Anti-diarrheal effect of piperine possibly through the interaction with inflammation inducing enzymes: In vivo and in silico studies.

Piperine is a natural alkaloid that possesses a variety of therapeutic properties, including anti-inflammatory, antioxidant, antibacterial, and anticarcinogenic activities. The present study aims to assess the medicinal benefits of piperine as an anti-diarrheal agent in a chick model by utilizing in vivo and in silico techniques. For this, castor oil was administered orally to 2-day-old chicks to cause diarrhea. Bismuth subsalicylate (10 mg/kg), loperamide (3 mg/kg), and nifedipine (2.5 mg/kg) were used as positive controls, while the vehicle was utilized as a negative control. Two different doses (25 and 50 mg/kg b.w.) of the test sample (piperine) were administered orally, and the highest dose was tested with standards to investigate the synergistic activity of the test sample. In our findings, piperine prolonged the latent period while reducing the number of diarrheal feces in the experimental chicks during the monitoring period (4 h). At higher doses, piperine appears to reduce diarrheal secretion while increasing latency in chicks. Throughout the combined pharmacotherapy, piperine outperformed bismuth subsalicylate and nifedipine in terms of anti-diarrheal effects with loperamide. In molecular docking, piperine exhibited higher binding affinities towards different inflammatory enzymes such as cyclooxygenase 1 (-7.9 kcal/mol), cyclooxygenase 2 (-8.4 kcal/mol), nitric oxide synthases (-8.9 kcal/mol), and L-type calcium channel (-8.8 kcal/mol), indicating better interaction of PP with these proteins. In conclusion, piperine showed a potent anti-diarrheal effect in castor oil-induced diarrheal chicks by suppressing the inflammation and calcium ion influx induced by castor oil.

Neurotoxicity of Synthetic Cathinones / Neurotoksycznosc syntetycznych katynonów.

Synthetic cathinones are the group of the most frequently identified so-called new psychoactive substances with a strong stimulating effect and high addictive potential. It is now believed that the use of these compounds increases the risk of sporadic forms of neurodegenerative diseases. The article presents current views on the mechanisms of neurotoxicity of synthetic cathinones, including: blood-brain barrier damage, mitochondrial dysfunction, oxidative stress, neuroinflammation and hyperthermia. Further understanding of the cellular and molecular processes underlying neurotoxicity and associated clinical manifestations is essential in the development of therapeutic strategies for the prevention and treatment of neuropsychiatric disorders resulting from the intake of synthetic cathinones.

Nicotine receptor partial agonists for smoking cessation.

BACKGROUND: Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist). This is an update of a Cochrane Review first published in 2007. OBJECTIVES: To assess the effectiveness of nicotine receptor partial agonists, including varenicline and cytisine, for smoking cessation. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's Specialised Register in April 2022 for trials, using relevant terms in the title or abstract, or as keywords. The register is compiled from searches of CENTRAL, MEDLINE, Embase, and PsycINFO.  SELECTION CRITERIA: We included randomised controlled trials that compared the treatment drug with placebo, another smoking cessation drug, e-cigarettes, or no medication. We excluded trials that did not report a minimum follow-up period of six months from baseline. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods. Our main outcome was abstinence from smoking at longest follow-up using the most rigorous definition of abstinence, preferring biochemically validated rates where reported. We pooled risk ratios (RRs), using the Mantel-Haenszel fixed-effect model. We also reported the number of people reporting serious adverse events (SAEs). MAIN RESULTS: We included 75 trials of 45,049 people; 45 were new for this update. We rated 22 at low risk of bias, 18 at high risk, and 35 at unclear risk. We found moderate-certainty evidence (limited by heterogeneity) that cytisine helps more people to quit smoking than placebo (RR 1.30, 95% confidence interval (CI) 1.15 to 1.47; I2 = 83%; 4 studies, 4623 participants), and no evidence of a difference in the number reporting SAEs (RR 1.04, 95% CI 0.78 to 1.37; I2 = 0%; 3 studies, 3781 participants; low-certainty evidence). SAE evidence was limited by imprecision. We found no data on neuropsychiatric or cardiac SAEs. We found high-certainty evidence that varenicline helps more people to quit than placebo (RR 2.32, 95% CI 2.15 to 2.51; I2 = 60%, 41 studies, 17,395 participants), and moderate-certainty evidence that people taking varenicline are more likely to report SAEs than those not taking it (RR 1.23, 95% CI 1.01 to 1.48; I2 = 0%; 26 studies, 14,356 participants). While point estimates suggested increased risk of cardiac SAEs (RR 1.20, 95% CI 0.79 to 1.84; I2 = 0%; 18 studies, 7151 participants; low-certainty evidence), and decreased risk of neuropsychiatric SAEs (RR 0.89, 95% CI 0.61 to 1.29; I2 = 0%; 22 studies, 7846 participants; low-certainty evidence), in both cases evidence was limited by imprecision, and confidence intervals were compatible with both benefit and harm. Pooled results from studies that randomised people to receive cytisine or varenicline showed that more people in the varenicline arm quit smoking (RR 0.83, 95% CI 0.66 to 1.05; I2 = 0%; 2 studies, 2131 participants; moderate-certainty evidence) and reported SAEs (RR 0.67, 95% CI 0.44 to 1.03; I2 = 45%; 2 studies, 2017 participants; low-certainty evidence). However, the evidence was limited by imprecision, and confidence intervals incorporated the potential for benefit from either cytisine or varenicline. We found no data on neuropsychiatric or cardiac SAEs. We found high-certainty evidence that varenicline helps more people to quit than bupropion (RR 1.36, 95% CI 1.25 to 1.49; I2 = 0%; 9 studies, 7560 participants), and no clear evidence of difference in rates of SAEs (RR 0.89, 95% CI 0.61 to 1.31; I2 = 0%; 5 studies, 5317 participants), neuropsychiatric SAEs (RR 1.05, 95% CI 0.16 to 7.04; I2 = 10%; 2 studies, 866 participants), or cardiac SAEs (RR 3.17, 95% CI 0.33 to 30.18; I2 = 0%; 2 studies, 866 participants). Evidence of harms was of low certainty, limited by imprecision. We found high-certainty evidence that varenicline helps more people to quit than a single form of nicotine replacement therapy (NRT) (RR 1.25, 95% CI 1.14 to 1.37; I2 = 28%; 11 studies, 7572 participants), and low-certainty evidence, limited by imprecision, of fewer reported SAEs (RR 0.70, 95% CI 0.50 to 0.99; I2 = 24%; 6 studies, 6535 participants). We found no data on neuropsychiatric or cardiac SAEs. We found no clear evidence of a difference in quit rates between varenicline and dual-form NRT (RR 1.02, 95% CI 0.87 to 1.20; I2 = 0%; 5 studies, 2344 participants; low-certainty evidence, downgraded because of imprecision). While pooled point estimates suggested increased risk of SAEs (RR 2.15, 95% CI 0.49 to 9.46; I2 = 0%; 4 studies, 1852 participants) and neuropsychiatric SAEs (RR 4.69, 95% CI 0.23 to 96.50; I2 not estimable as events only in 1 study; 2 studies, 764 participants), and reduced risk of cardiac SAEs (RR 0.32, 95% CI 0.01 to 7.88; I2 not estimable as events only in 1 study; 2 studies, 819 participants), in all three cases evidence was of low certainty and confidence intervals were very wide, encompassing both substantial harm and benefit. AUTHORS' CONCLUSIONS: Cytisine and varenicline both help more people to quit smoking than placebo or no medication. Varenicline is more effective at helping people to quit smoking than bupropion, or a single form of NRT, and may be as or more effective than dual-form NRT. People taking varenicline are probably more likely to experience SAEs than those not taking it, and while there may be increased risk of cardiac SAEs and decreased risk of neuropsychiatric SAEs, evidence was compatible with both benefit and harm. Cytisine may lead to fewer people reporting SAEs than varenicline. Based on studies that directly compared cytisine and varenicline, there may be a benefit from varenicline for quitting smoking, however further evidence could strengthen this finding or demonstrate a benefit from cytisine. Future trials should test the effectiveness and safety of cytisine compared with varenicline and other pharmacotherapies, and should also test variations in dose and duration. There is limited benefit to be gained from more trials testing the effect of standard-dose varenicline compared with placebo for smoking cessation. Further trials on varenicline should test variations in dose and duration, and compare varenicline with e-cigarettes for smoking cessation.

A narrative review of the neuropharmacology of synthetic cathinones-Popular alternatives to classical drugs of abuse.

OBJECTIVE: To review the literature on the neuropharmacology of synthetic cathinones. METHODS: A comprehensive literature search was carried out across multiple databases (mainly PubMed, World Wide Web, and Google Scholar) using relevant keywords. RESULTS: Cathinones exhibit a broad toxicological profile, mimicking the effects of a wide variety of 'classic drugs' such as 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine and cocaine. Even small structural changes affect their interactions with key proteins. This article reviews existing knowledge of the mechanisms of action of cathinones at the molecular level, and key findings from research on their structure-activity relationship. The cathinones are also classified according to their chemical structure and neuropharmacological profiles. CONCLUSIONS: Synthetic cathinones represent one of the most numerous and widespread groups among new psychoactive substances. Initially developed for therapeutic purposes, they quickly started to be used recreationally. With a rapidly increasing number of new agents entering the market, structure-activity relationship studies are valuable for assessing and predicting the addictive potential and toxicity of new and potential future substances. The neuropharmacological properties of synthetic cathinones are still not fully understood. A full elucidation of the role of some key proteins, including organic cation transporters, requires detailed studies.

Synthetic Cathinone-Induced Myocarditis and Psychosis: A Case Report.

Psychoactive substances are a diverse group of chemical substances that are ever-evolving structurally. Novel psychoactive substances are being reported in and are becoming increasingly popular in East and Southeast Asia, with synthetic cathinones becoming the drugs of choice. The use of synthetic cathinones has increased significantly over the years. However, the easy accessibility of these substances and their potentially damaging health effects have raised many concerns. Herein, we present the case of a patient who ingested mixed synthetic cathinones and eventually developed acute myocarditis and subsequent psychotic symptoms. The delayed presentation of psychosis coupled with initial cardiovascular symptoms was a unique phenomenon, making differential diagnosis challenging. The association between the use of synthetic cathinones and psychosis and myocarditis should be explored in view of the lack of relevant clinical data and potentially dire outcomes.

Development of microparticles and microparticulated tablets containing piperine

Abstract Piper nigrum (black pepper) is used in Indian traditional medicine and its main alkaloid, Piperine (PIP), presents antioxidant, antitumor and neuroprotective pharmacological properties. This substance is insoluble in aqueous media and can irritate the gastrointestinal tract. Aiming to avoid these inconvenient characteristics and enable PIP oral administration, this study suggested the PIP microencapsulation through the emulsion-solvent evaporation method and the preparation of microparticulated tablets by direct compression. An UV-spectroscopy method was validated to quantify PIP. Microparticles and microparticulated tablets were successfully obtained and the microparticles exhibited excellent flow. The scanning electron microscopy images showed that PIP microparticles were intact after compression. The in vitro release showed a controlled release of PIP from microparticles and PIP microparticles from tablets in comparison to PIP and PIP tablets. The release profiles of PIP microparticles and the microparticulated tablets were similar. Therefore, tablets containing PIP microparticles are promising multiparticulated dosage forms because a tablet allows microparticles administration and the intact ones promote a controlled release, decreasing its irritating potential on the mucosa.

Synthetic cathinones and cardiotoxicity risks.

Abstract: Recently, there has been a worldwide rise in the popularity and abuse of synthetic cathinones. The spectrum of side effects caused by the intake of these drugs of abuse is very wide since they act on different systems with various mechanisms of action, they appear to be involved in different cardiac events, including myocardial infarction and sudden cardiac death due to fatal arrhythmias. Overall, khat users have a higher risk of death, recurrent myocardial ischemia, cardiogenic shock, ventricular arrhythmia, and stroke compared with non-khat user.

Cytisine Therapy Improved Smoking Cessation in the Randomized Screening and Multiple Intervention on Lung Epidemics Lung Cancer Screening Trial.

INTRODUCTION: Cytisine, a partial agonist-binding nicotine acetylcholine receptor, is a promising cessation intervention. We conducted a single-center, randomized, controlled trial (RCT) in Italy to assess the efficacy and tolerability of cytisine as a smoking cessation therapy among lung cancer screening participants. METHODS: From July 2019 to March 2020, the Screening and Multiple Intervention on Lung Epidemics RCT enrolled 869 current heavy tobacco users in a low-dose computed tomography screening program, with a randomized comparison of pharmacologic intervention with cytisine plus counseling (N = 470) versus counseling alone (N = 399). The primary outcome was continuous smoking abstinence at 12 months, biochemically verified through carbon monoxide measurement. RESULTS: At the 12-month follow-up, the quit rate was 32.1% (151 participants) in the intervention arm and 7.3% (29 participants) in the control arm. The adjusted OR of continuous abstinence was 7.2 (95% confidence interval: 4.6-11.2). Self-reported adverse events occurred more frequently in the intervention arm (399 events among 196 participants) than in the control arm (230 events among 133 participants, p < 0.01). The most common adverse events were gastrointestinal symptoms, comprising abdominal swelling, gastritis, and constipation. CONCLUSIONS: The efficacy and safety observed in the Screening and Multiple Intervention on Lung Epidemics RCT indicate that cytisine, a very low-cost medication, is a useful treatment option for smoking cessation and a feasible strategy to improve low-dose computed tomography screening outcomes with a potential benefit for all-cause mortality.

New steroidal alkaloids with anti-inflammatory and analgesic effects from Veratrum grandiflorum.

ETHNOPHARMACOLOGICAL RELEVANCE: "Li-Lu", the roots and rhizomes of Veratrum grandiflorum (Melianthiaceae), has been historically used as a traditional folk medicine for the treatment of wrist pain, fractures, sores, and inflammation in Yunnan Province, China. However, the anti-inflammatory and analgesic studies of this plant have seldom reported. AIM OF THE STUDY: To evaluate the anti-inflammatory and analgesic properties related to the traditional usage of V. grandiflorum both in vitro and in vivo, and further explore the accurate bioactive compounds from the medicinal plant. MATERIALS AND METHODS: Phytochemical investigation was carried out by chromatographic methods and their structures were established based on extensive spectra and comparison with corresponding data in the reported literatures. Anti-inflammatory activities were assessed by the suppression of lipopolysaccharide-activated inflammatory mediators in RAW 264.7 macrophage cells in vitro. Furthermore, anti-inflammatory and analgesic effects were evaluated based on carrageenan-induced paw edema and acetic acid-stimulated writhing in mice. RESULTS: The methanol extract (ME) of V. grandiflorum significantly alleviated the paw edema caused by carrageenan and the writhing numbers induced by acetic acid. Subsequent phytochemical investigation led to isolated of 21 steroidal alkaloids, including seven new compounds, veragranines C-I (1-7). Anti-inflammatory test indicated that steroidal alkaloids could decrease the expression of cyclooxygenase-2 (COX-2), interleukin-1ß (IL-1ß), and tumor necrosis factor α (TNF-α) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells at a concentration of 5.0 µg/ml in vitro, comparable to DXM. Moreover, five new steroidal alkaloids (2, 4, 5, 6, and 7) and two major steroidal alkaloids (9 and 13) significantly decreased the numbers of writhing in mice at the doses of 0.5 and/or 1.0 mg/kg (p < 0.01/0.05), roughly comparable to Dolantin™ at 10.0 mg/kg. CONCLUSIONS: The investigation supported the traditional use of V. grandiflorum and provided new steroidal alkaloids as potent analgesic agents.

Multiple targets of Nrf 2 inhibitor; trigonelline in combating urethane-induced lung cancer by caspase-executioner apoptosis, cGMP and limitation of cyclin D1 and Bcl2.

OBJECTIVE: Among other types of cancerous lesions, lung cancer is one of the prevalent causes of death. Trigonelline is a plant alkaloid, a significant constituent in coffee, and has shown health benefits in several disorders. The present study aims to investigate the potential therapeutic role of trigonelline in lung cancer. MATERIALS AND METHODS: Seventy-five BALB/C mice were assigned to five groups and treated for 150 days as follows (1): normal control group; (2) trigonelline only (50 mg/kg/ P.O) daily for the last thirty days; (3) urethane (1.5 g/kg B.w/i.p) at day one and sixty; (4) urethane and carboplatin (15 mg/kg i.p) for the last thirty days; and (5) urethane and trigonelline for the last thirty days. Tumor size was measured while blood and lung were collected for biochemical, western blotting analysis, and histological examinations. RESULTS: Urethane demonstrated significant changes in all biochemical and molecular parameters and histological examinations. In animals pretreated with urethane, trigonelline significantly reduced tumor size and restored Nrf2, NF-кB p65, Bcl-2, Cyclin D1, ICAM-1, and MMP-2, along with improving cGMP and active caspase three and refining histological architectures. CONCLUSIONS: Nrf2 signaling may be a promising therapeutic target for adenocarcinoma protection or management. Due to its multiple therapeutic effects on Nrf2, cyclin D1, NF-кB pathways, and the BAX/Bcl2 axis, trigonelline significantly induced cell cycle arrest and apoptosis.https://www.europeanreview.org/wp/wp-content/uploads/Graphical_Abstract-1.jpg.

The inhibition of interaction with serum albumin enhances the physiological activity of curcumin by increasing its cellular uptake.

Based on the free drug hypothesis, we hypothesized that food compounds that bind stronger to BSA than CUR inhibit the binding between BSA and CUR, and that this results in an increase of the cellular uptake and physiological activities of CUR. To verify this hypothesis, food compounds that bind stronger to BSA than CUR were identified. When THP-1 monocytes were co-treated with the identified compounds (e.g., piperine) and CUR, cell viability significantly decreased, suggesting that the physiological activity of CUR was enhanced. Also, when THP-1 macrophages were co-treated with CUR and the identified compounds following LPS + IFNγ treatment, the decrement of TNF-α was higher compared to treatment with CUR only. Furthermore, the cellular uptake of CUR was increased during this co-treatment. Such results verify our hypothesis, and provide insights into the development of ways to enhance the physiological activities of various food compounds via focusing on their interaction with albumin.

Intoxicación severa por Nicotiana glauca (Palán Palán) con miocardio atontado / Severe poisoning by Nicotiana glauca (Palán Palán) with stunned myocardium

Resumen Nicotiana glauca también llamada Palán Palán, es un arbusto con hojas verdes azuladas y despulidas y una flor amarilla tubular pendulante que presenta alcaloides piridínicos, como nicotina, nornicotina, anatabina y anabastina (análogo estructural de la Nicotina). Se presenta el caso clínico de una paciente de 50 años con cuadro agudo de debilidad muscular generalizada que evoluciona con paro respiratorio, tras la ingesta accidental de una cantidad desconocida de hojas de Nicotiana glauca, cultivadas en una huerta hogareña mediante técnica de hidroponía y confundidas por su conviviente con espinaca. Presentó aumento de lactato y Troponina Ultra Sensible e Hipoquinesia Global de Ventrículo Izquierdo en el ecocardiograma, compatible con Aton tamiento Miocárdico (AM), que evolucionó favorablemente. Si bien hay pocos reportes, se han informado muertes de animales y humanos, tras la ingesta accidental de Nicotiana glauca. El inicio del cuadro es rápido, con patrón bifásico, con vómitos y estímulo simpático, seguido por bloqueo ganglionar y neuromuscular, pudiendo presentar paro respiratorio, shock, convulsiones y coma. El AM es una disfunción miocárdica prolongada con retorno gradual de la actividad contráctil, posterior a un episodio breve de isquemia grave, puede ser asintomático, pudiendo presentar alteraciones en el electrocardiograma, enzimas cardíacas o ecocardiograma. Generalmente presenta pronóstico favorable, pudiendo presentar insuficiencia cardíaca ante patologías concurrentes o aumento de requerimientos de oxígeno.

Abstract Nicotiana glauca is a shrub with bluish green leaves and a pendulous tubular yellow flower. It has pyridine alkaloids, such as nicotine, nornicotine, anatabine and anabastine (structural analog of Nicotine). We present the case of a 50 years old pa- tient with acute generalized muscle weakness that evolves to respiratory arrest, after accidentally ingesting an unknown quantity of Nicotiana glauca leaves, grown in a home vegetable garden, using a hydroponic technique and confused by her cohabiting with spinach. She presented increased lactate and Ultra Sensitive Troponin and Left Ventricular Global Hypokinesia in the echo- cardiogram, compatible with Myocardial Stunned, that it evolved favorably. There are few reports, animal and human deaths have been reported following accidental ingestion of Nicotiana glauca. The onset of the symptoms is early, with a biphasic pattern, with vomiting and sympathetic stimulation, followed by ganglionic and neuromuscular blockage and may present respiratory arrest, shock, seizures and coma. Myocardial Stunned is a prolonged myocardial dysfunction with gradual return of contractile activity after a brief episode of severe ischemia, it can be asymptomatic, and it can present alterations in the electrocardiogram, cardiac enzymes or echocardiogram. Generally presents a benign prognosis, being able to present heart failure with concurrent patholo- gies or increased requirements.

Effect of Cytisine vs Varenicline on Smoking Cessation: A Randomized Clinical Trial.

Importance: Cytisine is more effective than placebo and nicotine replacement therapy for smoking cessation. However, cytisine has not been tested against the most effective smoking cessation medication, varenicline, which is associated with adverse events known to lead to discontinuation of therapy. Objective: To examine whether standard cytisine treatment (25 days) was at least as effective as standard varenicline treatment (84 days) for smoking cessation. Design, Setting, and Participants: This noninferiority, open-label randomized clinical trial with allocation concealment and blinded outcome assessment was undertaken in Australia from November 2017 through May 2019; follow-up was completed in January 2020. A total of 1452 Australian adult daily smokers willing to make a quit attempt were included. Data collection was conducted primarily by computer-assisted telephone interview, but there was an in-person visit to validate the primary outcome. Interventions: Treatments were provided in accordance with the manufacturers' recommended dosage: cytisine (n = 725), 1.5-mg capsules taken 6 times daily initially then gradually reduced over the 25-day course; varenicline (n = 727), 0.5-mg tablets titrated to 1 mg twice daily for 84 days (12 weeks). All participants were offered referral to standard telephone behavioral support. Main Outcomes and Measures: The primary outcome was 6-month continuous abstinence verified using a carbon monoxide breath test at 7-month follow-up. The noninferiority margin was set at 5% and the 1-sided significance threshold was set at .025. Results: Among 1452 participants who were randomized (mean [SD] age, 42.9 [12.7] years; 742 [51.1%] women), 1108 (76.3%) completed the trial. Verified 6-month continuous abstinence rates were 11.7% for the cytisine group and 13.3% for the varenicline group (risk difference, -1.62% [1-sided 97.5% CI, -5.02% to ∞]; P = .03 for noninferiority). Self-reported adverse events occurred less frequently in the cytisine group (997 events among 482 participants) compared with the varenicline group (1206 events among 510 participants) and the incident rate ratio was 0.88 (95% CI, 0.81 to 0.95; P = .002). Conclusions and Relevance: Among daily smokers willing to quit, cytisine treatment for 25 days, compared with varenicline treatment for 84 days, failed to demonstrate noninferiority regarding smoking cessation. Trial Registration: anzctr.org.au Identifier: ACTRN12616001654448.

An updated review on synthetic cathinones.

Cathinone, the main psychoactive compound found in the plant Catha edulis Forsk. (khat), is a ß-keto analogue of amphetamine, sharing not only the phenethylamine structure, but also the amphetamine-like stimulant effects. Synthetic cathinones are derivatives of the naturally occurring cathinone that largely entered the recreational drug market at the end of 2000s. The former "legal status", impressive marketing strategies and their commercial availability, either in the so-called "smartshops" or via the Internet, prompted their large spread, contributing to their increasing popularity in the following years. As their popularity increased, the risks posed for public health became clear, with several reports of intoxications and deaths involving these substances appearing both in the social media and scientific literature. The regulatory measures introduced thereafter to halt these trending drugs of abuse have proved to be of low impact, as a continuous emergence of new non-controlled derivatives keep appearing to replace those prohibited. Users resort to synthetic cathinones due to their psychostimulant properties but are often unaware of the dangers they may incur when using these substances. Therefore, studies aimed at unveiling the pharmacological and toxicological properties of these substances are imperative, as they will provide increased expertise to the clinicians that face this problem on a daily basis. The present work provides a comprehensive review on history and legal status, chemistry, pharmacokinetics, pharmacodynamics, adverse effects and lethality in humans, as well as on the current knowledge of the neurotoxic mechanisms of synthetic cathinones.

The safety and tolerability of alkaloids from Alstonia scholaris leaves in healthy Chinese volunteers: a single-centre, randomized, double-blind, placebo-controlled phase I clinical trial.

CONTEXT: Capsule of alkaloids from the leaf of Alstonia scholaris (L.) R.Br. (Apocynaceae) (CALAS) is a new investigational botanical drug (No. 2011L01436) for bronchitis, post-infectious cough and asthma. OBJECTIVE: To observe the clinical safety and tolerability of CALAS. MATERIALS AND METHODS: Subjects were assigned to eight cohorts, and each received randomly CALAS or placebo in one of single ascending dose (SAD) of 8, 40, 120, 240, 360, 480, or in one of multiple ascending dose (MAD) of 40 or 120 mg, three times daily for 7 days. Each cohort contained two placebo subjects. RESULTS: Sixty-two enrolled volunteers completed the study and no serious adverse events and clinically significant changes in vital signs, electrocardiography, and upper abdominal Doppler ultrasonography were observed. The ratios of treatment-emergent adverse events (TEAEs) were reported in 11/46 (23.91%) of CALAS groups and 3/16 (18.75%) of the placebo group (p > 0.05), respectively, based on the results of SAD and MAD. All TEAEs were mild, transient, and disappeared without any intervention. The TEAEs possibly related to CALAS treatment were as followings: hiccups (4/46: 8%), dry mouth and nausea (3/46: 6%), increased sleep (2/46: 4%), abdominal distension (1/46: 2%), bilirubin elevated (1/46: 2%). DISCUSSION AND CONCLUSIONS: CALAS is safe and well-tolerated with no unexpected or clinically relevant safety concerns up to a single dose of 360 mg and three times daily for 7 days up to 120 mg in healthy Chinese volunteers, supporting further Phase II studies.

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.

Risk factors of poor prognosis in patients with pyrrolidine alkaloid-induced hepatic sinusoidal obstruction syndrome after transjugular intrahepatic portosystemic shunt.

AIMS: Transjugular intrahepatic portosystemic shunt (TIPS) is an effective method in treating patients with severe hepatic sinusoidal obstruction syndrome induced by pyrrolidine alkaloids (PA-HSOS). However, some patients still have poor postoperative prognosis. So, we aim to evaluate the predictors associated with poor outcomes in PA-HSOS patients receiving TIPS. METHODS: Patients who were diagnosed as PA-HSOS and received TIPS in our hospital between January 2013 and April 2019 were reviewed retrospectively. Baseline information and clinical data were collected. The hazard ratios (HRs) of factors associated with poor prognosis were analyzed by Cox proportional hazard analysis. The Kaplan-Meier method was used to analyze and compare the cumulative incidence of the poor results and survival rate of patients. RESULTS: During a median of 19.25-month follow-up, death occurred in 17 patients. We found that prothrombin time at baseline with an adjusted HR 1.110 (95% confidence interval 1.014-1.216, p = 0.024) and serum total bilirubin of 9 mg/dl 5 days after TIPS with an adjusted HR 1.114 (95% confidence interval 1.042-1.190, p = 0.001) were independent risk factors for death. The 1-year and 5-year survival rate were 86.2% and 82.1%, respectively. The 1-year survival rate in patients with prothrombin time > 17.85 s at baseline and serum total bilirubin > 9 mg/dl at 5 days after TIPS was significantly lower than that of patients below the corresponding threshold, respectively. CONCLUSIONS: Prolonged prothrombin time at baseline and increased serum total bilirubin levels 5 days after TIPS are independent risk factors for predicting death after TIPS treatment in PA-HSOS patients.