Muscle Strength Decline Caused by Eperisone Hydrochloride: A Case Report.

A 65-year-old female with thoracic spinal stenosis and incomplete paraplegia underwent T11-T12 posterior thoracic interbody fusion. During postoperative rehabilitation, she experienced thigh pain, involuntary lower limb convulsions, and muscle fatigue. Despite being prescribed eperisone hydrochloride for relief, her muscle strength decreased after 14 doses. This adverse effect, not listed in the latest Chinese medication instructions, subsided 4 days after discontinuation. This case suggests eperisone hydrochloride potentially caused reversible muscle strength decline, highlighting its potential unsuitability for incomplete paraplegia patients due to possible further muscle strength reduction. We propose updating the medication instructions to alert clinicians to this risk.

Bioavailability and Cardiometabolic Effects of Xanthohumol: Evidence from Animal and Human Studies.

Xanthohumol is the main prenylflavonoid in hops and has been associated with a wide range of health benefits, due to its anti-inflammatory, anti-oxidative, and cancer-preventive properties. Increasing evidence suggests that xanthohumol positively affects biomarkers associated with metabolic syndrome and cardiovascular diseases (CVDs). This review summarizes the effects of xanthohumol supplementation on body weight, lipid and glucose metabolism, systemic inflammation, and redox status. In addition, it provides insights into the pharmacokinetics of xanthohumol intake. Animal studies show that xanthohumol exerts beneficial effects on body weight, lipid profile, glucose metabolism, and other biochemical parameters associated with metabolic syndrome and CVDs. Although in vitro studies are increasingly elucidating the responsible mechanisms, the overall in vivo results are currently inconsistent and quantitatively insufficient. Pharmacokinetic and safety studies confirm that intake of xanthohumol is safe and well tolerated in both animals and humans. However, little is known about the metabolism of xanthohumol in the human body, and even less about its effects on body weight and CVD risk factors. There is an urgent need for studies investigating whether the effects of xanthohumol on body weight and cardiometabolic parameters observe in animal studies are reproducible in humans, and what dosage, formulation, and intervention period are required.

Xanthohumol Microbiome and Signature in Healthy Adults (the XMaS Trial): Safety and Tolerability Results of a Phase I Triple-Masked, Placebo-Controlled Clinical Trial.

SCOPE: Xanthohumol, a prenylflavonoid from hops, has been extensively studied preclinically but has undergone limited research in human subjects. A triple-masked, placebo-controlled phase I clinical trial was conducted to examine the safety and tolerability of xanthohumol. METHODS AND RESULTS: Thirty healthy volunteers were randomized to 24 mg day-1 xanthohumol (99.8% pure) or placebo for eight weeks. Comprehensive metabolic panels, complete blood counts, body weight, vital signs, and health-related quality of life questionnaires were assessed every two weeks. Participants were interviewed for adverse events (AEs) throughout the trial. Thirteen of 14 (93%) and 14 of 16 (88%) participants completed the trial in the placebo and xanthohumol groups, respectively. There were no withdrawals due to AEs. There were no clinically relevant, between-group differences in laboratory biomarkers, body weight, vital signs, or health-related quality of life. There were no severe or FDA-defined serious AEs, but non-serious AEs are documented in both the placebo (n = 42) and xanthohumol (n = 58) groups. CONCLUSION: Over an eight-week period, 24 mg daily xanthohumol was safe and well-tolerated by healthy adults.

Reinforcing and discriminative-stimulus effects of two pyrrolidine-containing synthetic cathinone derivatives in rats.

The molecular and behavioral aspects of α-pyrrolidinopentiophenone (α-PVP) have been characterized; however, how the structural modification of α-PVP affects its abuse potential is still unknown. In this study, we investigated the abuse potential of two pyrrolidinylated second-generation cathinones:4-chloro-α-pyrrolidinopentiophenone (4cl-α-PVP) and 4-chloro-α-pyrrolidinopropiophenone (4cl-α-PPP). Male Sprague-Dawley rats were trained to self-administer methamphetamine (METH, 0.05 mg·kg-1·infusion-1), α-PVP (0.05 mg·kg-1·infusion-1), 4cl-α-PVP (0.05 mg·kg-1·infusion-1), and 4cl-α-PPP (0.5 mg·kg-1·infusion-1) under a fixed ratio (FR) 1 reinforcement schedule for 10 sessions. The discriminative-stimulus effect of METH (0.8 mg/kg) from saline was tested under an FR10 schedule of food delivery. α-PVP, 4cl-α-PVP and 4cl-α-PPP produced reinforcement behaviors and presented an inverted U-shaped dose effect. The reinforcing potency was displayed with a rank order of α-PVP (0.029 mg·kg-1·infusion-1) > METH (0.040 mg·kg-1·infusion-1) > 4cl-α-PVP (0.094 mg·kg-1·infusion-1) > 4cl-α-PPP (0.51 mg·kg-1·infusion-1). All three drugs were fully substituted for the discriminative-stimulus effects of METH in rats. The substitution potency for discriminative-stimulus effects of α-PVP (ED50 = 0.4 mg/kg) was approximately equal to that of METH (ED50 = 0.3 mg/kg), while the discriminative potency of 4cl-α-PVP (ED50 = 1.0 mg/kg) and 4cl-α-PPP (ED50 = 5 mg/kg) was approximately 3 and 16-fold less than that of METH. The rank order of potency was α-PVP ≈ METH >4cl-α-PVP > 4cl-α-PPP. The present data demonstrated that 4cl-α-PVP and 4cl-α-PPP produced reinforcing effects and fully and dose-dependently substituted for the subjective effects of METH, suggesting that both 4cl-α-PVP and 4cl-α-PPP have abuse potential that may be similar to METH.

Xanthohumol microbiome and signature in healthy adults (the XMaS trial): a phase I triple-masked, placebo-controlled clinical trial.

BACKGROUND: Natural products may provide a source for the discovery and development of adjunctive pharmacological interventions to modulate the inflammatory pathways contributing to chronic disease. Xanthohumol, a flavonoid from the hops plant (Humulus lupulus), has antioxidant and anti-inflammatory properties and may act as a prebiotic to the intestinal microbiota. Xanthohumol is not currently approved as a drug by the US Food and Drug Administration (FDA), but is available as a dietary supplement and ingredient in medical foods. To formally test the safety of xanthohumol, a phase I clinical trial ("XMaS") was designed and approved under an Investigational New Drug application to the US FDA. The main objective is to examine the clinical safety and subjective tolerability of xanthohumol in healthy adults compared to placebo. Additional aims are to monitor biomarkers related to inflammation, gut permeability, bile acid metabolism, routes, and in vivo products of xanthohumol metabolism, and to evaluate xanthohumol's impact on gut microbial composition. METHODS: The safety and tolerability of xanthohumol in healthy adults will be evaluated in a triple-masked, randomized, placebo-controlled trial. Participants will be randomized to either 24 mg/day of xanthohumol or placebo for 8 weeks. Blood cell counts, hepatic and renal function tests, electrolytes, and self-reported health-related quality of life measures will be collected every 2 weeks. Participants will be queried for adverse events throughout the trial. Xanthohumol metabolites in blood, urine, and stool will be measured. Biomarkers to be evaluated include plasma tumor necrosis factor-alpha, various interleukins, soluble CD14, lipopolysaccharide-binding protein, fecal calprotectin, and bile acids to assess impact on inflammatory and gut permeability-related mechanisms in vivo. Stool samples will be analyzed to determine effects on the gut microbiome. DISCUSSION: This phase I clinical trial of xanthohumol will assess safety and tolerability in healthy adults, collect extensive biomarker data for assessment of potential mechanism(s), and provide comparison data necessary for future phase II trials in chronic disease(s). The design and robustness of the planned safety and mechanistic evaluations planned provide a model for drug discovery pursuits from natural products. TRIAL REGISTRATION: ClinicalTrials.gov NCT03735420 . Registered on November 8, 2018.

2-Hydroxy-4-methoxybenzophenone Enhances the Suppression of Superoxide Anion Radicals Generated via UVA-induced Photosensitizing by t-Butyl Methoxydibenzoylmethane.

4-tert-Butyl-4'-methoxydibenzoylmethane (BMDM) is widely used throughout the world as a highly effective UVA absorber that can prevent the progression of photoaging in skin. However, due to its low photostability, BMDM is also known for the disadvantage of having a reduced capability to absorb UVA during prolonged exposure to sunlight. Although many studies have been carried out to overcome this disadvantage of BMDM, little attention has been paid to how the radicals generated from BMDM during UV exposure influence the skin. Therefore, the purpose of this study was twofold: One goal was to clarify the influence of radicals on human skin using cytotoxicity as a parameter. The second was to propose a solution that could reduce the radical formation while taking photostability into consideration. Using ESR spin trapping and superoxide dismutase (SOD) treatment, the radicals produced by the UV exposure of BMDM were shown to be superoxide anion radicals (•O2-). HaCaT keratinocytes exposed to UVA in the presence of BMDM showed a significant reduction in cell viability, indicating that the radicals produced from BMDM have a harmful influence on the skin. UVA exposure coincidently led to a reduction of UVA absorbance by BMDM. Interestingly, 2-hydroxy-4-methoxybenzophenone (Benzophenone-3; BP3) reduced both the radical formation and the cytotoxicity resulting from the UVA-exposure of BMDM, while also restoring its UVA absorbance. In conclusion, the results show that BMDM and BP3 is an effective combination to reduce the influence of UVA-exposed BMDM on the skin and to prevent the loss of UVA absorbance by BMDM during UV exposure.

Characteristic of neuropsychological deficits in patients diagnosed with manganese encephalopathy due to ephedrone use - case series analysis. / Charakterystyka deficytów neuropsychologicznych u pacjentów z rozpoznana encefalopatia manganowa zazywajacych efedron ­ analiza przypadków.

AIM: The study presents neuropsychological characteristic of 16 individuals with manganese-induced parkinsonism due to intravenous ephedrone use. MATERIAL AND METHODS: Overall cognitive function screening as well as full examination of various cognitive domains (verbal learning, visual memory, working memory, executive functions, construction and visuospatial functions) with the use of elastic neuropsychological test battery were performed. Dyshartric speech disorders were also precisely evaluated. Additionally, all individuals filled in the Beck Depression Inventory (BDI), which is used to assess mood. RESULTS: All patients had evident dysarthric speech disorders accompanied with palilalia and writing disorders (micrographia) in the majority of investigated individuals. Neuropsychological screening diagnosis showed no overall cognitive deficits at the level of dementia. Mild decrease in verbal learning and visual memory processes was found; as well as ideomotor but no construction praxis disorders. Results of working memory and executive function assessment indicated decrease in cognitive flexibility and logical conceptualization abilities, as well as set-shifting disorders. Patients varied significantly in their severity of executive dysfunction. Duration of ephedrone use was found nonsignificant for patients' cognition. The mean BDI score indicated moderate depression. Higher level of depressive symptoms was associated with poorer overall cognitive screening, decrease of visual and verbal learning as well as phonemic verbal fluency.

Hyperthermia Increases Neurotoxicity Associated with Novel Methcathinones.

Hyperthermia is one of the severe acute adverse effects that can be caused by the ingestion of recreational drugs, such as methcathinones. The effect of hyperthermia on neurotoxicity is currently not known. The primary aim of our study was therefore to investigate the effects of hyperthermia (40.5 °C) on the neurotoxicity of methcathinone (MC), 4-chloromethcathinone (4-CMC), and 4-methylmethcathinone (4-MMC) in SH-SY5Y cells. We found that 4-CMC and 4-MMC were cytotoxic (decrease in cellular ATP and plasma membrane damage) under both hyper- (40.5 °C) and normothermic conditions (37 °C), whereby cells were more sensitive to the toxicants at 40.5 °C. 4-CMC and 4-MMC impaired the function of the mitochondrial electron transport chain and increased mitochondrial formation of reactive oxygen species (ROS) in SH-SY5Y cells, which were accentuated under hyperthermic conditions. Hyperthermia was associated with a rapid expression of the 70 kilodalton heat shock protein (Hsp70), which partially prevented cell death after 6 h of exposure to the toxicants. After 24 h of exposure, autophagy was stimulated by the toxicants and by hyperthermia but could only partially prevent cell death. In conclusion, hyperthermic conditions increased the neurotoxic properties of methcathinones despite the stimulation of protective mechanisms. These findings may be important for the understanding of the mechanisms and clinical consequences of the neurotoxicity associated with these compounds.

Differential effects of synthetic psychoactive cathinones and amphetamine stimulants on the gut microbiome in mice.

The list of pharmacological agents that can modify the gut microbiome or be modified by it continues to grow at a high rate. The greatest amount of attention on drug-gut microbiome interactions has been directed primarily at pharmaceuticals used to treat infection, diabetes, cardiovascular conditions and cancer. By comparison, drugs of abuse and addiction, which can powerfully and chronically worsen human health, have received relatively little attention in this regard. Therefore, the main objective of this study was to characterize how selected synthetic psychoactive cathinones (aka "Bath Salts") and amphetamine stimulants modify the gut microbiome. Mice were treated with mephedrone (40 mg/kg), methcathinone (80 mg/kg), methamphetamine (5 mg/kg) or 4-methyl-methamphetamine (40 mg/kg), following a binge regimen consisting of 4 injections at 2h intervals. These drugs were selected for study because they are structural analogs that contain a ß-keto substituent (methcathinone), a 4-methyl group (4-methyl-methamphetamine), both substituents (mephedrone) or neither (methamphetamine). Mice were sacrificed 1, 2 or 7 days after treatment and DNA from caecum contents was subjected to 16S rRNA sequencing. We found that all drugs caused significant time- and structure-dependent alterations in the diversity and taxonomic structure of the gut microbiome. The two phyla most changed by drug treatments were Firmicutes (methcathinone, 4-methyl-methamphetamine) and Bacteriodetes (methcathinone, 4-methyl-methamphetamine, methamphetamine, mephedrone). Across time, broad microbiome changes from the phylum to genus levels were characteristic of all drugs. The present results signify that these selected psychoactive drugs, which are thought to exert their primary effects within the CNS, can have profound effects on the gut microbiome. They also suggest new avenues of investigation into the possibility that gut-derived signals could modulate drug abuse and addiction via altered communication along the gut-brain axis.

Clinical characteristics of eperisone-induced immediate-type hypersensitivity.

BACKGROUND: Eperisone is a commonly prescribed oral muscle relaxant, but few studies have been conducted of eperisone-induced hypersensitivity reactions. OBJECTIVE: The purpose of this study was to investigate the clinical manifestations of eperisone-induced immediate-type hypersensitivity, and to evaluate the role of an intradermal test (IDT) in eperisone-induced anaphylaxis. METHODS: This study was based on a retrospective review of medical records from 23 patients diagnosed as eperisone-induced immediate-type hypersensitivity with certain or probable causality. Intradermal tests were performed with a sterile 10 mg/mL eperisone solution. RESULTS: Immediate-type hypersensitivity reactions to eperisone occurred within 15 minutes in 8.7%, within 30 minutes in 52.2%, and within 60 minutes in 82.6% of the patients, cumulatively. All patients showed cutaneous symptoms. Gastrointestinal symptoms were the second-most frequent (65.2%), respiratory symptoms (56.5%) followed, and cardiovascular symptoms were the least (39.1%). Nine (39.1%) patients were categorized as severe anaphylaxis. The mean onset time of severe anaphylaxis was 28.89 minutes, which was significantly shorter than non-severe anaphylaxis (p = 0.011). Five patients among the severe anaphylaxis group were evaluated with IDT, and all showed positive results. In contrast, all of the four patients who have done IDT among the moderate anaphylaxis group showed negative results. There was a significant relationship between severe anaphylaxis and positive IDT results (p = 0.008). CONCLUSIONS: Eperisone-induced immediate-type hypersensitivity is not uncommon in Korea, and the IDT could be a useful and safe diagnostic tool, especially in severe anaphylaxis.

Study Design of a Phase II Clinical Trial to Assess the Efficacy and Safety of Eperisone in Japanese Type 2 Diabetes Patients with Risk and Non-risk Alleles of CDKAL1.

Genetic variation in Cdk5 Regulatory Associated Protein 1-Like 1 (CDKAL1) is associated with the development of type 2 diabetes (T2D). Dysfunction of CDKAL1 impairs the translation of proinsulin, which leads to glucose intolerance. Eperisone, an antispasmodic agent, has been shown to ameliorate glucose intolerance in Cdkal1-deficient mice. We have launched a phase II clinical study to investigate the potential anti-diabetic effect of eperisone in T2D patients carrying risk or non-risk alleles of CDKAL1. The primary endpoint is the change of hemoglobin A1c (HbA1c) levels. We also examined whether the efficacy of eperisone in T2D patients is associated with CDKAL1 activity.

[When sunscreens do not help: allergic contact dermatitis to UV filters]. / Wenn Sonnenschutzprodukte nicht mehr helfen: Allergisches Kontaktekzem auf UV-Filter.

Ultraviolet (UV) filters may cause allergic and more frequently photoallergic contact dermatitis. Therefore, a photopach test should always be performed in case of a suspected contact sensitivity to UV filters. We report a case of a 65-year-old woman with a recurrent erythema of the face and décolleté after sun exposure despite application of a sunscreen. The (photo)patch test revealed a contact sensitivity to the UV filter butyl-methoxybenzoylmethane. Treatment with a topical glucocorticoid and avoidance of the particular UV filter led to a rapid improvement.

Dissociation of reward and effort sensitivity in methcathinone-induced Parkinsonism.

Methcathinone-induced Parkinsonism is a recently described extrapyramidal syndrome characterized by globus pallidus and substantia nigra lesions, which provides a unique model of basal ganglia dysfunction. We assessed motivated behaviour in this condition using a novel cost-benefit decision-making task, in which participants decided whether it was worth investing effort for reward. Patients showed a dissociation between reward and effort sensitivity, such that pallidonigral complex dysfunction caused them to become less sensitive to rewards, while normal sensitivity to effort costs was maintained.

Patterns of use and toxicity of new para-halogenated substituted cathinones: 4-CMC (clephedrone), 4-CEC (4-chloroethcatinone) and 4-BMC (brephedrone).

OBJECTIVE: This paper aims to present results of the analysis of clephedrone (4-CMC), 4-chloroethcathinone (4-CEC), and brephedrone (4-BMC) on recreational drug markets and a systematic review of all the available information concerning these substances. MATERIAL AND METHODS: Samples collected by the drug checking service of the Spanish harm reduction NGO-Energy Control were analyzed and systematic research was conducted. Between June 2014 and October 2016, 1,471 samples with at least one NPS were analyzed, 397 of which contained cathinones. RESULTS: Clephedrone was found in 29 samples, brephedrone in 8, and both were present in 2 samples. 4-Chloroethcathinone was detected in 5 samples. Eleven out of the 47 purchased samples (23.4%) were tested to contain the substance the user expected. Samples received were mainly sold as 3-MMC, MDMA, ketamine, and other cathinones. No literature on the effects or toxicity of these substances was found; the only information available was on internet fora. On many posts, users exhibit concerns about potential toxicity and side effects of using these substances. CONCLUSION: Since the emergence of these substances could prove to be the next step to the cat-and-mouse game existing between drug producers and legislation, further clinical and epidemiological research should be carried out in order to build evidence to support policy for public health issues.

Endocrine Activity of AVB, 2MR, BHA, and Their Mixtures.

Personal care products are used increasingly, resulting in growing concern concerning their potential disruption of normal hormonal functions. Recent results on the bioaccumulation of cosmetic ingredients in wildlife and humans point to the need for an in-depth analysis for endocrine activity, in particular with respect to their influence on the androgen (AR), glucocorticoid (GR), and thyroid hormone receptors (TRs). Furthermore, humans are commonly exposed simultaneously to complex mixtures of endocrine active compounds. We have therefore examined 3 frequently used cosmetic ingredients: 2-methylresorcinol (2MR), butylated hydroxyanisole (BHA) and avobenzone (AVB), for (anti)-androgen-, (anti)-glucocorticoid-, and (anti)-thyroid hormone-like activities. Their binary and ternary mixtures at EC50 or IC50 concentrations have also been examined for anti-androgen-, glucocorticoid-, and thyroid hormone-like activities. In the MDA-kb2 reporter cell line, compounds possessed anti-androgen-, glucocorticoid-, and anti-glucocorticoid-like activities (except AVB). A new cell line, GH3.TRE-Luc, was used to evaluate anti-thyroid and thyroid hormone-like activities. The combinations 2MR + BHA and 2MR + BHA + AVB have glucocorticoid-like activity: only 2MR + AVB has anti-androgen-like activity. On the other hand, binary and ternary mixtures of compounds showed no thyroid hormone-like activity. Thus, in addition to identifying new endocrine disrupting compounds, it is also necessary to determine the effects of their mixtures in order to assess fully their risk to human health.

The Growing Problem of New Psychoactive Substances (NPS).

The term "new psychoactive substances" (NPS) can be defined as individual drugs in pure form or in complex preparations that are not scheduled under the Single Convention on Narcotic Drugs (1961) or the Convention on Psychotropic Substances (1971). NPS may be categorized by chemical structure, by psychoactive properties, by biological targets, or by source (plant, synthetic, or combined). The emergence of hundreds of NPS in the past decade is challenging for public health and drug policies globally. The novelty of NPS, their ambiguous legal status, ability to evade toxicological tests, swift adaptation to legal restrictions, global Internet marketing, and scant public knowledge of their adverse effects are among the key drivers of this twenty-first century phenomenon. Multi-disciplinary research in areas of biology, epidemiology, prevention, and web analytics are needed to develop effective responses in a domain capable of overwhelming current international conventions and national drug control policies. Ultimately, research-guided prevention education will fortify societies against this tidal wave.

Neurotoxicology of Synthetic Cathinone Analogs.

The present review briefly explores the neurotoxic properties of methcathinone, mephedrone, methylone, and methylenedioxypyrovalerone (MDPV), four synthetic cathinones most commonly found in "bath salts." Cathinones are ß-keto analogs of the commonly abused amphetamines and display pharmacological effects resembling cocaine and amphetamines, but despite their commonalities in chemical structures, synthetic cathinones possess distinct neuropharmacological profiles and produce unique effects. Among the similarities of synthetic cathinones with their non-keto analogs are their targeting of monoamine systems, the release of neurotransmitters, and their stimulant properties. Most of the literature on synthetic cathinones has focused on describing their properties as psychostimulants, their behavioral effects on locomotion, memory, and potential for abuse, whereas descriptions of their neurotoxic properties are not abundant. The biochemical gauges of neurotoxicity induced by non-keto analogs are well studied in humans and experimental animals and include their ability to induce neuroinflammation, oxidative stress, excitotoxicity, temperature alterations as well as dysregulation of neurotransmitter systems and induce changes in monoamine transporters and receptors. These neurotoxicity gauges will serve as parameters to discuss the effects of the four previously mentioned synthetic cathinones alone or in combination with either another cathinone or with some of their non-keto analogs. Bath salts are not a defined combination of drugs and may consist of one synthetic cathinone compound or combinations of more cathinones. Furthermore, this review also presents some of the mechanisms that are thought to underlie this toxicity. A better understanding of the cellular and molecular mechanisms involved in the synthetic cathinones-induced neurotoxicity should contribute to generate modern therapeutic approaches to prevent or attenuate the adverse consequences of use of these drugs in humans.