Towards better antivenoms: navigating the road to new types of snakebite envenoming therapies.

Snakebite envenoming is a significant global health challenge, and for over a century, traditional plasma-derived antivenoms from hyperimmunized animals have been the primary treatment against this infliction. However, these antivenoms have several inherent limitations, including the risk of causing adverse reactions when administered to patients, batch-to-batch variation, and high production costs. To address these issues and improve treatment outcomes, the development of new types of antivenoms is crucial. During this development, key aspects such as improved clinical efficacy, enhanced safety profiles, and greater affordability should be in focus. To achieve these goals, modern biotechnological methods can be applied to the discovery and development of therapeutic agents that can neutralize medically important toxins from multiple snake species. This review highlights some of these agents, including monoclonal antibodies, nanobodies, and selected small molecules, that can achieve broad toxin neutralization, have favorable safety profiles, and can be produced on a large scale with standardized manufacturing processes. Considering the inherent strengths and limitations related to the pharmacokinetics of these different agents, a combination of them might be beneficial in the development of new types of antivenom products with improved therapeutic properties. While the implementation of new therapies requires time, it is foreseeable that the application of biotechnological advancements represents a promising trajectory toward the development of improved therapies for snakebite envenoming. As research and development continue to advance, these new products could emerge as the mainstay treatment in the future.

Pulmonary involvement from animal toxins: the cellular mechanisms.

Venomous animals and their venom have always been of human interest because, despite species differences, coevolution has made them capable of targeting key physiological components of our bodies. Respiratory failure from lung injury is one of the serious consequences of envenomation, and the underlying mechanisms are rarely discussed. This review aims to demonstrate how toxins affect the pulmonary system through various biological pathways. Herein, we propose the common underlying cellular mechanisms of toxin-induced lung injury: interference with normal cell function and integrity, disruption of normal vascular function, and provocation of excessive inflammation. Viperid snakebites are the leading cause of envenomation-induced lung injury, followed by other terrestrial venomous animals such as scorpions, spiders, and centipedes. Marine species, particularly jellyfish, can also inflict such injury. Common pulmonary manifestations include pulmonary edema, pulmonary hemorrhage, and exudative infiltration. Severe envenomation can result in acute respiratory distress syndrome. Pulmonary involvement suggests severe envenomation, thus recognizing these mechanisms and manifestations can aid physicians in providing appropriate treatment.

Transient depersonalisation/derealisation syndrome from tramadol.

Depersonalisation/derealisation (DD) syndrome is often associated with severe traumatic experiences and the use of certain medications. Our patient reported experiencing a transient DD phenomenon a few hours after taking 37.5 mg of tramadol, together with etoricoxib, acetaminophen and eperisone. His symptoms subsided upon tramadol discontinuation, suggesting the possibility of tramadol-induced DD. A study of the patient's cytochrome P450 (CYP) 2D6 polymorphism, which mainly metabolises tramadol, indicated normal metaboliser status with reduced function. The concomitant administration of the CYP2D6 inhibitor, etoricoxib, would have led to higher concentrations of the serotonergic parent tramadol, providing an explanation for the patient's symptoms.

Cannabis and adverse cardiovascular events: A systematic review and meta-analysis of observational studies.

Background: Cannabis is the most used illicit drug in the world. Global trends of decriminalization and legalization of cannabis lead to various forms of cannabis use and bring great concerns over adverse events, particularly in the cardiovascular (CV) system. To date, the association between cannabis and adverse CV events is still controversial. Purpose: We aim to conduct a systematic review and meta-analysis to assess the adverse CV events from cannabis use. Patients and methods: A systematic search for publications describing the adverse CV events of cannabis use, including acute myocardial infarction (MI) and stroke, was performed via PubMed, Scopus, and Cochrane Library databases. Data on effect estimates in individual studies were extracted and combined via random-effects meta-analysis using the DerSimonian and Laird method, a generic inverse-variance strategy. Results: Twenty studies with a total of 183,410,651 patients were included. The proportion of males was 23.7%. The median age and follow-up time were 42.4 years old (IQR: 37.4, 50.0) and 6.2 years (IQR: 1.7, 27.7), respectively. The prevalence of cannabis use was 1.9%. Cannabis use was not significantly associated with acute MI (pooled odds ratio (OR): 1.29; 95%CI: 0.80, 2.08), stroke (pooled OR 1.35; 95%CI: 0.74, 2.47), and adverse CV events (pooled OR: 1.47; 95%CI: 0.98, 2.20). Conclusion: The risk of adverse CV events including acute MI and stroke does not exhibit a significant increase with cannabis exposure. However, caution should be exercised when interpreting the findings due to the heterogeneity of the studies.

Pulmonary involvement from animal toxins: the cellular mechanisms

Abstract Venomous animals and their venom have always been of human interest because, despite species differences, coevolution has made them capable of targeting key physiological components of our bodies. Respiratory failure from lung injury is one of the serious consequences of envenomation, and the underlying mechanisms are rarely discussed. This review aims to demonstrate how toxins affect the pulmonary system through various biological pathways. Herein, we propose the common underlying cellular mechanisms of toxin-induced lung injury: interference with normal cell function and integrity, disruption of normal vascular function, and provocation of excessive inflammation. Viperid snakebites are the leading cause of envenomation-induced lung injury, followed by other terrestrial venomous animals such as scorpions, spiders, and centipedes. Marine species, particularly jellyfish, can also inflict such injury. Common pulmonary manifestations include pulmonary edema, pulmonary hemorrhage, and exudative infiltration. Severe envenomation can result in acute respiratory distress syndrome. Pulmonary involvement suggests severe envenomation, thus recognizing these mechanisms and manifestations can aid physicians in providing appropriate treatment.

Towards better antivenoms: navigating the road to new types of snakebite envenoming therapies

Abstract Snakebite envenoming is a significant global health challenge, and for over a century, traditional plasma-derived antivenoms from hyperimmunized animals have been the primary treatment against this infliction. However, these antivenoms have several inherent limitations, including the risk of causing adverse reactions when administered to patients, batch-to-batch variation, and high production costs. To address these issues and improve treatment outcomes, the development of new types of antivenoms is crucial. During this development, key aspects such as improved clinical efficacy, enhanced safety profiles, and greater affordability should be in focus. To achieve these goals, modern biotechnological methods can be applied to the discovery and development of therapeutic agents that can neutralize medically important toxins from multiple snake species. This review highlights some of these agents, including monoclonal antibodies, nanobodies, and selected small molecules, that can achieve broad toxin neutralization, have favorable safety profiles, and can be produced on a large scale with standardized manufacturing processes. Considering the inherent strengths and limitations related to the pharmacokinetics of these different agents, a combination of them might be beneficial in the development of new types of antivenom products with improved therapeutic properties. While the implementation of new therapies requires time, it is foreseeable that the application of biotechnological advancements represents a promising trajectory toward the development of improved therapies for snakebite envenoming. As research and development continue to advance, these new products could emerge as the mainstay treatment in the future.

Suicidal attempts and self-poisoning: 1-year retrospective cohort study from the quaternary hospital in Thai metropolitan area.

Background and Aims: In Thailand, suicide is the leading cause of death among middle-aged adults. We believe suicide characteristics depend on different cultural/socioeconomic status. This study aimed to describe the characteristics and associated factors of suicidal attempts by self-poisoning in Bangkok, the metropolitan city of Thailand. Methods: Records of all patients visiting the emergency department of King Chulalongkorn Memorial Hospital, Bangkok, Thailand, with self-poisoning suicidal attempts throughout 2021 were collected and analyzed. Results: Self-poisoning accounted for 110 attempts (by 74 patients). Females aged 11-30 were the most prevalent group. Pharmaceutical agents were commonly used. Most patients (86.4%) had underlying psychiatric illness(es), mostly major depressive disorder. Female, history of psychiatric illness and follow-ups, personality comorbid, and previous attempts reached statistical significance by univariate regression for factors associated with reattempting suicide, but only personality comorbid was significant from multivariable study (p = 0.02). Reattempting mostly recurred within 8 days after the prior attempt. Conclusion: Majority of self-poisoned patients in Bangkok were young adults taking medications, which differs from the overall Thai population where most instances involve patients of older patients (30-50 years) and ingestion of agricultural substances. Appropriate strategies are needed for specific psychosocial/socioeconomic contexts and within the critical period after previous nonfatal attempts.

Alprazolam and lorazepam overdose and the absence of brainstem reflexes.

Benzodiazepines (BZDs) rarely cause respiratory depression and death. On the other hand, high-dose BZDs may lead to profound sedation and diminished brainstem functions that mimic other structural brain lesions as described in our case: a 70-year-old unresponsive woman. She was hypothermic and had rapid shallow breathing. Her Glasgow Coma Scale score was E1V1M4, with pinpoint pupils and absent corneal, oculocephalic and oculovestibular reflexes. Other physical exams, laboratory testing and brain imaging were unremarkable. After two doses of 0.4 mg naloxone and intravenous thrombolytics were given, there were no significant responses, and the diagnosis remained a mystery. The cause of her unconsciousness was uncovered when her husband found empty bags of 80 tablets of alprazolam and lorazepam. Her consciousness and brainstem reflexes improved dramatically after 0.25 mg of intravenous flumazenil. The blood for BZDs concentration showed alprazolam 268 ng/mL (20-40 ng/mL), lorazepam 861 ng/mL (20-250 ng/mL) and their metabolites.

Malayan Pit Viper Envenomation and Treatment in Thailand.

INTRODUCTION: The Malayan pit viper (MPV; Calloselasma rhodostoma) is a hematotoxic snake found in all regions of Thailand and many countries in Southeast Asia. Treatment of MPV envenomation varies among facilities due to their capabilities. MATERIALS AND METHODS: This study was a retrospective review of patients with MPV envenomation who were reported to the Ramathibodi Poison Center from 1 July 2016 to 30 June 2018. RESULTS: Of the 167 patients (median age, 40.5 years; range, 1.3-87.0 years) bitten by an MPV, the most common bite site was the foot (29.3%). Most patients reached the hospital within 1 hour of being bitten. One-hundred fifty-six patients (93.4%) had local effects from envenomation; 17 patients (10.2%) had severe local complications including necrotizing fasciitis (3.0%) and compartment syndrome (7.2%). Systemic effects such as hemorrhage and abnormal hemostasis occurred in 147 patients (88.0%). Additional effects included abnormal venous clotting time in 123 patients (73.7%), unclotted 20-minute whole blood clotting time in 57 patients (34.1%), low platelet counts (<50,000/µL) in 29 patients (17.4%), prolonged international normalized ratio (>1.2) in 51 patients (30.5%), and systemic bleeding in 14 patients (8.4%). The median onset of bleeding disorder was 6 hours. Monitoring for 24, 48, and 49 hours after bite enabled detection of systemic effects in 94.2%, 99.3%, and 100.0%, respectively. Three hundred fifteen courses of antivenin were administered to 144 patients (86.2%). All the patients who received antivenin recovered from bleeding disorder. Only 7.0% of antivenin doses were administered without Thai Red Cross indications. Allergic reactions from antivenin occurred in 34.7% of the 144 patients. One hundred thirty patients (77.8%) received antibiotics, and 32 patients (19.2%) required surgical management, including debridement and fasciotomy. CONCLUSION: MPV envenomation results in local and systemic effects. Most systemic effects were abnormal clotting test results. Most patients reported onset of bleeding disorder within 48 hours.

Escitalopram, bupropion, lurasidone, lamotrigine and possible vortioxetine overdose presented with serotonin syndrome and diffuse encephalopathy: A case report.

BACKGROUND: Psychotropic drugs can cause neurological effects when overdosed. This study reports a case of psychotropic drugs overdose presenting with serotonin toxicity and encephalopathy. CASE PRESENTATION: A 20-year-old female with major depression presented with agitation 3 h after an overdose on multiple medications. Her current medications were vortioxetine, lamotrigine, lurasidone, and bupropion (extended-release). Vital signs showed hyperthermia and tachycardia. Neurological examination was remarkable for mydriasis and hyperreflexia with inducible ankle clonus. The electrocardiography showed sinus tachycardia with QTc 480 ms. Twelve hours later, she became obtunded and developed subcortical myoclonus. The electroencephalogram demonstrated a diffuse encephalopathy pattern without epileptic activities. She was diagnosed with serotonin syndrome based on Hunter Serotonin Toxicity Criteria. Myoclonus and abnormal vital signs resolved within hours after cyproheptadine administration, but she remained unconscious for 3.5 days. Urine drug screening was positive for benzodiazepines and metabolites, lamotrigine, escitalopram, and hydroxybupropion. This suggested she had overdosed on escitalopram which had been previously prescribed. Unfortunately, vortioxetine and lurasidone could not be detected by our current facilities. CONCLUSION: This case exhibited serotonin syndrome and encephalopathy from overdose of multiple psychotropic agents. Her prolonged depressed consciousness could be explained by the half-life of the drugs and possible drug interactions.

Poisoning of glutaraldehyde-containing products: clinical characteristics and outcomes.

OBJECTIVE: This study describes the clinical characteristics, outcomes, and factors at presentation associated with death of cases poisoned by glutaraldehyde (GA)-containing products. METHODS: We performed a 5-year retrospective cohort study (July 2013-June 2018) using data from the Ramathibodi Poison Center. RESULTS: There were 244 cases included in this study. Most were men with a median age of 37 years. The GA-containing products were mainly used as farm disinfectants (99.2%), with a median concentration of 15%. Most products (76.2%) contained co-formulants such as cationic detergents and formaldehyde.Most circumstances were accidental (56.9%). The others were suicide attempts by ingestion, except one patient who intentionally injected GA subcutaneously. The most common route of exposure was ingestion (95.0%). Local symptoms in areas of exposure were common. Ingestion resulted in more severe local effects than other routes, and corrosive effects occurred in 23 cases (9.4%). Systemic signs and symptoms occurred in 149 patients (61.1%). Systemic effects included abnormal vital signs, desaturation, altered mental status, hypo/hypernatremia, hypokalemia, low bicarbonate/metabolic acidosis, acute kidney injury (AKI), hepatitis, and rhabdomyolysis. Systemic effects mostly resulted from ingestion. Most patients had mild severity, received only supportive treatment, and fully recovered. The median length of hospital stay was 2 days. The one case of subcutaneous injection developed both local and systemic effects but survived. The mortality rate was 3.7%. Multivariate analysis indicated that either neurological symptoms or AKI at presentation were associated with death. CONCLUSIONS: In our study, patients were exposed to GA-containing products that were mainly used as farm disinfectants and were generally co-formulated with other substances. Poisoning with these products commonly resulted in mild local irritative symptoms. However, some cases developed corrosive symptoms, systemic effects, or even died. As neurological symptoms or AKI could prognosticate deaths; physicians should look for these factors in patients with GA exposure at presentation for close monitoring and aggressive treatment.

Hematotoxic Manifestations and Management of Green Pit Viper Bites in Thailand.

INTRODUCTION: Green pit vipers (GPV) are widely distributed throughout Thailand and are responsible for significant morbidity. The primary objective of this study was to characterize clinical presentations and treatment methods for GPV bites. The secondary objective was to demonstrate the earliest and latest onset of hematotoxicity. METHODS: GPV bites reported to the Ramathibodi Poison Center between July 1, 2016, and June 30, 2018, were analyzed. RESULTS: There were 288 GPV cases within the study period. Patients were predominantly male (62.8%), and the median age was 40 years (interquartile range (IQR) 22.8-58). Median time from envenomation to hospital presentation was 1 hour (IQR 0.5-2). Patients were primarily bitten on the finger (27.4%). Most patients reported swelling (90.3%). Necrosis and compartment syndrome occurred in 13 and 9 cases, respectively. Systemic effects occurred in 190 cases (65.9%), with median onset 15 hours (IQR 6-28.3) post-bite. Venous clotting time (VCT) showed the highest percentage of abnormalities. Systemic bleeding occurred in 13 cases (4.5%). Monitoring patients for 24, 48, and 72 hours after bites detected 62.7%, 85.9%, and 96.5% of cases with systemic effects, respectively. In total, 184 patients (62.5%) were treated, sometimes repeatedly, with antivenoms (285 courses, 949 vials). The most common indication was prolonged VCT (144 courses, 50.5%). Recurrent systemic effects after antivenom occurred in 11 cases (6.1% of patients received antivenom). No recurrence presented as systemic bleeding. Adverse reactions to antivenom were reported in 44 courses (15.4% of 285 courses), being anaphylaxis in 19 courses (6.7%). Other treatments included antibiotics (192 cases, 66.7%), surgical intervention (10, 34.7%), and blood components (4, 1.4%). CONCLUSION: Most GPV bites result in envenomation. The most frequent local effect is mild swelling. Systemic bleeding is uncommon. The current recommendation of a 3-day follow-up can detect up to 96% of patients who may require antivenom. No severe morbidity or mortality is reported. Antivenoms are primarily indicated by prolonged VCT. Side effects of antivenom are minimal.

Complex regional pain syndrome following a centipede bite: a case report.

Context: Complex Regional Pain Syndrome (CRPS) is a chronic neuropathic pain condition associated with autonomic features. To date, the development of CRPS following centipede bite has not been reported. We report a case of CRPS likely secondary to a centipede bite.Case details: A 31-year-old female was bitten by a centipede on the right 2nd toe. She was initially treated with analgesics, and two weeks later developed severe pain, allodynia, pruritus, and edema of the right foot, with hyperpigmentation over the affected toe. The X-ray, ultrasound, electromyography, nerve conduction velocity studies of the foot, blood chemistries, and erythrocyte sedimentation rate showed no abnormalities. The patient was diagnosed with CRPS type 1 by fulfilling the Budapest criteria. She was treated with gabapentin, amitriptyline, desloratadine, and fluoxetine, along with physical rehabilitation. Clinical symptoms gradually improved, and resolved at approximately 9 months with persistent hyperpigmentation.Discussion: Centipede bite may be an eliciting event for CRPS. It is unknown whether direct bite trauma or envenomation was the primary etiology in this case. Awareness of this condition is important for early diagnosis and appropriate management.

Association of adiponectin gene polymorphisms with knee osteoarthritis.

AIM: To investigate the possible relationship of adiponectin (ADIPOQ) gene polymorphisms, plasma adiponectin, and the risk of knee osteoarthritis (OA). METHODS: A total of 398 subjects, 202 knee OA patients and 196 healthy individuals, were enrolled in the case-control study. Genotyping at +45T/G (rs2241766) and +276G/T (rs1501299) loci was performed using polymerase chain reaction-restriction fragment length polymorphism. Plasma adiponectin levels were assessed using enzyme-linked immunosorbent assay. OA severity was determined using the Kellgren-Lawrence (KL) grading system. RESULTS: No significant associations were observed in the genotype distributions and allele frequencies at two loci of +45T/G and +276G/T polymorphisms in the ADIPOQ between knee OA patients and control subjects. There was a significant association between genotype distribution of +276G/T polymorphism and KL grade 2, 3 or 4 (P = 0.037, P = 0.046, P = 0.016, respectively). At +45T/G locus, the percentage of GG genotype was notably greater in control subjects (13.40%) compared with OA subjects (1.70%) (P = 0.023). Plasma adiponectin was markedly decreased in OA subjects compared with control subjects (P = 0.03). Likewise, circulating adiponectin in OA subjects was notably lesser than that in control subjects in GG genotype of +45T/G (P = 0.029) and +276G/T polymorphisms (P = 0.012). CONCLUSION: Polymorphisms +45T/G and +276G/T of the ADIPOQ gene might not be responsible for OA susceptibility among Thais.