Autoimmune colitis and neutropenia in adjuvant anti-PD-1 therapy for malignant melanoma: efficacy of Vedolizumab, a case report

Immune checkpoint inhibitors (ICIs) represent an important advance in the adjuvant treatment of patients with high-risk melanoma. Although the safety profile of anti-programmed cell death protein-1 (PD-1) is fairly acceptable, different immune-related adverse events (irAEs) are described. Herein we report for the first time a notably multidisciplinary combined approach on a malignant melanoma (MM) patient treated with anti-PD-1 antibody in adjuvant setting. In this novel approach, corticosteroid-refractory immune-mediated colitis (IMC) was effectively treated with Vedolizumab, a selective blockade of the α4β7 integrin and corticosteroids were successfully administered for autoimmune neutropenia. Notably, our patient also express HLA-B*35, a potential biomarker for predicting a genetic basis of autoimmune susceptibility. Our experience offers a possible future perspective about the use of Vedolizumab together with immunotherapy in a strategic early approach for high-risk patients genotyped for HLA.

Ca2+ channel blockade reduces cocaine’s vasoconstriction and neurotoxicity in the prefrontal cortex

Cocaine profoundly affects both cerebral blood vessels and neuronal activity in the brain. The vasoconstrictive effects of cocaine, concurrently with its effects on neuronal [Ca2+]i accumulation are likely to jeopardize neuronal tissue that in the prefrontal cortex (PFC) could contribute to impaired self-regulation and compulsive cocaine consumption. Here we used optical imaging to study the cerebrovascular and neuronal effects of acute cocaine (1 mg/kg i.v.) and to examine whether selective blockade of L-type Ca2+ channels by Nifedipine (NIF) (0.5 mg/kg i.v.) would alleviate cocaine’s effects on hemodynamics (measured with cerebral blood volume, HbT), oxygenation (measured with oxygenated hemoglobin, HbO2) and neuronal [Ca2+]i, which were concomitantly measured in the PFC of naive rats. Our results show that in the PFC acute cocaine significantly reduced flow delivery (HbT), increased neuronal [Ca2+]i accumulation and profoundly reduced tissue oxygenation (HbO2) and these effects were significantly attenuated by NIF pretreatment. They also show that cocaine-induced vasoconstriction is distinct from its increase of neuronal [Ca2+]i accumulation though both of them contribute to hypoxemia and both effects were attenuated by NIF. These results provide evidence that blockade of voltage-gated L-type Ca2+ channels might be beneficial in preventing vasoconstriction and neurotoxic effects of cocaine and give support for further clinical investigations to determine their value in reducing cocaine’s neurotoxicity in cocaine use disorders.

Lateral habenula M2 muscarinic receptor control of neuronal activity and cocaine seeking behavior

The lateral habenula (LHb) plays a central role in balancing reward and aversion by opposing the contributions of brain reward nuclei. Using a rat cocaine self-administration model, we previously found that LHb inhibition or non-selective blockade of LHb muscarinic acetylcholine receptors (mAChRs) led to persistent cocaine seeking despite its signaled unavailability. As understanding roles for the LHb and cholinergic signaling in behavioral control is important to psychiatric illness and addiction, we examine how mAChRs act on LHb neurons using in vitro electrophysiology. We find that different groups of LHb neurons are depolarized or hyperpolarized by the cholinergic agonist carbachol (CCh), and that CCh could inhibit GABAergic and glutamatergic synaptic inputs to these cells. Presynaptic CCh effects were reversed by the M2 mAChR (M2R) antagonist AFDX-116, but not by pirenzepine, an M1R antagonist. Contemporaneous measurement of CCh effects on synaptic inhibition and excitation in LHb neurons showed a smaller effect on inhibition, suggesting a net shift in synaptic integration toward greater inhibition by mAChRs. Synaptic currents elicited by light-activation of ventral tegmental area (VTA) axons in the LHb, following channelrhodopsin-2 transfection of VTA, were also inhibited by M2Rs, suggesting the VTA as at least one M2R-sensitive LHb afferent. Finally, Go-NoGo cocaine seeking studies showed that blockade of LHb M2Rs, and not M1Rs, triggered continued cocaine seeking. These data identify LHb M2Rs as a potential control point of LHb function that enables withholding responses for cocaine and define cellular mechanisms through which mAChRs modulate LHb activity.

An old friend: 25 years of meloxicam use in Russia.

25 years ago, a new non-steroidal anti-inflammatory drug (NSAID) – meloxicam (Movalis®) – entered the clinical practice of our country. This drug was the first embodiment of the concept of selective blockade of cyclooxygenase 2 – the main pathway followed by pharmacological science to create a safe NSAID. A series of large-scale, well-organized randomized controlled trials and observational post-registration studies have confirmed the good efficacy and low incidence of adverse reactions (ADR) when using meloxicam. In our country, this drug has become one of the most popular analgesics. Until now, the original meloxicam has enjoyed a high level of trust among Russian doctors and patients. The reason for this is a long and very extensive experience in the clinical use of meloxicam (over 25 years, 63.7 million packages of the original drug were sold, which means that millions of our Russian citizens were treated with it), as well as a large number of clinical studies conducted by Russian scientists. So, to date, there are 36 Russian studies (n=8498) assessing the efficacy and safety of the original meloxicam in a variety of diseases and clinical conditions. Practically all of these studies have shown good therapeutic results: on average, pain relief is 50–75% of the initial level; good or excellent assessment of the drug effect in 70–80% of patients. The incidence of HP was on average 10.5±5.4%, and there were no serious life-threatening complications. This review briefly presents the data of Russian and major foreign clinical studies, which studied the therapeutic potential and safety of meloxicam.

The efficacy of thoracic epidural anesthesia for breast surgeries

Thoracic epidural anesthesia provides selective blockade for the surgical site, with diminished requirements of opioids and local anaesthetics. If the efficacy of the same is better or equivalent to general anesthesia, the adverse effects with the later can be avoided. Hence this study was conducted to know the effectiveness of thoracic epiduralanesthesia in breast surgeries using 1.5% lignocaine with adrenaline.This prospective cross-sectional study was conducted in the department of Anaesthesiology in association with the Department of Surgery at Raja Muthaiah Medical College and Hospital, Chidambaram from January 2013 to June 2014. Adult female patients aged between 18-60 years belonging to ASA class I, class II and class III undergoing breast surgeries were included in the study. Patients with bleeding diathesis and local infections were excluded from the study. A total of thirty cases were included in the study and efficacy of epidural anaesthesia was determined by monitoring vitals in the peri-operative period. Results were analysed using Statistical package for Social Sciences (SPSS) version 17.Heart rate, blood pressure (both systolic and diastolic) and mean arterial pressure were significantly different with respect to time. Mean duration of rescue analgesia was found to be 127.33±27.62 minutes. Also 10%, 23.3%, 13.3% and 6.7% of cases reported bradycardia, shivering, hypotension and nausea during the intra operative period whereas 10% of cases reported backache and nausea, each during the post-operative period.Thoracic epidural anesthesia for breast surgeries provides good analgesia with minimal amount of drugs without significant complications.

Effect of Glucocorticoid Receptor Antagonism on Alcohol Self-Administration in Genetically-Selected Marchigian Sardinian Alcohol-Preferring and Non-Preferring Wistar Rats

Alcoholism is a chronically relapsing disorder characterized by high alcohol intake and a negative emotional state during abstinence, which contributes to excessive drinking and susceptibility to relapse. Stress, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and alterations in glucocorticoid receptor (GR) function have been linked to transition from recreational consumption to alcohol use disorder (AUD). Here, we investigated the effect of pharmacological antagonisms of GR on alcohol self-administration (SA) using male and female Wistar and Marchigian Sardinian alcohol-preferring (msP) rats, a rodent line genetically selected for excessive alcohol drinking and highly sensitive to stress. Animals were trained to self-administer 10% (v/v) alcohol. Once a stable alcohol SA baseline was reached, we tested the effect of the GR antagonists mifepristone (0.0, 10, 30 and 60 mg/kg; i.p.) and CORT113176 (0.0, 10, 30 and 60 mg/kg) on alcohol SA. To evaluate whether the effects of the two compounds were specific for alcohol, the two drugs were tested on a similar saccharin SA regimen. Finally, basal blood corticosterone (CORT) levels before and after alcohol SA were determined. Systemic injection with mifepristone dose-dependently reduced alcohol SA in male and female Wistars but not in msPs. Administration of CORT113176 decreased alcohol SA in male and female Wistars as well as in female msPs but not in male msP rats. At the highest dose, mifepristone also reduced saccharin SA in male Wistars and female msPs, suggesting the occurrence of some nonspecific effects at 60 mg/kg of the drug. Similarly, the highest dose of CORT113176 (60 mg/kg) decreased saccharin intake in male Wistars. Analysis of CORT levels revealed that females of both rat lines had higher blood levels of CORT compared to males. Alcohol consumption reduced CORT in females but not in males. Overall, these findings indicate that selective blockade of GR selectively reduces alcohol SA, and genetically selected msP rats are less sensitive to this pharmacological manipulation compared to heterogeneous Wistars. Moreover, results suggest sex differences in response to GR antagonism and the ability of alcohol to regulate GR transmission.

Microdose Lithium Protects against Pancreatic Islet Destruction and Renal Impairment in Streptozotocin-Elicited Diabetes

Psychiatric use of lithium has been associated with hypoglycemic effects, but its effect on type 1 diabetes mellitus (T1D) is unknown. In streptozotocin (STZ) induced murine models of T1D, microdose lithium therapy improved hyperglycemia, attenuated body weight loss and prevented early signs of diabetic kidney injury. This beneficial effect was associated with preservation of pancreatic islet histology and β-cell production of insulin as well as mitigated oxidative damage of islets. Mechanistically, lithium in islets cells induced inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β), the major molecular target of lithium that has been recently implicated in non-canonical regulation of Nrf2 activity. In turn, Nrf2 antioxidant response was potentiated in islets, marked by nuclear translocation of Nrf2 and augmented expression of its target antioxidant enzyme heme oxygenase 1 (HO-1). Conversely, cotreatment with trigonelline, a selective blockade of Nrf2, offset the lithium enhanced Nrf2 antioxidant response in islets, blunted the protective effect of lithium on pancreatic islets and β-cells, and abolished the hypoglycemic activity of lithium in STZ-injured mice. Collectively, our findings suggest that microdose lithium confers a protective effect on islet β-cells via targeting the GSK3β-regulated Nrf2 antioxidant response and thereby ameliorates T1D and its related kidney impairment.