A homologous series of novel cationic surfactants, 1-(2-(alkanoyloxy)ethyl)-1,4-diazabicyclo[2.2.2]octane-1-ium bromides (DAB‑est‑n, where n = 9, 11, 13, 15, 17), bearing an ester fragment between the head group and the hydrophobic tail, was synthesized with overall yields of 68-82% and characterized by IR, [1]H NMR spectroscopy, high‑resolution mass spectrometry, and elemental analysis. A DAB-est-15 crystal was characterized by X-ray diffraction analysis. The self‑assembly of surfactants in aqueous solution was investigated using tensiometry, conductometry, fluorimetry, and spectrophotometry. The introduction of the ester group led to a twofold reduction in aggregation thresholds compared to the non‑functionalized analogue (0.5 mM vs. 1 mM). Spectrophotometry revealed a high solubilizing capacity of DAB‑est‑n toward Orange OT and the antidiabetic drug glipizide. The ability to integrate into the lipid bilayer of liposomes was confirmed by turbidimetry and electrophoretic light scattering. The ester‑containing surfactants showed enhanced biodegradability (up to 61%) compared to DAB‑16 and low hemolytic activity for DAB‑est‑9 and DAB‑est‑11. The homologous series of cationic surfactants was used to modify transfersomes for transdermal therapy of type 1 diabetes. Cationic transfersomes modified with DAB‑est‑13 efficiently encapsulated insulin (encapsulation efficiency 58 ± 2%) and were formulated in Carbopol®940 gel. Additionally, in vitro release kinetics revealed a sustained, non-Fickian diffusion profile for insulin-loaded transfersomes. Ex vivo studies on mouse skin demonstrated that modification significantly improved transdermal permeation, yielding an enhancement ratio of 1.8 compared to free insulin. Transdermal delivery of insulin using cationic transfersomes effectively reduced blood glucose levels to values comparable to those in healthy mice in vivo, whereas the gel formulations of free insulin or unmodified transfersomes showed no efficacy.

Diabetes mellitus is a chronic metabolic disorder affecting millions worldwide, necessitating the effective management of blood glucose levels through anti-diabetic medications. Sulfonylureas and Biguanides, particularly Gliclazide, Glimepiride, Glipizide, Glibenclamide, and Metformin, are commonly used in combination therapies for improved glycemic control. Several methods, including UV spectrophotometry, high-performance liquid chromatography, high-performance thin-layer chromatography, micellar chromatography, and liquid chromatography-mass spectrometry, were assessed for their effectiveness. This study evaluates various analytical techniques employed to ensure the quality, efficacy, and safety of these formulations, under the ICH guidelines. RP-HPLC emerged as the most reliable technique, demonstrating superior sensitivity, precision, and linearity, with optimized retention times and low detection limits. LC-ESI-MS/MS exhibited the highest sensitivity, precision, and linearity, making it suitable for pharmacokinetic studies. Spectrophotometric and electrochemical methods provided cost-effective alternatives but lacked sensitivity. RP-HPLC and MS-based techniques can enhance data processing efficiency. These advancements will strengthen pharmaceutical quality control, ensure the safety and efficacy of anti-diabetic drug formulations, while optimizing therapeutic outcomes for diabetes management.

Several studies have supported Dr Gideon Koren’s 1993 landmark article, “Medications Which Can Kill a Toddler with One Tablet or Teaspoonful.” Although each study has its own merits, most focus solely on pediatric overdoses, and few provide an exhaustive reference list for real-time evaluation of ingestions in children and adults. The following xenobiotics warrant special attention because of their potential to cause serious outcomes, even after exposure to small volumes. This list does not imply that all pediatric exposures to these agents result in fatality, and the absence of a xenobiotic from this list does not indicate that it is necessarily safe. α1-Adrenergic agonists and imidazoline receptor agonists: Clonidine, guanfacine, naphazoline, oxymetazoline, tetrahydrozoline, xylazine (veterinary). Sulfonylureas: Chlorpropamide, glyburide, glipizide, glimepiride. Calcium channel blockers: Verapamil, diltiazem, nifedipine, amlodipine, nicardipine, nimodipine; β-Blockers: Metoprolol, labetalol, propranolol, sotalol. Tricyclic antidepressants: Imipramine, desipramine, amitriptyline, nortriptyline. Opioids: Codeine, hydrocodone, methadone, morphine, heroin. Antidiarrheals: Diphenoxylate plus atropine, loperamide. Salicylates and methyl salicylate: Oil of wintergreen, bismuth subsalicylate, mentholated balms, paramao or lawang root oil . Antipsychotics: Loxapine, thioridazine, chlorpromazine. Antimalarials: Chloroquine, hydroxychloroquine, quinine, primaquine. Antiarrhythmics: Quinidine, disopyramide, procainamide, flecainide, amiodarone. Camphor: A terpenoid used as an analgesic, antipruritic agent, and component of cooling gels, ointments, balms, mothballs, household fragrances, and essential oils. Oral camphor use occurs in some regions for religious ceremonies, traditional remedies, aphrodisiacs, or lactation suppression. Nonalkaloid toxic lignan: Podophyllin, podofilox. Unique plant toxins: Colchicine. Oral acetylcholinesterase inhibitors: Rivastigmine, donepezil, galantamine, carbamate pesticides. Methylxanthines: Theophylline, 1,3-dimethylxanthine, caffeine. Other opioids: Buprenorphine, fentanyl. Toxic alcohols: Methanol, ethylene glycol, diethylene glycol. Caustics and other household products: Acidic or alkaline household products, hydrofluoric acid, selenious acid, acetonitrile, methylene chloride. Accidental overdoses continue to occur regularly despite the implementation of various safety measures, including widespread public education, the use of childproof containers, and easy access to poison control centers. In the US, poison control centers receive more than 2.4 million calls annually, with more than 50% involving children younger than 6 years. Most pediatric accidental ingestions involve household cleaning products and analgesics, followed by cosmetics, foreign objects, and dietary supplements. Adult overdoses may be unintentional but often involve larger total doses or high-risk medications, including opioids and sedative-hypnotics. America's Poison Centers identify the 5 most common substance classes as analgesics, household cleaners, antidepressants, cosmetic or personal care items, and cardiovascular drugs. The number of ingestions involving cleaning products increased sharply during the COVID-19 pandemic but has since declined.

Despite a global decline in incidence, leprosy remains a major public health concern, with India accounting for over 55% of cases worldwide, highlighting the unmet need to characterize hypothetical proteins of M. leprae as novel therapeutic targets against emerging drug-resistant strains. The three-dimensional homology structure and characteristics of ML0099 was predicted using an artificial intelligence-driven approach implemented through the AlphaFold 3 server and deepTHMM. Molecular docking with phospholipase substrates with different head moieties, coupled with large-scale virtual screening of ∼3600 FDA-approved drugs, was performed to identify promising therapeutic candidates followed by molecular dynamics analysis to validate the affinity for bound compounds. This study demonstrated that ML0099 is likely a member of the CULP protein family, containing an N-terminal signal peptide and a conserved pentapeptide motif (GxSxG), a hallmark of lipolytic enzymes. Structural analysis further identified conserved catalytic residues-Ser175, Asp268, and His299-forming a putative catalytic triad. The phosphatidyl-choline exhibited the most favourable substrate binding profile upon docking, predicting it's optimal enzymatic substrate. Virtual screening of FDA-approved compounds identified Zileuton and Glipizide as promising candidates, exhibiting binding energies of -8.5 to -9.1 kcal/mol along with stable interaction networks. Subsequent molecular dynamics simulations, MM-PBSA/GBSA and PCA analysis confirmed the stability of the protein-ligand complexes. Computational and AI-driven approaches demonstrated the potential biological role of ML0099 and identified the repurposed drugs Zileuton and Glipizide as promising inhibitors, providing a robust foundation for future experimental validation and therapeutic development.

Glipizide (GPZ), a biopharmaceutics classification system Class II antidiabetic drug with low aqueous solubility and a high melting point, presents challenges for fused deposition modeling (FDM) 3D printing due to the elevated processing temperatures commonly required. This study investigated low-temperature hot-melt extrusion (HME) and FDM 3D printing for the fabrication of personalized immediate-release GPZ tablets using vinylpyrrolidone-vinyl acetate copolymer (KVA64)-based filaments. GPZ-loaded filaments containing KVA64, mannitol (MAN), and triethyl citrate (TEC) were successfully prepared at 60 °C and printed at 90 °C. Among six formulations investigated, the filament composed of 12% w/w GPZ, 69% w/w KVA64, 10% w/w MAN, and 9% w/w TEC exhibited suitable flexibility, feedability, and moisture resistance. DSC, PXRD, and TGA findings were consistent with a partially amorphous GPZ dispersion containing residual crystalline domains, with no detectable thermal degradation under the processing conditions. A mixed-level factorial design was used to investigate the effects of infill pattern, number of shells, and layer thickness on GPZ release at 10 min. After Bonferroni adjustment for multiple comparisons, infill pattern, number of shells, and the infill pattern × layer thickness interaction remained statistically significant, whereas the main effect of layer thickness did not. Grid infill and fewer shells generally promoted faster drug release, while the effect of layer thickness depended on the infill architecture. Dose-adjusted tablets containing 5, 7.5, 10, and 15 mg GPZ were produced by modifying tablet thickness while maintaining a constant diameter. Thinner tablets exhibited faster dissolution because of their higher surface area-to-volume ratios. However, the 15 mg tablet did not meet the immediate-release dissolution criterion at 30 min, indicating that height-based scaling alone is insufficient for maintaining immediate-release performance at higher doses. These findings demonstrate the potential of low-temperature HME-FDM printing for personalized GPZ tablets while emphasizing the need to optimize both tablet geometry and internal architecture across the intended dose range.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) like semaglutide have transformed type 2 diabetes mellitus (T2DM) management, yet emerging concerns highlight potential risks of accelerated sarcopenia and subsequent metabolic disruptions. This case-driven hypothesis explores a 53-year-old male with T2DM diagnosed in 2014, who experienced progressive glycemic failure despite standard therapies, including metformin, glipizide, sitagliptin, and empagliflozin. Transition to dulaglutide 1.5 mg for 1.5 years followed by semaglutide (titrated from 0.25 to 1 mg weekly starting September 2024) resulted in weight loss from 84 kg to 70 kg by September 2025, accompanied by sarcopenic symptoms (muscle weakness, reduced mobility) and refractory hyperglycemia (fasting glucose 300 mg/dL, HbA1c 9%), persisting post-discontinuation on September 1, 2025, despite metformin and empagliflozin. We posit that semaglutide may precipitate acute sarcopenia via unexpected GLP-1R-mTOR-satellite cells axis crosstalk, disrupting AMPK-mTOR balance to suppress anabolic mTORC1/IGF-1 signaling (potentially by 25-35%) while enhancing catabolic FOXO/ubiquitin-proteasome and excessive autophagy pathways. This could extend to myokine reprogramming (elevated myostatin/GDF15, reduced irisin/IL-15), glucagon/α-cell compensation inducing hyperglucagonemia (15-25% rise), microbiome-bile acid shifts fostering low-grade inflammation (IL-6/TNF-α upregulation by 10-15%), mitochondrial mass reduction (20-25% via AMPK), and NMJ disassembly, collectively impairing muscle as the primary glucose sink (reducing GLUT4-mediated uptake by 35-45%) and initiating a «muscle-glucose feedback loop» with hepatic gluconeogenesis amplification, yielding treatment-resistant hyperglycemia.Supporting evidence from cohorts (e.g., 24-month study showing ASMI/grip strength declines in 432 patients), longitudinal analyses (NMJ degradation with CAF22/NfL elevations in 141 men), secondary trials (9.3% psoas volume loss in 51 MASLD cases), and case reports (fatigue in a 74-year-old, rhabdomyolysis in a 47-year-old) aligns with this framework, as does in vitro data linking GLP-1 excess to kinesin-1/GLUT4 inhibition and ATP depletion (20-30%). This novel hypothesis underscores sarcopenia's role in GLP-1RA-induced metabolic paradoxes, urging prospective studies on muscle-preserving interventions like resistance training or GLP-1R modulators to refine T2DM paradigms and inspire multidisciplinary research into endocrine-muscle interactions.

Sulfonylureas are a cornerstone of type 2 diabetes therapy despite interindividual variability in response. Despite well-documented sex-based differences, pharmacogenomic and genome-wide association studies (GWAS) have largely overlooked sex as a biological variable. We conducted the first sex-stratified GWAS of hemoglobin A1c (HbA1c) response to sulfonylureas in Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial participants (N = 871). Variants meeting genome-wide (P < 5.0 × 10[-8]) and suggestive (P < 5.0 × 10[-6]) significance were assessed for replication in the Pharmacogenomics of Metformin (PMET1) cohort. Replicated variants were further analyzed in the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) cohort to assess acute insulin and glucose responses to a single glipizide dose. Genome-wide significant loci with sex-specific effects were identified: KAZN, KIF2B, SLC39A10, and SPINK5 (combined-sex); CRACR2A, KCNK2, and TENM2 (male-only); and NACPH2 (female-only). Two suggestive variants in the TMEM64/NECAB1 locus, associated with reduced HbA1c response to sulfonylureas in the male-only ACCORD analysis, were directly replicated in the PMET1 male-only cohort. In SUGAR-MGH, one replicated variant (rs6471250-C) was significantly associated with reduced peak insulin in males (P = 0.035) but not females (P = 0.40), demonstrating sex-specific functional effects. This study identified statistically supported and biologically plausible loci with prior evidence linking nearby genes to pathways relevant to sulfonylurea action, including insulin secretion, insulin regulation/sensitivity, calcium signaling, potassium-channel biology, and glucose transport. The findings highlight sex-specific differences in sulfonylurea response, providing mechanistic insights and underscoring the importance of sex-specific precision medicine. Identification of genetic variants influencing sex-specific response could inform dosing to optimize sulfonylureas.

The glycemic response to metformin is highly variable, yet the genetic determinants of metformin pharmacokinetics remain poorly characterized. In the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), an ancestrally diverse cohort, we evaluated clinical and genetic factors associated with plasma metformin concentrations. Plasma metformin concentrations were measured in 745 participants who completed a standardized acute metformin challenge in SUGAR-MGH. Higher metformin concentrations were associated with older age (β=2.5 ng/mL per year, p = 0.02), lower eGFR (β=-3.5 ng/mL per ml/min/1.73m2, p = 4.5 × 10-4), and lower BMI (β=-7.3 ng/mL per kg/m2, p = 1.3 × 10-4). African ancestry was associated with lower metformin concentrations compared to European ancestry (β=-72.6 ng/mL, p = 0.036). A genome-wide association study (GWAS) identified four African ancestry-specific genetic variants significantly associated with higher metformin concentrations (p < 5 × 10-8) as well as several suggestive loci near genes implicated in glucose metabolism, including USP36 and DGKB. Top variants associated with metformin concentration were not associated with glycemic response endpoints following the metformin challenge, including fasting glucose at Visit 2, change in HOMA-IR, and change in fasting insulin between visits. Previously reported metformin transporter variants showed no significant associations with metformin concentration. These findings represent the first GWAS of metformin plasma concentrations and provide a novel resource for future studies of metformin pharmacogenetics.

Diabetes mellitus (DM) is one of the world's most common non-communicable diseases. DM is a group of metabolic disorders in which blood glucose levels increase due to reduced insulin production or action, resulting in hyperglycemia. Various anti-diabetic medications, including insulin, metformin, glimepiride, glipizide, and thiazolidinedione, are used to control hyperglycemia in diabetic patients. These anti-diabetic medications have been shown to affect the gingiva, bone, fibroblast cells, pulpal tissues, dental stem cells, saliva, teeth, and oral microbiome. Metformin (a biguanide), insulin, and oral sulfonylureas (glipizide and glimepiride) have regenerative and host-modulating effects. Metformin and insulin can promote the growth of osteoblasts (bone-forming cells) and periodontal ligament fibroblasts and enhance the differentiation of mesenchymal stem cells to repair the lost periodontal tissues. Metformin is used in both systemic and local forms as a gel or scaffolds along with periodontal therapy (scaling and root planing) and surgical procedures to promote repair of periodontal tissues, alveolar bone defects, furcation defects, and osseointegration of dental implants. Although the effect of metformin on oral tissues is well established, the role of other anti-diabetic drugs on the oral and periodontal tissues is not comprehensively discussed. Thus, this review aims to discuss the positive and negative effects of various anti-diabetic medications on the oral cavity.

Patients often suffer from hypertension, hyperlipidemia, and diabetes, requiring long-term polypharmacy. These drugs may alter gut microbiota composition, leading to adverse effects, but the underlying mechanisms are unclear. We selected 23 common drugs from ChEMBL, identified their metabolites via DrugBank, and used TargetNet and GeneCardsSuite to find drug targets and human proteins. Cross-analysis revealed 15 shared human side-effect protein targets. Molecular docking and Structure-activity relationship analyses assessed interactions with human and bacterial proteins. Eight compounds, including metabolites of amlodipine, metoprolol, glipizide, and fenofibrate, showed significant binding to human and gut bacterial proteins. Based on our in silico models, we predict that specific structural modifications could potentially enhance efficacy while minimizing microbial disruption and adverse reactions. Molecular dynamics simulations suggest that these modified drugs might computationally maintain therapeutic interactions while reducing gut microbiota disruption. Our findings highlight the impact of these drugs on gut microbiota and side effects via shared protein targets. Supported by in silico models and preliminary in vitro assays, we think that precision medicine, probiotic co-administration, or drug structure modifications could potentially serve as future strategies to mitigate complications and side effects in elderly patients, warranting further in vivo and clinical validation.

For prehospital providers, there are several causes for the patient with altered mental status or being unconscious to include the mnemonic AEIOU TIPS for Alcohol and acidosis, Endocrine, Epilepsy, Electrolytes, Encephalopathy, Infection, Opiates, Overdose, Uremia, Underdose, Trauma (head injury and blood loss), Insulin, Poisoning, Psychosis, Stroke, Seizure, and Syncope. Hypoglycemia, or low blood glucose level, is one of the most common causes of altered mental status for patients with and without diabetes. Estimates are that 1 to 2 percent of prehospital encounters and 7% of refusals are for hypoglycemia.[1][2] Diabetes mellitus often referred to as "diabetes" or "sugar" by laypeople is the most common endocrine disorder where the body does not either produce enough insulin or has a resistance to the circulating insulin, and is characterized by high blood sugar levels over prolonged periods. The three main types of diabetes are type I (previously referred to as insulin-dependent diabetes mellitus (IDDM) or juvenile-onset), type II (formerly referred to as non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset) and gestational.[3] Insulin is an anabolic hormone produced in the beta cells of the pancreatic islets. The primary function of insulin is to regulate the metabolism of carbohydrates, protein, and fat through the absorption of glucose sugar from the blood into the liver, fat, and skeletal muscle cells. These small glucose molecules are then converted into larger molecules and stored for later usage.  Type 1 Diabetes Mellitus (T1DM) [4] This condition is commonly referred to as insulin-dependent diabetes or previously as childhood/adolescent-onset diabetes. It accounts for approximately 5% to 10% of all cases of diabetes. It can be related to the autoimmune destruction of insulin-producing beta cells in the islets of the pancreas from different causes, including genetic susceptivity, viral illness, toxins or alcohol-induced pancreatitis, or some dietary factors.  The age group affected is usually children and adolescents, but adults can develop T1DM.  As the name "insulin-dependent" implies, it requires the administration of subcutaneous insulin via intermittent injections or pump infusion. Type 2 Diabetes Mellitus (T2DM) [4] [5] This variant is commonly referred to as non-insulin diabetes or previously as adult-onset diabetes.  It accounts for approximately 90% of all cases of diabetes.  It is related to the desensitization of insulin/insulin resistance (response to insulin becomes diminished) in various tissues. Initially, there is an increase in insulin production, but this decreases over time. T2DM most commonly presents in persons older than 45 years, but it increasingly occurs in children, adolescents, and younger adults due to rising levels of obesity, physical inactivity, and energy-dense diets. Gestational Diabetes Mellitus (GDM) Hyperglycemia first detected during pregnancy is classified as gestational diabetes mellitus (GDM). Although it can occur anytime during pregnancy, GDM generally affects pregnant women during the second and third trimesters. According to the American Diabetes Association (ADA), GDM complicates 7% of all pregnancies. Women with GDM and their offspring have an increased risk of developing type 2 diabetes mellitus in the future.  Types of Therapies [6] Therapy for hyperglycemia is dependant upon how much insulin the body is producing, or how well that insulin that is produced is working.  The majority of patients with T2DM will be on an oral type of medication.  Patients with T1DM will be on a combination of either long-acting insulin with short-acting as a sliding scale, intermediate-acting insulin with short-acting insulin as a sliding scale, combination premixed insulin, or be on an insulin pump. Hypoglycemia  One of the public health concerns for diabetes mellitus and unintended complications for the reduction in blood glucose levels is hypoglycemia.[1][7][8] Hypoglycemia, by definition, is a plasma glucose concentration below 70 mg/dL, with most patients not having signs or symptoms until the plasma glucose concentrations drop below 55 mg/dL.[9]  Low plasma glucose concentration that requires assistance from another individual qualifies as severe hypoglycemia, and by context, all EMS encounters fall into this category.[1][10]  There has been an increase in morbidity (poor quality of life, series falls or car accidents, dementia, and hospitalization) and mortality related to severe hypoglycemia.[1]  Based upon 2015 data from NEMSIS, prehospital activation for diabetes-related cases accounts for about 2.3% of all activations, with the primary EMS encounter being hypoglycemia.[11] Patients experiencing severe hypoglycemia or other diabetes-related concerns typically reach out for help by calling 911 who may dispatch a fire department or EMS agency depending on the jurisdiction. Care is then provided by the first on scene provider who may be an emergency medical technician (EMT) intermediate or advanced emergency medical technician (IEMT or AEMT) or paramedic. Treat and release versus transport of patients with hypoglycemia by EMS providers depends on the clinical guidelines or protocols from either the state or regional level by medical directors. It is important to understand that patients with severe hypoglycemia are at a higher risk of having complications related to the hypoglycemic state.  Villani et al. indicated that approximately 50% of patients with severe hypoglycemia required transport to the hospital, and of that group, 41.3% were admitted to the hospital.[12][13][14]  One of the first studies on the topic of treating and releasing hypoglycemic patients in the field was "Development and Evaluation of Criteria Allowing Paramedics to Treat and Release Patients Presenting with Hypoglycemia: A Retrospective Study" published in Prehospital and Disaster Medicine in 1991.   Their study design proposed five criteria that would allow for appropriate release that would not require additional treatment from prehospital providers to include: 1. The patient has a history of type 1 or type 2 diabetes. 2. Blood sugar prior to treatment is below 4.4 mmol/L or 80 mg/dL. 3. Blood sugar after treatment is equal to or greater than 4.4 mmol/L or 80 mg/dL. 4. The patient has a normal mental status within 10 minutes of treatment.  5. The patient does not have any other complicating factors that required ED evaluation to such alcohol, chest pain, dyspnea, injuries related to falls, and/or renal dialysis. A 2016 study by Rostykus et al. reviewed prehospital clinical guidelines for hypoglycemia in 185 EMS agencies in the United States.  It revealed that less than half allowed for non-transport of patients with hypoglycemia after the low plasma glucose level was corrected.[15] A study by Moffet et al. looked at hypoglycemic patients treated by EMS in Alameda County from 2013 to 2015 and found that the transport rate was 13.5%. The demographic trends for those non-transported patients were adult patients < 60 years of age, males, finger stick blood glucose levels > 60 mg/dl, and EMS arrival times between 1800 and 0600.[1]