Single-dose nonsteroidal anti-inflammatory drugs in horses have no impact on concentrations of cytokines or growth factors in autologous protein solution and platelet-rich plasma.

OBJECTIVE: To determine the effects of a single dose of the NSAIDs phenylbutazone, firocoxib, flunixin meglumine, and ketoprofen on concentrations of growth factors and cytokines in autologous protein solution (APS) and platelet-rich plasma (PRP). ANIMALS: 6 adult university-owned horses. METHODS: For the first phase, 6 horses were randomized to receive ketoprofen (1,000 mg) or flunixin meglumine (500 mg) IV. Blood was obtained and processed for APS (Pro-Stride) and PRP (Restigen) before and 6 hours after administration of NSAIDs. Horses underwent a 2-week washout period, after which the protocol was repeated using a crossover design. For the second phase, following at least a 2-week washout period, the study protocol was repeated with phenylbutazone (1 g) or firocoxib (57 mg) administered orally. Plasma was collected 6 hours after administration for evaluation of drug concentrations, and APS and PRP were analyzed for concentrations of drug, platelets, leukocytes, and several growth factors and cytokines (PDGF, fibroblast growth factor, TGF-ß1, IL-1ß, IL-10, IL-6, IL-8, and tumor necrosis factor-α) before and 6 hours after administration of NSAIDs using immunoassays. RESULTS: There were no significant differences in concentrations of cytokines or growth factors before or after administration of any NSAID. There were significant differences in concentrations of leukocytes and platelets based on both product and time. NSAID concentrations in plasma were not significantly different from concentrations in APS and PRP. CLINICAL RELEVANCE: These results help guide clinicians on the appropriate use of these NSAIDs in conjunction with the processing of APS and PRP, which is unlikely to significantly alter the final product after single-dose administration.

[A case of severe rhabdomyolysis after γ-butyrolactone withdrawal].

γ-butyrolactone is a colorless transparent liquid used in the production of drugs such as cyclopropylamine and pyrrolidone, and is also used as an industrial solvent, diluent, curing agent, etc., and is listed as the third category of precursor chemicals control. There is less clinical exposure to γ-butyrolactone and insufficient studies on its withdrawal response. This article reports a case of severe life-threatening rhabdomyolysis in a patient with γ-butyrolactone withdrawal. After active treatment, the patient eventually recovered. The clinical characteristics and treatment methods of γ-butyrolactone withdrawal reaction were summarized, suggesting that severe withdrawal reaction may occur in γ-butyrolactone.

Clinical effect of ethanol co-use in patients with acute drug toxicity involving the use of central nervous system depressant recreational drugs.

BACKGROUND AND IMPORTANCE: Patients who use recreational drugs frequently co-ingest ethanol, which is considered a central nervous system (CNS) depressant. The clinical relevance of this in acute toxicity involving other CNS depressants is not well described. OBJECTIVE: To assess the clinical impact of ethanol co-use in patients presenting to the emergency department (ED) with acute toxicity involving the use of CNS depressant drugs. DESIGN, SETTINGS AND PARTICIPANTS: A retrospective multicentre study using data from the Euro-DEN Plus database from January 2014 to December 2019. OUTCOMES MEASURE AND ANALYSIS: Comparison of epidemiologic and clinical characteristics, ED and hospital management of patients with CNS depressant intoxication with or without ethanol co-use. MAIN RESULTS: Although 7644 (17.5%) of the 43 633 presentations were included, ethanol was co-ingested in 3811 (49.9%). In total 53.3% required medical treatment, 14 patients died. Patients with ethanol co-use more frequently presented with a Glasgow Coma Scale (GCS) ≤8 (34.1% vs. 22.4%; P < 0.001), vomiting (8.1% vs. 4.6%; P < 0.001), anxiety (12 % vs. 6.4%; P < 0.001), agitation/aggression (22% vs. 14.7%; P < 0.001), seizures (3.8% vs. 2.4%; P < 0.001) and hypotension (7.5% vs. 4.6%; P < 0.001). They more often required ambulance transport (85.5% vs. 76.5%; P < 0.001), medical treatment (57.3% vs. 48.0%; P < 0.001), hospitalization (27.7% vs. 18.9%; P < 0.001), and admission to intensive care (12.2% vs. 4.0%; P < 0.001). Subgroup analysis showed that GCS ≤8 was particularly common in patients who combined ethanol with opioids or gamma-hydroxybutyrate (GHB)/gamma-butyrolactone (GBL). CONCLUSION: Co-use of ethanol with CNS-depressant drugs appears to increase the risk of adverse effects and is associated with a higher need for medical treatment, especially when ethanol is combined with opioids or GHB/GBL.

Cutaneous adverse drug reaction in a dog following firocoxib treatment.

A 9-year-old intact female toy poodle was presented with oedema around the neck, including pus and cutaneous necrosis, 2 days after starting firocoxib treatment and placement of a cervical collar for intervertebral disc disease. Cytology of the pus revealed predominantly mature neutrophils with fewer macrophages and lymphocytes, indicating sterile inflammation. Although a skin biopsy could have provided more diagnostic information, it was not performed at presentation. Firocoxib treatment was discontinued, and immunosuppressive therapy including cyclosporine was initiated, which significantly alleviated the skin lesions. The dog recovered fully in 7 weeks. The final diagnosis was a possible cutaneous adverse drug reaction to firocoxib based on history, clinical signs and response to therapy.

Characteristics of patients with analytically confirmed γ-hydroxybutyric acid/γ-butyrolactone (GHB/GBL)-related emergency department visits in Taiwan.

The recreational drug γ-hydroxybutyric acid (GHB) is a central nervous system depressant, and can produce euphoria at low doses. GHB is a controlled substance in Taiwan. However, the organic solvents γ-butyrolactone (GBL) and 1,4-butanediol (BD), which are unregulated, may be used as an alternative source of GHB. There is no clinical report of analytically confirmed GHB use in Taiwan. We retrospective reviewed the clinical characteristics from the medical charts between May 2017 and April 2020. The urine samples of patients presented to the emergency departments with drug-related complaints were sent for toxicological analysis. Patients with urine samples detected GHB >10 µg/mL by liquid chromatography/tandem mass spectrometry were included. Overall, 11 men and one woman with an average age of 35.3 ± 8.7 years were included. Most patients co-ingested amphetamine (n = 6) and initially presented with depressed consciousness levels (n = 7). One patient presented with out-of-hospital cardiac arrest and one with respiratory depression. All patients regained consciousness within 6 h of admission. All patients used GBL to evade conviction. Although patients recovered with supportive care, respiratory failure and cardiac arrest occurred after GHB/GBL use. It is important to legislate GBL and BD as controlled chemical substances in Taiwan.

Allergic Contact Dermatitis-Induced Stereospecificity.

Frequent allergens are known, but not whether allergens are enantiomer specific. Chemicals were tested on guinea pigs and humans to answer this question. Frullanoides showed evident allergic enantiospecificity, whereas the conclusion was shaded for α-methylene-γ-butyrolactone. A link between this chemical and chronic actinic dermatitis was proposed. No clear tendency to enantio-stereospecificity in inducing allergic contact dermatitis was ascertained. Future studies using contemporary analytical chemistry and new immunologic knowledge have to be undertaken to provide clearer mechanistic insights. This information may aid in attempts to decrease product allergenicity.

Effects of Nosema ceranae (Dissociodihaplophasida: Nosematidae) and Flupyradifurone on Olfactory Learning in Honey Bees, Apis mellifera (Hymenoptera: Apidae).

The health of insect pollinators, particularly the honey bee, Apis mellifera (Linnaeus, 1758), is a major concern for agriculture and ecosystem health. In response to mounting evidence supporting the detrimental effects of neonicotinoid pesticides on pollinators, a novel 'bee safe' butenolide compound, flupyradifurone (FPF) has been registered for use in agricultural use. Although FPF is not a neonicotinoid, like neonicotinoids, it is an excitotoxic nicotinic acetylcholine receptor agonist. In addition, A. mellifera faces threats from pathogens, such as the microsporidian endoparasite, Nosema ceranae (Fries et al. 1996). We therefore sought 1) to increase our understanding of the potential effects of FPF on honey bees by focusing on a crucial behavior, the ability to learn and remember an odor associated with a food reward, and 2) to test for a potential synergistic effect on such learning by exposure to FPF and infection with N. ceranae. We found little evidence that FPF significantly alters learning and memory at short-term field-realistic doses. However, at high doses and at chronic, field-realistic exposure, FPF did reduce learning and memory in an olfactory conditioning task. Infection with N. ceranae also reduced learning, but there was no synergy (no significant interaction) between N. ceranae and exposure to FPF. These results suggest the importance of continued studies on the chronic effects of FPF.

Field rates of Sivanto™ (flupyradifurone) and Transform® (sulfoxaflor) increase oxidative stress and induce apoptosis in honey bees (Apis mellifera L.).

Pesticide exposures can have detrimental impacts on bee pollinators, ranging from immediate mortality to sub-lethal impacts. Flupyradifurone is the active ingredient in Sivanto™ and sulfoxaflor is the active ingredient in Transform®. They are both relatively new insecticides developed with an intent to reduce negative effects on bees, when applied to bee-attractive crops. With the growing concern regarding pollinator health and pollinator declines, it is important to have a better understanding of any potential negative impacts, especially sub-lethal, of these pesticides on bees. This study reports novel findings regarding physiological stress experienced by bees exposed to field application rates of these two insecticides via a Potter Tower sprayer. Two contact exposure experiments were conducted-a shorter 6-hour study and a longer 10-day study. Honey bee mortality, sugar syrup and water consumption, and physiological responses (oxidative stress and apoptotic protein assays) were assessed in bees exposed to Sivanto™ and Transform®, and compared to bees in control group. For the longer, 10-day contact exposure experiment, only the Sivanto™ group was compared to the control group, as high mortality recorded in the sulfoxaflor treatment group during the shorter contact exposure experiment, made the latter group unfeasible to test in the longer 10-days experiment. In both the studies, sugar syrup and water consumptions were significantly different between treatment groups and controls. The highest mortality was observed in Transform® exposed bees, followed by the Sivanto™ exposed bees. Estimates of reactive oxygen/nitrogen species indicated significantly elevated oxidative stress in both pesticide treatment groups, when compared to controls. Caspase-3 protein assays, an indicator of onset of apoptosis, was also significantly higher in the pesticide treatment groups. These differences were largely driven by post exposure duration, indicating sub-lethal impacts. Further, our findings also emphasize the need to revisit contact exposure impacts of Sivanto™, given the sub-lethal impacts and mortality observed in our long-term (10-day) contact exposure experiment.

Safety of withholding intubation in gamma-hydroxybutyrate- and gamma-butyrolactone-intoxicated coma patients in the emergency department.

OBJECTIVE: The objective of this study was to determine if supportive care without endotracheal intubation in the emergency department (ED) was safe in the absence of complications in gamma-hydroxybutyrate (GHB)/gamma-butyrolactone (GBL) intoxicated patients with a decreased Glasgow Coma Scale (GCS) score. METHODS: This was a retrospective chart review of patients presenting to a Dutch tertiary urban ED with a reduced level of consciousness related to alleged GHB/GBL intoxication between April 2011-December 2014. Primary endpoint was major adverse events, defined by: upper airway obstruction not resolved with mayo tube or nasopharyngeal airway, hypoxia not resolved with 15 l of oxygen delivered via non-rebreathing mask, bradypnea not resolved after stimulation, intubation, bradycardia not resolved after intravenous atropine bolus, hypotension for which inotropes were started. RESULTS: Data of 209 patients were retrieved. Major adverse events were reported in five patients (2.4%; 95% CI: 0.8-5.5). Intubation with subsequent ICU admission was required for 1.4% of patients (95% CI: 0.3-4.1). The most frequently seen minor adverse events (N = 209) were: airway obstruction (22%), hypothermia (14.8%), hypoxia (12.9%), bradycardia (8.1%), hypotension (6.7%), bradypnea (5.7%), vomiting (5.3%). There were no deaths. None of the patients had signs of aspiration pneumonia or returned to our ED due to complications. CONCLUSION: Our study suggests that conservative airway management for patients with a decreased GCS due to suspected GHB intoxication may be safe. Major adverse events were present in 2.4% of patients, only 1.4% of patients required intubation. All minor adverse events were managed effectively with conservative treatment.

Transient Fanconi Syndrome After Treatment with Firocoxib, Cefadroxil, Tramadol, and Famotidine in a Maltese.

Fanconi syndrome is a renal proximal tubulopathy characterized by excessive urinary loss of glucose, amino acids, several electrolytes, and bicarbonate. Here, we report the case of transient Fanconi syndrome in a dog following administration of firocoxib, cefadroxil, tramadol, and famotidine. A 10 mo old Maltese was presented with lethargy, anorexia, vomiting, and weight loss. Transient Fanconi syndrome without azotemia was associated with firocoxib, cefadroxil, tramadol, and famotidine treatment. The dog received supportive care including IV fluids, gastroprotectants, and oral nutritional supplements. Two months after initial diagnosis and treatment, the dog showed complete resolution of glucosuria and aminoaciduria. The unique features of Fanconi syndrome in this case emphasize the potential renal tubular toxicity of this widely used multiple-drug combination.

Inpatient management of GHB/GBL withdrawal.

BACKGROUND: Gamma-hydroxybutyrate (GHB) and its precursor gamma-butyrolactone (GBL) are popular drugs of abuse used for their euphoric, (potential) anabolic, sedative, and amnestic properties. Daily use of GHB/GBL can lead to addiction and the possibility of withdrawal syndrome on cessation which results in tremor, tachycardia, insomnia, anxiety, hypertension, delirium, coma. AIM: To describe the baseline characteristics, treatment and retention in patients admitted for GHB/GBL withdrawal management. METHODS: A retrospective review of 4 consecutive cases of patients reporting GHB/GBL addiction who were admitted for inpatient management of withdrawal syndrome. RESULTS: All patients were using GHB/GBL daily, 1-1.5 ml per hour. One of them was using cannabis additionally, others were using alcohol, cocaine and amphetamine type stimulants. Psychiatric comorbidities as personality disorders, depression, anxiety and bigorexia were recognized. Patients were treated with benzodiazepines and/or clomethiazole, atypical and typical antipsychotics and beta-blockers. Delirium was developed in two patients. One patient completed detoxification and finished the treatment program. One patient completed detoxification but stopped his treatment earlier, two patients did not completed detoxification and left the program. CONCLUSION: GHB/GBL withdrawal can be severe and retention in program is poor. Polysubstance use, psychiatric co-morbidities and heavier GHB/GBL use as possible predictors of poor treatment outcome need consideration in treatment planning.

Clinical relevance of ethanol coingestion in patients with GHB/GBL intoxication.

OBJECTIVE: Ethanol intake can increase the sedative effects of gamma-hydroxybutyrate/gamma-butyrolactone (GHB/GBL), although the real clinical impact is unknown. We studied the clinical impact of the co-ingestion of ethanol in patients presenting to the Emergency Department (ED) with acute toxicity related to GHB/GBL use. METHOD: We performed a secondary analysis of the Euro-DEN Plus Registry (14 countries, 22 EDs) which includes 17,371 consecutive patients presenting to the ED with acute recreational drug toxicity over 39 consecutive months (October 2013 - December 2016). We compared the epidemiological and clinical characteristics and ED management of patients identified as presenting with acute toxicity related to lone GHB/GBL (Group A) or GHB/GBL combined with ethanol (Group B) without other concomitant drugs. RESULTS: A total of 609 patients were included (age 32 (8) years; 116 women (19%); Group A: 183 patients and Group B: 426). The most common features were reduction in consciousness (defined as Glasgow Coma Score <13 points: 56.1%) and agitation/aggressiveness (33.6%). Those with ethanol co-ingestion were younger patients (Group A/B: 31.5/33.1 years, p = 0.029) and ethanol co-ingestion was associated with a lower frequency of bradycardia (23.5%/15.7%, p = 0.027) and more frequent arrival at the ED by ambulance (68.3/86.6%; p < 0.001), reduction in consciousness (58.9%/49.1%; p = 0.031), need for treatment in the ED (49.2%/60.4%; p = 0.011), use of sedatives (20.1%/12.8%; p = 0.034), admission to critical care units (22.4%/55.3%; p < 0.001), and longer hospital stay (stay longer than 6 h: 16.9%/28.4%; p = 0.003). CONCLUSIONS: Co-ingestion of ethanol increases the adverse effects of patients intoxicated by GHB/GBL, leading to greater depression of consciousness, need for treatment, admission to the ICU and longer hospital stay.

Effects of spirodiclofen on life history traits and population growth of a spider mite predator Oligota flavicornis (Coleoptera: Staphyllinidae) based on the age-stage two-sex life table theory.

BACKGROUND: Knowledge of the compatibility between spirodiclofen and the predator Oligota flavicornis is an important aspect for the management of spider mites. RESULTS: We used the age-stage, two-sex life table to assess the effects of spirodiclofen on the life history traits and population growth of O. flavicornis. At the maximum recommended concentration (60 mg a.i. L-1 ) and also at twice the maximum recommended dosage (120 mg a.i. L-1 ), the preadult stages of O. flavicornis were significantly lengthened, while the adult longevity and fecundity decreased significantly. The finite rate (λ), intrinsic rate of increase (r), and net reproduction rate (R0 ) decreased, while the mean generation time (T) was longer after both the 60 and 120 mg a.i. L-1 treatments than it was in the control and 30 mg a.i. L-1 treatments. Life expectancy and reproductive value were higher in the control and 30 mg a.i. L-1 treatment than in the 60 and 120 mg a.i. L-1 treatments; the two higher concentrations were detrimental to the development of O. flavicornis. CONCLUSION: A proper combination of the O. flavicornis and spirodiclofen to control the spider mite, while avoiding the side effect of spirodiclofen, could be achieved based on the knowledge of life tables. © 2018 Society of Chemical Industry.

Differential effects of selective and non-selective cyclooxygenase inhibitors on fecal microbiota in adult horses.

Non-steroidal anti-inflammatory drugs (NSAIDs) are routinely used in both veterinary and human medicine. Gastrointestinal injury is a frequent adverse event associated with NSAID use and evidence suggests that NSAIDs induce gastrointestinal microbial imbalance (i.e., dysbiosis) in both animals and people. It is unknown, however, whether cyclooxygenase (COX)-2-selective NSAIDs induce dysbiosis, or if this phenomenon occurs in horses administered any class of NSAIDs. Therefore, our objectives were to determine whether the composition and diversity of the fecal microbiota of adult horses were altered by NSAID use, and whether these effects differed between non-selective and COX-2-selective NSAIDs. Twenty-five adult horses were randomly assigned to 1 of 3 groups: control (n = 5); phenylbutazone (n = 10); or, firocoxib (n = 10). Treatments were administered for 10 days. Fecal samples were collected every 5 days for 25 days. DNA was extracted from feces and the 16S rRNA gene amplified and sequenced to determine the composition of the microbiota and the inferred metagenome. While the fecal microbiota profile of the control group remained stable over time, the phenylbutazone and firocoxib groups had decreased diversity, and alteration of their microbiota profiles was most pronounced at day 10. Similarly, there were clear alterations of the inferred metagenome at day 10 compared to all other days, indicating that use of both non-selective and selective COX inhibitors resulted in temporary alterations of the fecal microbiota and inferred metagenome. Dysbiosis associated with NSAID administration is clinically relevant because dysbiosis has been associated with several important diseases of horses including abdominal pain (colic), colitis, enteric infections, and laminitis.

How can those engaging in chemsex best be supported? An online survey to gain intelligence in Greater Manchester.

Reports of sexualised drug taking (chemsex) have increased significantly in recent years. There is currently limited intelligence on chemsex outside of London. An anonymous survey was promoted via several sources including voluntary services and a sexual health clinic in order to establish the risks associated with chemsex, and how support services can best be tailored to meet the needs of those in Greater Manchester, UK. Quantitative and qualitative data were collected on demographics, drug use, sexual practices and barriers and facilitators to accessing support. Fifty-two men who have sex with men completed the online survey. Thirty-nine (75%) were HIV-positive and 11 (21%) were hepatitis C virus (HCV) positive, all of whom were HIV/HCV co-infected. The most commonly used drugs were mephedrone (81%) and gamma hydroxybutyrate/gamma butyrolactone (79%). Nineteen (37%) reported ever injecting drugs. High-risk sexual practices were reported by respondents. Barriers to accessing support included a fear of being recognised. Findings demonstrate those engaging in chemsex are participating in a number of high-risk sexual practices, taking substances with significant risks and administering these substances in potentially high-risk ways. Results demonstrate the need for promotion of existing services, with key areas to target where chemsex sessions are most commonly arranged. Results may be useful in other metropolitan cities, both for commissioning and tailoring of chemsex support services.

Contact dermatitis caused by tulips: identification of contact sensitizers in tulip workers of Kashmir Valley in North India.

BACKGROUND: Tulip, belonging to the genus Tulipa and family Liliaceae, is a spring-blooming perennial that grows from bulbs. Owing to manual handling, contact dermatitis can occur in professionals at any stage of the growth cycle of the tulip plant. OBJECTIVES: To determine the clinical pattern of contact dermatitis resulting from tulip plant cultivation, and to assess contact allergy in workers coming into contact with this plant. METHODS: One hundred and sixty-four tulip workers were screened, and 48 patients with suspected contact dermatitis were patch tested with 39 allergens, including haptens from the Indian baseline series, a plant series, and extracts from different parts of the tulip plant. RESULTS: Thirty-nine positive patch test reactions were observed in 21 patients. Seventeen patients showed positive reactions to either α-methylene-γ-butyrolactone or to tulip plant extract. Clinical relevance was observed for 13 of 17 positive patch test reactions. CONCLUSIONS: Contact dermatitis is an important health hazard in workers dealing with tulip bulbs. Further studies to identify and isolate other possible tulip allergens, and to quantify the amounts of allergens in different parts of the tulip plant, are recommended.

In vitro antitumor effect of a lignan isolated from Combretum fruticosum, trachelogenin, in HCT-116 human colon cancer cells.

The use of natural products in therapeutics has been growing over the years. Lignans are compounds with large pharmaceutical use, which has aroused interest in the search for new drugs to treat diseases. The present study evaluated the cytotoxicity of (-)-trachelogenin, a dibenzylbutyrolactone type lignan isolated from Combretum fruticosum, against several tumor and non-tumor cell lines using the MTT assay and its possible mechanism of action. (-)-Trachelogenin showed IC50 values ranging of 0.8-32.4µM in SF-295 and HL-60 cell lines, respectively and IC50 values >64µM in non-tumor cell lines. (-)-trachelogenin persistently induced autophagic cell death, with cytoplasmic vacuolization and formation of autophagosomes mediated by increasing LC3 activation and altering the expression levels of Beclin-1.

Pharmacological Treatment in γ-Hydroxybutyrate (GHB) and γ-Butyrolactone (GBL) Dependence: Detoxification and Relapse Prevention.

The misuse of γ-hydroxybutyrate (GHB) for recreational purposes has resulted in an increase in GHB-related problems such as intoxications, dependence and withdrawal in several countries in Europe, Australia and the US over the last decade. However, prevalence rates of misuse of GHB and its precursor, γ-butyrolactone (GBL), are still relatively low. In this qualitative review paper, after a short introduction on the pharmacology of GHB/GBL, followed by a summary of the epidemiology of GHB abuse, an overview of GHB dependence syndrome and GHB/GBL withdrawal syndrome is provided. Finally, the existing literature on management of GHB detoxification, both planned and unplanned, as well as the available management of GHB withdrawal syndrome, is summarized. Although no systematic studies on detoxification and management of withdrawal have been performed to date, general recommendations are given on pharmacological treatment and preferred treatment setting.