-
Applied Health Economics and Health... Jul 2024This study evaluated, in a Swedish setting, the cost effectiveness of fenfluramine (FFA) as an add-on to standard of care (SoC) for reducing seizure frequency in Dravet...
OBJECTIVE
This study evaluated, in a Swedish setting, the cost effectiveness of fenfluramine (FFA) as an add-on to standard of care (SoC) for reducing seizure frequency in Dravet syndrome, a severe developmental epileptic encephalopathy.
METHODS
Cost effectiveness of FFA+SoC compared with SoC only was evaluated using a patient-level simulation model with a lifetime horizon. Patient characteristics and treatment effects, including convulsive seizures, seizure-free days and mortality, were derived from FFA clinical trials. Resource use and costs included cost of drug acquisition, routine care and monitoring, as well as ongoing and emergency resources. Quality of life (QoL) estimates for patients and their caregivers were derived from clinical trial data. Robustness was evaluated by one-way sensitivity analysis, probabilistic sensitivity analysis and scenario analyses.
RESULTS
Lifetime cost of FFA+SoC was ~3 million SEK per patient compared with ~1.5 million SEK for SoC only. FFA+SoC generated 15% more QALYs than SoC only (21.2 vs 18.5 over a lifetime), resulting in an incremental cost-effectiveness ratio (ICER) of ~540,000 SEK. Moreover, FFA+SoC had a higher probability of being cost effective than SoC only from a willingness-to-pay threshold of 710,000 SEK. Results remained generally consistent across scenario analyses, with only few exceptions (exclusions of carer utility or FFA effect on sudden unexpected death in epilepsy).
CONCLUSION
Due to better seizure control, FFA is a clinically meaningful add-on therapy and was estimated to be a cost-effective addition to current SoC for patients with this rare disease in Sweden at a willingness-to-pay threshold of 1,000,000 SEK.
Topics: Humans; Sweden; Epilepsies, Myoclonic; Cost-Benefit Analysis; Fenfluramine; Female; Male; Standard of Care; Quality-Adjusted Life Years; Anticonvulsants; Adult; Adolescent; Child; Quality of Life; Young Adult; Cost-Effectiveness Analysis
PubMed: 38758509
DOI: 10.1007/s40258-024-00886-0 -
Ecotoxicology and Environmental Safety Jul 2024Methamphetamine (METH) is a psychostimulant drug belonging to the amphetamine-type stimulant class, known to exert male reproductive toxicity. Recent studies suggest...
Methamphetamine (METH) is a psychostimulant drug belonging to the amphetamine-type stimulant class, known to exert male reproductive toxicity. Recent studies suggest that METH can disrupt the gut microbiota. Furthermore, the gut-testis axis concept has gained attention due to the potential link between gut microbiome dysfunction and reproductive health. Nonetheless, the role of the gut microbiota in mediating the impact of METH on male reproductive toxicity remains unclear. In this study, we employed a mouse model exposed to escalating doses of METH to assess sperm quality, testicular pathology, and reproductive hormone levels. The fecal microbiota transplantation method was employed to investigate the effect of gut microbiota on male reproductive toxicity. Transcriptomic, metabolomic, and microbiological analyses were conducted to explore the damage mechanism to the male reproductive system caused by METH. We found that METH exposure led to hormonal disorders, decreased sperm quality, and changes in the gut microbiota and testicular metabolome in mice. Testicular RNA sequencing revealed enrichment of several Gene Ontology terms associated with reproductive processes, as well as PI3K-Akt signaling pathways. FMT conveyed similar reproductive damage from METH-treated mice to healthy recipient mice. The aforementioned findings suggest that the gut microbiota plays a substantial role in facilitating the reproductive toxicity caused by METH, thereby highlighting a prospective avenue for therapeutic intervention in the context of METH-induced infertility.
Topics: Animals; Methamphetamine; Male; Gastrointestinal Microbiome; Mice; Testis; Reproduction; Spermatozoa; Mice, Inbred C57BL; Central Nervous System Stimulants; Fecal Microbiota Transplantation
PubMed: 38754198
DOI: 10.1016/j.ecoenv.2024.116457 -
International Immunopharmacology Jun 2024The incidence of allergic reactions has risen steadily in recent years, prompting growing interest in the identification of efficacious and safe natural compounds that...
The incidence of allergic reactions has risen steadily in recent years, prompting growing interest in the identification of efficacious and safe natural compounds that can prevent or treat allergic diseases. Phellodendron amurense Rupr. has long been applied as a treatment for allergic diseases, whose primary component is phellodendrine. However, the efficacy of phellodendrine as a treatment for allergic diseases remains to be assessed. Mast cells are the primary effectors of allergic reactions, which are not only activated by IgE-dependent pathway, but also by IgE-independent pathways via human MRGPRX2, rat counterpart MRGPRB3. As such, this study explored the effect and mechanism of phellodendrine through this family receptors in treating allergic diseases in vitro and in vivo. These analyses revealed that phellodendrine administration was sufficient to protect against C48/80-induced foot swelling and Evans blue exudation in mice, and suppressed C48/80-induced RBL-2H3 rat basophilic leukemia cells degranulation, and β-HEX, HIS, IL-4, and TNF-α release. Moreover, phellodendrine could reduce the mRNA expression of MRGPRB3 and responsiveness of MRGPRX2 by altering its structure. It was able to decrease Ca levels, phosphorylation levels of CaMK, PLCβ1, PKC, ERK, JNK, p38, and p65, and inhibit the degradation of IκB-α. These analyses indicate that berberine inhibits the activation of PLC and downregulates the release of Ca in the endoplasmic reticulum by altering the conformation of MRGPRB3/MRGPRX2 protein, thereby inhibiting the activation of PKC and subsequently inhibiting downstream MAPK and NF-κB signaling, ultimately suppressing allergic reactions. There may thus be further value in studies focused on developing phellodendrine as a novel anti-allergic drug.
Topics: Animals; Rats; Mast Cells; Cell Degranulation; Mice; Humans; Hypersensitivity; Receptors, G-Protein-Coupled; Anti-Allergic Agents; Cytokines; p-Methoxy-N-methylphenethylamine; Male; Phellodendron; Cell Line, Tumor; Nerve Tissue Proteins; Mice, Inbred BALB C; NF-kappa B; Signal Transduction; Receptors, Neuropeptide
PubMed: 38744172
DOI: 10.1016/j.intimp.2024.112256 -
Journal of the Science of Food and... May 2024The excessive salt intake associated with Douchi has become a topic of controversy. Addressing this concern and enhancing its market competitiveness necessitates the...
BACKGROUND
The excessive salt intake associated with Douchi has become a topic of controversy. Addressing this concern and enhancing its market competitiveness necessitates the application of salt reduction fermentation in Douchi. Therefore, to promote the application of salt reduction fermentation in Douchi, a comprehensive study was undertaken aiming to investigate the differences in biogenic amines, volatile compounds and non-volatile compounds in Douchi with varying salt content.
RESULTS
The findings unequivocally demonstrate that salt hampers the formation of metabolites in Douchi. As the salt content increased, there was a significant decrease (P < 0.05) in the levels of total acid, amino-type nitrogen and free amino acids in Douchi. Notably, when the salt content exceeded 80 g kg, there was a substantial reduction (P < 0.05) in putrescine, lactic acid and malic acid levels. Similarly, when the salt content surpassed 40 g kg, β-phenethylamine and oxalic acid levels exhibited a significant decline (P < 0.05). Furthermore, the results of E-nose and principal component analysis based on headspace solid phase microextraction gas chromatography-mass spectrometry revealed notable discrepancies in the volatile compound content between Douchi samples with relatively low salt content (40 and 80 g kg) and those with relatively high salt content (120, 160 and 200 g kg) (P < 0.05). By employing partial least squares discriminant analysis, eight distinct volatile compounds, including o-xylene, benzaldehyde and 1-octen-one, were identified. These compounds exhibited higher concentrations in Douchi samples with relatively low salt content (40 and 80 g kg). The sensory results showed that Douchi samples with lower salt content exhibited higher scores in the soy sauce-like and Douchi aroma attributes.
CONCLUSION
In conclusion, this study significantly enhances our understanding of the impact of salt on metabolites in Douchi and provides invaluable insights for the development of salt reduction fermentation in this context. © 2024 Society of Chemical Industry.
PubMed: 38738583
DOI: 10.1002/jsfa.13574 -
Chirality May 2024Among different substance classes, New Psychoactive Substances (NPS) comprise chiral amphetamines for stimulant and empathic effects. There is little knowledge in terms...
Among different substance classes, New Psychoactive Substances (NPS) comprise chiral amphetamines for stimulant and empathic effects. There is little knowledge in terms of clinical studies about possibly different effects of the two enantiomers of novel amphetamine derivatives. For this reason, there is a big demand for enantioseparation method development of this new substance class. Regarding gas chromatography, cyclodextrins proved to be effective for enantioseparation of NPS. In our attempt, an Astec® Chiraldex™ G-PN column containing 2,6-di-O-pentyl-3-propionyl-γ-cyclodextrin and a Lipodex™ D column containing heptakis-(2,6-di-O-pentyl-O-acetyl)-β-cyclodextrin as chiral selector served as stationary phases in a Shimadzu GCMS-QP2010 SE system. Because of the special coating, maximum temperature is limited to 200 °C isothermal or 220 °C in programmed mode. To ensure detection, trifluoroacetic anhydride (TFAA) was used to increase sample volatility. As a result, 35 amphetamines were tested as their TFAA-derivatives. A screening method with a temperature gradient from 140 °C to 200 °C at a heating ramp of 1 °C per minute and final time of 5 min, showed baseline separation for seven and partial separations for 16 trifluoro acetylated amphetamines using the Chiraldex™ G-PN column. Six baseline and nine partial separations were observed with the Lipodex™ D column, respectively.
Topics: Stereoisomerism; Amphetamines; Chromatography, Gas; Cyclodextrins; Temperature; Gas Chromatography-Mass Spectrometry
PubMed: 38736271
DOI: 10.1002/chir.23676 -
Journal of the American Academy of... May 2024Youth today are burdened by significant mental health challenges. In 2022, 25% of adolescents aged 12 to 17 years experienced a mental illness, with 20% experiencing a...
Youth today are burdened by significant mental health challenges. In 2022, 25% of adolescents aged 12 to 17 years experienced a mental illness, with 20% experiencing a depressive episode, 12.5% reporting serious thoughts of suicide, and 17% meeting criteria for a substance use disorder. Close to 5% of adolescents experience posttraumatic stress disorder. Impairing psychiatric symptoms remain present in upwards of 40% of adolescents after receiving existing mental health services, so it is necessary to identify additional and more effective treatment options. We propose there is an acceptable benefit-to-risk calculation that supports trialing classic serotonergic psychedelics (eg, psilocybin) and phenethylamine compounds with empathogenic and entactogenic range of effects (eg, 3,4-methylenedioxymethamphetamine [MDMA]) in combination with psychotherapy among select adolescents aged 16 to 17 years. Specifically, we propose testing these treatments among adolescents aged 16 to 17 years who are experiencing treatment-resistant manifestations of psychiatric disorders (ie, multiple failed trials of current evidence-based treatments) or psychiatric disorders that are in line with the current evidence base for adults as determined, for example, by the breakthrough designation of the US Food and Drug Administration for a particular psychedelic medicine (eg, psilocybin for major depressive disorder, MDMA for posttraumatic stress disorder).
PubMed: 38734406
DOI: 10.1016/j.jaac.2024.03.021 -
Progress in Neuro-psychopharmacology &... Jul 2024Methamphetamine (METH) is a major health problem without effective pharmacological treatment. Cannabidiol (CBD), a component of the Cannabis sativa plant, is believed to...
Methamphetamine (METH) is a major health problem without effective pharmacological treatment. Cannabidiol (CBD), a component of the Cannabis sativa plant, is believed to have the potential to inhibit drug-related behavior. However, the neurobiological mechanisms responsible for the effects of CBD remain unclear. Several studies have proposed that the suppressing effects of CBD on drug-seeking behaviors could be through the modulation of the dopamine system. The hippocampus (HIP) D1-like dopamine receptor (D1R) is essential for forming and retrieving drug-associated memory. Therefore, the present study aimed to investigate the role of D1R in the hippocampal CA1 region on the effects of CBD on the extinction and reinstatement of METH-conditioned place preference (CPP). For this purpose, different groups of rats over a 10-day extinction period were administered different doses of intra-CA1 SCH23390 (0.25, 1, or 4 μg/0.5 μl, Saline) as a D1R antagonist before ICV injection of CBD (10 μg/5 μl, DMSO12%). In addition, a different set of animals received intra-CA1 SCH23390 (0.25, 1, or 4 μg/0.5 μl) before CBD injection (50 μg/5 μl) on the reinstatement day. The results revealed that the highest dose of SCH23390 (4 μg) significantly reduced the accelerating effects of CBD on the extinction of METH-CPP (P < 0.01). Furthermore, SCH23390 (1 and 4 μg) in the reinstatement phase notably reversed the preventive effects of CBD on the reinstatement of drug-seeking behavior (P < 0.05 and P < 0.001, respectively). In conclusion, the current study revealed that CBD made a shorter extinction period and suppressed METH reinstatement in part by interacting with D1-like dopamine receptors in the CA1 area of HIP.
Topics: Animals; Methamphetamine; Cannabidiol; Extinction, Psychological; Male; Receptors, Dopamine D1; Benzazepines; Rats, Wistar; Rats; Dose-Response Relationship, Drug; Drug-Seeking Behavior; Hippocampus; Dopamine Antagonists; CA1 Region, Hippocampal
PubMed: 38729234
DOI: 10.1016/j.pnpbp.2024.111025 -
Current Opinion in Psychiatry Jul 2024The pace of psychedelic treatments continues to increase. Regulation and coherent clinical guidance have not been established. A philosophical divide limits effective... (Review)
Review
PURPOSE OF REVIEW
The pace of psychedelic treatments continues to increase. Regulation and coherent clinical guidance have not been established. A philosophical divide limits effective resolution of a practice delivery quandary: is this primarily a pharmacological or psychotherapeutic intervention?
RECENT FINDINGS
Lykos (formerly MAPS) has submitted its new drug application (NDA) request to the FDA for 3-4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for PTSD and is expecting a response by the summer of 2024. Australia endorsed psilocybin and MDMA for regulated use in 2023. Multiple phase II and III clinical trials are also being conducted in the United States and Europe to study the use of psilocybin. Currently, Colorado and Oregon have legalized psilocybin in different manners. In Colorado, plants containing psilocybin, ibogaine, dimethyltryptamine (DMT) and mescaline (other than peyote) are now legal to possess, share and cultivate. Guidelines for regulated treatment with psilocybin containing mushrooms are in process with service delivery to begin early in 2025. In Oregon, clients must complete a preparation session with a licensed facilitator before consuming psilocybin products at a licensed service center. A prescription is not required. It is expected that other states will follow suit with a ballot measure likely in Massachusetts this year. Additionally, in the United States, the DEA, state boards, pharmaceutical distributors, and professional liability carriers all share mounting concerns about the in-home use of compounded ketamine used as a psychedelic therapeutic via remote prescribing.
SUMMARY
Psychedelic treatments are rapidly entering the mainstream of medical care delivery in the United States. Clinical guidelines are urgently needed to ensure well tolerated practice and coherent regulation. The delivery of this guidance is limited by a core philosophical disagreement. Resolution of this conflict will be needed to deliver coherent clinical guidelines. Current research and clinical experience provide a solid foundation for practical clinical guidance and the introduction of psychedelics into healthcare.
Topics: Hallucinogens; Humans; Psilocybin; Psychotherapy; United States; N-Methyl-3,4-methylenedioxyamphetamine; Stress Disorders, Post-Traumatic
PubMed: 38726805
DOI: 10.1097/YCO.0000000000000946 -
Scientific Reports May 2024This cross-sectional study aims to evaluate the immune system status and hematological disturbances among individuals who abuse amphetamines and cannabis. Substance...
This cross-sectional study aims to evaluate the immune system status and hematological disturbances among individuals who abuse amphetamines and cannabis. Substance abuse, particularly of amphetamines and cannabis, has been associated with various adverse effects on the body, including potential impacts on the immune system and hematological parameters. However, limited research has been conducted to comprehensively assess these effects in a cross-sectional design. Additionally, fungal infections are on the rise internationally, and immune-compromised people are particularly susceptible. The study will recruit a sample of amphetamine and cannabis abusers (n = 50) at the Eradah Hospital in the Qassim Region of Buraydah and assess their sociodemographic and biochemical variables, including blood indices and differential WBC indices, liver, and kidney profiles. Additionally, 50 sputum samples in total were cultured for testing for fungus infections. To obtain the descriptive statistics, the data was imported into Microsoft Excel and subjected to statistical analysis using SPSS 22.0. Amphetamine and cannabis abuser's sociodemographic variables analysis observed that the majority (52%) were aged 18-30, with 56% in secondary school. Unemployment was a significant issue, and most had no other health issues. The majority (50%) had 5-10 years of abuse, while 32% had less than 5 years, and only 18% had been drug abusers for more than 10 years. There were significant changes (p < 0.001) in all different leukocyte blood cells, including neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Furthermore, a microscopic examination of blood films from individuals who misuse the combination of the medications "amphetamine and cannabis" reveals hazardous alterations in Neutrophils. Out of 50, 35 sputum samples showed positive growth on Sabouraud dextrose agar (SDA) with chloramphenicol antibiotic, indicating a unicellular fungal growth. The present study explores the immune system and hematological disturbances linked to amphetamine and cannabis abuse, providing insights into health risks and targeted interventions. The findings complement previous research on drug users' hematological abnormalities, particularly in white blood cells. Routine hematological tests help identify alterations in homeostatic conditions, improving patient knowledge and preventing major issues. Further research is needed on multi-drug abuse prevention, early detection, and intervention. The cross-sectional design allows for a snapshot of the immune system and hematological status among abusers, laying the groundwork for future longitudinal studies. Key Words: Drug Effect, Immunity, Epidemiology, Oxidative Stress, Inflammation.
Topics: Humans; Adult; Male; Female; Cross-Sectional Studies; Young Adult; Adolescent; Marijuana Abuse; Saudi Arabia; Immune System; Amphetamine-Related Disorders; Amphetamine
PubMed: 38719969
DOI: 10.1038/s41598-024-61182-4 -
WMJ : Official Publication of the State... May 2024Tarka (trandolapril/verapamil hydrohloride extended-release) is a fixed-dose combination antihypertensive drug formed from verapamil hydrochloride and trandolapril....
INTRODUCTION
Tarka (trandolapril/verapamil hydrohloride extended-release) is a fixed-dose combination antihypertensive drug formed from verapamil hydrochloride and trandolapril. Toxicologic manifestations of Tarka overdose are altered mental status, bradycardia, hypotension, atrioventricular block (first-degree), hyperglycemia, metabolic acidosis, and shock.
CASE PRESENTATION
We report a case of Tarka toxicity in a 2-year-old girl who presented with altered mental status, cardiogenic shock, hypotension, bradycardia, severe metabolic acidosis, hyperglycemia, and first-degree atrioventricular block. We started fluid resuscitation, epinephrine, norepinephrine, and insulin. Because of the patient's hyperlactatemia and hypotension despite standard therapies, we initiated intravenous lipid emulsion (ILE) therapy, after which her condition improved promptly.
DISCUSSION
Tarka overdose may be life-threatening as it can cause cardiogenic shock. In our patient, the regression of lactate elevation in a short time with ILE therapy and the improvement of her general condition highlight the importance of ILE.
CONCLUSIONS
ILE is an alternative treatment method for acute lipophilic drug intoxications, such as Tarka.
Topics: Humans; Female; Fat Emulsions, Intravenous; Insulin; Drug Overdose; Verapamil; Child, Preschool; Drug Combinations; Antihypertensive Agents; Hypoglycemic Agents; Indoles
PubMed: 38718248
DOI: No ID Found