Tesofensine, a novel antiobesity drug, silences GABAergic hypothalamic neurons.

Obesity is a major global health epidemic that has adverse effects on both the people affected as well as the cost to society. Several anti-obesity drugs that target GLP-1 receptors have recently come to the market. Here, we describe the effects of tesofensine, a novel anti-obesity drug that acts as a triple monoamine neurotransmitter reuptake inhibitor. Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH). We found that tesofensine induces a greater weight loss in obese rats than lean rats, while differentially modulating the neuronal ensembles and population activity in LH. In Vgat-ChR2 and Vgat-IRES-cre transgenic mice, we found for the first time that tesofensine inhibited a subset of LH GABAergic neurons, reducing their ability to promote feeding behavior, and chemogenetically silencing them enhanced tesofensine's food-suppressing effects. Unlike phentermine, a dopaminergic appetite suppressant, tesofensine causes few, if any, head-weaving stereotypy at therapeutic doses. Most importantly, we found that tesofensine prolonged the weight loss induced by 5-HTP, a serotonin precursor, and blocked the body weight rebound that often occurs after weight loss. Behavioral studies on rats with the tastant sucrose indicated that tesofensine's appetite suppressant effects are independent of taste aversion and do not directly affect the perception of sweetness or palatability of sucrose. In summary, our data provide new insights into the effects of tesofensine on weight loss and the underlying neuronal mechanisms, suggesting that tesofensine may be an effective treatment for obesity and that it may be a valuable adjunct to other appetite suppressants to prevent body weight rebound.

Plain language review: what are biosimilar medicines and how can they be used to treat people with cancer?

WHAT IS THIS SUMMARY ABOUT?: The aim of this plain language review article is to help you to understand biosimilar medicines (called biosimilars) by giving a summary of biologic medicines and biosimilars. It is based on the experience of an international panel of physicians with expertise on biosimilars who discussed and agreed on the topics and information included in this review article. Biologic medicines are medicines that come from living organisms such as bacteria and animal or plant cells. Biosimilars are a group of approved biologic medicines that are similar to original biologic medicines that are already available. This review explains how biosimilars are developed and approved, and how they are used to treat people with cancer. It also answers some common important questions people with cancer might have when taking biosimilars. The purpose of this plain language review is to help you to understand the findings from recent research. This review reports information from peer-reviewed literature and other sources available in the public domain (e.g., regulatory documents or product information labels). The findings may differ from those of other review articles. Health professionals should make treatment decisions based on all available evidence.

Role of antioxidative activity in the docosahexaenoic acid's enteroprotective effect in the indomethacin-induced small intestinal injury model.

Therapeutic effect of non-steroidal anti-inflammatory drugs (NSAIDs) has been related with gastrointestinal injury. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (PUFA), can prevent gastric and small intestinal damage. Nonetheless, contribution of antioxidative action in the protective effect of DHA has not been evaluated before in the small intestine injury after indomethacin treatment. Pathogenesis of NSAID-induced small intestinal injury is multifactorial, and reactive oxidative species have been related to indomethacin's small intestinal damage. The present work aimed to evaluate antioxidative activity in the protective action of DHA in the indomethacin-induced small intestinal damage. Female Wistar rats were gavage with DHA (3 mg/kg) or omeprazole (3 mg/kg) for 10 days. Each rat received indomethacin (3 mg/kg, orally) daily to induce small intestinal damage. The total area of intestinal ulcers and histopathological analysis were performed. In DHA-treated rats, myeloperoxidase and superoxide dismutase activity, glutathione, malondialdehyde, leukotriene, and lipopolysaccharide (LPS) levels were measured. Furthermore, the relative abundance of selective bacteria was assessed. DHA administration (3 mg/kg, p.o.) caused a significant decrease in indomethacin-induced small intestinal injury in Wistar rats after 10 days of treatment. DHA's enteroprotection resulted from the prevention of an increase in myeloperoxidase activity, and lipoperoxidation, as well as an improvement in the antioxidant defenses, such as glutathione levels and superoxide dismutase activity in the small intestine. Furthermore, we showed that DHA's enteroprotective effect decreased significantly LPS levels in indomethacin-induced injury in small intestine. Our data suggest that DHA's enteroprotective might be attributed to the prevention of oxidative stress.

An international comparative analysis and roadmap to sustainable biosimilar markets.

Background: Although biosimilar uptake has increased (at a variable pace) in many countries, there have been recent concerns about the long-term sustainability of biosimilar markets. The aim of this manuscript is to assess the sustainability of policies across the biosimilar life cycle in selected countries with a view to propose recommendations for supporting biosimilar sustainability. Methods: The study conducted a comparative analysis across 17 countries from North America, South America, Asia-Pacific, Europe and the Gulf Cooperation Council. Biosimilar policies were identified and their sustainability was assessed based on country-specific reviews of the scientific and grey literature, validation by industry experts and 23 international and local non-industry experts, and two advisory board meetings with these non-industry experts. Results: Given that European countries tend to have more experience with biosimilars and more developed policy frameworks, they generally have higher sustainability scores than the other selected countries. Existing approaches to biosimilar manufacturing and R&D, policies guaranteeing safe and high-quality biosimilars, exemption from the requirement to apply health technology assessment to biosimilars, and initiatives counteracting biosimilar misconceptions are considered sustainable. However, biosimilar contracting approaches, biosimilar education and understanding can be ameliorated in all selected countries. Also, similar policies are sometimes perceived to be sustainable in some markets, but not in others. More generally, the sustainability of the biosimilar landscape depends on the nature of the healthcare system and existing pharmaceutical market access policies, the experience with biosimilar use and policies. This suggests that a general biosimilar policy toolkit that ensures sustainability does not exist, but varies from country to country. Conclusion: This study proposes a set of elements that should underpin sustainable biosimilar policy development over time in a country. At first, biosimilar policies should guarantee the safety and quality of biosimilars, healthy levels of supply and a level of cost savings. As a country gains experience with biosimilars, policies need to optimise uptake and combat any misconceptions about biosimilars. Finally, a country should implement biosimilar policies that foster competition, expand treatment options and ensure a sustainable market environment.

Effect of nitric oxide-cyclic GMP-K+ channel pathway blockers, naloxone and metformin, on the antinociception induced by the diuretic pamabrom.

Pamabrom is a diuretic that is effective in treating premenstrual syndrome and primary dysmenorrhea. The aim of this study was to examine the effect of metformin and modulators of the opioid receptor-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-K+ channel pathway on the local antinociception induced by pamabrom. The rat paw 1% formalin test was used to assess the effects. Rats were treated with local administration of pamabrom (200-800 µg/paw) or indomethacin (200-800 µg/paw). The antinociception of pamabrom or indomethacin was evaluated with and without the local pretreatment of the blockers. Local administration of pamabrom and indomethacin produced dose-dependent antinociception during the second phase of the test. Local pretreatment of the paws with naloxone (50 µg/paw), l-nitro-arginine methyl ester (10-100 µg/paw), or 1H-(1,2,4)-oxadiazolo[4,2-a]quinoxalin-1-one (10-100 µg/paw) reverted the antinociception induced by local pamabrom, but not of indomethacin. Similarly, the K+ channel blockers glibenclamide, glipizide, 4-aminopyridine, tetraethylammonium, charybdotoxin, or apamin reverted the pamabrom-induced antinociception, but not of indomethacin. Metformin significantly blocked the antinociception of pamabrom and indomethacin. Our data suggest that pamabrom could activate the opioid receptor-NO-cGMP-K+ channel pathway to produce its peripheral antinociception in the formalin test. Likewise, a biguanide-dependent mechanism could be activated by pamabrom and indomethacin to generate antinociception.

Medication errors in a children's inpatient antineoplastic chemotherapy facility.

BACKGROUND: Due to many antineoplastic drugs' toxicity and narrow therapeutic window, medication errors are a health concern in pediatric oncology patients. This study aimed to identify and classify medication errors in a pediatric inpatient chemotherapy facility and evaluate the outcomes of these medication errors. METHODS: We conducted an observational retrospective study over 5 months in a chemotherapy facility for pediatric patients. The evaluation consisted of the review of the available medical records. The medication errors detected were manually recorded in a medical logbook. The International Classification for Patient Safety was adjusted to our clinical setting for the analysis, the terminology, and the classification system. A descriptive analysis was performed. RESULTS: A total of 286 medical records were reviewed; one type of medication error was noted in at least 97.6%, and 962 errors were identified totally, with an overall rate of 3.36 errors per visit. Most errors occurred in the documentation stage (643; 66.8%), followed by the administration stage (227; 23.6%). Of all medication errors, 37.2% had the potential to cause injury, but only five reached the patient (0.5%), and only two (0.2%) resulted in a severe harmful incident. CONCLUSIONS: Medication errors were common, especially at the documentation stage. Better documentation strategies need to be implemented to reduce the rate of near misses and prevent potential adverse events.

INTRODUCCIÓN: Los errores de medicación son un problema de salud en niños con cáncer debido a la toxicidad y a la estrecha ventana terapéutica de muchos fármacos antineoplásicos. El objetivo de este estudio fue identificar y clasificar los errores de medicación en un centro de quimioterapia para pacientes pediátricos hospitalizados, así como evaluar los resultados de estos errores de medicación. MÉTODOS: Se llevó a cabo un estudio observacional retrospectivo realizado durante un periodo de 5 meses en un centro de quimioterapia para pacientes pediátricos. La evaluación consistió en la revisión de las historias clínicas disponibles. Los errores de medicación detectados fueron registrados manualmente en una bitácora. Para el análisis, la terminología y el sistema de clasificación, la Clasificación Internacional para la Seguridad del Paciente se ajustó a nuestro entorno clínico. Se realizó un análisis descriptivo. RESULTADOS: Se revisaron 286 historias clínicas; se observó un tipo de error de medicación al menos en el 97.6%. En total se identificaron 962 errores de medicación, con una tasa general de 3.36 errores por visita. En la etapa de documentación fue donde más errores ocurrieron (643; 66.8%), seguido de la etapa de administración (227; 23.6%). De todos los errores de medicación, el 37.2% tuvo el potencial de causar lesiones, pero solo cinco llegaron al paciente (0.5%) y solo dos (0.2%) provocaron un incidente dañino severo. CONCLUSIONES: Los errores de medicación fueron comunes, especialmente en la etapa de documentación. Es necesario implementar mejores estrategias de documentación para reducir la tasa de cuasi accidentes y prevenir posibles eventos adversos.

Medication errors in a children's inpatient antineoplastic chemotherapy facility / Errores de medicación en un centro de quimioterapia antineoplásica para pacientes pediátricos hospitalizados

Abstract Background: Due to many antineoplastic drugs' toxicity and narrow therapeutic window, medication errors are a health concern in pediatric oncology patients. This study aimed to identify and classify medication errors in a pediatric inpatient chemotherapy facility and evaluate the outcomes of these medication errors. Methods: We conducted an observational retrospective study over 5 months in a chemotherapy facility for pediatric patients. The evaluation consisted of the review of the available medical records. The medication errors detected were manually recorded in a medical logbook. The International Classification for Patient Safety was adjusted to our clinical setting for the analysis, the terminology, and the classification system. A descriptive analysis was performed. Results: A total of 286 medical records were reviewed; one type of medication error was noted in at least 97.6%, and 962 errors were identified totally, with an overall rate of 3.36 errors per visit. Most errors occurred in the documentation stage (643; 66.8%), followed by the administration stage (227; 23.6%). Of all medication errors, 37.2% had the potential to cause injury, but only five reached the patient (0.5%), and only two (0.2%) resulted in a severe harmful incident. Conclusions: Medication errors were common, especially at the documentation stage. Better documentation strategies need to be implemented to reduce the rate of near misses and prevent potential adverse events.

Resumen Introducción: Los errores de medicación son un problema de salud en niños con cáncer debido a la toxicidad y a la estrecha ventana terapéutica de muchos fármacos antineoplásicos. El objetivo de este estudio fue identificar y clasificar los errores de medicación en un centro de quimioterapia para pacientes pediátricos hospitalizados, así como evaluar los resultados de estos errores de medicación. Métodos: Se llevó a cabo un estudio observacional retrospectivo realizado durante un periodo de 5 meses en un centro de quimioterapia para pacientes pediátricos. La evaluación consistió en la revisión de las historias clínicas disponibles. Los errores de medicación detectados fueron registrados manualmente en una bitácora. Para el análisis, la terminología y el sistema de clasificación, la Clasificación Internacional para la Seguridad del Paciente se ajustó a nuestro entorno clínico. Se realizó un análisis descriptivo. Resultados: Se revisaron 286 historias clínicas; se observó un tipo de error de medicación al menos en el 97.6%. En total se identificaron 962 errores de medicación, con una tasa general de 3.36 errores por visita. En la etapa de documentación fue donde más errores ocurrieron (643; 66.8%), seguido de la etapa de administración (227; 23.6%). De todos los errores de medicación, el 37.2% tuvo el potencial de causar lesiones, pero solo cinco llegaron al paciente (0.5%) y solo dos (0.2%) provocaron un incidente dañino severo. Conclusiones: Los errores de medicación fueron comunes, especialmente en la etapa de documentación. Es necesario implementar mejores estrategias de documentación para reducir la tasa de cuasi accidentes y prevenir posibles eventos adversos.

Pharmacogenomic study of anthracycline-induced cardiotoxicity in Mexican pediatric patients.

Background: The aim of this study was to evaluate the association between well-defined genetic risk variants in SLC28A3, RARG and UGT1A6 and anthracycline-induced cardiotoxicity in Mexican pediatric patients. Methods: We tested a cohort of 79 children treated with anthracyclines for the presence of SLC28A3-rs7853758, RARG-rs2229774 and UGT1A6-rs17863783. Results: The SLC28A3-rs7853758 variant was more frequent in this cohort, while the UGT1A6-rs17863783 and RARG-rs2229774 variants were present at lower frequencies. A clinically important decrease of fractional shortening was associated with SLC28A3-rs7853758 variant. Conclusion: In this cohort, 39.2% of patients carried the protective SLC28A3 variant. A small number of tested patients have the risk variants of UGT1A6 and RARG. None of the patients shared the two risk variants.

Comparing the copper binding features of alpha and beta synucleins.

Amyloid aggregation of α-synuclein (AS) is one of the hallmarks of Parkinson's disease (PD). Copper ions specifically bind at the N-terminus of AS, accelerating protein aggregation. Its protein homolog ß-synuclein (BS) is also a copper binding protein, but it inhibits AS aggregation. Here, a comparative spectroscopic study of the Cu2+ binding properties of AS and BS has been performed, using electronic absorption, circular dichroism (CD) and electronic paramagnetic resonance (EPR). Our comparative spectroscopic study reveals striking similarities between the Cu2+ binding features of the two proteins. The Cu2+ binding site at the N-terminal group of BS protein, modeled by the BS (1-15) fragment is identical to that of AS; however, its rate of reduction is three times faster as compared to the AS site, consistent with BS having an additional Met residue in its Met1-Xn-Met5-Xn-Met10 motif. The latter is also evident in the cyclic voltammetry studies of the Cu-BS complex. On the other hand, the Cu2+ binding features of the His site in both proteins, as modeled by AS(45-55) and BS(60-70), are identical, indicating that the shift in the His position does not affect its coordination features. Finally, replacement of Glu46 by Ala does not alter Cu2+ binding to the His site, suggesting that the familial PD E46K mutation would not impact copper-induced aggregation. While further studies of the redox activity of copper bound to His50 in AS are required to understand the role of this site in metal-mediated aggregation, our study contributes to a better understanding of the bioinorganic chemistry of PD.

Citral inhibits the nociception in the rat formalin test: effect of metformin and blockers of opioid receptor and the NO-cGMP-K+ channel pathway.

The objective of the present study was to scrutinize the effect of nitric oxide (NO), cyclic GMP (cGMP), potassium channel blockers, and metformin on the citral-produced peripheral antinociception. The rat paw 1% formalin test was used to assess nociception and antinociception. Rats were treated with local peripheral administration of citral (10-100 µg/paw). The antinociception of citral (100 µg/paw) was evaluated with and without the local pretreatment of naloxone, NG-L-nitro-arginine methyl ester (L-NAME, a NO synthesis inhibitor), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, a soluble guanylyl cyclase inhibitor), metformin, opioid receptors antagonists, and K+ channel blockers. Injection of citral in the rat paw significantly decreased the nociceptive effect of formalin administration during the two phases of the test. Local pretreatment of the paws with L-NAME and ODQ did not reduced the citral-induced antinociception. Glipizide or glibenclamide (Kir6.1-2; ATP-sensitive K+ channel blockers), tetraethylammonium or 4-aminopyridine (KV; voltage-gated K+ channel blockers), charybdotoxin (KCa1.1; big conductance calcium-activated K+ channel blocker), apamin (KCa2.1-3; small conductance Ca2+-activated K+ channel antagonist), or metformin, but not the opioid antagonists, reduced the antinociception of citral. Citral produced peripheral antinociception during both phases of the formalin test. These effects were due to the activation of K+ channels and a biguanide-dependent mechanism.

Role of the NO-cGMP-K+ channels pathway in the peripheral antinociception induced by α-bisabolol.

The aim of this study was to examine if the peripheral antinociception of α-bisabolol involves the participation of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) synthesis followed by K+ channel opening in the formalin test. Wistar rats were injected in the dorsal surface of the right hind paw with formalin (1%). Rats received a subcutaneous injection into the dorsal surface of the paw of vehicles or increasing doses of α-bisabolol (100-300 µg/paw). To determine whether the peripheral antinociception induced by α-bisabolol was mediated by either the opioid receptors or the NO-cGMP-K+ channels pathway, the effect of pretreatment (10 min before formalin injection) with the appropriate vehicles, naloxone, naltrexone, NG-nitro-l-arginine methyl ester (L-NAME), 1H-[1,2,4]-oxadiazolo[4,2-a]quinoxalin-1-one (ODQ), glibenclamide, glipizide, apamin, charybdotoxin, tetraethylammonium, or 4-aminopyridine on the antinociceptive effects induced by local peripheral α-bisabolol (300 µg/paw) were assessed. α-Bisabolol produced antinociception during both phases of the formalin test. α-Bisabolol antinociception was blocked by L-NAME, ODQ, and all the K+ channels blockers. The peripheral antinociceptive effect produced by α-bisabolol was not blocked by the opioid receptor inhibitors. α-Bisabolol was able to active the NO-cGMP-K+ channels pathway to produce its antinoceptive effect. The participation of opioid receptors in the peripheral local antinociception induced by α-bisabolol is excluded.

Toxicokinetics of temephos after oral administration to adult male rats.

Temephos (Tem) is the larvicide of choice to control mosquito transmission of dengue, Zika, and chikungunya. The toxicokinetic and toxicological information of temephos is very limited. The aim of this work was to determine the toxicokinetics and dosimetry of temephos and its metabolites. Male Wistar rats were orally administered temephos (300 mg/kg) emulsified with saline solution and sacrificed over time after dosing. Temephos and its metabolites were analyzed in blood and tissues by high performance liquid chromatography-diode array detector. At least eleven metabolites were detected, including temephos-sulfoxide (Tem-SO), temephos-oxon (Tem-oxon), temephos-oxon-sulfoxide (Tem-oxon-SO), temephos-oxon-SO-monohydrolyzed (Tem-oxon-SO-OH), 4,4´-thiodiphenol, 4,4´-sulfinyldiphenol, and 4,4´-sulfonyldiphenol or bisphenol S (BPS). The mean blood concentrations of temephos were fitted to a one-compartment model for kinetic analysis. At 2 h, the peak was reached (t1/2 abs = 0.38 h), and only trace levels were detected at 36 h (t1/2 elim = 8.6 h). Temephos was detected in all tissues and preferentially accumulated in fat. Temephos-sulfone-monohydrolyzed (Tem-SO2-OH) blood levels remained constant until 36 h and gradually accumulated in the kidney. Tem-oxon was detected in the brain, liver, kidney, and fat. Clearance from the liver and kidney were 7.59 and 5.52 ml/min, respectively. These results indicate that temephos is well absorbed, extensively metabolized, widely distributed and preferentially stored in adipose tissue. It is biotransformed into reactive metabolites such as Tem-oxons, Tem-dioxons, and BPS. Tem-SO2-OH, the most abundant metabolite of temephos, could be used as an exposure biomarker for toxicokinetic modeling. These results could provide critical insight into the dosimetry and toxicity of temephos and its metabolites.

Synergistic protective effects between docosahexaenoic acid and omeprazole on the gastrointestinal tract in the indomethacin-induced injury model.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used drugs due to their antipyretic, anti-inflammatory, and analgesic properties. However, NSAIDs can cause adverse reactions, mainly gastrointestinal damage. Omeprazole (OMP) exhibits gastroprotective activity, but its protection is limited at the intestinal level. For this reason, it is essential to utilize a combination of therapies that provide fewer adverse effects, such as the combined treatment of OMP and docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid with anti-inflammatory, analgesic, and gastroprotective activities. The objective of this study was to evaluate the pharmacological interaction between DHA and OMP in a murine model of indomethacin-induced gastrointestinal damage. The gastroprotective and enteroprotective effects of DHA (0.3-10 mg/kg, p.o.), OMP (1-30 mg/kg, p.o.), or the combination treatment of both compounds (3-56.23 mg/kg, p.o.) were evaluated in the indomethacin-induced gastrointestinal damage model (30 mg/kg, p.o.). Since DHA and OMP exhibited a protective effect in a dose-responsive fashion, the ED30 for each individual compound was determined and a 1:1 combination of DHA and OMP was tested. Isobolographic analysis was used to determine any pharmacodynamic interactions. Since the effective experimental dose ED30 (Zexp) of the combined treatment of DHA and OMP was lower than the theoretical additive dose (Zadd; p < .05) in both the stomach and small intestine their protective effects were considered synergistic. These results indicate that the synergistic protective effects from combined treatment of DHA and OMP could be ideal for mitigating damage generated by NSAIDs at the gastrointestinal level.

Pharmacokinetic evaluation of two pirfenidone formulations in patients with idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by an abnormal activation of lung epithelium and fibroblasts, as well as an excessive accumulation of extracellular matrix. Pirfenidone was introduced as a therapeutic option for IPF and chronic hypersensitive pneumonitis (cHP), a related disease. However, high plasma concentrations, which can be achieved even at recommended doses, are frequently associated with adverse events. Hence, an extended release formulation (XP), yielding lower peak plasma concentrations, has been developed. The aim of this study was to compare the pharmacokinetic properties of XP with those of the immediate (IR) formulation in patients with IPF or cHP. Data were analyzed using two pharmacokinetic approaches, conventional non compartmental analysis and a population analysis using the nonlinear mixed effects model technique. Results observed with both approaches were consistent. Drug exposure was similar with both formulations. However, XP exhibited less concentration fluctuations and a longer mean resident time. These results suggest that XP could be a feasible option to reduce adverse events associated to pirfenidone elevated concentrations. Nevertheless, efficacy studies are required to fully document the therapeutic potential of XP.

Participation of the opioid receptor - nitric oxide - cGMP - K+ channel pathway in the peripheral antinociceptive effect of nalbuphine and buprenorphine in rats.

The aim of this study was to examine if the peripheral antinociceptive effects of the opioid agonist/antagonist nalbuphine and buprenorphine involve the sequential participation of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) synthesis followed by K+ channel opening in the formalin test. Wistar rats (180-220 g) were injected in the dorsal surface of the right hind paw with formalin (1%). Rats received a subcutaneous (s.c.) injection into the dorsal surface of the paw of vehicles or increasing doses of nalbuphine (50-200 µg/paw) or buprenorphine (1-5 µg/paw) 20 min before formalin injection into the paw. Nalbuphine antinociception was reversed by the s.c. injection into the paw of the inhibitor of NO synthesis (NG-nitro-l-arginine methyl ester (L-NAME)), by the inhibitor of guanylyl cyclase (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)), by the Kir6.1-2, ATP-sensitive K+ channel inhibitors (glibenclamide and glipizide), by the KCa2.1-3, small conductance Ca2+-activated K+ channel blocker (apamin), by the KCa1.1, large conductance Ca2+-activated K+ channel blocker (charybdotoxin), and by the KV, voltage-dependent K+ channel inhibitors (4-aminopyridine (4-AP) and tetraethylammonium chloride (TEA)). The antinociceptive effect produced by buprenorphine was blocked by the s.c. injection of 4-AP and TEA but not by L-NAME, ODQ, glibenclamide, glipizide, apamin, or charybdotoxin. The present results provide evidence for differences in peripheral mechanisms of action between these opioid drugs.

Efficacy and safety of oral magnesium supplementation in reducing febrile neutropenia episodes in children with solid tumors treated with cisplatin-based chemotherapy: randomized clinical trial.

PURPOSE: Hypomagnesemia has been associated with febrile neutropenia (FN) in pediatric patients receiving cisplatin-based chemotherapy (CDDPBC). The primary aim was to determine whether oral magnesium supplementation reduces FN episodes in pediatric patients with solid tumors treated with CDDPBC. METHOD: This randomized clinical trial, with open-label, single-center, parallel group and superiority design was conducted in Hospital Infantil de Mexico Federico Gomez at Mexico City. Children ≥ 9 years with solid tumors that were to receive a CDDPBC cycle were invited to participate. Each chemotherapy cycle with CDDPBC was randomly assigned to receive oral magnesium supplementation (250 mg/day) or not receive magnesium supplementation (control group). Efficacy was determined by relative risks (RR) with 95% confidence intervals (95% CI) as well as with numbers needed to treat (NNT). Active surveillance was conducted to assess safety in both groups. Analyses were carried out by intention to treat. ClinicalTrials.gov number NCT03449693. RESULTS: One hundred and one chemotherapy cycles with CDDPBC were analyzed (50 in the magnesium supplement arm and 51 in control group). Baseline clinical characteristics were similar comparing both groups. Oral magnesium supplementation reduces FN episodes compared to control group [RR 0.53, (95% CI 0.32-0.89), NNT = 4]. In the supplemented group, patients had fewer episodes of septic shock secondary to FN [RR 0.43, (95% CI 0.02-0.94), NNT = 6] and FN appeared on average 5 days later (p = 0.031). Hypomagnesemia episodes and adverse events were similar across both groups. CONCLUSION: Oral supplementation with magnesium reduces FN episodes neutropenia in pediatric patients with solid tumors treated with CDDPBC.

The Challenges of Switching Therapies in an Evolving Multiple Biosimilars Landscape: A Narrative Review of Current Evidence.

With the increasing availability of biosimilars, the practice of switching therapies for non-medical reasons between an originator biologic and an analogous biosimilar has become more common. The evidence to support this practice mostly comes from single-switch randomized controlled trials (RCTs) and real-world (RW) evidence studies. However, as more biosimilars of the same originator enter the market, multiple switching events between originators and biosimilars is becoming a reality, despite limited evidence to support the efficacy and safety of such practice. Some countries have established guidelines, policies, or laws related to interchangeability and/or automatic substitution, whereas others have left these practices unregulated or controlled by other components of the healthcare system. Collectively, guidelines on single non-medical switching are often vague, with even less focus given to multiple non-medical switching, leaving this practice mostly unregulated. This narrative review will first discuss the current regulatory perspectives on non-medical switching and challenges associated with switching therapies, particularly with the availability of multiple biosimilars. We will then review the current evidence from RCTs and RW studies in the light of three different multiple-switch scenarios currently taking place in clinical practice: switching between an originator and a single biosimilar, switching between biosimilars of the same originator, and the clinical practice of switching back to the originator (i.e., switchbacks) after a failure of the initial non-medical switch to the analogous biosimilar.

Oral Ciprofloxacin Pharmacokinetics in Healthy Mexican Volunteers and Other Populations: Is There Interethnic Variability?

BACKGROUND: There is evidence that the pharmacokinetics of certain drugs in Mexicans may differ with respect to other ethnic groups. On the other hand, there is controversy about the existence of interethnic variability in the pharmacokinetics of ciprofloxacin. AIM OF THE STUDY: To study oral ciprofloxacin pharmacokinetics in Mexicans at various dose levels and make comparisons with other populations in order to gain insight on interethnic variability. METHODS: Healthy Mexican volunteers received oral ciprofloxacin as 250 mg and 500 mg immediate-release tablets or a 1,000 mg extended-release formulation. Plasma concentration against time curves were constructed, and pharmacokinetic parameters were compared with those reported for other populations. RESULTS: Ciprofloxacin pharmacokinetics in Mexicans was linear and no significant differences between males and females were detected. When several populations were compared, it appeared that bioavailability in Mexicans was similar to that of Caucasians, being lower than that of Asians. These variations were attenuated when data were normalized by body weight. CONCLUSIONS: Ciprofloxacin pharmacokinetics exhibit interethnic variability, Asians exhibiting an increased bioavailability with regard to Mexicans and Caucasians. Data suggest that these differences are due to body weight.