammatory infiltration, and tumor cell apoptosis. Though headache and stroke are reported as rare side effects, stroke subtype and etiology are uncharacterized, with no RCVS reported to our knowledge. A moyamoya animal model, a pathophysiologically distinct entity from RCVS, demonstrated that using imiquimod to induce TLR-7 activation resulted in a phenotypic change in vascular smooth muscle cells. In vivo, imiquimod also led to diminished internal carotid artery blood flow, while inhibiting TLR-7 resulted in decreased stenosis. These findings suggest that imiquimod-mediated TLR-7 agonism can directly alter cerebrovascular smooth muscle behavior - a mechanism that is biologically plausible as a contributor to the acute vasospasm observed in RCVS. Topical imiquimod is thought to trigger systemic reactions secondary to increased production and circulation of cytokines originating from dermal absorption. Further studies are warranted to evaluate the risk of topical imiquimod use as it relates to cerebral vascular emergencies. We recommend that clinicians consider systemic effects of topical medications as potential contributors to neurologic sequelae.

Chronic Mild Stress Protocol Applied to Male Rats, From Peripuberty to Adulthood, Negatively Affects Reproductive Outcomes and Offspring Development.

Fischer Leonardo Wensing LW, Simas Joana Noguères JN, Nunes Marina M, Mendes Talita Biude TB et al.

Depression is often observed in reproductive age. After the COVID-19 pandemic, it became more evident mainly in adolescents. The exposure to stressful situations is strongly related to mental diseases development. In 2009, the Food and Drug Administration (FDA) approved the escitalopram for treatment of depression in children and adolescents. To evaluate the effects of paternal chronic mild stress (CMS), with or without escitalopram treatment, on sperm chromatin protamination, testicular SIRT1 expression, reproductive outcomes, and offspring development using a rat model. Forty-four peripubertal male rats were randomly distributed into four groups: sham-control (SC), escitalopram (E), stress (S), and stress + escitalopram (ES). Animals in the stress and stress+escitalopram groups were subjected to a CMS protocol consisting of nine randomly applied stressors over 8 weeks (postnatal Days 41-97). Escitalopram (10 mg/kg/day) was administered by gavage from postnatal Day 70 for 4 weeks. At adulthood, males were mated with healthy nulliparous females to evaluate reproductive outcomes and offspring development. Testes and epididymides were collected on postnatal Day 114 for the assessment of sperm chromatin protamination and SIRT1 immunoexpression. CMS and/or escitalopram treatment reduced sperm chromatin protamination, SIRT1 immunoexpression in the seminiferous epithelium, placental thickness, and increased the frequency of skeletal abnormalities in the offspring. CMS alone also reduced gravid uterus weight, litter weight, fetal weight, total placental weight, implantation, and gestational indices, while increasing preimplantation loss. Paternal exposure to CMS from peripuberty to adulthood was associated with impaired reproductive outcomes and offspring development, including skeletal abnormalities, reduced sperm chromatin protamination and decreased testicular SIRT1 immunoexpression. Escitalopram treatment was associated with reduced sperm chromatin protamination, decreased testicular SIRT1 immunoexpression, and an increased frequency of skeletal abnormalities in the offspring.

Double-blind, placebo-controlled randomised clinical trial on flexible doses of escitalopram and naltrexone in the treatment of men with compulsive sexual behaviour disorder: study protocol presentation.

Lew-Starowicz Michał M, Draps Małgorzata M, Wilk Kacper K, Wisniewski Pawel P et al.