Drug Monotherapy Research Articles

Evaluating the performance of machine-learning regression models for pharmacokinetic drug-drug interactions.

Combination therapy or concomitant drug administration can be associated with pharmacokinetic drug-drug interactions, increasing the risk of adverse drug events and reduced drug efficacy. Thus far, machine-learning models have been developed that can classify drug-drug interactions. However, to enable quantification of the pharmacokinetic effects of a drug-drug interaction, regression-based machine learning should be explored. Therefore, this study investigated the use of regression-based machine learning to predict changes in drug exposure caused by pharmacokinetic drug-drug interactions. Fold changes in exposure relative to substrate drug monotherapy were collected from 120 clinical drug-drug interaction studies extracted from the Washington Drug Interaction Database and SimCYP compound library files. Drug characteristics (features) were collected such as structure, physicochemical properties, in vitro pharmacokinetic properties, cytochrome P450 metabolic activity, and population characteristics. Three different regression-based supervised machine-learning models were then applied to the prediction task: random forest, elastic net, and support vector regressor. Model performance was evaluated using fivefold cross-validation. Strongest performance was observed with support vector regression, with 78% of predictions within twofold of the observed exposure changes. The results show that changes in drug exposure can be predicted with reasonable accuracy using regression-based machine-learning models trained on data available early in drug discovery. This has potential applications in enabling earlier drug-drug interaction risk assessment for new drug candidates.

TMIC-28. COMBINING INDUCED NEURAL STEM CELL THERAPY AND IMMUNOMODULATION IN GLIOBLASTOMA

Abstract Glioblastoma (GBM) is an aggressive malignant adult brain tumor and is characterized by poor prognosis and survival outcome. Insufficient drug accumulation to the tumor site and development of monotherapy drug resistance are critical challenges to overcome in combating GBM. Human induced neural stem cells (hiNSC) therapy is promising due to the stem cells’ innate capability to migrate to the tumors and deliver therapeutics. We previously have developed spheroidal iNSCs and engineered them to constitutively secrete pro-apoptotic protein TRAIL—hiNeuroS-TRAIL. However, investigating a combination therapy along with hiNeuroS-TRAIL therapy is needed to potentially avoid monotherapy resistance and enhance overall treatment durability. One of the GBM hallmarks is its immunosuppressed tumor microenvironment (TME). GBM-associated macrophages and microglia (GAMs) display pro-tumoral phenotypes in TME—inhibiting their ability to target the tumor cells or recruit other immune cells. In humans, higher glioma grade is associated with higher expression of Mer Tyrosine Kinase Receptor (MerTK) in both GBM cells and GAMs. Activation of MerTK in GAMs and GBM cells exacerbates immunosuppression and tumor progression respectively. Inhibiting MerTK activation via a small molecule drug, MRX-2843 and combining with hiNeuroS-TRAIL demonstrated robust synergistic tumor killing effects in vitro (CDI=0.22) and ex vivo (CDI=0.18). Additionally, the preliminary data for in vivo pilot study revealed that the median survival for the combination therapy treated group of mice extended over 24 days whereas the median survival for control, MRX-2843, and hiNeuroS-TRAIL treated groups of mice were 16, 18, and 21 days respectively. We think that combining these two therapies could significantly extend the survival in our murine model of GBM. Therefore, we will be optimizing dose concentration and cell counts for single agent therapies, and we will then repeat in vivo y synergy study with optimized therapies and a larger sample size to fully uncover the potential of this combination therapy.

Safety of Anti-Angiogenic Drugs in Pediatric Patients with Solid Tumors: A Systematic Review and Meta-Analysis.

Cancer is a clinical condition that can benefit from anti-angiogenic drugs (AADs). Given the low prevalence and the heterogeneity of childhood cancers, information about the safety of these drugs in pediatric patients is partially assessed. The aim of this study was to evaluate the safety of AADs in pediatric patients with solid tumors. Clinical trials and observational studies were searched in PubMed, ISI Web of Science, and ClinicalTrials database For each included study, adverse events (AEs) were extracted. A meta-analysis was conducted by pooling proportions of AEs using a random intercept logistic regression model. Seventy studies were retrieved. Most part were clinical trials (55 out of 70), and only fifteen observational studies were found. Overall, proportion of serious and non-serious AEs of AADs used as monotherapy was 46% and 89%, respectively. Proportions of serious AEs varied among drugs: sunitinib, 79%; lenvatinib, 64%; sorafenib, 48%; ramucirumab, 41%; pazopanib, 30%; and vandetanib, 27%. A higher proportion of non-serious hematological AEs was found in the patients receiving pazopanib with respect to sunitinib and lenvatinib. The safety profile of AADs has been extensively investigated for mostly drugs in phase I and II trials and is limited to acute toxicities. Overall, one out of two patients using AAD drugs in monotherapy experienced a serious AE despite proportions varied per single drugs. When AADs were combined with standard chemotherapy, the proportion of AEs varied in relation to the single combinations.

N-2-Hydroxypropylmethacrylamide-Polycaprolactone Polymeric Micelles in Co-delivery of Proteasome Inhibitor and Polyphenol: Exploration of Synergism or Antagonism.

Breast cancer leads to the highest mortality among women resulting in a major clinical burden. Multidrug therapy is more efficient in such patients compared to monodrug therapy. Simultaneous combinatorial or co-delivery garnered significant interest in the past years. Caffeic acid (CFA) (a natural polyphenol) has received growing attention because of its anticarcinogenic and antioxidant potential. Bortezomib (BTZ) is a proteasome inhibitor and may be explored for treating breast cancer. Despite its high anticancer activity, the low water solubility and chemical instability restrict its efficacy against solid tumors. In the present study, we designed and investigated a HP-PCL (N-2-hydroxypropylmethacrylamide-polycaprolactone) polymeric micellar (PMCs) system for the simultaneous delivery of BTZ and CFA in the treatment of breast cancer. The designed BTZ+CFA-HP-PCL PMCs were fabricated, optimized, and characterized for size, zeta potential, surface morphology, and in vitro drug release. Developed nanosized (174.6 ± 0.24 nm) PMCs showed enhanced cellular internalization and cell cytotoxicity in both MCF-7 and MDA-MB-231 cells. ROS (reactive oxygen species) levels were highest in BTZ-HP-PCL PMCs, while CFA-HP-PCL PMCs significantly (p < 0.001) scavenged the ROS generated in 2',7'-dichlorofluorescein diacetate (DCFH-DA) assay. The mitochondrial membrane potential (MMP) assay revealed intense and significant green fluorescence in both types of cancer cells when treated with BTZ-HP-PCL PMCs (p < 0.001) indicating apoptosis or cell death. The pharmacokinetic studies revealed that BTZ-HP-PCL PMCs and BTZ+CFA-HP-PCL PMCs exhibited the highest bioavailability, enhanced plasma half-life, decreased volume of distribution, and lower clearance rate than the pure combination of drugs. In the organ biodistribution studies, the combination of BTZ+CFA showed higher distribution in the spleen and the heart. Overall findings of in vitro studies surprisingly resulted in better therapeutic efficiency of BTZ-HP-PCL PMCs than BTZ+CFA-HP-PCL PMCs. However, the in vivo tumor growth inhibition study performed in tumor-induced mice concluded that the tumor growth was inhibited by both BTZ-HP-PCL PMCs and BTZ+CFA-HP-PCL PMCs (p < 0.0001) more efficiently than pure BTZ and the combination (BTZ+CFA), which may be due to the conversion of boronate ester into boronic acid. Henceforth, the combination of BTZ and CFA provides further indications to be explored in the future to support the hypothesis that BTZ may work with polyphenol (CFA) in the acidic environment of the tumor.

Combined Application of Aminoglycosides and Ascorbic Acid in the Elimination of Proteus mirabilis Rods Responsible for Causing Catheter-Associated Urinary Tract Infections (CAUTIs)-A Molecular Approach.

Proteus mirabilis is a common cause of catheter-associated urinary tract infections (CAUTIs). In this study, we verified the effectiveness of amikacin or gentamicin and ascorbic acid (AA) co-therapy in eliminating uropathogenic cells, as well as searched for the molecular basis of AA activity by applying chromatographic and fluorescent techniques. Under simulated physiological conditions, a combined activity of the antibiotic and AA supported the growth (threefold) of the P. mirabilis C12 strain, but reduced catheter colonization (≤30%) in comparison to the drug monotherapy. Slight modifications in the phospholipid and fatty acid profiles, as well as limited (≤62%) 2',7'-dichlorofluorescein fluorescence, corresponding to the hydroxyl radical level, allowed for the exclusion of the hypothesis that the anti-biofilm effect of AA was related to membrane perturbations of the C12 strain. However, the reduced (≤20%) fluorescence intensity of propidium iodide, as a result of a decrease in membrane permeability, may be evidence of P. mirabilis cell defense against AA activity. Quantitative analyses of ascorbic acid over time with a simultaneous measurement of the pH values proved that AA can be an effective urine acidifier, provided that it is devoid of the presence of urease-positive cells. Therefore, it could be useful in a prevention of recurrent CAUTIs, rather than in their treatment.

The synergistic effect and mechanisms of flavonoids and polysaccharides from Houttuynia cordata on H1N1-induced pneumonia in mice

Ethnopharmacological relevanceHouttuynia cordata Thunb. (HC, Saururaceae family) is a classical Traditional Chinese Medicine used to treat pneumonia clinically. The total flavonoids (HCF) and polysaccharides (HCP) are key medicinal components of H. cordata involved in its beneficial effect on viral pneumonia. Aim of the studyThe purpose of the study is to investigate the synergistic or complementary effects of combination of HCF and HCP on viral pneumonia as well as the mechanisms underlying. Materials and methodsHCF or HCP were administrated separately or combined in different proportions on influenza virus H1N1 - infected mice. The survival and lung weight of mice were recorded. The synergistic effect on HCF and HCP combination was calculated by Chou-Talalay method. H&E staining was performed to detect lung histomorphology. Western blot, immunohistochemistry and enzyme linked immunosorbent assay were done to analyze the representative protein expression in lung and intestine tissues. AB - PAS staining on intestine tissue sections was performed to evaluate the histopathology of intestines. Bacterial genomic DNA was extracted and sequenced for gut microbiota analysis. ResultsIn H1N1 lethally infected mice, the combined administration of HCF and HCP significantly increased the survival rate and prolonged the life span of mice, compared with mono-drug therapy. The viral pneumonia was remarkably improved by HCF and HCP combination reflected by lower lung index, more intact lung morphology, and less inflammatory cells and mediators. Furthermore, the combination of HCF and HCP regulated intestinal microbiota, significantly reduced the proportion of pathogenic Proteobacteria and the secretion of proinflammatory cytokine in gut. The combined HCF and HCP showed synergistic effect on reducing lung and intestine injury. The complementary interaction was also found in HCF and HCP combined therapy, as HCF provided the significant antiviral activity and HCP markedly improved intestinal physical barrier and increased the protein expression involving removal of edema. ConclusionsOur findings indicated that combination of HCF and HCP from H. cordata synergistically alleviated H1N1-induced viral pneumonia in mice via multimodal regulation of both pulmonary and intestinal homeostasis, which might imply novel therapeutic strategy for treating viral pneumonia.

CURRENT DIVERSIFICATION IN THE SELECTION OF MOLECULE(s) FOR THE TREATMENT OF HYPERTENSION

The study was carried out on the current diversification of antihypertensive drugs prescribed for the treatment of hypertensive patients irrespective of age and sex in the Government Hospitals of Khulna city, Bangladesh. The study covered only the indoor hypertensive patients. The frequency of hypertension was found maximum with patients above 40 years of age. The study showed that the prevalence of hypertension was more common in females compared to males. Among the therapeutic classes, Calcium channel blockers (CCB) were used most frequently (27%). Diuretics (25%) and Beta-blocker (24%) fell in the 2nd and 3rd position respectively. ACE inhibitors (18%) were also used frequently, but angiotensin-II antagonist, alpha-blocker and centrally acting antihypertensive drugs were used only in limited cases. Both combination therapy (57%) and monotherapy (43%) were used for the management of hypertension. Among the combinations, diuretics and ACE inhibitors combination was prescribed in most cases (20%). There was no combination of two or more molecules under the same therapeutic class. In case of mono-drug therapy metoprolol was used most frequently (25%) which was followed by amlodipine (20%) and nifedipine (18%). When individual drug molecules irrespective of their use either in combination or as single drug were taken into account, it was found that furosemide was most frequently (21%) used. Amlodipine (16%), nifedipine and atenolol (13%) followed furosemide.

Skin rash associated with combined cytotoxic chemotherapy and immunotherapy for cancer: A retrospective single-center case series.

In recent years, the development of combination therapies with immune checkpoint inhibitors (ICIs) and cytotoxic anticancer drugs has radically changed the management of diverse malignancies and significantly improved patient outcomes. Several clinical trials have shown that skin rash caused by combination therapy with ICIs and cytotoxic drugs may be more frequent and severe than that developing after administration of ICIs alone or cytotoxic drug monotherapy. However, most reports provide little information on severity, treatment, post-diagnosis course, and recurrence of rashes on drug rechallenges. We aimed to describe the experience of skin rashes developing within 2 weeks from the first administration of combination therapy with ICIs and cytotoxic drugs in 11 patients visiting our dermatology department. This study included seven men and four women, and the patients' median age was 52 years. The primary disease was non-small-cell lung cancer in eight patients, cervical cancer in two patients, and esophageal cancer in one patient. Nine patients had a maculopapular rash and two patients developed erythema multiforme-like eruptions. The skin rash was often accompanied by extracutaneous symptoms, such as fever (n=9), mucositis (n=4), and liver dysfunction (n=2). In all cases, the symptoms improved with topical steroid therapy alone, with no patients exhibiting severe symptoms requiring systemic steroids or immunosuppressive agents. In addition, when the causative drugs were re-administered after recovery from the rash, only two patients relapsed with accompanying systemic symptoms, and all patients except one were able to continue treatment using the same drug regimen. Although it was suggested that the rash caused by the combination therapy of ICIs and cytotoxic drugs may be more prominent than that caused by each agent alone, comprehensive judgment, including histopathological examination, may indicate the feasibility of continuing the treatment regimen for cancer.

Systematic Review and Meta-Analysis on Human African Trypanocide Resistance.

Background Human African trypanocide resistance (HATr) is a challenge for the eradication of Human African Trypansomiaisis (HAT) following the widespread emergence of increased monotherapy drug treatment failures against Trypanosoma brucei gambiense and T. b. rhodesiense that are associated with changes in pathogen receptors. Methods: Electronic searches of 12 databases and 3 Google search websites for human African trypanocide resistance were performed using a keyword search criterion applied to both laboratory and clinical studies. Fifty-one publications were identified and included in this study using the PRISMA checklist. Data were analyzed using RevMan and random effect sizes were computed for the statistics at the 95% confidence interval. Results: Pentamidine/melarsoprol/nifurtimox cross-resistance is associated with loss of the T. brucei adenosine transporter 1/purine 2 gene (TbAT1/P2), aquaglyceroporins (TbAQP) 2 and 3, followed by the high affinity pentamidine melarsoprol transporter (HAPT) 1. In addition, the loss of the amino acid transporter (AAT) 6 is associated with eflornithine resistance. Nifurtimox/eflornithine combination therapy resistance is associated with AAT6 and nitroreductase loss, and high resistance and parasite regrowth is responsible for treatment relapse. In clinical studies, the TbAT1 proportion of total random effects was 68% (95% CI: 38.0–91.6); I2 = 96.99% (95% CI: 94.6–98.3). Treatment failure rates were highest with melarsoprol followed by eflornithine at 41.49% (95% CI: 24.94–59.09) and 6.56% (3.06–11.25) respectively. HATr-resistant phenotypes used in most laboratory experiments demonstrated significantly higher pentamidine resistance than other trypanocides. Conclusion: The emergence of drug resistance across the spectrum of trypanocidal agents that are used to treat HAT is a major threat to the global WHO target to eliminate HAT by 2030. T. brucei strains were largely resistant to diamidines and the use of high trypanocide concentrations in clinical studies have proved fatal in humans. Studies to develop novel chemotherapeutical agents and identify alternative protein targets could help to reduce the emergence and spread of HATr.

Optimizing the use of lenvatinib in combination with pembrolizumab in patients with advanced endometrial carcinoma.

IntroductionThe combination of lenvatinib plus pembrolizumab demonstrated a relevant clinical benefit in patients with endometrial carcinoma. The safety profile was consistent with the established profiles of each drug in monotherapy, with the most frequent adverse events being hypertension, an on-target effect, hypothyroidism, diarrhea, nausea, vomiting, loss of appetite, fatigue, and weight loss.Areas coveredWe first review the rationale based on the combination of a VEGFR inhibitor and an immune checkpoint inhibitor, highlighting the main pharmacokinetic and pharmacodynamic features of lenvatinib. Next, we focus on the common adverse events associated with lenvatinib and guide how to optimally prevent, detect, and manage them, while minimizing interruptions during lenvatinib treatment.DiscussionThe side effects profile of lenvatinib is very well known, being similar across different tumor types. Most toxicities can be preventable. An appropriate, proactive, and thorough management of lenvatinib toxicities during treatment is required to maximize potential lenvatinib efficacy. Adverse events should be detected as early as possible, by both carefully monitoring the patient from lenvatinib initiation and preventing their occurrence. Patients should be followed also during treatment as some adverse events, e.g., cardiac dysfunction might appear later. Increased awareness on risk to benefit ratio among clinicians would be helpful to avoid dose interruptions or discontinuation of lenvatinib, with preferring other medical interventions and supportive care.

“Efficacy of Combination drug therapy of Oxybutynin and Desmopressin in enuresis in children in comparison to one drug therapy or any other combination drug therapy : A Systematic review and Meta-analysis”

Background: This Systematic review was undertaken to bring forward some solution to the old stubborn neglected problem of enuresis in children which appears to be left out in the race of scientific advancements. The pathogenesis of disease so far understood is supposed to be the result of three factors of Polyuria, Overactive bladder and difficulties in arousal from sleep. However pinpointing the extent and role of each one in an individual case is a difficult time and resource consuming job. The aim of study is to help front line clinicians in decision making in poor resource limited developing countries, so that children and families are not abandoned to suffer on their own without any hope for a speedy solution, when they come forward asking for help. Methods: We hypothesized that combination therapy of Desmopressin and oxybutynin in usual therapeutic doses at outset, might be a solution. To accumulate evidence an extensive search was done as per PRISMA 2020 guideline for properly designed double blind Randomized clinical trials to back up any such decision. Databases searched were PubMed, Embase, Google Scholar, Scopus and web of science. Clinical trial registry platforms, open access grey areas and cross references were also searched. Data obtained was analyzed by random effect model , at 95% confidence interval with Mantel Haenszel test for risk ratio. Protocol was registered at PROSPERO Results: There was lack of robust randomized data for any nodal network meta-analysis. Nine studies were included for analysis having experimental or Intervention arm as combination therapy versus Desmopressin mono drug therapy as comparator. Synthesis of data and meta-analysis was done using Cochrane Revman version 5.4 There was lack of studies for comparison to Oxybutynin and Imipramine mono drug therapy, hence they are discussed in tabular form only There is some hope in other combinations also in new entrants in the armamentarium against enuresis in children like Tolterodine, Solifenacin, Propiverine. A favorable outcome was observed for this combination therapy at outset in whatever studies we found, but risk of bias is there and superiority can be said as only marginal. More robust evidence is needed from scientific researchers for different pharmacological combination therapies at outset to decrease the gap from the point of seeking help to control of enuresis. Conclusion: We recommend trial of Desmopressin Oxybutynin combination therapy at the time of seeking help in resource poor developing countries to tackle this stigmatized socially unacceptable problem of children at present. This will also help in generating more robust data in favor or against any such decision for future reference and analysis. But we can say that the scientific fraternity is still far behind in properly designed randomized and blinded trials for any clear and evidence based medicine for this entity. Bangladesh Journal of Medical Science Vol. 21 No. 04 October’22 Page : 685-697

215.9: Achievement of Persistent Mixed Chimerism in Recipients of Matched and Mismatched Living Donor Kidney Transplants in a Tolerance Induction Protocol

Purpose: The induction of tolerance to kidney transplants after development of specific unresponsiveness of recipient immune cells to donor alloantigens allows elimination of maintenance immunosuppressive (IS) drugs while preventing graft loss due to rejection. We have previously reported successful induction of mixed chimerism and tolerance in recipients of fully HLA-matched living donor kidney and hematopoietic cell (HCT) transplants. This work continues in HLA-mismatched transplants, wherein achieving persistent mixed chimerism is more challenging. Methods: Living donors underwent hematopoietic stem cell mobilization and leukopheresis 6 weeks before kidney donation. The recipient conditioning regimen for the HCT consisted of 10 doses of total lymphoid irradiation (TLI) and 5 doses of anti-thymocyte globulin (ATG) following kidney transplant, with HCT on day 11. The HCT consisted of CD34+ hematopoietic progenitor cells and CD3+ cells. Twenty-nine patients received fully HLA-matched living donor transplants. Twenty-five patients received HLA-mismatched (1-haplotype matched) living donor transplants with an escalating dose of CD3+ cells to enhance HCT engraftment. Six patients recently received HLA-mismatched living donor transplants with substitution of a dose of total body irradiation (TBI) for the final dose of TLI. Results: Of the 29 fully HLA-matched living donor transplants, complete IS drug withdrawal was achieved in 24, all of whom had at least 6 months of persistent mixed chimerism. Of the 24, 17 are alive, well and have been off IS drugs from 4 to 14 years without evidence of rejection. Two off IS drugs died due to cardiovascular events at 2 and 3 years. Two returned to IS drugs after loss of chimerism at 1 year followed by acute rejection at 4 years off IS drugs, and 3 after relapse of kidney disease at 1, 5 and 6 years off IS drugs. In the 25 1-haplotype matched living donor transplants, mixed whole blood chimerism persisted in 10 (mean 20% chimerism) at the end of the 1st year posttransplant while immunosuppression was reduced to tacrolimus monotherapy. Chimerism was lost during the 2nd year in the 5 who were withdrawn from monotherapy; they returned to IS drug(s). Mixed chimerism without rejection has persisted in 3 maintained on IS monotherapy, for up to 5 years. The recent addition of a dose of TBI markedly increased levels and stability of mixed chimerism during the 1st year posttransplant. Conclusions: The loss of chimerism during withdrawal of IS drug monotherapy in the HLA-mismatched transplants may have been due to the low level of whole blood chimerism, a contrast to the HLA-matched. A very low single dose of TBI added to the TLI/ATG conditioning regimen increased early chimerism. The stability of high levels of mixed chimerism after complete IS drug withdrawal during the 2nd year posttransplant is the subject of continuing investigation.

Comparing the efficacy and safety of tenofovir and adefovir or combined drug treatment for the treatment of chronic hepatitis B infection: a systematic review and meta-analysis.

BackgroundChronic hepatitis B (CHB) affects a vast population globally. A variety of drugs are available for the treatment of CHB, including tenofovir (TDF) and adefovir (ADV). However, the efficacy of monotherapy drug treatment is inconclusive, the safety and efficacy of TDF remain unclear, more data are needed to be included and combined drug treatment is considered to exhibit higher efficacy. To explore this issue, we performed a current literature review and meta-analysis to compare the efficacy and safety of ADV vs. TDF, TDF vs. ADV + lamivudine (LAM); TDF vs. ADV + entecavir (ETV).MethodsWe systematically searched China National Knowledge Infrastructure, the Cochrane Library, Embase, PubMed, Chinese VIP, and Wanfang Data, for relevant clinical trials since July 2015, all included studies were based on PICOS principles and evaluated independently by the reviewers in accordance with the Cochrane Handbook (Rob2.0). A meta-analysis was performed by using Review Manager 5.4.ResultsWe included a total of 32 studies, including 31 randomized controlled trials and one retrospective study involving 2,473 patients. The results revealed a low risk of bias in included studies, that the virologic response of TDF was superior to ADV (P<0.05). And TDF was also superior to ADV in Serum creatinine levels, Immunologic function, and safety profile. However, when ADV was combined with other medications, it was superior to TDF in alanine aminotransferase (ALT) level and Tbil level and adverse reactions, but on other indicators, TDF was superior to drug combination therapy.ConclusionsResults showed that TDF was superior to ADV in the parameters of ALT, hepatitis B virus (HBV)-DNA reduction, HBeAg-negative conversion rate, safety, and total bilirubin levels in patients with CHB. However, when ADV was combined with LAM or ETV, they often showed the same therapeutic effect as TDF in parameters such as ALT level and Tbil level and combined therapy can effectively reduce the occurrence of adverse reactions. In this study, because the sample source countries were limited, a greater number of global studies are needed in the future to verify the current findings.

Hypolipidemic activity of the polysaccharide L-rhamnopyranosyl-6-O-methyl-galacturonan in combined administration with HMG-CoA reductase and cholesterol absorption inhibitors

Introduction . Dyslipidemia treatment in many cases requires carefully selected combination of lipid-lowering drugs including bile acid sequestrants. A promising compound is L-rhamnopyranosyl-6- O -methyl-galacturonan (L-RAG), a polysaccharide obtained from the birch leaves ( Betula pendula L.). Aim . To evaluate the lipid-lowering activity of L-RAG administered in combination with the HMG-CoA reductase inhibitor rosuvastatin or the cholesterol absorption inhibitor ezetimibe. Materials and methods . Hyperlipidemia in hamsters was reproduced by synthetic diet supplemented with 0.3 % cholesterol and 11 % coconut oil (HFCD). At the end of the experiment the levels of triacylglycerols (TAG), bile acids, total cholesterol (TC), cholesterol of low-density lipoproteins (LDL-C) and high-density lipoproteins (HDL-C) were determined in the blood serum using Chronolab Systems S. L. enzymatic kits (Spain), and atherogenic index (AI) was calculated. Results and discussion . L-RAG demonstrates a lipid-lowering effect in a model of diet-induced hyperlipidemia in hamsters. The decrease in the TC level was mainly caused by a decrease in the content of cholesterol in the atherogenic LDL fraction, which led to a decrease in AI. The use of rosuvastatin and ezetimibe in combination with L-RAG leads to a better lipid-lowering effect. The additive effect of the polysaccharide is mainly due to a decrease in the level of bile acids in the blood serum, which indicates its ability to absorb them in the intestinal lumen and interrupt enterohepatic circulation, acting like bile acid sequestrants. Conclusion . It was shown that administration of L-RAG together with ezetimibe or rosuvastatin led to a better decrease in the TC, TAG, LDL-C levels than with polysaccharide monotherapy or comparison drugs alone. The obtained data substantiate the prospects of using L-RAG in the complex therapy of hyperlipidemia.

Somatostatin analogues in treatment-refractory meningioma: a systematic review with meta-analysis of individual patient data.

Treatment-refractory meningiomas have a dismal prognosis and limited treatment options. Meningiomas express high-densities of somatostatin receptors (SSTR), thus potentially susceptible to antitumorigenic effects of somatostatin analogues (SSA). Evidence for SSA in meningiomas is scarce, and it is unclear if published literature would either (1) support wider use of SSA, if (2) more evidence is desirable, or if (3) available evidence is sufficient to discard SSA. We addressed the need for more evidence with a systematic review and meta-analysis. We performed an individual patient data (IPD) meta-analysis. Main outcomes were toxicity, best radiological response, progression-free survival, and overall survival. We applied multivariable logistic regression models to estimate the effect of SSA on the probability of obtaining radiological disease control. The predictive performance was evaluated using area under the curve and Brier scores. We included 16 studies and compiled IPD from 8/9 of all previous cohorts. Quality of evidence was overall ranked "very low." Stable disease was reported in 58% of patients as best radiological response. Per 100mg increase in total SSA dosage, the odds ratios for obtaining radiological disease control was 1.42 (1.11 to 1.81, P = 0.005) and 1.44 (1.00 to 2.08, P = 0.05) for patients treated with SSA as monodrug therapy vs SSA in combination with everolimus, respectively. Low quality of evidence impeded exact quantification of treatment efficacy, and the association between response and treatment may represent reverse causality. Yet, the SSA treatment was well tolerated, and beneficial effect cannot be disqualified. A prospective trial without bias from inconsistent study designs is warranted to assess SSA therapy for well-defined meningioma subgroups.

Effects of magnesium valproate adjuvant therapy on patients with dementia: A systematic review and meta-analysis.

Background:Current research has found contradictory results on the treatment of magnesium valproate (VPM) in patients with dementia (PwD).Objectives:Here, we conducted a meta-analysis to evaluate the efficacy and safety of VPM in the adjuvant treatment of PwD.Purpose:Current research has found contradictory results on the treatment of VPM in PwD. Here, we conducted a meta-analysis to evaluate the efficacy and safety of VPM in the adjuvant treatment of PwD.Methods:MEDLINE via PubMed, Cochrane Library, EBSCO, Embase, China National Knowledge (CNKI), and Wan Fang databases were researched to gather relevant data on magnesium valproate assistant therapy for patients with dementia (PwD) by using medical subject headings and term words.Results:After the final screening, 22 RCT studies (a total of 1899 participants) were included in this meta-analysis, which compared VPM adjuvant treatment with antidementia or psychotropic drug monotherapy. Significant differences were found in the scores on mini-mental state examination (P = .028), Alzheimer disease assessment scale cognitive subscale (P < .05), Bech-Rafaelsen Mania Rating Scale (P < .05), behavioral pathology in Alzheimer disease rating scale (P = .001), activities of daily living (P < .05), and Pittsburgh Sleep Quality Index (P < .05). Besides, the levels of inflammatory factors including IL-1β, IL-6, and TNF-α were significantly lower than those in the monotherapy group (P < .05). While there was no increase in the incidence of adverse events (P = .383), VPM as an assistant therapy is generally well tolerated in PwD.Conclusion:By meta-analysis, evidence was found to support VPM additional used for the treatment of cognitive function, psychiatric symptoms, or disease improvement in PwD. VPM may be a potential drug to aid in the treatment of dementia patients. However, there was lack of enough evidence to classification of dementia severity in our inclusion study. More research is still needed, including clinical trials evaluating VPM as a complementary therapy.

Evaluation of Bone Metabolism in Children Using Antiseizure Drugs: A Single-Center Experience and Review of the Literature

AbstractThe effect of anti-seizure drugs (ASDs) on bone mineral density (BMD) is a controversial topic. This study investigated the effect of monotherapy and polytherapy drugs separately. Patients with a history of epilepsy treated with the same ASDs for more than 6 months were included in the study. Data regarding patient demographics, biochemical markers related to bone metabolism (calcium, phosphorus, alkaline phosphatase, parathyroid hormone, vitamin D), and BMD with dual-energy X-ray absorptiometry (DXA) were collected and compared. In total, 104 children with epilepsy using valproic acid (VPA), levetiracetam (LEV), carbamazepine (CBZ) alone or in combination and 22 healthy controls were evaluated. The ages of the children (64 boys, 62 girls) ranged between 2 and 17, with a mean of 9.50 ± 4.03 years. BMD or Z-scores did not differ among the monotherapy groups or between them and the polytherapy group. The lowest mean Z-score was in the VPA group but without statistical significance. Alkaline phosphatase levels were significantly higher in the group using CBZ. Calcium levels significantly differed between the groups (p = 0.001). The CBZ and LEV groups had the lowest calcium levels. However, phosphorus and vitamin D measurements did not significantly differ by ASDs used. Unfortunately, low vitamin D levels were evident in all children with epilepsy and even among controls. Physical activity, sun exposure, and calcium intake might be recommended in children treated with ACDs and in combination with additional risk factors monitoring via DXA should be considered. Further studies in a large population are necessary to judge which ASDs are more at risk to reduce bone mineralization than others.

Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis

ObjectivesTo characterize individual participant level response distributions to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration from 1979 to...

Nimodipine vs. Milrinone - Equal or Complementary Use? A Retrospective Analysis.

BackgroundCerebral vasospasm (CVS) continues to account for high morbidity and mortality in patients surviving the initial aneurysmal subarachnoid hemorrhage (SAH). Nimodipine is the only drug known to reduce delayed cerebral ischemia (DCI), but it is believed not to affect large vessel CVS. Milrinone has emerged as a promising option. Our retrospective study focused on the effectiveness of the intra-arterial application of both drugs in monotherapy and combined therapy.MethodsWe searched for patients with aneurysmal SAH, angiographically confirmed CVS, and at least one intra-arterial pharmacological angioplasty. Ten defined vessel sections on angiograms were assessed before and after vasodilator infusion. The improvement in vessel diameters was compared to the frequency of DCI-related cerebral infarction before hospital discharge and functional outcome reported as the modified Rankin Scale (mRS) score after 6 months.ResultsBetween 2014 and 2021, 132 intra-arterial interventions (144 vascular territories, 12 bilaterally) in 30 patients were analyzed for this study. The vasodilating effect of nimodipine was superior to milrinone in all intradural segments. There was no significant intergroup difference concerning outcome in mRS (p = 0.217). Only nimodipine or the combined approach could prevent DCI-related infarction (both 57.1%), not milrinone alone (87.5%). Both drugs induced a doubled vasopressor demand due to blood pressure decrease, but milrinone alone induced tachycardia.ConclusionsThe monotherapy with intra-arterial nimodipine was superior to milrinone. Nimodipine and milrinone may be used complementary in an escalation scheme with the administration of nimodipine first, complemented by milrinone in cases of severe CVS. Milrinone monotherapy is not recommended.

Effects of Folic Acid and Vitamin B12 Supplementation on the Efficacy and Toxicity of Pemetrexed in the Management of Advanced Stage Non-Squamous Non-Small Cell Lung Cancer

Pemetrexed (PMT) is a multi-target antifolate that has been confirmed for the treatment of lung cancer. It has significantly boosted the survival rate of patients with non-squamous non-small-cell lung cancer. Multiple Phase II clinical trials have demonstrated that pemetrexed is an effective monotherapy for a range of solid tumors, including colorectal, breast, neck, and head malignancies. Methods for consolidating pemetrexed with other chemotherapeutics and novel molecularly targeted drugs are currently under investigation. Pemetrexed is currently recommended for first-line dose management with platinum chemotherapies, second-line monotherapy drugs, and, in modern chemotherapy protocols, as continuation therapy following first-line therapy. Vitamin B12 (VB12) and folic acid (FA) supplements can aid to minimize the cytotoxicity of pemetrexed. FA/VB12 has been suggested to have an antagonistic effect on pemetrexed's efficacy. Patients who accept FA/VB12 have a higher tolerance for PMT and a longer lifespan. In this study, the pharmacodynamics, pharmacokinetics, and toxicity of pemetrexed were studied, as well as the implications of FA/VB12 as a co-medication with pemetrexed-based chemotherapy.