pyrimidinones and Diarrhea

Combining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti-PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n = 26), or durvalumab and trametinib given concomitantly (cohort B, n = 20) or sequentially (cohort C, n = 22) for patients with BRAF-wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy. Objective responses were observed in 69.2% (cohort A), 20.0% (cohort B) and 31.8% (cohort C) of patients, with evidence of improved tumor immune infiltration and durable responses in a subset of patients with available biopsy samples. In conclusion, combined MAPK inhibition and anti-PD-L1 therapy may provide treatment options for patients with advanced melanoma.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Cohort Studies; Diarrhea; Exanthema; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinases; Mutation; Oximes; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Young Adult

Sustained viral suppression with antiretroviral therapy improves clinical outcomes for HIV-infected individuals. Study M05-730 evaluated the long-term antiviral activity, safety, tolerability, emergence of resistance, and compliance with once-daily (QD) versus twice-daily (BID) lopinavir/ritonavir (LPV/r) combination therapy in treatment-naïve, HIV-1-infected subjects through 96 weeks. Antiretroviral-naïve subjects with HIV-1 RNA levels >1000 copies/ml were randomized to LPV/r QD (N = 333) or BID (N = 331) with tenofovir DF and emtricitabine. Through 96 weeks, 77 subjects from each group discontinued prematurely; adverse or HIV-related events contributed to discontinuation of 36 subjects overall, with no significant differences between treatment groups. At 96 weeks, 216 QD subjects (64.9%) and 229 BID subjects (69.2%) had HIV-1 RNA <50 copies/ml (p = 0.249) by intent-to-treat analysis. Evaluation of the time to virologic failure indicated that 85.0% and 80.7% of QD and BID subjects, respectively, maintained virologic suppression through 96 weeks (p = 0.638). QD subjects demonstrated greater adherence levels. There were no significant differences in virologic response when subjects were analyzed according to baseline disease state. Emergence of postbaseline resistance mutations occurred at similar low rates in each dosing group. Diarrhea was the most common moderate-to-severe drug-related adverse event reported; the most common Grade 3+ laboratory abnormalities were elevations of total cholesterol and triglycerides, occurring with similar incidence regardless of LPV/r dosing frequency. QD dosing of LPV/r was associated with similar durability of viral suppression and low rates of genotypic resistance and treatment-limiting adverse events as compared with BID dosing in treatment-naïve subjects through 96 weeks of treatment.

Topics: Adenine; Anti-HIV Agents; Deoxycytidine; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Emtricitabine; HIV Infections; HIV-1; Humans; Lopinavir; Organophosphonates; Pyrimidinones; Ritonavir; Tenofovir

Antiretroviral-naive HIV-1-infected volunteers received zidovudine/lamivudine plus either lopinavir/ritonavir (n=104) or efavirenz (n=51). Lopinavir/ritonavir-treated subjects demonstrating 3 consecutive monthly HIV-1 RNA levels <50 copies/mL started lopinavir/ritonavir monotherapy. In previous-failure=failure analysis, 48% (lopinavir/ritonavir) and 61% (efavirenz) maintained HIV-1 RNA at <50 copies/mL through week 96, (P= .17; 95% confidence interval [CI] for the difference, -29% to 4%); in noncompletion=failure analysis, 60% (lopinavir/ritonavir) and 63% (efavirenz) maintained HIV-1 RNA at <50 copies/mL at week 96 (P= .73; 95% CI for the difference, -19% to 13%). Significant sparing of peripheral lipoatrophy was noted in the lopinavir/ritonavir simplification strategy. This study has provided important information for future studies using treatment simplified to lopinavir/ritonavir monotherapy.

Topics: Acquired Immunodeficiency Syndrome; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Diarrhea; Drug Therapy, Combination; Glucose Tolerance Test; HIV Protease Inhibitors; Humans; Lopinavir; Nausea; Pyrimidinones; Ritonavir; RNA, Viral; Time Factors; Treatment Outcome; Viral Load

Recent data indicate that fosamprenavir/ritonavir as part of an initial antiretroviral regimen in HIV-1-infected patients is associated with favourable efficacy and tolerability and in the KLEAN study (kaletra versus lexiva with epivir and abacavir in antiretroviral-naive patients) it was found to be non-inferior to lopinavir/ritonavir in association with abacavir/lamivudine. In our open-label, observational study conducted in 82 therapy-nasmall yi, Ukrainianve HIV-1-infected patients followed-up for 18 months, virological and immunological efficacy was comparable in subjects receiving a fosamprenavir/ritonavir-based and a lopinavir/ritonavir-based treatment (proportions of patients with HIV RNA <50 copies/mL at month 18 were 76.9% and 74.4%, respectively, when discontinuations were counted as failures). At the same time, frequency of treatment discontinuations and adverse events were similar in both groups, whereas incidence of diarrhoea and hypertriglyceridaemia was significantly higher in lopinavir-treated patients than in fosamprenavir-treated ones (53.5% vs. 25.6% and 69.8% vs. 43.6%, respectively; P < 0.01). In subjects with virological failure, no viral protease resistance mutations were detected by genotype analysis.

Topics: Adult; Anti-HIV Agents; Carbamates; Diarrhea; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV Protease; HIV-1; Humans; Hypertriglyceridemia; Lopinavir; Male; Middle Aged; Organophosphates; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Treatment Failure; Treatment Outcome

Lopinavir/ritonavir (LPV/r) has been the gold standard in first line rescue treatment for many years. No other boosted protease inhibitor (PI/r) has managed to demonstrate that it is superior to LPV/r. In this regard, the TITAN study compared the efficacy and safety of darunavir (DRV/r) in 595 patients, at a dose of 600/100 mg two times a day against the normal LPV/r dose, combined with at least 2 other optimised antiretroviral drugs. The efficacy of the treatment at 48 weeks (VL<400 copies/mL) was significantly higher in the DRV/r goup compared to the LPV/r group, both in the analysis by protocol (77% vs. 68%), the non-inferiority of DRV/r being demonstrated (estimated difference +9%, 95% CI 2-16), and by intention to treat (77% vs. 67%), the superiority of DRV/r being demonstrated (estimated difference 10%, 95% CI 2-17%). The incidence of diarrhoea and increase in triglycerides was higher in the LPV/r group. The differences in efficacy of both treatments in favour of DRV/r started to be seen from a basal primary mutation in the protease, with these differences increasing as the number of these mutations increased. In patients with virological failure, DRV/r protected the protease and reverse transcriptase against mutations, thus preserving future therapeutic options. We have some theoretical and clinical data available that enables us to consider the possibility of administering DRV/r once a day in some patients with a few mutations in the protease and in those where this dosing regime is considered important. With the results of the TITAN study, DRV/r must be considered the new gold standard in first line rescue, at least in those patients with a primary mutation in the protease.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Darunavir; Diarrhea; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lopinavir; Male; Prognosis; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Salvage Therapy; Sulfonamides

Diarrhea is a major side effect of ErbB receptor tyrosine kinase inhibitors (TKIs) in cancer chemotherapy. Here, we show that the primary mechanism of ErbB TKI diarrhea is activation of basolateral membrane potassium (K+) channels and apical membrane chloride (Cl-) channels in intestinal epithelia and demonstrate the efficacy of channel blockers in a rat model of TKI diarrhea. Short-circuit current in colonic epithelial cells showed that the TKIs gefitinib, lapatinib, and afatinib do not affect basal secretion but amplify carbachol-stimulated secretion by 2- to 3-fold. Mechanistic studies with the second-generation TKI afatinib showed that the amplifying effect on Cl- secretion was Ca2+ and cAMP independent, was blocked by CF transmembrane conductance regulator (CFTR) and K+ channel inhibitors, and involved EGFR binding and ERK signaling. Afatinib-amplified activation of basolateral K+ and apical Cl- channels was demonstrated by selective membrane permeabilization, ion substitution, and channel inhibitors. Rats that were administered afatinib orally at 60 mg/kg/day developed diarrhea with increased stool water from approximately 60% to greater than 80%, which was reduced by up to 75% by the K+ channel inhibitors clotrimazole or senicapoc or the CFTR inhibitor (R)-BPO-27. These results indicate a mechanism for TKI diarrhea involving K+ and Cl- channel activation and support the therapeutic efficacy of channel inhibitors.

Topics: Acetamides; Afatinib; Animals; Cell Membrane Permeability; Clotrimazole; Colon; Cystic Fibrosis Transmembrane Conductance Regulator; Diarrhea; Disease Models, Animal; Epithelial Cells; ErbB Receptors; Female; Humans; Intestinal Mucosa; Neoplasms; Oxazines; Potassium Channel Blockers; Potassium Channels; Protein Kinase Inhibitors; Pyrimidinones; Pyrroles; Rats; Trityl Compounds

The combination therapy of dabrafenib and trametinib revolutionized the treatment for BRAF V600-mutated melanoma. Various adverse events have been reported for this treatment, most notably fever. Herein, we report two cases of novel an adverse event, namely sudden and significant elevation of plasma D-dimer level induced by this therapy. In the first case, the remarkable elevation of plasma D-dimer level up to 87.4 mg/dL was noted on day 11, and in the second case, the plasma D-dimer level reached 125.5 mg/dL on day 25. In both cases, D-dimer levels gradually decreased after the cessation of this therapy. Although the exact cause is not clear, we assume two possible hypotheses: the first is that the combination therapy may induce disseminated intravascular coagulation, and the second is that the therapy induced pathological condition of secondary thrombotic microangiopathies. Our cases suggest that this thrombotic adverse event should not be overlooked, and coagulation parameters need to be monitored during the course of this treatment.

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Fatigue; Female; Fever; Fibrin Fibrinogen Degradation Products; Humans; Imidazoles; Melanoma; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome; Vomiting

Diarrhea is one of the most important causes of mortality in the developing world, being responsible for 2.5 million deaths each year. Many of these deaths are caused by enterotoxigenic strains of bacteria, like

Topics: Bacterial Toxins; Cell Line; Cystic Fibrosis Transmembrane Conductance Regulator; Diarrhea; Enterotoxins; Enzyme Inhibitors; Escherichia coli Proteins; Gastrointestinal Hormones; Humans; Intestinal Mucosa; Natriuretic Peptides; Pyrimidinones; Receptors, Enterotoxin

Bile acid diarrhea (BAD) is common with ileal resection, Crohn's disease, and diarrhea-predominant irritable bowel syndrome. Here, we demonstrate the efficacy of cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor (

Topics: Animals; Cell Line; Cells, Cultured; Chenodeoxycholic Acid; Chlorides; Cystic Fibrosis Transmembrane Conductance Regulator; Diarrhea; Female; Humans; Intestinal Mucosa; Intestinal Secretions; Mice; Oxazines; Pyrimidinones; Pyrroles; Rats; Rats, Sprague-Dawley

Topics: Animals; Cystic Fibrosis Transmembrane Conductance Regulator; Diarrhea; Dose-Response Relationship, Drug; Female; Humans; Intestines; Mice; Molecular Structure; Oxazines; Pyrimidinones; Pyrroles

The novel antibiotic MBX-500, dosed at 100, 200, or 400 mg/kg twice daily for 7 days, was evaluated for the treatment of Clostridium difficile infection (CDI) in the gnotobiotic pig model. MBX-500 increased survival at all doses and at high doses improved clinical signs and reduced lesion severity, similar to vancomycin. Our results show that MBX-500 is an effective antibiotic for the treatment of diarrhea associated with CDI and prevents severe systemic disease.

Topics: Animals; Anti-Bacterial Agents; Clostridioides difficile; Clostridium Infections; Colon; Diarrhea; Disease Models, Animal; Drug Evaluation, Preclinical; Fluoroquinolones; Germ-Free Life; Kaplan-Meier Estimate; Pyrimidinones; Severity of Illness Index; Swine; Treatment Outcome; Vancomycin

Topics: Diarrhea; Drug-Related Side Effects and Adverse Reactions; Herb-Drug Interactions; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones

Hyperthyroidism has been described after highly active antiretroviral therapy for AIDS and has been attributed to late onset immune reconstitution. The team reports a young Polynesian man with AIDS who responded to highly active antiretroviraltherapy. However, 15 months after initiation of antiretroviral therapy, he was hospitalized for hypokalemic thyrotoxic periodic paralysis, an unusual manifestation of hyperthyroidism which typically occurs in young Asian males.

Topics: Acquired Immunodeficiency Syndrome; Adult; Antiretroviral Therapy, Highly Active; Autoimmunity; Diarrhea; Drug Combinations; Genetic Predisposition to Disease; Graves Disease; Hawaii; Humans; Hypokalemic Periodic Paralysis; Iodine Radioisotopes; Lamivudine; Lopinavir; Male; Native Hawaiian or Other Pacific Islander; Polynesia; Pyrimidinones; Thyrotoxicosis; Zidovudine

To determine and compare rates of diarrhea in patients receiving an antiretroviral regimen containing lopinavir-ritonavir versus nelfinavir and in patients who received these drugs sequentially.. Retrospective cohort analysis.. Hospital-based human immunodeficiency virus (HIV) clinic.. Four hundred one participants in the HIV Atlanta VA Cohort Study who were prescribed lopinavir-ritonavir or nelfinavir from 1996-2002.. Chart review identified episodes of diarrhea that potentially were associated with an antiretroviral agent. Data collected included antidiarrheal agents dispensed, baseline viral load and CD4+ cell counts, demographic variables, and previous therapy Diarrhea associated with an antiretroviral regimen occurred in 175 (49%) of 354 patients receiving nelfinavir and 17 (17%) of 99 patients receiving lopinavir-ritonavir (p < 0.001). Treatment for the diarrhea occurred in 118 (33%) of 354 patients receiving nelfinavir and 9 (9%) of 99 receiving lopinavir-ritonavir (p < 0.001). Patients in the lopinavir-ritonavir group were more likely to have received highly active antiretroviral therapy and azithromycin than patients receiving nelfinavir, and they had lower baseline CD4+ cell counts (p < or = 0.01 for each comparison). The average number of months/person-year of diarrhea treatment was 2.0 for the nelfinavir group and 0.13 for the lopinavir-ritonavir group. Of the 10 antiretroviral-naive patients who received lopinavir-ritonavir, none needed treatment for diarrhea, whereas 78 (36%) of 217 antiretroviral-naive patients who received nelfinavir required treatment for diarrhea. Of the 52 patients who had been taking nelfinavir and were switched to lopinavir-ritonavir, they were more likely to start antidiarrheal treatment while taking nelfinavir (14 [27%]) than while receiving lopinavir-ritonavir (3 [6%]) (p = 0.004).. Patients receiving lopinavir-ritonavir were significantly less likely to have diarrhea or to require treatment for diarrhea than patients receiving nelfinavir. The same results occurred when the drugs were given to the same patients sequentially (nelfinavir followed by lopinavir-ritonavir). The diarrhea associated with lopinavir-ritonavir was less frequent, less severe, and shorter in duration than diarrhea associated with nelfinavir.

Topics: Adult; Anti-Retroviral Agents; Antidiarrheals; Antiretroviral Therapy, Highly Active; Cohort Studies; Diarrhea; Georgia; HIV Infections; Humans; Incidence; Lopinavir; Middle Aged; Nelfinavir; Pyrimidinones; Retrospective Studies; Ritonavir; United States; United States Department of Veterans Affairs

Topics: Adult; Anti-HIV Agents; Diarrhea; Female; Humans; Lopinavir; Male; Pyrimidinones