Anthelmintic resistance in human and animal pathogenic helminths has been spreading in prevalence and severity. Multidrug resistance is a widespread problem in livestock animals. The use of available ...pharmacology-based information is critical to the design of successful future approaches for parasite control. Relevant scientific work supporting the main strategies to optimize anthelmintic therapy in ruminants under the current drug-resistance scenario is described here. We emphasize the need for further integrated pharmaco-parasitological knowledge to extend the lifespan of both traditional and novel anthelmintic compounds, and to progress in the identification of complementary/alternative measures of parasite control in livestock animals.
Considering the increasing concern regarding the development of drug resistance, the use of pharmacology-based information is critical to design successful strategies for future helminth parasite control in livestock.
Integrated pharmacokinetic/pharmacodynamic and clinical pharmacology knowledge is required to preserve both well-established and modern anthelmintics.
Assessment of drug disposition in the host and comprehension of the mechanisms of drug influx/efflux/detoxification in different target helminths, have signified relevant progress in anthelmintic therapy in ruminants.
Different pharmacokinetic-based approaches to enhance parasite exposure (pharmacokinetic optimisation) and the use of a mixture of molecules from different chemical families (drug combinations) have been assessed as valid strategies to control resistant parasites and to slow the selection for further resistance.
Identification/development of complementary and/or alternative (i.e., bioactive phytochemicals) measures seems critical to achieve sustained parasite control in livestock.
Chronic rhinosinusitis (CRS) has been differentiated clinically into CRS without nasal polyps and CRS with nasal polyps, with both forms subjected to glucocorticosteroid and antibiotic treatments ...and, if not successful, to nasal and sinus surgery tailored to endoscopic and computed tomographic scan findings. The elaboration of endotypes based on pathomechanisms involving different immune responses offers new possibilities in terms of prediction of prognosis and risks and sophisticated guidance in personalized pharmacotherapy, surgical approaches, and innovative treatment approaches in the CRS field with various biologics. Surgical approaches can vary from classical functional endoscopic sinus surgery to extended and “reboot” approaches, with the idea to completely remove the dysfunctional and inflamed mucosa and replace it with a newly grown healthy mucosa. Biologics in this field are targeting the type 2 cytokines IL-4, IL-5, and IL-13, as well as IgE. Phase I and II study results are promising, and phase III studies are currently being performed. The development of endotype-driven integrated care pathways appreciating these innovations are now needed for the management of CRS.
Emapalumab-Izsg (hereafter referred to as emapalumab) Gamifant
®
is a monoclonal antibody directed against interferon gamma that is available as an intravenous infusion. Emapalumab is being ...developed by Novimmune and Swedish Orphan Biovitrum for the treatment of haemophagocytic lymphohistiocytosis (HLH). In November 2018, emapalumab received its first global approval in the USA, for the treatment of paediatric (newborn and older) and adult patients with primary HLH, who have refractory, recurrent or progressive disease or intolerance to conventional HLH therapy. Emapalumab is under regulatory review in the EU for the treatment of primary HLH. This article summarizes the milestones in the development of emapalumab leading to this first global approval for HLH in the USA.
Obesity is a global epidemic that contributes to a number of health complications including cardiovascular disease, type 2 diabetes, cancer and neuropsychiatric disorders. Pharmacotherapeutic ...strategies to treat obesity are urgently needed. Research over the past two decades has increased substantially our knowledge of central and peripheral mechanisms underlying homeostatic energy balance. Homeostatic mechanisms involve multiple components including neuronal circuits, some originating in hypothalamus and brain stem, as well as peripherally-derived satiety, hunger and adiposity signals that modulate neural activity and regulate eating behavior. Dysregulation of one or more of these homeostatic components results in obesity. Coincident with obesity, reward mechanisms that regulate hedonic aspects of food intake override the homeostatic regulation of eating. In addition to functional interactions between homeostatic and reward systems in the regulation of food intake, homeostatic signals have the ability to alter vulnerability to drug abuse. Regarding the treatment of obesity, pharmacological monotherapies primarily focus on a single protein target. FDA-approved monotherapy options include phentermine (Adipex-P®), orlistat (Xenical®), lorcaserin (Belviq®) and liraglutide (Saxenda®). However, monotherapies have limited efficacy, in part due to the recruitment of alternate and counter-regulatory pathways. Consequently, a multi-target approach may provide greater benefit. Recently, two combination products have been approved by the FDA to treat obesity, including phentermine/topiramate (Qsymia®) and naltrexone/bupropion (Contrave®). The current review provides an overview of homeostatic and reward mechanisms that regulate energy balance, potential therapeutic targets for obesity and current treatment options, including some candidate therapeutics in clinical development. Finally, challenges in anti-obesity drug development are discussed.
Objective
: аssessment of orlistat, liraglutide and sibutramine consumption in the Russian Federation as drugs recommended by the Russian clinical guidelines for the pharmacotherapy of obesity.
...Material and methods.
From IQVIA database, the information was selected on retail sales and procurement of the specified drugs at the expense of the federal and regional budgets in the period of 2011–2021. The consumed volumes of each drug were recalculated into the number of defined daily doses (DDDs) for each international nonproprietary name in accordance with the World Health Organization methodology.
Results
. It was demonstrated that over a 10-year period there was a tendency to reduce the consumption of drugs for the treatment of obesity from 83.03 million DDDs in 2011 to 71.7 million in 2021. Sibutramine consumption dominated throughout the observation period: its share ranged from 76% to 84%. The proportion of people receiving obesity pharmacotherapy in the Russian Federation was about 0.5%. Herewith 58–66% of DDDs sales took place in 3 regions: Moscow, Moscow Region and Saint Petersburg.
Conclusion
. Low efficacy, high frequency of adverse effects, frequent weight gain after therapy termination, as well as low orientation of doctors to the need for pharmacotherapy are probably the main factors determining the low prevalence of using drugs for the treatment of obesity in Russia.
Background
Brivaracetam (BRV), cenobamate (CNB), eslicarbazepine acetate (ESL), lacosamide (LCM) and perampanel (PER) are antiseizure medications (ASMs) approved for adjunctive treatment of ...focal-onset seizures. So far, no randomised controlled trial directly compared the efficacy and safety of these drugs.
Objective
We estimated the comparative efficacy and safety of these ASMs for the treatment of focal-onset seizures in adults with epilepsy using a network meta-analysis (NMA).
Methods
We systematically searched (June week 4, 2021) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institutes of Health Clinical Trials Registry (
http://www.clinicaltrials.gov
). There were no date limitations or language restrictions. Randomised, double-blinded, controlled, parallel-group, add-on studies that compared oral BRV, CNB, ESL, LCM, and PER versus any comparator over maintenance periods of at least 12 weeks and included adult patients with focal seizures uncontrolled by concomitant ASMs were identified. The efficacy outcomes were the proportions of patients with ≥ 50% and 100% reduction in baseline seizure frequency during the maintenance period. The tolerability outcomes were the proportions of participants who experienced at least one treatment-emergent adverse event (TEAE) and experienced at least one TEAE leading to discontinuation. Effect sizes were estimated by network meta-analyses within a frequentist framework. The hierarchy of competing interventions was established using the surface under the cumulative ranking curve (SUCRA).
Results
Sixteen trials (BRV:
n
= 3, CNB:
n
= 1, ESL:
n
= 4, LCM:
n
= 4, PER:
n
= 4) were included, overall enrolling 4507 patients randomised to add-on active treatments (BRV = 803, CNB = 221, ESL =9 90, LCM = 1104, and PER = 1389) and 2246 to add-on placebo. Cenobamate was associated with a higher rate of ≥ 50% seizure frequency reduction than BRV odds ratio (OR) 2.02, 95% confidence interval (CI) 1.11–3.66, ESL (OR 1.93, 95% CI 1.07–3.48), LCM (OR 1.86, 95% CI 1.04–3.32), and PER (OR 2.07, 95% CI 1.16–3.70). There was a not statistically significant trend favouring CNB over ESL, LCM and PER for the seizure freedom outcome. Brivaracetam (OR 0.61, 95% CI 0.44–0.86) and LCM (OR 0.60, 95% CI 0.40–0.88) were associated with a lower proportion of participants experiencing TEAEs compared to ESL, and patients treated with PER were associated with a higher risk to experience at least one TEAE (OR 1.42, 95% CI 1.02–1.96) than BRV. According to SUCRA, CNB had the greatest likelihood of being the best option for the ≥ 50% and 100% seizure frequency reduction, and BRV and LCM had the highest probabilities of being the best-tolerated treatments.
Conclusions
Cenobamate ranked best for efficacy, and BRV and LCM were best tolerated over the other comparators. Although NMAs cannot replace direct comparisons, they may support physicians in clinical decision making.
Vitamin D for the management of asthma Martineau, Adrian R; Cates, Christopher J; Urashima, Mitsuyoshi ...
Cochrane database of systematic reviews,
09/2016, Letnik:
2019, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Background
Several clinical trials of vitamin D to prevent asthma exacerbation and improve asthma control have been conducted in children and adults, but a meta‐analysis restricted to double‐blind, ...randomised, placebo‐controlled trials of this intervention is lacking.
Objectives
To evaluate the efficacy of administration of vitamin D and its hydroxylated metabolites in reducing the risk of severe asthma exacerbations (defined as those requiring treatment with systemic corticosteroids) and improving asthma symptom control.
Search methods
We searched the Cochrane Airways Group Trial Register and reference lists of articles. We contacted the authors of studies in order to identify additional trials. Date of last search: January 2016.
Selection criteria
Double‐blind, randomised, placebo‐controlled trials of vitamin D in children and adults with asthma evaluating exacerbation risk or asthma symptom control or both.
Data collection and analysis
Two review authors independently applied study inclusion criteria, extracted the data, and assessed risk of bias. We obtained missing data from the authors where possible. We reported results with 95% confidence intervals (CIs).
Main results
We included seven trials involving a total of 435 children and two trials involving a total of 658 adults in the primary analysis. Of these, one trial involving 22 children and two trials involving 658 adults contributed to the analysis of the rate of exacerbations requiring systemic corticosteroids. Duration of trials ranged from four to 12 months, and the majority of participants had mild to moderate asthma. Administration of vitamin D reduced the rate of exacerbations requiring systemic corticosteroids (rate ratio 0.64, 95% CI 0.46 to 0.90; 680 participants; 3 studies; high‐quality evidence), and decreased the risk of having at least one exacerbation requiring an emergency department visit or hospitalisation or both (odds ratio (OR) 0.39, 95% CI 0.19 to 0.78; number needed to treat for an additional beneficial outcome, 27; 963 participants; 7 studies; high‐quality evidence). There was no effect of vitamin D on % predicted forced expiratory volume in one second (mean difference (MD) 0.48, 95% CI ‐0.93 to 1.89; 387 participants; 4 studies; high‐quality evidence) or Asthma Control Test scores (MD ‐0.08, 95% CI ‐0.70 to 0.54; 713 participants; 3 studies; high‐quality evidence). Administration of vitamin D did not influence the risk of serious adverse events (OR 1.01, 95% CI 0.54 to 1.89; 879 participants; 5 studies; moderate‐quality evidence). One trial comparing low‐dose versus high‐dose vitamin D reported two episodes of hypercalciuria, one in each study arm. No other study reported any adverse event potentially attributable to administration of vitamin D. No participant in any included trial suffered a fatal asthma exacerbation. We did not perform a subgroup analysis to determine whether the effect of vitamin D on risk of severe exacerbation was modified by baseline vitamin D status, due to unavailability of suitably disaggregated data. We assessed two trials as being at high risk of bias in at least one domain; neither trial contributed data to the analysis of the outcomes reported above.
Authors' conclusions
Whilst we are confident that Vitamin D reduced the risk of asthma exacerbation in these trials (high quality GRADE assessment), we recognise that there is uncertainty about how these findings might be applied in practice. More research is needed to clarify whether there is a difference in effect between adults and children and with respect to asthma severity, baseline vitamin D status and doses.
The efficacy of all pharmacotherapies for patients suffering from tics were unclear. Literatures were searched from Medline, Embase, The Cochrane Library, and four Chinese databases. The primary ...efficacy outcome scale was defined as the Yale Global Tic Severity Scale (YGTSS). Overall estimates of pooled weighted mean difference (WMD) with 95% confidence interval (CI) were calculated for each outcome measure. A total of 53 trials were included. Meta-analysis suggested that alpha-2 adrenergic agonist agents and atypical antipsychotic agents were effective in improving tics, which included the maximum number of trials. Typical antipsychotic agents were associated with severer side-effects than alpha-2 adrenergic agonist agents. Besides, Traditional Chinese Medicine showed positive effects in YGTSS (NingDong Granule: WMD=-7.100, 95% CI, -10.430- -3.770; 5-Ling Granule: WMD=-11.300, 95% CI, -14.208- -8.392), while glutamate modulators (D-serine, N-Acetylcysteine and riluzole) might not be working. In summary, alpha-2 adrenergic agonist agents were associated with the optimal weigh between efficacy and safety. However, the significant factor of limited trials and sample sizes discounted these findings. Further better studies are necessary to ascertain them.
Ageing is associated with several changes in human organs, which result in altered medication pharmacokinetics and pharmacodynamics. Ageing is also associated with changes in human body functions, ...such as impaired vision, hearing, swallowing, motor and cognitive functions, which can affect the adequate intake and administration of drugs. As a consequence, older people, and especially patients older than 75 years, are the main users of many drugs and they frequently use 5 drugs or more long‐term (i.e. polypharmacy). All this increases the complexity of adequate drug intake, administration and adherence. However, there is a lack of evidence on the considerations that should be taken into account to ensure appropriate drug prescribing to older people. This review article summarizes the most clinically relevant changes in human organ and body functions and the consequential changes in pharmacokinetics and pharmacodynamics in older people, along with possible dosing consequences or alternatives for drugs frequently prescribed to this patient population. Recommendations are given on how ageing could be considered in clinical drug development, drug authorization and appropriate prescribing.
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