Safety Of Pharmacological Interventions Research Articles

Chronopharmacokinetics: A Brief Analysis of the Influence of Circadian Rhythm on the Absorption, Distribution, Metabolism, and Elimination of Drugs

Chronopharmacokinetics is a specialized field within pharmacokinetics that focuses on how the timing of drug administration affects the absorption, distribution, metabolism, and elimination of drugs. The circadian rhythm, governed by the body's biological clock, plays a crucial role in pharmacokinetics, which encompasses the absorption, distribution, metabolism, and elimination of drugs. These pharmacokinetic processes are subject to daily variations influenced by the circadian rhythm. Drug absorption can fluctuate due to changes in gastrointestinal function, such as motility and gastric pH, and blood circulation. Similarly, the distribution of drugs in the body is influenced by factors such as tissue perfusion, plasma protein binding, and cell membrane permeability, all of which are modulated by the circadian rhythm. Metabolism, especially hepatic metabolism, can also experience circadian variations that affect the rate at which drugs are processed and converted into active or inactive metabolites. Finally, the elimination of drugs, primarily through renal function, can show circadian rhythms that impact the excretion of compounds from the body. Understanding these circadian fluctuations is essential to optimize the efficacy and safety of pharmacological treatments, as dosages and administration times could be adjusted to align with the peaks of biological clock activity. Thus, treatments can be more effective and have fewer side effects by leveraging the circadian variability in pharmacokinetic processes.

Systematic literature review to inform the Portuguese recommendations for the management of Raynaud's phenomenon and digital ulcers in systemic sclerosis and other connective tissue diseases.

To perform a systematic literature review (SLR) aimed at evaluating the efficacy and safety of pharmacological and non-pharmacological treatments for Raynaud's phenomenon (RP) and digital ulcers (DU) in patients with systemic sclerosis (SSc) and other connective tissue diseases (CTD), in order to inform the Portuguese recommendations for managing RP and DU in these patients. A SLR was conducted until May 2022 to identify studies assessing the efficacy and safety of pharmacological and non-pharmacological interventions for RP and DU in SSc and other CTD. Eligible study designs included randomized controlled trials (RCTs), controlled clinical trials, and their extensions for assessing efficacy and safety of interventions. Observational studies with a comparator were included for evaluating the efficacy and safety of non-pharmacological interventions and safety of pharmacological interventions. The risk of bias of each study was assessed using standard tools. Out of 71 publications meeting the inclusion criteria, 59 evaluated pharmacological and 12 non-pharmacological interventions. We found moderate quality evidence supporting the efficacy of calcium channel blockers, phosphodiesterase-5 inhibitors, and intravenous prostacyclin analogues in reducing RP frequency, severity, and duration. Intravenous iloprost had a small to moderate effect size in improving DU healing. Phosphodiesterase-5 inhibitors were effective in reducing total DU count, new DU occurrence, and enhancing DU healing. Bosentan effectively prevented new DU in SSc patients. No new safety concerns were associated with these treatments. The studies on non-pharmacological interventions were, in general, of low quality, and had a small sample size. Warming measures decreased frequency and duration of RP attacks; laser therapy improved RP-related outcomes; local oxygen-ozone therapy improved RP outcomes as an add-on therapy; bone marrow mononuclear cell implantation improved DU-associated pain; periarterial sympathectomy and vascular bypass reduced DU number and finger amputation risk. The available evidence supports the efficacy and safety of pharmacological interventions, namely nifedipine, sildenafil, iloprost, and bosentan in treating RP and DU in patients with SSc and other CTD. Scarce and low-quality evidence does support the use of some non-pharmacological interventions but with only a modest effect size. This SLR underscores the limited availability of high-quality evidence for determining the optimal treatment.

Efficacy and Safety of Pharmacological Treatment in Patients with Complex Regional Pain Syndrome: A Systematic Review and Meta-Analysis.

Complex regional pain syndrome (CRPS) is a disabling condition that usually affects the extremities after trauma or surgery. At present, there is no FDA-approved pharmacological treatment for patients with CRPS. We performed this systematic review and meta-analysis to evaluate the efficacy and safety of pharmacological therapies and determine the best strategy for CRPS. We searched the databases, including PubMed, Embase, Cochrane, Web of Science, Scopus, and ClinicalTrials.gov, for published eligible randomized controlled trials (RCTs) comparing pharmacological treatment with placebo in CRPS patients. Target patients were diagnosed with CRPS according to Budapest Criteria in 2012 or the 1994 consensus-based IASP CRPS criteria. Finally, 23 RCTs comprising 1029 patients were included. We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to rate certainty (confidence in evidence and quality of evidence). Direct meta-analysis showed that using bisphosphonates (BPs) (mean difference [MD] -2.21, 95% CI -4.36--0.06, p = 0.04, moderate certainty) or ketamine (mean difference [MD] -0.78, 95% CI -1.51--0.05, p = 0.04, low certainty) could provide long-term (beyond one month) pain relief. However, there was no statistically significant difference in the efficacy of short-term pain relief. Ketamine (rank p = 0.55) and BPs (rank p = 0.61) appeared to be the best strategies for CRPS pain relief. Additionally, BPs (risk ratio [RR] = 1.86, 95% CI 1.34-2.57, p < 0.01, moderate certainty) and ketamine (risk ratio [RR] = 3.45, 95% CI 1.79-6.65, p < 0.01, moderate certainty) caused more adverse events, which were mild, and no special intervention was required. In summary, among pharmacological interventions, ketamine and bisphosphonate injection seemed to be the best treatment for CRPS without severe adverse events.

Comparative Efficacy and Safety of Pharmacological Interventions in Patients with Dementia-Related Agitation or Aggression: A Network Meta-Analysis

Comparative Efficacy and Safety of Pharmacological Interventions in Patients with Dementia-Related Agitation or Aggression: A Network Meta-Analysis

Retrospective Cohort Study Comparing Efficacy and Safety of Pharmacological Intervention and Phototherapy in Moderate to Severe Psoriasis Patients in a Real-World Setting

Abstract Methotrexate (MTX) is one of the first-line systemic treatment options in patients with moderate-to-severe plaque psoriasis and can be combined with narrow band UVB phototherapy (Nb-UVB). However, such a combination is rarely used for optimal duration due to safety and efficacy concerns. The aim of this study was to assess efficacy and safety of methotrexate (MTX) combination with low doses of Nb-UVB versus MTX monotherapy in patients with moderate-to-severe plaque psoriasis in a real-world setting. Retrospective psoriasis patient medical chart review was performed for the period from 2013 till 2019. The combination therapy group (Group 1, n = 74) received MTX 10 mg s/c once a week for four to six weeks and 311 nm UVB phototherapy according to the skin type and protocol of administration — three times a week; undergoing 10–24 procedures in the treatment course. The monotherapy group (Group 2, n = 57) was treated, using MTX as monotherapy 2.5 mg two times a day orally for five days (4–6 treatment courses in total). The combination therapy group achieved decrease of mean PASI at the end of the 2nd week of treatment by 38% vs monotherapy group 21%. Combination of low dose subcutaneous MTX and Nb-UVB therapy provides better treatment outcomes and normalisation of immunochemical parameters than for MTX monotherapy. This combination also showed a favourable tolerability profile.

Machine Learning in Modeling Disease Trajectory and Treatment Outcomes: An Emerging Enabler for Model-Informed Precision Medicine.

The increasing breadth and depth of resolution in biological and clinical data, including -omics and real-world data, requires advanced analytical techniques like artificial intelligence (AI) and machine learning (ML) to fully appreciate the impact of multi-dimensional population variability in intrinsic and extrinsic factors on disease progression and treatment outcomes. Integration of advanced data analytics in Quantitative Pharmacology is crucial for drug-disease knowledge management, enabling precise, efficient and inclusive drug development and utilization - an application we refer to as model-informed precision medicine. AI/ML enables characterization of the molecular and clinical sources of heterogeneity in disease trajectory, advancing end point qualification and biomarker discovery, and informing patient enrichment for proof-of-concept studies as well as trial designs for efficient evidence generation incorporating digital twins and virtual control arms. Explainable ML methods are valuable in elucidating predictors of efficacy and safety of pharmacological treatments, thereby informing response monitoring and risk mitigation strategies. In oncology, emerging opportunities exist for development of the next generation of disease models via ML-assisted joint longitudinal modeling of high-dimensional biomarker data such as circulating tumor DNA and radiomics profiles as predictors of survival outcomes. Finally, mining real-world data leveraging ML algorithms enables understanding of the impact of exclusion criteria on clinical outcomes, thereby informing rational design of appropriately inclusive clinical trials through data-driven broadening of eligibility criteria. Herein, we provide an overview of the aforementioned contexts of use of ML in drug-disease modeling based on examples across multiple therapeutic areas including neurology, rare diseases, autoimmune diseases, oncology and immuno-oncology.

Clinical characteristics, management, and prevention of coronavirus disease 2019

Abstract Coronavirus disease 2019 (COVID-19) is the third severe acute respiratory disease of the 21st century and the most aggressive global pandemic to date. The whole population has been susceptible to the disease, particularly the emerging variants of the virus. The core pathophysiological mechanism is viral sepsis that can lead to the respiratory tract disorders and even systemic disorders such as cytokine release syndrome, thrombosis, abnormal angiogenesis, and multiple organ dysfunction. Despite only few licensed treatments to date, rapid advances have been made in exploring the effectiveness and safety of pharmacological interventions and vaccines. However, three pillars of preventative and control measures - proactive contact tracing, wearing facial masks, and social distancing - are essential to combat the ongoing pandemic. As the number of patients recovering from COVID-19 rapidly increases, the world has entered the era of caring for patients during the convalescence phase. This phase still represents a largely unmet medical need globally.

MSR97 Systematic Literature Review of the Efficacy and Safety of Pharmacological Treatments and Septal Reduction Therapies for Obstructive Hypertrophic Cardiomyopathy

To systematically identify studies evaluating the efficacy and safety of pharmacological interventions and septal reduction therapies (SRT) used to treat obstructive hypertrophic cardiomyopathy (HCM).

Conformity assessment of medicines containing antibiotics – A multivariate assessment

Pharmaceutical products must meet quality requirements to ensure the efficacy and safety of pharmacological treatment. Non-compliance of medicines can cause economic losses and compromise the patient's health. In this work, the risks of false compliance/non-compliance decisions for parenteral antibiotics (cephalothin, ciprofloxacin and metronidazole) were evaluated on the basis of analytical results, measurement uncertainties and specification limits. Physicochemical and biological quality assays were performed according to pharmacopeial procedures. Measurement uncertainties were determined using the bottom-up approach or the probability of false-positive/false-negative results. The risks of false compliance/non-compliance decisions were estimated using the frequentist approach and Monte Carlo simulations. Guard-bands were determined through a validated spreadsheet for calculating univariate and multivariate acceptance limits. All risk values (particular risks and total risk, consumer's or producer's risk) were below the maximum permissible risk value. The univariate and multivariate guard-bands defined more restrictive specification values, reducing the risks of false compliance/non-compliance decisions. One antibiotic presented unsatisfactory results regarding the drug content and was classified as out of specification product. The application of risk management tools in the pharmaceutical area contributes to improving the quality and safety of products and supports decision-making.

A systematic literature review informing the consensus statement on efficacy and safety of pharmacological treatment with interleukin-6 pathway inhibition with biological DMARDs in immune-mediated inflammatory diseases

ObjectivesInforming an international task force updating the consensus statement on efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) selectively targeting interleukin-6 (IL-6) pathway in the context of immune-mediated inflammatory...

Approach to the Treatment of Pediatric Dystonia

Dystonia is the most common movement disorder in the pediatric population. It can affect normal motor development and cause significant motor disability. The treatment of pediatric dystonia can be very challenging as many children tend to be refractory to standard pharmacological interventions. Pharmacological treatment remains the first-line approach in pediatric dystonia. However, despite the widespread use of different ani-dystonia medications, the literature is limited to small clinical studies, case reports, and experts’ opinions. Botulinum neurotoxin (BoNT) is a well-established treatment in adults with focal and segmental dystonia. Despite the widespread use of BoNT in adult dystonia the data to support its use in children is limited with the majority extrapolated from the spasticity literature. For the last 2 decades, deep brain stimulation (DBS) has been used for a wide variety of dystonic conditions in adults and children. DBS gained increased popularity in the pediatric population because of the dramatic positive outcomes reported in some forms of genetic dystonia and the subsequent consensus that DBS is generally safe and effective. This review summarizes the available evidence supporting the efficacy and safety of pharmacological treatment, BoNT, and DBS in pediatric dystonia and provides practical frameworks for the adoption of these modalities.

Comparison of fluoxetine with other selective serotonin reuptake inhibitors in the treatment of premature ejaculation: A systematic review and meta-analysis.

The primary goal of this systematic review and meta-analysis was to compare the efficacy and safety of fluoxetine with other oral pharmaceuticals in the treatment of premature ejaculation (PE). We searched through databases including CNKI, PubMed, EMBASE and Cochrane to find research published up to 31 March 2022. PROSPERO was used to pre-register this meta-analysis (registration number CRD42022315459). Two separate writers extracted relevant details from all of the papers included in the study. To analyse the quality of literature publishing, we used the Cochrane risk of bias tool. The severity of premature ejaculation was determined using intravaginal ejaculatory latency time (IELT), and the effectiveness and safety of pharmacological interventions were determined using standardized mean difference (SMD) and risk ratio (RR) values with matching 95% confidence level intervals (95% CIs). Our meta-analysis includes a total of ten trials to investigate into the differences in treatment efficacy and safety between fluoxetine and other medicines. The findings revealed that fluoxetine was more effective than placebo in treating PE, whereas sertraline and paroxetine were more effective than fluoxetine (p < 0.05). The side effects of the medications were not significantly different, and they were all acceptable. The results of the sensitivity analysis were unaffected by the removal of any of the articles. There was no evidence of bias in the media. This meta-analysis examined the differences in efficacy and safety between fluoxetine and other oral medications and can be used by clinicians in the treatment of PE.

The Standard of Care Definitions on COVID-19 Pharmacological Clinical Trials: A Systematic Review.

Background: Standard of Care (SoC) has been used with different significance across Randomized Clinical Trials (RCTs) on the treatment of Covid-19. In the context of a living systematic review on pharmacological interventions for COVID-19, we assessed the characteristics of the SoC adopted in the published RCTs. Methods: We performed a systematic review searching Medline, Pubmed, Embase, Cochrane Covid-19 register, international trial registers, medRxiv, bioRxiv, and arXiv up to April 10, 2021. We included all RCTs comparing any pharmacological intervention for Covid-19 against any drugs, placebo, or SoC. All trials selected have been classified as studies with SoC including treatments under investigation for COVID-19 (SoC+); studies with SoC without specifications regarding the potential therapies allowed (SoC-); studies including as control groups Placebo (P) or active controls (A+). Results: We included in our analysis 144 RCTs, comprising 78,319 patients. Most of these trials included SoC (108; 75.0%); some in all arms of the study (69.7%) or just as independent comparators (30.3%). Treatments under investigation for COVID-19 in other trials were included in the SoC (SoC+) in 67 cases (62.0%), Thirty-one different therapeutic agents (alone or in combination) were counted within the studies with SoC+: mostly hydroxychloroquine or chloroquine (28), lopinavir/ritonavir (20) or azithromycin (16). No specification was given regarding treatment allowed in the control groups (SoC-) in 41 studies (38.0%). Conclusion: Our analysis shows that the findings emerging from several clinical trials regarding the efficacy and safety of pharmacological intervention for COVID-19 might be jeopardized by the quality of control arms.

Interventions for palliative symptom control in COVID-19 patients.

Interventions for palliative symptom control in COVID-19 patients.

Comparative effectiveness and safety of 32 pharmacological interventions recommended by guidelines for coronavirus disease 2019: a systematic review and network meta-analysis combining 66 trials.

Background:The global pandemic coronavirus disease 2019 (COVID-19) has become a major public health problem and presents an unprecedented challenge. However, no specific drugs were currently proven. This study aimed to evaluate the comparative efficacy and safety of pharmacological interventions in patients with COVID-19.Methods:Medline, Embase, the Cochrane Library, and clinicaltrials.gov were searched for randomized controlled trials (RCTs) in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/SARS-CoV. Random-effects network meta-analysis within the Bayesian framework was performed, followed by the Grading of Recommendations Assessment, Development, and Evaluation system assessing the quality of evidence. The primary outcome of interest includes mortality, cure, viral negative conversion, and overall adverse events (OAEs). Odds ratio (OR) with 95% confidence interval (CI) was calculated as the measure of effect size.Results:Sixty-six RCTs with 19,095 patients were included, involving standard of care (SOC), eight different antiviral agents, six different antibiotics, high and low dose chloroquine (CQ_HD, CQ_LD), traditional Chinese medicine (TCM), corticosteroids (COR), and other treatments. Compared with SOC, a significant reduction of mortality was observed for TCM (OR = 0.34, 95% CI: 0.20–0.56, moderate quality) and COR (OR = 0.84, 95% CI: 0.75–0.96, low quality) with improved cure rate (OR = 2.16, 95% CI: 1.60–2.91, low quality for TCM; OR = 1.17, 95% CI: 1.05–1.30, low quality for COR). However, an increased risk of mortality was found for CQ_HD vs. SOC (OR = 3.20, 95% CI: 1.18–8.73, low quality). TCM was associated with decreased risk of OAE (OR = 0.52, 95% CI: 0.38–0.70, very low quality) but CQ_HD (OR = 2.51, 95% CI: 1.20–5.24) and interferons (IFN) (OR = 2.69, 95% CI: 1.02–7.08) vs. SOC with very low quality were associated with an increased risk.Conclusions:COR and TCM may reduce mortality and increase cure rate with no increased risk of OAEs compared with standard care. CQ_HD might increase the risk of mortality. CQ, IFN, and other antiviral agents could increase the risk of OAEs. The current evidence is generally uncertain with low-quality and further high-quality trials are needed.

Efficacy and Safety of Pharmacologic Interventions in Patients Experiencing a Gout Flare: A Systematic Review and Network Meta-Analysis.

To compare the relative efficacy and safety of pharmacologic antiinflammatory interventions for gout flares. We searched Ovid Medline, Embase, and Cochrane library for randomized controlled trials (RCTs) that compared pharmacologic antiinflammatory treatment of gout flares. We conducted a network meta-analysis (NMA) using a frequentist framework and assessed the certainty of evidence and made conclusions using the Grading of Recommendations Assessment, Development, and Evaluation for NMA. In the 30 eligible RCTs, canakinumab provided the highest pain reduction at day 2 and at longest follow-up (mean difference relative to acetic acid derivative nonsteroidal antiinflammatory drugs [NSAIDs] -41.12 [95% confidence interval (95% CI) -53.36, -29.11] on a 0-100 scale at day 2, and mean difference -12.84 [95% CI -20.76, -4.91] at longest follow-up; both moderate certainty; minimum important difference -19). Intravenous or intramuscular corticosteroids were inferior to canakinumab but may be better than the other commonly used interventions (low to very low certainty). For joint tenderness, canakinumab may be the most effective intervention at day 2. Acetic acid derivative NSAIDs improved joint swelling better than ibuprofen NSAIDs at day 2 (mean difference -0.29 [95% CI -0.56, -0.02] on a 0-4 scale; moderate certainty) and improved patient global assessment (PtGA) greater than ibuprofen NSAIDs at the longest follow-up (mean difference -0.44 [95% CI -0.86, -0.02]; moderate). Canakinumab may be superior to other alternatives and intravenous or intramuscular corticosteroids may be the second best in pain reduction. Acetic acid derivative NSAIDs may be superior to ibuprofen NSAIDs in improving joint swelling and PtGA.

Evoked Potential as a Pain Evaluation Index for Neonatal Procedural Pain

Frequent pain has short- and long-term negative influences on the development of the brain and nerves and cognition, motion, and behavior of neonates. Neonates staying in the Neonatal Intensive Care Unit frequently receive painful procedures many times a day. Heel lance is one of the most frequently performed painful procedures for blood sampling, but the pain of heel lance has been not sufficiently managed for a long time. Due to the lack of the analgesic effect and safety of pharmacological intervention, the pain relief for neonatal heel lance is being searched for in diverse combinations of non-pharmacological interventions. To develop pain relief for the heel lance, the Premature Infant Pain Profile (PIPP) comprised of a mixture of physiological and behavioral indices is frequently used as a pain evaluation index, but several problems of PIPP have been pointed out with regard to neonatal pain evaluation, and pain evaluation using PIPP alone interferes with the development of pain relief for neonatal heel lance. Recently, evoked potentials (EP) after heel lance have been attracting attention as an index of evaluating pain objectively and quantitatively for neonates unable to express pain with words. EP detects more sharply pain stimulation and may enable continuous evaluation of neonatal pain along with growth and development. The development of EP-based pain evaluation promotes the development of pain relief for neonatal heel lance.

Influence of drug–drug interactions on effectiveness and safety of direct-acting antivirals against hepatitis C virus

ObjectivesDirect-acting antivirals are the recommended treatment for hepatitis C-infected patients. Drug–drug interactions with concomitant treatments can cause lack of effectiveness and/or safety. The objective of this study is to characterise...

Efficacy and safety of pharmacological interventions in epicardial adipose tissue: A protocol for systematic review and network meta-analysis

Efficacy and safety of pharmacological interventions in epicardial adipose tissue: A protocol for systematic review and network meta-analysis

Efficacy and safety of pharmacological interventions in metabolic syndrome: protocol for systematic review and network meta-analysis

Efficacy and safety of pharmacological interventions in metabolic syndrome: protocol for systematic review and network meta-analysis