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Determining drug dose in the era of targeted therapies: playing it (un)safe?

Targeted therapies against phosphatidylinositol 3-kinase (PI3K), Bruton's tyrosine kinase (BTK), and B-cell lymphoma-2 (BCL-2) are approved … inical experience with targeted therapies have pointed to dose reductions, intermittent dosing, and drug combinations as strategies to overcome treatment intolerance and resistance.

Rational designing of peptide-ligand conjugates-based immunotherapy for the treatment of complicated malaria.

AIMS: Malaria deaths occur primarily due to complicated malaria associated with the sequestration of Plasmodium falciparum-infected erythrocyte (PfIE) in the capillary microvasculature. This study aims to design peptide ligand conjugates (PLCs) for treating complicated malaria using various in silico techniques. The PLC includes a natural ligand for the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1): expressed explicitly on the surface of PfIE, and a highly immunogenic peptide derived from the commonly used peptide vaccines in malaria-endemic countries. The ligand is predicted t

Divergent Analyses of Genetic Relatedness and Evidence-Based Assessment of Therapeutics of Staphylococcus aureus from Semi-intensive Dairy Systems.

Use of antibiotics without following standard guidelines is routine practice in developing countries which is giving rise to genetic divergence and increased drug resistance. The current study analyzed genetic divergence and drug resistance by S. aureus and therapeutic efficacy of novel antibiotic combinations. The study revealed that 42.30% (minimum 20%-maximum 70%) of milk samples are positive for S. aureus. Study also revealed seven SNPs in the S. aureus nuc gene (c.53A>G, c.61A>G, c.73T>C, c.93C>A, c.217C>T, c.280T>C, and c.331T>A). Local isolates Staph-2 and Staph-3 were closely related t

Perillyl alcohol for pediatric TP53- and RAS-mutated SHH-medulloblastoma: an in vitro and in vivo translational pre-clinical study.

PURPOSE: Inhalation of perillyl alcohol (POH) recently emerged as an investigational promising antiglioma strategy. However, little attention has been paid to its therapeutic potential for other brain tumors, especially in the pediatric setting. METHODS: The effects of POH were explored in medulloblastoma cell models belonging to the SHH variant with activation of RAS (ONS-76) or with TP53 mutations (DAOY and UW402), by means of proliferation and invasion assays. Interactions with methotrexate, thiotepa, or ionizing radiation were also assessed. Mice bearing subcutaneous tumors were treated w

Assessment of the Effects of Dietary Vitamin D Levels on Olanzapine-Induced Metabolic Side Effects: Focus on the Endocannabinoidome-Gut Microbiome Axis.

Vitamin D deficiency is associated with poor mental health and dysmetabolism. Several metabolic abnormalities are associated with psychotic diseases, which can be compounded by atypical antipsychotics that induce weight gain and insulin resistance. These side-effects may be affected by vitamin D levels. The gut microbiota and endocannabinoidome (eCBome) are significant regulators of both metabolism and mental health, but their role in the development of atypical antipsychotic drug metabolic side-effects and their interaction with vitamin D status is unknown. We studied the effects of different

The role of Cryptococcus neoformans histone deacetylase genes in the response to antifungal drugs, epigenetic modulators and to photodynamic therapy mediated by an aluminium phthalocyanine chloride nanoemulsion in vitro.

Cryptococcus is a globally distributed fungal pathogen that primarily afflicts immunocompromised individuals. The therapeutic options are limited and include mostly amphotericin B or fluconazole, alone or in combination. The extensive usage of antifungals allowed the selection of resistant pathogens posing threats to global public health. Histone deacetylase genes are involved in Cryptococcus virulence, and in pathogenicity and resistance to azoles in Candida albicans. Aiming to assess whether histone deacetylase genes are involved in antifungal response and in synergistic drug interactions, w

High-level resistance to bictegravir and cabotegravir in subtype A- and D-infected HIV-1 patients failing raltegravir with multiple resistance mutations.

OBJECTIVES: The second-generation integrase strand transfer inhibitor (INSTI) bictegravir is becoming accessible in low- and middle-income countries (LMICs), and another INSTI, cabotegravir, has recently been approved as a long-acting injectable. Data on bictegravir and cabotegravir susceptibility in raltegravir-experienced HIV-1 subtype A- and D-infected patients carrying drug resistance mutations (DRMs) remain very scarce in LMICs. PATIENTS AND METHODS: HIV-1 integrase (IN)-recombinant viruses from eight patients failing raltegravir-based third-line therapy in Uganda were genotypically and

The vaginal sheet: an innovative form of vaginal film for the treatment of vaginal infections.

Objective: To develop and characterize a new form of vaginal film.Significance: This formulation is intended to overcome some known limitations of traditional dosage forms. It has an absorptive intention to control symptoms and to improve the treatment of vaginal infections characterized by excessive fluid. The vaginal sheet is a thick drug delivery system easy to manipulate, nontoxic and composed by biocompatible macromolecules and polymers, such as gelatin and chitosan.Methods: The sheets were prepared by formulating gelatin or chitosan based gels isolated or in combination, in association w

Clinical effects of the three CFTR potentiator treatments curcumin, genistein and ivacaftor in patients with the CFTR-S1251N gating mutation.

BACKGROUND: The natural food supplements curcumin and genistein, and the drug ivacaftor were found effective as CFTR potentiators in the organoids of individuals carrying a S1251N gating mutation, possibly in a synergistic fashion. Based on these in vitro findings, we evaluated the clinical efficacy of a treatment with curcumin, genistein and ivacaftor, in different combinations. METHODS: In three multi-center trials people with CF carrying the S1251N mutation were treated for 8 weeks with curcumin+genistein, ivacaftor and ivacaftor+genistein. We evaluated change in lung function, sweat chlor

Glycyrrhizin: An alternative drug for the treatment of COVID-19 infection and the associated respiratory syndrome?

Safe and efficient drugs to combat the current COVID-19 pandemic are urgently needed. In this context, we have analyzed the anti-coronavirus potential of the natural product glycyrrhizic acid (GLR), a drug used to treat liver diseases (including viral hepatitis) and specific cutaneous inflammation (such as atopic dermatitis) in some countries. The properties of GLR and its primary active metabolite glycyrrhetinic acid are presented and discussed. GLR has shown activities against different viruses, including SARS-associated Human and animal coronaviruses. GLR is a non-hemolytic saponin and a po

Methadone does not potentiate the effect of doxorubicin in canine tumour cell lines.

Opioid receptor activation was shown to enhance the efficacy of anti-neoplastic drugs in several human cancer cell lines. In these cell lines, doxorubicin increased the number of opioid receptors and methadone concurrently enhanced cellular doxorubicin uptake. Triggered through lay press and media, animal owners started to challenge veterinary oncologists with questions about methadone use in anti-cancer therapy. Especially in veterinary medicine, where side effects of chemotherapy are tolerated to a lesser extent and hence smaller doses are given, agents potentiating chemotherapeutic agents w

Treatment of Recurrent Urinary Tract Infection Symptoms with Urinary Antiseptics Containing Methenamine and Methylene Blue: Analysis of Etiology and Treatment Outcomes.

PURPOSE: Urinary antiseptics including methenamine and methylene blue are used in the symptomatic treatment of urinary tract infections (UTIs). PATIENTS AND METHODS: This was a prospective, double-blind, randomized, double-dummy safety and efficacy study of 2 urinary antiseptic combinations in the symptomatic treatment of recurrent cystitis: methenamine 120mg + methylene blue 20mg (Group A) versus acriflavine 15mg + methenamine 250mg + methylene blue 20mg + Atropa belladonna L. 15mg (Group B). All subjects underwent pretreatment urine culture and antibiotic sensitivity tests prior to 3-day or

Effect of aliskiren on the anticonvulsant activity of antiepileptic drugs against 6 Hz-induced psychomotor seizures in mice.

Drug-drug interactions should be considered during the pharmacological treatment in patients with epilepsy and coexisting hypertension. Experimental studies in rodents showed that antihypertensive drugs which block the renin-angiotensin system (RAS) are able to decrease seizure severity. The anticonvulsant efficacy of several antiepileptic drugs (AEDs) was enhanced in different seizure models following concomitant treatment with RAS inhibitors. The current study examined the combined treatment with AEDs (carbamazepine, valproate, phenobarbital, clonazepam, ethosuximide, levetiracetam) and alis

Use and prescription appropriateness of drugs for peptic ulcer and gastrooesophageal reflux disease in hospitalized older people.

PURPOSE: The aims of this study were to assess the prevalence of use and prescription appropriateness of drugs for peptic ulcer and gastrooe … of peptic ulcer or gastrointestinal hemorrhages, advanced age, Helicobacter Pylori) or gastro-toxic drug combinations, according to the criteria provided by the reimbursement rules of the Agenzia Italiana del Farmaco (NOTA 1 and 48). RESULTS: Among 4715 enrolled patients, 3899 were discharged alive. At hospital discharge, 2412 (61.9%, 95%CI: 60.3-63.4%) patients w …

Thymoquinone enhances the anticancer activity of doxorubicin against adult T-cell leukemia in vitro and in vivo through ROS-dependent mechanisms.

AIMS: Adult T-cell leukemia (ATL) is a mature T-cell neoplasm associated with human T-cell lymphotropic virus (HTLV-1) infection. Major limitations in Doxorubicin (Dox) chemotherapy are tumor resistance and severe drug complications. Here, we combined Thymoquinone (TQ) with low concentrations of Dox and determined anticancer effects against ATL in cell culture and animal model. MAIN METHODS: HTLV-1 positive (HuT-102) and HTLV-1 negative (Jurkat) CD4+ malignant T-cell lines were treated with TQ, Dox and combinations. Viability and cell cycle effects were determined by MTT assay and flow cytome

Comparison of different combinations of maximum medical therapy for lowering intraocular pressure in primary open angle glaucoma: 12-month retrospective consecutive case series.

PURPOSE: To compare the efficacy and safety of two combinations of maximum medical therapy for lowering intraocular pressure (IOP) in primary open angle glaucoma (POAG). STUDY DESIGN: A retrospective consecutive case series. METHODS: A retrospective consecutive case series study including 82 eyes of 82 subjects with POAG treated with maximum medical therapy to lower IOP. Enrolled patients were divided into 2 groups: the triple maximum medical therapy (TMT) group, comprising POAG patients who were treated with tafluprost, brimonidine and the fixed drug combination (FDC) brinzolamide/timolol;

Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study.

Cancer treatments have evolved from indiscriminate cytotoxic agents to selective genome- and immune-targeted drugs that have transformed the outcomes of some malignancies1. Tumor complexity and heterogeneity suggest that the 'precision medicine' paradigm of cancer therapy requires treatment to be personalized to the individual patient2-6. To date, precision oncology trials have been based on molecular matching with predetermined monotherapies7-14. Several of these trials have been hindered by very low matching rates, often in the 5-10% range15, and low response rates. Low matching rates may be

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… Essentially, for de novo combinations, we started patients at about 50% of the usual dose of each drug for two drug combinations, and at about one-third of the dose of each drug for three-drug combinations. … Wheler J , Lee JJ & Kurzrock R Unique molecular landscapes in cancer: implications for individualized, curated drug combinations. Cancer research 74 , 7181 – 7184 ( 2014 ). 25326492 10.1158/0008-5472.CAN-14-2329 PMC4292868 7. …

Centrally Acting Agents for Obesity: Past, Present, and Future.

For many years, obesity was believed to be a condition of overeating that could be resolved through counseling and short-term drug treatment. Obesity was not recognized as a chronic disease until 1985 by the scientific community, and 2013 by the medical community. Pharmacotherapy for obesity has advanced remarkably since the first class of drugs, amphetamines, were approved for short-term use. Most amphetamines were removed from the obesity market due to adverse events and potential for addiction, and it became apparent that obesity pharmacotherapies were needed that could safely be administer

An Animal Model of Abacavir-Induced HLA-Mediated Liver Injury.

Genome-wide association studies indicate that several idiosyncratic adverse drug reactions are highly associated with specific human leukocyte antigen (HLA) alleles. For instance, abacavir, a human immunodeficiency virus reverse transcriptase inhibitor, induces multiorgan toxicity exclusively in patients carrying the HLA-B*57:01 allele. However, the underlying mechanism is unclear due to a lack of appropriate animal models. Previously, we developed HLA-B*57:01 transgenic mice and found that topical application of abacavir to the ears induced proliferation of CD8+ lymphocytes in local lymph nod

Endoperoxide-based compounds: cross-resistance with artemisinins and selection of a Plasmodium falciparum lineage with a K13 non-synonymous polymorphism.

BACKGROUND: Owing to the emergence of multiresistant Plasmodium falciparum parasites in Southeast Asia, along with the impressive decrease in the efficacy of the endoperoxide compound artemisinin and of artemisinin-based combination therapies, the development of novel antimalarial drugs or combinations is required. Although several antiplasmodial molecules, such as endoperoxide-based compounds, are in advanced research or development, we do not know whether resistance to artemisinin derivatives might impact the efficacy of these new compounds. OBJECTIVES: To address this issue, the antiplasmo