Evaluating the drug interactions in kratom usage: clinical application

Estetrol, a Natural Estrogen with Selective Tissue activity (NEST)

Agomelatine is a new agent with a unique pharmacological profile, as the first melatonergic antidepressant. Its antidepressant efficacy has been demonstrated in the treatment of major depressive disorder (MDD) at a dose of 25 mg/day. Expectations from antidepressant therapies now go beyond efficacy alone, to include advantages in tolerability and safety. Due to its pharmacological profile, agomelatine does not induce the side-effects typical of other therapies, such as selective serotonin reuptake inhibitors (i.e. gastrointestinal disorders, weight gain, serotonergic syndrome and insomnia). Moreover, a placebo-controlled trial in MDD comparing the effects of agomelatine and venlafaxine on sexual dysfunction (another significant side-effect with current antidepressant medications) indicated the very favourable profile of agomelatine; in the same study, there was similar antidepressant efficacy in the same two groups. A double-blind, placebo-controlled trial investigating the effect of abrupt cessation of treatment demonstrated the absence of discontinuation symptoms with agomelatine, which was in contrast with the results observed with paroxetine. The ability of an antidepressant to relieve sleep complaints with no sedative effects is a key advantage because sleep complaints are a major presenting feature of depression. Again due to its unique pharmacological profile, agomelatine has been shown to positively influence disturbed circadian rhythms in depressed patients by significantly improving all phases of disturbed sleep and the overall quality of sleep, with a favourable impact on daytime alertness. In conclusion, experience with agomelatine across a range of clinical studies suggests that this compound offers a novel approach to the treatment of depression combining efficacy, even in severe depression, with an extremely favourable side-effect profile and sleep regulation. These properties give agomelatine a definite clinical advantage in the treatment of depression.

appears neither logical nor beneficial to patients.

RationaleKetamine produces dissociative, psychomimetic, anxiolytic, antidepressant, and anesthetic effects in a dose dependent manner. It has a complex mechanism of action that involve alterations in other glutamate receptors. The metabotropic glutamate receptor 5 (mGluR5) has been investigated in relation to the psychotic and anesthetic properties of ketamine, while its role in mediating the therapeutic effects of ketamine remains unknown.ObjectivesWe investigated the role of mGluR5 on the antidepressant, anxiolytic and fear memory-related effects of ketamine in adult male Wistar rats.MethodsTwo sets of experiments were conducted. We first utilized the positive allosteric modulator CDPPB to investigate how acute mGluR5 activation regulates the therapeutic effects of ketamine (10 mg/kg). We then tested the synergistic antidepressant effect of mGluR5 antagonism and ketamine by combining MTEP with a sub-effective dose of ketamine (1 mg/kg). Behavioral despair, locomotor activity, anxiety-like behavior, and fear memory were respectively assessed in the forced swim test (FST), open field test (OFT), elevated plus maze (EPM), and auditory fear conditioning.ResultsEnhancing mGluR5 activity via CDPPB occluded the antidepressant effect of ketamine without changing locomotor activity. Furthermore, concomitant administration of MTEP and ketamine exhibited a robust synergistic antidepressant effect. The MTEP + ketamine treatment, however, blocked the anxiolytic effect observed by sole administration of MTEP or the low dose ketamine.ConclusionsThese findings suggest that suppressed mGluR5 activity is required for the antidepressant effects of ketamine. Consequently, the antagonism of mGluR5 enhances the antidepressant effectiveness of low dose ketamine, but eliminates its anxiolytic effects.

In order to improve medication safety, more epidemiological data on the prevalence and clinical relevance of drug interactions are required. We developed an interface for mass analysis using the Clinical Decision Support Software (CDSS) MediQ and a multidimensional classification (Zurich Interaction System (ZHIAS)) incorporating the Operational Classification of Drug Interactions (ORCA). These were applied to 359,207 cross-sectional prescriptions from 84,607 psychiatric inpatients collected through the international AMSP program. MediQ issued 2,308 "high" and 71,112 "average" danger interaction alerts. Among these, after ORCA reclassification, there were 151 contraindicated and 4,099 provisionally contraindicated prescriptions. The ZHIAS provided further detailed categorical information on recommended management and specific increased risks (QTc prolongation being the most frequent one) associated with interactions. We developed a highly efficient solution for the identification and classification of drug interactions in large prescription data sets; this solution may help to reduce the frequency of overalerting and improve acceptance of the efficacy of CDSS in reducing the occurrence of potentially harmful drug interactions.

POTENTIAL DRUG–DRUG INTERACTIONS IN PEOPLE LIVING WITH HIV/AIDS USING ANTIRETROVIRAL THERAPY AND PSYCHOTROPIC MEDICATIONS

The current study aimed at identifying and quantifying critical drug interactions in neurological inpatients using clinical decision support software (CDSS). Reclassification of interactions with a focus on clinical management aimed to support the development of CDSS with higher efficacy to reduce overalerting and improve medication safety in clinical practice. We conducted a cross-sectional study in consecutive patients admitted to the neurology ward of a tertiary care hospital. We developed a customized interface for mass analysis with the CDSS MediQ, which we used for automated retrospective identification of drug interactions during the first day of hospitalization. Interactions were reclassified according to the Zurich Interaction System (ZHIAS), which incorporates the Operational Classification of Drug Interactions (ORCA). Dose adjustments for renal impairment were also evaluated. In 484 patients with 2812 prescriptions, MediQ generated 8 "high danger," 518 "average danger," and 1233 "low danger" interaction alerts. According to ZHIAS, 6 alerts involved contraindicated and 33 alerts involved provisionally contraindicated combinations, and 327 alerts involved a conditional and 1393 alerts involved a minimal risk of adverse outcomes. Thirty-five patients (6.2%) had at least one combination that was at least provisionally contraindicated. ZHIAS also provides categorical information on expected adverse outcomes and management recommendations, which are presented in detail. We identified 13 prescriptions without recommended dose adjustment for impaired renal function. MediQ detected a large number of drug interactions with variable clinical relevance in neurological inpatients. ZHIAS supports the selection of those interactions that require active management, and the effects of its implementation into CDSS on medication safety should be evaluated in future prospective studies.

Background/Objectives: Solanum macrocarpon L. has been studied for its neuroprotective potential and memory-enhancing properties. Research suggests that bioactive compounds, including flavonoids, alkaloids, and phenolics, contribute to its cognitive benefits. These compounds may help protect against oxidative stress, neuroinflammation, and cholinergic dysfunction factors in memory impairment. This study was undertaken to investigate the effects of S. macrocarpon ethanolic leaf extract (SMEE) on the memory, anxiety-like behavior, and brain antioxidant status of scopolamine (SCOP, 100 μM)-induced amnesic zebrafish (Danio rerio) and thus to understand its possible mechanism of action. Methods: Adult zebrafish (n = 100) were divided into two cohorts (±SCOP) of five experimental groups: (I) control; (II) galantamine (GAL, 1 mg/L), serving as a positive control for both behavioral and biochemical assessments; (III-V) three groups treated with SMEE (1, 3, and 6 mg/L); (VI) scopolamine (SCOP, 100 μM); (VII) SCOP (100 μM) combined with GAL (1 mg/L); and (VIII-X) three groups treated with SCOP (100 μM) plus SMEE (1, 3, and 6 mg/L). The treatment lasted 23 days and amnesia was induced by a single dose of SCOP (100 μM) before testing. Results: The phenolic characterization from the samples was performed by using HPLC-PDA chromatography. Following HPLC analysis, an in silico pharmacokinetic evaluation was conducted using the ADMET model to investigate the pharmacological and toxicological profiles of the identified compounds. Spatial memory was evaluated through the Y-maze and novel object recognition (NOR) tests, while anxiety-like behavior was assessed using the novel tank diving test (NTT), novel approach test (NAT), and light-dark test (LDT). The zebrafish were euthanized, and homogenates of isolated brain samples were assayed for acetylcholinesterase (AChE) activity and brain antioxidant markers. The HPLC analysis revealed that the main major compounds in the extract were chlorogenic acid and rutin, both recognized for their significant antioxidant properties. Conclusions: SMEE enhanced memory by inhibiting AChE, alleviated SCOP-induced anxiety-like behavior, and significantly decreased oxidative stress markers. These findings support the potential role of SMEE in counteracting SCOP-induced cognitive and behavioral dysfunctions, related to dementia conditions.

693 Background: The purpose of this study was to develop and implement a procedure to reduce severe pain from pancreatic cancer due to overactive sympathetic nerve activity using transvascular radiofrequency (RF) nerve ablation. Methods: 20 patients with severe abdominal pain from unresectable pancreatic cancer were enrolled and 19 treated with transvascular energy. Angio-CT/MRI were used to assess the tumor and plan the procedure. After accessing the vessel through a standard transfemoral or transbrachial approach, transvascular RF energy was delivered via catheter sequentially to multiple sites, including the celiac trunk, common hepatic artery, and/or splenic artery. All treated patients were evaluated within 24 hours, after 24 hours, 7 days, 4-6 weeks, and 3-months post-procedure for the following outcomes: adverse events, pain severity (VAS, 1-10), quality of life assessment (EORTC-30, 0-7), and opioid use. Results: Responding femoral patients (N=16) represented 84% of treated patients with a mean pain reduction of 4.16 on the VAS pain scale (baseline of 7.81 to 3.65), or 53.3% improvement, at 7-days post-procedure. At 4-6 weeks post-procedure, responding patients (N=9) reported a mean 4.67 reduction on the VAS pain scale (baseline of 7.89 to 3.22), or 59.2% improvement. 100% of responding patients were at zero opioid use at 7-days post-procedure, while 73% of responding patients (N=11) were at zero opioid use at 4-6 weeks post-procedure. In a post hoc analysis, pain reduction remained consistent at 3 months post-procedure, where surviving patients in the responder group (N=6) reported a mean pain reduction of 5.08 (baseline 7.75 to 2.67) or 65.6% improvement. In addition to lasting pain relief, all responding patients (N=6) experienced remarkable improvement in global health (mean 76.5% improvement), functional ability (mean 51.5% improvement), and symptom management (mean 50.4% improvement). Additionally, 100% of responding patients (N=7) were opioid free at their 3-month post-procedure follow-up which highlights the potential for a non-opioid alternative in a highly opioid-reliant disease. This procedure therefore has the potential to provide clinically significant and long-term pain relief, reduce the dependence on opioids for pain management, and improve day-to-day living during end-stage cancer. There were no device or procedure-related serious adverse events. The number of patients decreased over time due to natural disease progression, including deaths unrelated to the procedure or device. Conclusions: RF ablation of the somatosensory nerve via a transfemoral approach to the celiac plexus showed significant pain relief, improved quality of life, and reduced opioid use. These promising feasibility results prove that transvascular RF nerve ablation is both safe and effective in reducing severe pain from pancreatic carcinoma.

Functional expression of nicotinic acetylcholine receptors containing rat α7 subunits in human SH-SY5Y neuroblastoma cells

Aripiprazole (OPC-14597) is a novel antipsychotic agent with an unusual pharmacological profile that is atypical of compounds affecting the dopaminergic system. This agent is a quinolinone derivative related to OPC-4392 (Fig. 1). OPC-4392 acts on dopamine (DA) neurons and their nerve terminals as an autoreceptor agonist, eliciting inhibitory effects on ventral tegmental and nigral DA neurons (14,20). OPC-4392 has no postsynaptic DA receptor blocking activities (20). In clinical trials OPC-4392 improved the negative and the positive symptoms of chronic schizophrenic patients, such as hallucination, delusion, and psychiatric excitement. Similar effects on negative symptoms were observed with other DA autoreceptor agonists, such as EMD 49980, talipexole and terguride (8,20,17). Further attempts to develop a useful antipsychotic drug that displays both presynaptic DA agonistic and postsynaptic DA antagonistic activities and improves negative as well as positive symptoms in schizophrenic patients resulted in the discovery of aripiprazole. An early phase 11 clinical study on aripiprazole was recently performed in 56 schizophrenic patients by M. Toru et al. in Japan (24). According to the assessment by BPRS in this study, significant global improvement of negative symptoms (emotional withdrawal, motor retardation, blunted affect) and positive signs (suspiciousness, unusual thoughts, hallucinatory behaviors) was achieved. Negligible side effects, including mild extrapyramidal symptoms, were encountered. Aripiprazole may be considered a useful antipsychotic agent with a unique pharmacological profile.

β 2-agonists—from pharmacological properties to everyday clinical practice : Introduction

Background: Methadone maintenance treatment (MMT) is an effective treatment for opioid use disorder. However, subtherapeutic dosing may lead to continued opioid use by failing to suppress opioid withdrawal and craving. Preclinical and pilot experimental research suggests that cannabinoids may reduce opioid withdrawal and craving. We sought to test whether the association between low methadone dose and illicit opioid use differs according to concurrent cannabis use patterns. Methods: Data for this study were derived from two community-recruited cohorts of people (≥18 years old) who use illicit drugs in Vancouver, Canada. We used generalized estimating equations to estimate the adjusted association between lower daily MMT dose (<90 mg/day) and daily illicit opioid use, testing for interaction between dose and daily cannabis use. Results: Between December 2005 and December 2018, 1389 participants reported MMT enrolment and were included in the study. We observed a significant interaction (p<0.01) between daily cannabis and lower MMT dose on concurrent daily illicit opioid use: lower MMT doses increased the odds of daily illicit opioid use by 86% (adjusted odds ratio [AOR]=1.86, 95% confidence interval [CI]=1.61-2.16) during periods of no or low-frequency cannabis use and by 30% during periods of daily cannabis use (AOR=1.30, 95% CI=1.01-1.67). Discussion: This study provides preliminary observational evidence that cannabis may mitigate some of the negative effects of subtherapeutic MMT dosing, guiding future clinical investigations into the safety and efficacy of cannabis and cannabinoids as adjunct treatment for MMT.

There are few studies on the pharmacological properties of Valeriana prionophylla Standl. (VP), known as “Valeriana del monte”, and used in Mesoamerican folk medicine to treat sleep disorders. This study examines the pharmacological effects of the hydroalcoholic extract of the dry rhizome using the open field, rota rod, elevated plus-maze (EPM), forced swimming (FST), strychnine- and pentobarbital-induced sleeping time, PTZ-induced seizures, and the inhibitory avoidance tests. VP did not show any protective effect against PTZ-induced convulsions. In the EPM, exhibited an anxiolytic-like effect through the effective enhancement of the entries (38.5%) and time spent (44.7%) in the open arms, when compared with control group. Time spent and the numbers of entrances into the enclosed arms were decreased, similar to those effects observed with diazepam. In the FST, acute treatment with VP, produced a dose-dependent decrease in immobility time, similarly to imipramine. VP also produced a significant dose-dependent decrease in the latency of sleeping time, while producing an increase in total duration of sleep; influenced memory consolidation of the animals only at lower doses, unlike those that produced anti-depressant and anxiolytic effects. In summary, the results suggest that VP presents several psychopharmacological activities, including anxiolytic, antidepressant, and hypno-sedative effects.

The opioid epidemic has had a significant, negative impact in the United States, and people living with HIV/AIDS (PLWHA) represent a vulnerable sub-population that is at risk for negative sequela from prolonged opioid use or opioid use disorder (OUD). PLWHA are known to suffer from HIV-related pain and are commonly treated with opioids, leading to subsequent addictive disorders. PLWHA and OUD are at an increased risk for attrition in the HIV care continuum, including suboptimal HIV laboratory testing, delayed entry into HIV care, and initiation or adherence to antiretroviral therapy. Barriers to OUD treatment, such as medication-assisted therapy, are also apparent for PLWHA with OUD, particularly those living in rural areas. Additionally, PLWHA and OUD are at a high risk for serious drug–drug interactions through antiretroviral-opioid metabolic pathway-related inhibition/induction, or via the human ether-a-go-go-related gene potassium ion channel pathways. HIV-associated neurocognitive disorders can also be potentiated by the off-target inflammatory effects of opioid use. PLWHA and OUD might require more intensive, individualized protocols to sustain treatment for the underlying opioid addiction, as well as to provide proactive social support to aid in improving patient outcomes. Advancements in the understanding and management of PLWHA and OUD are needed to improve patient care. This review describes the effects of prescription and non-prescription opioid use in PLWHA.