Chronotropic Responses to GLP-1 Receptor Agonists and Sitagliptin in Atria from Diabetic Rats.

ABSTRACT: Type 2 Diabetes Mellitus (T2DM) increases the risk of cardiovascular diseases. Therefore, elucidation of the cardiovascular effects of antidiabetics is crucial. Incretin-based therapies are increasingly used for T2DM treatment as monotherapy and in combination. We aimed to study the effects of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) and sitagliptin on beating rates in isolated atria from diabetic rats. The chronotropic responses to GLP-1 RAs and sitagliptin as monotherapy and in combinations with metformin, pioglitazone, and glimepiride in isolated atria from control and diabetic rats were determined. GLP-1 (7-36), GLP-1 (9-36), and Exendin-4 (1-39) produced increases in beating rates in both control and diabetic rat atria. However, sitagliptin increased the beating frequency only in the diabetic group. Exendin (9-39), L-NAME, and indomethacin blocked responses to GLP-1 RAs but not the response to sitagliptin. Glibenclamide, 4-aminopyridine, apamin, charybdotoxin, superoxide dismutase, and catalase incubations did not change responses to GLP-1 RAs and sitagliptin. GLP-1 RAs increase beating rates in isolated rat atrium through GLP-1 receptor, nitric oxide, and cyclooxygenase pathways but not potassium channels and reactive oxygen radicals.

A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2023.

With 54 new drugs and seven cellular and gene therapy products, the approvals by the US Food and Drug Administration (FDA) recovered 2023 from the 2022 dent back to the levels of 2020-2021. As in previous years of this annual review, we assign these new drugs to one of three levels of innovation: first drug against a condition ("first-in-indication"), first drug using a novel molecular mechanism ("first-in-class"), and "next-in-class," i.e., a drug using an already exploited molecular mechanism. We identify four (7%) "first-in-indication," 22 (36%) "first-in-class," and 35 (57%) "next-in-class" drugs. By treatment area, rare diseases (54%) and cancer drugs (23%) were once again the most prevalent (and partly overlapping) therapeutic areas. Other continuing trends were the use of accelerated regulatory approval pathways and the reliance on biopharmaceuticals (biologics). 2023 marks the approval of a first therapy based on CRISPR/Cas9 gene editing.

Optimization of enzyme-linked immunosorbent assay kit protocol to detect trimethylamine N-oxide levels in humans.

The serum level of trimethylamine N-oxide (TMAO), a gut microbiota metabolite associated with diabetes, cancer, inflammatory and neurological diseases, can be determined by the micro-enzyme-linked immunosorbent assay (ELISA) method. However, we had problems obtaining accurate standard curves with the original kit protocol from Bioassay Technology Laboratory. We aimed to acquire proper standard curves by modifying the kit protocol in this study. First, we evaluated the human TMAO ELISA kit protocols and other human ELISA kits. We maintained the incubation times longer and increased the wash cycle. Moreover, we incubated the standards containing biotinylated antibody in the wells alone. Then we washed the wells and added streptavidin-HRP for the second incubation step. The data of original and modified ELISA kit protocol were analyzed with Student's t-test. We measured higher absorbance with lower standard solution concentration in experiments that followed the original kit protocol. After investigating other human TMAO ELISA kits, we noticed that the SunRed Biotechnology Company and MyBioSource companies suggested similar protocols to the Bioassay Technology Laboratory company. The ELK Biotechnology ELISA protocol was different from others. However, since there is no biotinylated antibody in the standard solution in the ELK biotechnology kit, we changed some steps by examining other human ELISA protocols from different companies. After performing the modified protocol, we found that the absorbances of the standard solutions were consistent with their concentrations, and we obtained an accurate standard curve. Higher R2 values and lower absolute difference of standard concentrations were found in the modified kit protocol. The human TMAO ELISA protocol, which we modified in this study, will enable researchers to obtain more reliable results and prevent them from failing time and resources.

A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2022.

While new drug approvals by the U.S. Food and Drug Administration (FDA) had remained stable or even increased in the first 2 years of the COVID-19 pandemic, the 37 newly approved drugs in 2022 are considerably less than the 53 and 50 new drugs approved in 2020 and 2021, respectively, and less than the rolling 10-year average of 43. As in previous years of this annual review, we assign these new drugs to one of three levels of innovation: first drug against a condition ("first-in-indication"), first drug using a novel molecular mechanism ("first-in-class"), and "next-in-class," i.e., a drug using an already exploited molecular mechanism. We identify two "first-in-indication" (ganaxolon and teplizumab), 20 (54%) "first-in-class," and 17 (46%) "next-in-class" drugs. By treatment area, rare diseases and cancer drugs were once again the most prevalent (partly overlapping) therapeutic areas. Other continuing trends were the use of accelerated regulatory approval pathways and the reliance on biopharmaceuticals (biologics).

Iron in infectious diseases friend or foe?: The role of gut microbiota.

Iron is a trace element involved in metabolic functions for all organisms, from microorganisms to mammalians. Iron deficiency is a prevalent health problem that affects billions of people worldwide, and iron overload could have some hazardous effect. The complex microbial community in the human body, also called microbiota, influences the host immune defence against infections. An imbalance in gut microbiota, dysbiosis, changes the host's susceptibility to infections by regulating the immune system. In recent years, the number of studies on the relationship between infectious diseases and microbiota has increased. Gut microbiota is affected by different parameters, including mode of delivery, hygiene habits, diet, drugs, and plasma iron levels during the lifetime. Gut microbiota may influence iron levels in the body, and iron overload and deficiency can also affect gut microbiota composition. Novel researches on microbiota shed light on the fact that the bidirectional interactions between gut microbiota and iron play a role in the pathogenesis of many diseases, especially infections. A better understanding of these interactions may help us to comprehend the pathogenesis of many infectious and metabolic diseases affecting people worldwide and following the development of more effective preventive and/or therapeutic strategies. In this review, we aimed to present the iron-mediated host-gut microbiota interactions, susceptibility to bacterial infections, and iron-targeted therapy approaches for infections.

A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2021.

The second year of the COVID-19 pandemic had no adverse effect on the number of new drug approvals by the US Food and Drug Administration (FDA). Quite the contrary, with a total of 50 new drugs, 2021 belongs to the most successful FDA years. We assign these new drugs to one of three levels of innovation: (1) first drug against a condition ("first-in-indication"), (2) first drug using a novel molecular mechanism ("first-in-class"), and (3) "next-in-class", i.e., a drug using an already exploited molecular mechanism. We identify 21 first-in-class, 28 next-in-class, and only one first-in-indication drugs. By treatment area, the largest group is once again cancer drugs, many of which target specific genetic alterations. Every second drug approved in 2021 targets an orphan disease, half of them being cancers. Small molecules continue to dominate new drug approvals, followed by antibodies and non-antibody biopharmaceuticals. In 2021, the FDA continued to approve drugs without strong evidence of clinical effects, best exemplified by the aducanumab controversy.

Medical students' knowledge and awareness levels about biologics and biosimilars: the earlier the better?

BACKGROUND: Although most studies about physician knowledge and attitude toward biosimilars have been conducted on specialists, studies addressing this issue among medical students are missing. OBJECTIVE: We aimed to evaluate the knowledge and awareness levels of biologics and biosimilars of medical students who will encounter these products soon. METHODS: In this cross-sectional study, 228 medical students were grouped as preclinical (Years 1,2,3) and clinical (Years 4,5,6). Students were given a survey including demographic (grade and gender) and questions about assessing their knowledge about biologics and biosimilars. RESULTS: Clinical students' knowledge was better than preclinical students (54% and 25%, respectively). Students did not know much about biosimilars (7-20%) and thought a biosimilar is identical to its generic product (35%). More than 90% of the students thought that a lesson about biologics should be included in the medical curriculum. CONCLUSIONS: Our study showed that medical students had inadequate knowledge about biosimilars. We suggest that to establish a positive attitude toward prescribing biosimilars, knowledge about biologics and biosimilars should be delivered to physicians early, while they are still medical students, by including this topic into the medical curriculum.

Sex-related susceptibility in coronavirus disease 2019 (COVID-19): Proposed mechanisms.

The importance of sex differences is increasingly acknowledged in the incidence and treatment of disease. Accumulating clinical evidence demonstrates that sex differences are noticeable in COVID-19, and the prevalence, severity, and mortality rate of COVID-19 are higher among males than females. Sex-related genetic and hormonal factors and immunological responses may underlie the sex bias in COVID-19 patients. Angiotensin-converting enzyme 2 (ACE2) and transmembrane protease/serine subfamily member 2 (TMPRSS2) are essential proteins involved in the cell entry of SARS-CoV-2. Since ACE2 is encoded on the X-chromosome, a double copy of ACE2 in females may compensate for virus-mediated downregulation of ACE2, and thus ACE2-mediated cellular protection is greater in females. The X chromosome also contains the largest immune-related genes leading females to develop more robust immune responses than males. Toll-like receptor-7 (TLR-7), one of the key players in innate immunity, is linked to sex differences in autoimmunity and vaccine efficacy, and its expression is greater in females. Sex steroids also affect immune cell function. Estrogen contributes to higher CD4+ and CD8+ T cell activation levels, and females have more B cells than males. Sex differences not only affect the severity and progression of the disease, but also alter the efficacy of pharmacological treatment and adverse events related to the drugs/vaccines used against COVID-19. Administration of different drugs/vaccines in different doses or intervals may be useful to eliminate sex differences in efficacy and side/adverse effects. It should be noted that studies should include sex-specific analyses to develop further sex-specific treatments for COVID-19.

Which proteinase-activated receptor-1 antagonist is better?: Evaluation of vorapaxar and parmodulin-2 effects on human left internal mammary artery endothelial function.

OBJECTIVE: Endothelial dysfunction occurs as an early event in cardiovascular disease. Previously, vorapaxar, a proteinase-activated receptor-1 antagonist, was shown to cause endothelial damage in a cell culture study. Therefore, our study aimed to compare the effects of vorapaxar and parmodulin-2, proteinase-activated receptor-1 biased agonist, on human left internal mammary artery endothelial function in vitro. METHOD: Isolated arteries were hung in the organ baths. Acetylcholine responses (10-11-10-6 M) were obtained in endothelium-intact tissues the following incubation with vorapaxar/parmodulin-2 (10-6 M) to determine the effects of these molecules on the endothelium-dependent relaxation. Subsequently, endothelium-dependent relaxation responses of tissues were investigated in the presence of L-NAME (10-4 M), L-arginine (10-5 M), indomethacin (10-5 M), and charybdotoxin-apamin (10-7 M) in addition to vorapaxar/parmodulin-2 incubation. Besides, the effect of these molecules on endothelium-independent relaxation response was evaluated with sodium nitroprusside (10-11-10-6 M). Finally, the sections of human arteries were imaged using a transmission electron microscope, and the integrity of the endothelial layer was evaluated. RESULTS: We found that vorapaxar caused significant endothelial dysfunction by disrupting nitric oxide and endothelium-derived hyperpolarizing factor-dependent relaxation mechanisms. Parmodulin-2 did not cause endothelial damage. Neither vorapaxar nor parmodulin-2 disrupted endothelium-independent relaxation responses. The effect of vorapaxar on the endothelial layer was supported by the transmission electron microscope images. CONCLUSION: Parmodulin-2 may be a better option than vorapaxar in treating cardiovascular diseases since it can inhibit PAR-1 without caused endothelial dysfunction.

Knowledge level and attitude towards complementary and alternative treatment methods among medical students: a cross-sectional survey study in Turkey.

OBJECTIVE: People often use complementary and alternative medicine (CAM) methods in Turkey, but reliability of the application of these methods is controversial. Considering the role of medical students (i.e. physician candidates) in sustainable health, their perspectives on CAM methods are important. This report explores the level of knowledge, experience, and preferences for the use of CAM methods among medical school students. MATERIAL AND METHODS: A survey about the use of CAM and interest in CAM methods was applied to 101 first-year and 87 fifth-year medical school students. The binary and multinomial logistic regression models were used for statistical analysis. RESULTS: Sixteen percent of the first-year and 9% of the fifth-year students were familiar with "The Regulation on Traditional and Complementary Medical Practices" published by the Ministry of Health of Turkey in 2014. While participants reported the most familiarity with acupuncture treatment, they were the most unfamiliar with prolotherapy among all CAM methods. Seeking advice from a licensed physician before applying CAM methods was the general agreement among the participants. Interest in learning and practicing hypnosis was the highest-rated CAM method among the participants. CONCLUSIONS: Increasing knowledge and awareness of CAM methods by including them into the medical curriculum would be essential for the correct use of CAM methods.