Efficacy and safety of fenfluramine in the treatment of Dravet syndrome - literature review

Dravet Syndrome is a severe, drug-resistant, and rare epileptiform disorder that is typically presented in the first year of life in an otherwise healthy child. It is characterized by prolonged seizures that are often resistant to current anti-epileptic drug regimens, which made them poorly controlled, and almost 50% of patients experience at least four tonic-clonic seizures per month. There are three new medicines: stiripentol, cannabidiol, and fenfluramine, with documented efficacy and safety as adjunctive therapies in pharmacoresistant Dravet syndrome treatment. This study aimed to assess the efficacy and safety of fenfluramine in the treatment of Dravet syndrome. Our study material consisted of publications, which were found in PubMed, Google Scholar, and Embase databases. In order to find the proper publications, the search has been conducted with the use of a combination of keywords like: “fenfluramine”, “Dravet syndrome”, “epilepsy treatment”, “Dravet syndrome pediatric patients”. The first step was to find proper publications from the last 10 years. The second step was to carry out an overview of the found publications. Results of mentioned studies proved that in Dravet syndrome, fenfluramine provided a significantly greater reduction in convulsive seizure frequency compared with placebo. No patient developed valvular heart disease or pulmonary arterial hypertension, the side effects that occurred during its use were mild and the drug was generally well-tolerated. The bioequivalence and tolerability of single oral doses of fenfluramine hydrochloride oral solution in the fed and fasted states support drug administration without regard to meals. Fenfluramine may represent a new important treatment option for Dravet syndrome.

How I Treat Relapsed Multiple Myeloma

Despite recent advances multiple myeloma remains an incurable disease for most of the patients and initial remission will be followed by relapses requiring therapy. For many, there will be several remissions and relapses until resistance develops to all available therapies. With the introduction of several new agents, myeloma treatment has changed drastically and there are new options for the management of relapsed or refractory disease, including new drug classes with distinct mechanisms of action and cellular therapies. However, resistance to major drug classes used in first line remain the most critical factor for the choice of treatment at relapse. Continuous lenalidomide-based therapy is used extensively at first line and resistance to lenalidomide has become the key factor for the choice of salvage therapy. Daratumumab is increasingly used in first line and soon patients that relapse while on daratumumab will become a common challenge. Three-drug regimens are standard approach to manage relapsed disease. Adding drugs with new mechanisms of activity can improves outcomes and overcomes class resistance but, until now, while the biology is important, can offer only limited guidance for the choice of therapy.

Nutraceuticals for Prevention of Chemotherapy-Induced Peripheral Neuropathy

A wide range of neurologic complications, including central neurotoxicity conditions and peripheral neurotoxicity, are associated with antineoplastic drug regimens. Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common and severe cancer treatment-related adverse effect, as well as the most diffuse type of neurotoxicity, because about one third of all patients who undergo chemotherapy may experience this side effect. CIPN can negatively impact the long-term quality of life of cancer survivors, and can lead to dose reduction of the chemotherapy agent, or possible cessation of treatment. Unfortunately, although several agents and protocols have been proposed, no prophylactic strategies have proven useful yet. Therefore, new alternative therapies have been considered for CIPN prevention. In this chapter, the authors analyze the potential applications of nutrients, dietary supplements and herbal products, such as single herbs, the Kampo medicine goshajinkigan and other herbal combinations, for CIPN prevention.

A review on liposomal amphotericin b in antifungal therapy

To reduce the in-vivo toxicity of the broad-spectrum antifungal drug amphotericin B, various lipid formulations of amphotericin B, ranging from lipid complexes to small unilamellar liposomes, have been developed and subsequently commercialized. These structurally diverse formulations differ in their serum pharmacokinetics as well as their tissue localization, tissue retention, and toxicity. This difference can affect the choice of formulation for a given infection, the time of initiation of treatment, and the dosing regimen. Although preclinical studies have shown similarities in the in-vitro and in-vivo antifungal activity of the formulations with comparable dosing, their acute, and chronic toxicity. Profiles are not the same, and this has a significant impact on their therapeutic indices, especially in high-risk, immunosuppressed patients. With the recent introduction of new antifungal drugs to treat the increasing numbers of infected patients, the amphotericin B lipid formulations are now being studied to evaluate their potential in combinational drug regimens. With proven efficacy demonstrated during the past decade, it is expected that amphotericin B lipid formulations will remain an important part of antifungal drug therapy.

Comparison of the Effects of Oral Midazolam and Intranasal Dexmedetomidine on Preoperative Sedation and Anesthesia Induction in Children Undergoing Surgeries

Background and Purpose: Premedication with either oral midazolam or intranasal dexmedetomidine prior to surgery remains less than ideal. The aim of this study was to investigate whether the combination of those two drug regimens would have any beneficial effects on the preoperative sedation and the children’s compliance during anesthesia inhalation induction.Experimental Approach: One hundred thirty-eight children aged 2–6 years were randomly allocated into three groups: Group M with oral midazolam 0.5 mg kg−1, Group D with intranasal dexmedetomidine 2 μg kg−1, and Group M + D with intranasal dexmedetomidine 1 μg kg−1 plus oral midazolam 0.5 mg kg−1. The primary outcome was the children’s compliance during inhalation induction with sevoflurane. The secondary outcomes included the preoperative sedative effects, behavior scores, parental separation anxiety scores, and the postoperative incidence of emergence agitation and recovery time.Results: Subjects in Group M + D showed higher satisfaction scores of compliance (p = 0.0049) and mask acceptance (MAS) (p = 0.0049) during anesthesia inhalation induction. Subjects in Group M + D had a significantly shorter time than those in Groups M and D to achieve the desired sedation level (p < 0.001) and remained at a higher sedation score in the holding area and up to the anesthesia induction after drug administration (p < 0.001).Conclusion and Implications: We conclude that pediatric patients premedicated with intranasal dexmedetomidine 1 μg kg−1 plus oral midazolam 0.5 mg kg−1 had significantly improved anesthesia induction compliance, and quicker onset to achieve and maintain a satisfactory level of sedation than those premedicated separately with two drugs. Therefore, the combined premed regimen is a greater choice when we are expecting a higher quality of sedation and a smoother anesthesia induction in children undergoing the surgeries.

Mathematical characterization of population dynamics in breast cancer cells treated with doxorubicin

The development of chemoresistance remains a significant cause of treatment failure in breast cancer. We posit that a mathematical understanding of chemoresistance could assist in developing successful treatment strategies. Towards that end, we have developed a model that describes the effects of the standard chemotherapeutic drug doxorubicin on the MCF-7 breast cancer cell line. We assume that the tumor is composed of two subpopulations: drug-resistant cells, which continue proliferating after treatment, and drug-sensitive cells, which gradually transition from proliferating to treatment-induced death. The model is fit to experimental data including variations in drug concentration, inter-treatment interval, and number of doses. Our model recapitulates tumor growth dynamics in all these scenarios (as quantified by the concordance correlation coefficient, CCC > 0.95). In particular, superior tumor control is observed with higher doxorubicin concentrations, shorter inter-treatment intervals, and a higher number of doses (p < 0.05). Longer inter-treatment intervals require adapting the model parameterization after each doxorubicin dose, suggesting the promotion of chemoresistance. Additionally, we propose promising empirical formulas to describe the variation of model parameters as functions of doxorubicin concentration (CCC > 0.78). Thus, we conclude that our mathematical model could deepen our understanding of the effects of doxorubicin and could be used to explore practical drug regimens achieving optimal tumor control.

Nanoscale characterization of drug-induced microtubule filament dysfunction using super-resolution microscopy

Background The integrity of microtubule filament networks is essential for the roles in diverse cellular functions, and disruption of its structure or dynamics has been explored as a therapeutic approach to tackle diseases such as cancer. Microtubule-interacting drugs, sometimes referred to as antimitotics, are used in cancer therapy to target and disrupt microtubules. However, due to associated side effects on healthy cells, there is a need to develop safer drug regimens that still retain clinical efficacy. Currently, many questions remain open regarding the extent of effects on cellular physiology of microtubule-interacting drugs at clinically relevant and low doses. Here, we use super-resolution microscopies (single-molecule localization and optical fluctuation based) to reveal the initial microtubule dysfunctions caused by nanomolar concentrations of colcemid. Results We identify previously undetected microtubule (MT) damage caused by clinically relevant doses of colcemid. Short exposure to 30–80 nM colcemid results in aberrant microtubule curvature, with a trend of increased curvature associated to increased doses, and curvatures greater than 2 rad/μm, a value associated with MT breakage. Microtubule fragmentation was detected upon treatment with ≥ 100 nM colcemid. Remarkably, lower doses (< 20 nM after 5 h) led to subtle but significant microtubule architecture remodelling characterized by increased curvature and suppression of microtubule dynamics. Conclusions Our results support the emerging hypothesis that microtubule-interacting drugs induce non-mitotic effects in cells, and establish a multi-modal imaging assay for detecting and measuring nanoscale microtubule dysfunction. The sub-diffraction visualization of these less severe precursor perturbations compared to the established antimitotic effects of microtubule-interacting drugs offers potential for improved understanding and design of anticancer agents.

Association of co-prescribing of opioid and benzodiazepine substitutes with incident falls and fractures among older adults: a cohort study

ObjectiveExamine the association between the co-prescribing of opioids, benzodiazepines, gabapentinoids (pregabalin and gabapentin) and selective serotonin reuptake inhibitors/serotonin and norepinephrine reuptake inhibitors (SSRI/SNRIs) in different combinations and the risk of falls and fractures.DesignRetrospective cohort study from 2015 to 2018.SettingMedicare enrolment and claims data.ParticipantsMedicare beneficiaries with both chronic pain and anxiety disorders in 2016 with continuous enrolments in Parts A and B from 2015 to 2016 who were prescribed any combination of opioid, benzodiazepine, gabapentinoid and SSRI/SNRI in 2017 for ≥7 days, as documented in their Medicare Part D coverage.InterventionsAny combination of use of seven drug regimens (benzodiazepine +opioid; benzodiazepine +gabapentinoid; benzodiazepine +SSRI/SNRI; opioid +gabapentinoid; opioid +SSRI/SNRI; gabapentinoid +SSRI/SNRI; ≥3 drug classes).Main outcomesFirst event of fall and the first event of fracture after the index date, which was the first day of combination drug use that lasted ≥7 days in 2017.ResultsA total of 47 964 patients (mean [SD] age, 75.9 [7.1]; 78.0% woman) with diagnoses of both chronic pain and anxiety were studied. The median (Q1–Q3) duration of drug combination use was 26 (14-30) days. After adjusting for demographic characteristics, chronic conditions and history of hospitalisation and fall or fracture, the co-prescribing of ≥3 drugs (adjusted HR [aHR], 1.38; 95% CI 1.14 to 1.67) and opioid plus gabapentinoid (aHR, 1.18; 95% CI 1.02 to 1.37) were associated with a high fall risk, compared with benzodiazepineplus opioid co-prescribing, findings consistent with the secondary analysis using inverse probability of treatment weighting with propensity scores. The co-prescribing of benzodiazepine plus gabapentinoid (aHR, 0.76; 95% CI 0.59 to 0.98) was associated with lower fracture risk compared with the co-prescribing of benzodiazepine plus opioid, though this finding was not robust.ConclusionsOur findings add to comparative toxicity research on different combinations of gabapentinoids and serotonergic agents commonly prescribed with or as substitutes for opioids and benzodiazepines in patients with co-occurring chronic pain and anxiety.

Bendamustine-Based Regimens as Salvage Therapy in Refractory/Relapsed Multiple Myeloma Patients: A Retrospective Real-Life Analysis by the Polish Myeloma Group

Multiple myeloma (MM) is an incurable disease and patients become refractory to the treatment in the course of the disease. Bendamustine-based regimens containing steroids and other agents are among the therapeutic options offered to MM patients. Here, we investigated the safety and the efficacy of bendamustine used in patients with refractory/relapsed MM (RRMM). The patients were treated with bendamustine and steroids (n = 52) or bendamustine, steroids and immunomodulatory agents or proteasome inhibitors (n = 53). Response rates, progression-free survival (PFS), overall survival (OS) and frequency of adverse events were compared between both study groups. Most efficacy measurements were better in patients treated with three-drug regimens: overall response rate (55% versus 37%, p = 0.062), median PFS (9 months versus 4 months, p < 0.001), median OS survival (18 months versus 12 months, p = 0.679). The benefit from combining bendamustine and steroids with an additional agent was found in subgroups previously treated with both lenalidmide and bortezomib, with stem cell transplant and with more than two previous therapy lines. Toxicity was similar in both study groups and bendamustine-based therapies were generally well-tolerated. Our study suggests that bendamustine may be an effective treatment for patients with RRMM. Three-drug regimens containing bendamustine, steroids and novel agents produced better outcomes and had acceptable toxicity. The efficacy of bendamustine combined with steroids was limited.