A phase I trial of LHC165 single agent and in combination with spartalizumab in patients with advanced solid malignancies.

BACKGROUND: LHC165 is a Toll-like receptor (TLR)-7 agonist that generates an effective tumor antigen-specific T-cell adaptive immune response as well as durable antitumor responses. We aimed to evaluate the safety, tolerability, efficacy, dose-limiting toxicities, and pharmacokinetics (PK) of LHC165 single agent (SA) ± spartalizumab [PDR001; anti-programmed cell death protein 1 (PD-1)] in adult patients with advanced solid tumors. MATERIALS AND METHODS: In this phase I/Ib, open-label, dose-escalation/expansion study, patients received LHC165 SA 100-600 µg biweekly through intratumoral (IT) injection and LHC165 600 µg biweekly + spartalizumab 400 mg Q4W through intravenous (IV) infusion. RESULTS: Forty-five patients were enrolled: 21 patients received LHC165 SA, and 24 patients received LHC165 + spartalizumab. The median duration of exposure was 8 weeks (range 2-129 weeks). No maximum tolerated dose was reached. Recommended dose expansion was established as LHC165 600 µg biweekly as SA and in combination with spartalizumab 400 mg Q4W. The most common drug-related adverse events (AEs) were pyrexia (22.2%), pruritus (13.3%), chills (11.1%), and asthenia (4.4%). The only serious AE (SAE) suspected to be related to the study drug was grade 3 pancreatitis (n = 1). Across all tumor types, overall response rate and disease control were 6.7% and 17.8%, respectively. Overall median progression-free survival (PFS) and immune-related PFS was 1.7 months. LHC165 serum PK demonstrated an initial rapid release followed by a slower release due to continued release of LHC165 from the injection site. CONCLUSIONS: LHC165 demonstrated acceptable safety and tolerability both as SA and in combination with spartalizumab, and evidence of limited antitumor activity was seen in adult patients with relapsed/refractory or metastatic solid tumors.

Assessing the Renal Outcomes of Semaglutide in Diabetic Kidney Disease: A Systematic Review.

Diabetic kidney disease (DKD) is a prevalent microvascular complication of diabetes, posing a significant health burden. Semaglutide, a glucagon-like peptide-1 receptor agonist, has shown promise in mitigating renal outcomes in DKD. This systematic review aimed to evaluate the renal effects of semaglutide in individuals with DKD. A comprehensive literature search identified six eligible studies, including two case reports and four cohorts, from diverse geographic locations. The primary outcomes assessed were changes in estimated glomerular filtration rate (eGFR) and albuminuria. Secondary outcomes included acute kidney injury (AKI) incidence and other renal biomarkers. The impact of semaglutide on eGFR was variable, with some studies reporting decreases and others showing improvements or no significant changes. Albuminuria, however, was more consistently reduced, particularly in patients with macroalbuminuria. Notably, the case reports described semaglutide-associated AKI, including acute interstitial nephritis, highlighting the need for careful monitoring during therapy. Beyond renal outcomes, semaglutide consistently improved glycemic control and promoted weight loss, with generally manageable gastrointestinal side effects. The findings suggest that semaglutide may effectively reduce albuminuria in DKD, potentially slowing disease progression. However, the risk of AKI and the variable impact on eGFR underscore the need for a personalized approach and vigilant monitoring, particularly in patients with advanced CKD. Future large-scale, long-term randomized controlled trials are warranted to definitively assess the renal benefits and risks of semaglutide in DKD.

Real-world safety profile of once-weekly semaglutide in people with type 2 diabetes: Analysis of pooled data from the SemaglUtide Real-world Evidence (SURE) programme.

AIM: To investigate, through post hoc analysis of nine studies from the SemaglUtide Real-world Evidence (SURE) programme, the safety of once-weekly (OW) semaglutide in adults with type 2 diabetes (T2D) and in subpopulations in routine clinical practice, complementing findings from the phase 3 randomized clinical trial (RCT) SUSTAIN programme. METHODS: The SURE studies had a duration of ~30 weeks and included adults with diagnosed T2D treated with OW semaglutide. Safety information, including hypoglycaemic events, were collected and analysed for the total study population and for patient subgroups based on baseline patient characteristics, baseline co-medication and prescriber specialty. RESULTS: Of the total 3505 patients, 24.3% reported adverse events (AEs), with most patients reporting non-serious (22.3%) and mild (17.1%) AEs. AEs mainly belonged to the gastrointestinal disorders system organ class (16.3% of patients). In total, 5.1% of patients reported AEs that led to treatment discontinuation, 0.5% reported serious adverse drug reactions and 0.2% had an AE with a fatal outcome, reported as unrelated to treatment. Overall, 1.1% and 0.1% of patients reported level 2 and 3 hypoglycaemic events, respectively. A higher rate of level 2 hypoglycaemia was observed in patients with baseline microvascular complications treated with insulin versus those on insulin without these complications. CONCLUSIONS: Safety data reported in the real-world SURE studies were generally consistent with observations in phase 3 OW semaglutide RCTs. No new safety concerns were identified, highlighting that OW semaglutide is well tolerated by adults with T2D and in subpopulations in routine clinical practice.

G protein-coupled receptor (GPCR) pharmacogenomics.

The field of pharmacogenetics, the investigation of the influence of one or more sequence variants on drug response phenotypes, is a special case of pharmacogenomics, a discipline that takes a genome-wide approach. Massively parallel, next generation sequencing (NGS), has allowed pharmacogenetics to be subsumed by pharmacogenomics with respect to the identification of variants associated with responders and non-responders, optimal drug response, and adverse drug reactions. A plethora of rare and common naturally-occurring GPCR variants must be considered in the context of signals from across the genome. Many fundamentals of pharmacogenetics were established for G protein-coupled receptor (GPCR) genes because they are primary targets for a large number of therapeutic drugs. Functional studies, demonstrating likely-pathogenic and pathogenic GPCR variants, have been integral to establishing models used for in silico analysis. Variants in GPCR genes include both coding and non-coding single nucleotide variants and insertion or deletions (indels) that affect cell surface expression (trafficking, dimerization, and desensitization/downregulation), ligand binding and G protein coupling, and variants that result in alternate splicing encoding isoforms/variable expression. As the breadth of data on the GPCR genome increases, we may expect an increase in the use of drug labels that note variants that significantly impact the clinical use of GPCR-targeting agents. We discuss the implications of GPCR pharmacogenomic data derived from the genomes available from individuals who have been well-phenotyped for receptor structure and function and receptor-ligand interactions, and the potential benefits to patients of optimized drug selection. Examples discussed include the renin-angiotensin system in SARS-CoV-2 (COVID-19) infection, the probable role of chemokine receptors in the cytokine storm, and potential protease activating receptor (PAR) interventions. Resources dedicated to GPCRs, including publicly available computational tools, are also discussed.

Cilostazol attenuates mirabegron-induced hepatic and renal toxicity in rats: regulation of metabolic, oxidative, and inflammatory pathways.

BACKGROUND: Mirabegron (MIRG) is a type of ß3 adrenoceptor agonist that is considered an alternative therapy for the treatment of overactive bladder (OAB) symptoms. Cilostazol (CITZ) is a selective inhibitor of phosphodiesterase (III) that has various pharmacological effects. OBJECTVE: The current study aimed to highlight the regulatory effects of CITZ on MIRG-induced toxicity. MATERIALS AND METHODS: Male rats were divided into six groups. Blood samples were collected to determine different hepatic and kidney function levels along with serum protein electrophoresis and inflammatory factor levels. Histopathological studies and oxidative stress (OS) were also assessed. Kidney and hepatic damage were detected following the administration of MIRG, especially at high doses, due to elevated OS, inflammation, and apoptotic marker levels. RESULTS: Rats receiving CITZ exhibited significant improvements in both hepatic and kidney functions, with decreased inflammation and OS. CONCLUSION: CITZ administration plays a beneficial role in alleviating hepatic and nephrotoxicity induced by MIRG by inhibiting OS and inflammation.

Efficacy and safety of peroxisome proliferator-activated receptor agonists for the treatment of primary biliary cholangitis: a meta-analysis of randomized controlled trials.

Background: Peroxisome proliferator-activated receptor (PPAR) agonists are recognised as a promising treatment for primary biliary cholangitis (PBC). However, the effects and safety of these agonists on PBC remain unexplored. Our study aimed to investigate the efficacy and safety of PPAR agonists in treating PBC. Methods: We searched Cochrane Library, and Web of Science, PubMed, and Embase databases from inception to 15 March 2024 for randomised controlled studies (RCTs) that enrolled individuals with PBC treated with PPAR agonists compared with placebo. The primary outcomes were biochemical response and normalization of the alkaline phosphatase (ALP) level. Results: Eight RCTs involving 869 participants in total were included. The meta-analysis revealed that compared to placebo, PPAR agonists increased the rate of biochemical response (RR: 5.53; 95% CI: 3.79, 8.06) and normalization of the ALP level (RR: 17.18; 95% CI: 5.61, 52.61). In addition, PPAR agonists can also reduce alanine aminotransferase (ALT) (MD: -12.69 U/L; 95% CI: -18.03, -7.35), aspartate aminotransferase (AST) (MD: -4.18 U/L; 95% CI: -7.28, -1.08), ALP (MD: -142.95 U/L; 95% CI: -167.29, -118.60), γ-glutamyltransferase (GGT) (MD: -63.03 U/L; 95% CI: -92.08, -33.98), and total cholesterol (TC) levels (SMD: -0.71; 95% CI: -1.38, -0.04), and there was no significant difference in overall adverse reactions (RR: 0.99; 95% CI: 0.92, 1.05), serious adverse reactions (RR: 1.10; 95% CI: 0.70, 1.72) between the two groups. Conclusion: PPAR agonists are safe and well-tolerated in patients with PBC and are effective in improving the rate of biochemical response and related biomarkers.

Neurocognitive performance of patients undergoing intravenous versus oral opioid agonist treatment: a prospective multicenter study on three-month treatment effects.

Introduction: The first-line treatment for opioid dependence is opioid agonist treatment (OAT) with oral opioids. However, in some cases, treatment with intravenous diacetylmorphine (IV-DAM) is indicated. Research on neurocognitive impairments and treatment effects of OAT - particularly with IV-DAM - on neurocognitive functioning, is scarce. The current study is the first to investigate the neurocognitive performance of individuals on OAT with IV-DAM. Using a prospective study design with two timepoints of measurement, the first aim was to assess the nature and extent of neurocognitive functioning in individuals with opioid dependence by comparing participants' neurocognitive performance with normative data of the general population on admission to treatment (baseline) and after an initial three-month period of OAT (study end). The second aim was to examine whether and to what extent neurocognitive performance would improve after three months on OAT. The third aim was to investigate whether, and if so, to what extent the treatment method (IV-DAM vs. oral opioids) would lead to higher neurocognitive improvements at study end. Methods: Forty-seven opioid-dependent individuals (baseline; 33 individuals at study end) participated in this study (mean age: 34.3 years; 27.7% female). Participants underwent neuropsychological testing with a battery of 12 tests covering different neurocognitive domains, including attention, memory, and executive functions. Results: Compared to normative data, opioid-dependent individuals showed impairments in almost every test both at baseline and at study end. At baseline, neurocognitive performance did not differ between individuals receiving IV-DAM or oral opioids for OAT. Compared to baseline, the neurocognitive performance did neither improve nor deteriorate after three months of treatment with neither IV-DAM nor oral opioids. However, a trend towards improvement was found for the memory domain. Discussion: Given that neurocognitive impairments should be considered in treatment planning and therapeutic interventions. Since a reduced cognitive performance may affect both the treatment outcome and the therapeutic relationship unfavorably, specific neurocognitive training at the beginning of treatment should be considered.

The dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist tirzepatide effects on body weight evolution, adiponectin, insulin and leptin levels in the combination of obesity, type 2 diabetes and menopause in mice.

AIM: Tirzepatide (Tzp), a novel dual agonist glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1, is approved for treating insulin resistance and obesity, and menopausal women consuming a high-calorie diet are a target to study the Tzp effect. Therefore, we aimed to allometrically scale body weight (BW) in Tzp-treated obese diabetic menopausal mice. MATERIALS AND METHODS: Three-month-old C57BL/6 female mice had bilateral ovariectomy (Ovx) or a sham procedure and for 12 weeks were fed a control diet or a high-fat and high sucrose diet (n = 120/each group [control (C), obese diabetic (Od), Ovx (O), sham (S), Tzp (T)]). Tzp was subcutaneously administered (10 nmol/kg) or vehicle once a day for an additional 4 weeks. The analysis considered log-transformed data and the allometric equation log y = log a + b log x. RESULTS: Od and OdO showed more upward slopes than C and CO. In C, BW was non-allometric by T administration. Od and OdO showed slightly positive slopes (more prominent in OdO than Od). OdT and OdOT showed negative slopes, significant intercepts, and more robust Pearson coefficients than untreated ones. A potent drug effect was seen with BW allometric decline. Interactions between diet versus Ovx and diet versus Tzp affected weight gain. Diet versus Ovx versus Tzp affected food intake. CONCLUSIONS: A model was developed to show three usual factors observed in mature women. Notably, Tzp improved the metabolism and weight loss of OdO mice. Tzp-treated mice showed negative allometric BW across treatment time, which is a quantitative assessment that allows better comparison between results.

A severe tremor caused by a beta2 agonist in a patient with asthma-chronic obstructive pulmonary disease overlap.

A 46-year-old male developed respiratory distress due to asthma-chronic obstructive pulmonary disease overlap and experienced severe tremor caused by beta2 agonist inhalant. We present our successful experience with tizanidine administration.

Transdermal pilocarpine on the skin over salivary glands to increase salivation: an in vivo study.

BACKGROUND: Hyposalivation is treated using oral cholinergic drugs; however, systemic side effects occasionally lead to discontinuation of treatment. We aimed to investigate the effects of transdermal pilocarpine on the salivary gland skin on saliva secretion and safety in rats. METHODS: Pilocarpine was administered to rats orally (0.5 mg/kg) or topically on the salivary gland skin (5 mg/body). Saliva volume, the number of sweat dots, and fecal weight were measured along with pilocarpine concentration in plasma and submandibular gland tissues. RESULTS: Saliva volume significantly increased 0.5 h after oral administration and 0.5, 3, and 12 h after topical administration. Fecal weight and sweat dots increased significantly 1 h after oral administration; however, no changes were observed after topical application. The pilocarpine concentration in the submandibular gland tissues of the topical group was higher than that in the oral group at 0.5, 3, and 12 h of administration. CONCLUSIONS: Pilocarpine application to salivary gland skin persistently increased salivary volume in rats without inducing sweating or diarrhea. Transdermal pilocarpine applied to the skin over the salivary glands may be an effective and safe treatment option for hyposalivation.

Efficacy and safety of switching from a dipeptidyl peptidase-4 inhibitor to oral semaglutide in Japanese patients with type 2 diabetes mellitus.

Background: Dipeptidyl peptidase-4 inhibitors (DPP-4is) are the most widely used oral hypoglycemic drugs in Japan. However, once-daily oral semaglutide has been reported to reduce glycated hemoglobin (HbA1c) and body weight (BW) without causing significant hypoglycemia. Here, we aimed to evaluate the efficacy and safety of switching from a DPP-4i to oral semaglutide in Japanese patients with type 2 diabetes (T2D). Methods: We performed a single-center retrospective study of the changes in HbA1c and BW in 68 patients with T2D who were switched from a DPP-4i and took oral semaglutide for ≥ 6 months, without changes in any other oral hypoglycemic agent. Results: Mean HbA1c decreased from 7.8 to 7.0% (p < 0.001) and BW decreased from 74.2 to 71.2 kg (p < 0.001) over 6 months. The decrease in HbA1c was more pronounced in participants with high baseline HbA1c (r = - 0.542, p < 0.001). There was also a trend (r = 0.236, p = 0.052) toward a decrease in BW in individuals with shorter disease duration. There were reductions in either HbA1c or BW in 65 participants (95.6%). In addition, the larger the decrease in HbA1c was, the greater was the decrease in BW (r = 0.480, p < 0.001). Eighteen participants (20.1%) discontinued the drug within 6 months, of whom 10 (11.6% of the total) did so because of suspected adverse effects and the discontinuation rate was the highest in older, non-obese patients. Conclusions: Switching from a DPP-4i to oral semaglutide may be useful for Japanese patients with T2D who have inadequate glycemic or BW control. However, its utility may be limited by gastrointestinal adverse effects in certain patients.

Advances in the clinical measurement of glucagon: from diagnosis to therapy.

Glucagon has many functions: it promotes glucose production, fatty acid oxidation, thermogenesis, energy consumption, lipolysis, and myocardial contraction, and suppresses lipogenesis, appetite, and gastrointestinal motility. Which of these functions are physiological and which are pharmacological is not fully understood. Although the Mercodia sandwich ELISA provides significantly higher specificity of glucagon measurement than does conventional competitive RIA, it cannot provide accurate plasma glucagon values in the presence of elevated cross-reacting plasma glicentin. This occurs in patients post-pancreatectomy or bariatric surgery and in around 30% of outpatients suspected for glucose intolerance who have not had surgery. Thus, our newly developed sandwich ELISA with higher specificity and higher sensitivity than the Mercodia sandwich ELISA is needed for accurate measurements of plasma glucagon in diabetic patients. It is expected that the new sandwich ELISA will contribute to personalized medicine for diabetes by its use in clinical tests to accurately diagnose the conditions of diabetic patients in order to design better individual treatment strategies. Meanwhile, clinical trials are being conducted worldwide to apply glucagon/GLP-1 receptor dual agonists and glucagon/GLP-1/GIP receptor triagonists to the treatment of obesity, fatty liver, and diabetes. Most clinical trials have shown that both types of drugs have stronger effects on weight reduction, improving fatty liver, and glucose tolerance than do the single GLP-1 receptor agonists. Glucagon is expected to be used as a new diagnostic marker and in a new therapeutic strategy based on a true understanding of its physiological and pharmacological functions.

Kidney and cardiovascular-protective benefits of combination drug therapies in chronic kidney disease associated with type 2 diabetes.

Given the substantial burden of chronic kidney disease associated with type 2 diabetes, an aggressive approach to treatment is required. Despite the benefits of guideline-directed therapy, there remains a high residual risk of continuing progression of chronic kidney disease and of cardiovascular events. Historically, a linear approach to pharmacologic management of chronic kidney disease has been used, in which drugs are added, then adjusted, optimized, or stopped in a stepwise manner based on their efficacy, toxicity, effects on a patient's quality of life, and cost. However, there are disadvantages to this approach, which may result in missing a window of opportunity to slow chronic kidney disease progression. Instead, a pillar approach has been proposed to enable earlier treatment that simultaneously targets multiple pathways involved in disease progression. Combination therapy in patients with chronic kidney disease associated with type 2 diabetes is being investigated in several clinical trials. In this article, we discuss current treatment options for patients with chronic kidney disease associated with type 2 diabetes and provide a rationale for tailored combinations of therapies with complementary mechanisms of action to optimize therapy using a pillar-based treatment strategy. [This article includes a plain language summary as an additional file].

Evidence-based review and frontiers of migraine therapy.

BACKGROUND: Cyclic vomiting syndrome (CVS) is identified as one of the "episodic syndromes that may be associated with migraine," along with benign paroxysmal torticollis, benign paroxysmal vertigo, and abdominal migraine. It has been proposed that CVS and migraine may share pathophysiologic mechanisms of hypothalamic activation and altered dopaminergic signaling, and impaired sensorimotor intrinsic connectivity. The past decade has brought groundbreaking advances in the treatment of migraine and other headache disorders. While many of these therapies have yet to be studied in episodic syndromes associated with migraine including CVS and abdominal migraine, the potential shared pathophysiology among these conditions suggests that use of migraine-specific treatments may have a beneficial role even in those for whom headache is not the primary symptom. PURPOSE: This manuscript highlights newer therapies in migraine. Calcitonin gene-related peptide (CGRP) and its relation to migraine pathophysiology and the therapies that target the CGRP pathway, as well as a 5HT1F receptor agonist and neuromodulation devices used to treat migraine are briefly discussed as they may potentially prove to be useful in the future treatment of CVS.

Real-World Evaluation of Once-Weekly Subcutaneous Semaglutide in Patients with Type 2 Diabetes Mellitus in Spain (SEMA-RW Study).

Although, in randomized clinical trials, once-weekly subcutaneous semaglutide (OW s.c.) has demonstrated superior efficacy in comparison with placebo and active controls in terms of glycemic control and body weight reduction in patients with type 2 diabetes mellitus (T2DM), these results need to be confirmed in a real-world (RW) setting. An RW ambispective study (6 months retrospective and 6 months prospective) was conducted in 10 tertiary hospitals in Spain. We evaluated changes in HbA1c and body weight in patients with T2DM treated with semaglutide OW s.c. Additionally, we analyzed different subgroups of patients treated with semaglutide OW s.c. as an add-on to glucose-lowering therapy. A total of 752 patients with a mean age of 60.2 years, a mean HbA1c level of 8.5%, a mean body weight of 101.6 kg, and a mean T2DM duration of 10 years were included. At 12 months, compared with baseline, there was a mean difference of -2.1% in HbA1c levels (p < 0.001) and a mean difference of 9.2 kg in body weight (p < 0.001). Moreover, there were statistically significant differences (p < 0.001) between baseline and month 12 in both HbA1c and body weight in the four subgroups receiving semaglutide OW s.c. as an add-on to glucose-lowering therapy. Semaglutide OW s.c. was well tolerated, with gastrointestinal disorders being the most commonly reported side effects. In this RW study, 12 months of treatment with semaglutide OW s.c. in patients with T2DM was associated with significant and clinically relevant improvements in glycemic control and weight loss, regardless of the glucose-lowering therapy received, and the overall safety profile was positive.

Safety and Efficacy of Combined Injection of Pure-µ-Opioid Agonist with Tramadol as an Opioid Induction Agent for Opioid-Naïve Cancer Patients.

Background: Tramadol is known to provide synergistic analgesia when used in combination with morphine. Objectives: The aims of this study were: (1) to introduce an opioid combination therapy using pure-µ-opioid receptor agonist (OPI) + tramadol injections (OPI + tramadol) and (2) to elucidate safety and efficacy of this combination therapy for opioid-naïve cancer pain patients. Methods: Opioid-naïve patients referred to our palliative care team (in Japan) who were unable to take oral medications and received OPI + tramadol as opioid induction agents were retrospectively investigated on the electric medical chart. OPI + tramadol dosage was adjusted to achieve the patient's pain as Numerical Rating Scale ≤4/10 or Support Team Assessment Schedule-Japanese ≤1. Patients' demography, doses of OPI and tramadol administered, and adverse events were analyzed. Results: A total of 44 patients were included. The primary organs of malignancy were pancreas (11), stomach (5), lung (4), breast (4), liver (4), and others (13). OPI injections administered were hydromorphone (39), morphine (6), oxycodone (1), and fentanyl (1). The starting doses of OPI (morphine equivalent) and tramadol were 6.05 ± 1.63 and 67.8 ± 13.6 mg/day, respectively, and the final doses of OPI (morphine equivalent) and tramadol were 8.14 ± 3.85 and 80.0 ± 28.5 mg/day, respectively. Treatment goals were achieved in all patients. There were three patients in whom OPI was switched owing to inadequate analgesia and no new side effects other than those known to occur when OPI or tramadol is administered appeared. Conclusion: The results suggest that this innovative and unique opioid therapy can be safely and effectively introduced to opioid-naïve cancer patients who are relatively close to the end of life.

Adiponectin prevents skin inflammation in rosacea by suppressing S6 phosphorylation in keratinocytes.

Numerous recent evidence highlights epidemiological connections between rosacea and metabolic disorders. However, the precise path through which metabolic factors impact rosacea risk is still unclear. Therefore, this study aims to investigate the role of adiponectin, a crucial adipokine that regulates metabolic homeostasis, in the pathogenesis of rosacea. We elucidated a detrimental feedback loop between rosacea-like skin inflammation and decreased levels of skin adiponectin. To elaborate, rosacea lesional skin exhibits diminished adiponectin expression compared to non-lesional areas in the same patients. Induction of rosacea-like inflammation reduced adiponectin levels in the skin by generating inflammatory cytokines that suppress adiponectin production from subcutaneous adipocytes. Conversely, complete depletion of adiponectin exacerbated rosacea-like features in the mouse model. Mechanistically, adiponectin deficiency led to heightened S6 phosphorylation, a marker of the mTORC1 signaling pathway, in the epidermis. Adiponectin significantly inhibited S6 phosphorylation in cultured keratinocytes. Notably, replenishing adiponectin whole protein or topically applying an agonist for adiponectin receptor 1 successfully improved rosacea-like features in mice. This study contributes to understanding the role of adiponectin in skin inflammation associated with rosacea pathophysiology, suggesting that restoring adiponectin function in the skin could be a potential therapeutic strategy.

Utility of an Alpha-1 Adrenergic Agonist in the Management of Chylothorax: A Case Series and Management Algorithm.

Chylothorax is the accumulation of lymphatic fluid (chyle) within the pleural space. There are multiple causes, including traumatic and non-traumatic mechanisms. Trauma can cause disruption of the thoracic duct either by direct damage or indirect crushing or avulsion mechanisms. Non-traumatic causes include infections, inflammatory processes, malignancies, and iatrogenic injury (during surgery or central venous access). The traditional management of traumatic chylothorax has been either a conservative approach, including complete Nil Per Os (NPO), or a low-fat diet with medium-chain triglyceride supplementation with the administration of somatostatin or its analog, octreotide, versus a surgical approach consisting of thoracic duct ligation. Recently a less invasive approach via thoracic duct embolization has gained popularity. There have been a few reports of the successful use of an α 1-adrenergic agonist (midodrine) as an adjunct in the conservative approach. We describe the utility of midodrine in three cases of chylothorax and propose a management algorithm. LEARNING POINTS: The initial diagnosis of chylothorax is based on clinical suspicion and proper imaging.The clinical success of midodrine use as a first-line medical treatment for chylothorax will support the use of midodrine before considering invasive procedures.We propose a management algorithm for patients with chylothorax that will stimulate researchers to conduct prospective studies to assess its efficacy.

Equine Pergolide Toxicity: A Case Series.

Veterinary medication exposure may result in human toxicity, with approximately 6,000 exposures to veterinary-only medications reported to poison centers in 2022. There is a paucity of literature on the management of poisoned patients secondary to pharmaceuticals intended for equine use. Pergolide is a dopamine and serotonin receptor agonist and is currently approved to treat equine Cushing's disease. It was previously approved in the United States (US) to treat Parkinson's disease in humans; however, it was withdrawn from the market in 2007 due to its association with valvular heart disease. We report two cases of pergolide toxicity in horse owners following unintentional ingestions. Both patients experienced similar clinical presentations resulting from their unintentional pergolide ingestions. Veterinary medication ingestion presents a unique challenge to clinicians as the drug may have limited human toxicity data and/or recommended animal dosing may differ greatly from human dosing. Case reports of human toxicity may assist with anticipating the clinical course and guiding medical decision-making.