pyrimidinones and Anemia

Nine clinical trials have analyzed whether the use of lopinavir-ritonavir (LPV/r) monotherapy could be a valid alternative to triple antiretroviral therapy. Four of these clinical trials included an analysis of risk factors for virological failure. The MONARK study evaluated monotherapy in treatment-naïve patients. The M03-613 trial evaluated monotherapy after a period of induction therapy with triple combination antiretroviral therapy. The study by Sprinz et al and the OK studies evaluated monotherapy as maintenance of virological suppression. The efficacy of monotherapy varied according to the scenario. In the scenario of induction-maintenance, the factors related to virological failure were suboptimal adherence and low baseline CD4 counts. In the scenario of maintenance, the factors related to virological failure were suboptimal adherence, nadir CD4 count and low hemoglobin. In treatment-naive patients, the risk of virological failure increased in patients who did not achieve a viral load of less than 400 copies/ml 4 weeks after initiating treatment and in those infected with non-B subtypes (a factor that was probably also related to suboptimal adherence).

Topics: Anemia; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Clinical Trials as Topic; Drug Combinations; Hemoglobins; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Multicenter Studies as Topic; Patient Compliance; Pilot Projects; Prospective Studies; Pyrimidinones; Randomized Controlled Trials as Topic; Risk Factors; Ritonavir; Treatment Outcome; Viral Load

Adavosertib selectively inhibits Wee1, which regulates intra-S and G2/M cell-cycle checkpoints. This study investigated dosing schedules for adavosertib monotherapy, determining the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) in patients with advanced solid tumors.Patients received oral adavosertib qd or bid on a 5/9 schedule (5 days on treatment, 9 days off) in 14-day cycles, or qd on one of two 5/2 schedules (weekly, or for 2 of 3 weeks) in 21-day cycles. Safety, efficacy, and pharmacokinetic analyses were performed.Sixty-two patients (female, 64.5%; median age, 61.5 years; most common primary tumors: lung [24.2%], ovary [21.0%]) received treatment (qd schedules, n = 50; bid schedules, n = 12) for 1.8 months (median). Median time to maximum adavosertib concentration was 2.2-4.1 h; mean half-life was 5-12 h. Adverse events (AEs) caused dose reductions, interruptions and discontinuations in 17 (27.4%), 25 (40.3%) and 4 (6.5%) patients, respectively. Most common grade ≥ 3 AEs were anemia, neutropenia (each n = 9, 14.5%) and diarrhea (n = 8, 12.9%). Seven (11.3%) patients experienced 10 treatment-related serious AEs (pneumonia n = 2 [3.2%], dehydration n = 2 [3.2%], anemia n = 1 [1.6%], febrile neutropenia n = 1 [1.6%], and thrombocytopenia n = 1 [1.6%]). Overall objective response rate was 3.4% (2/58); disease control rate was 48.4% (30/62); median progression-free survival was 2.7 months.MTDs were 125 mg (bid 5/9) and 300 mg (qd 5/9 and 5/2 for 2 of 3 weeks); RP2D was 300 mg (qd 5/2 for 2 of 3 weeks). The safety profile was manageable, acceptable, and generally concordant with the known safety profile.

Topics: Anemia; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Pyrazoles; Pyrimidinones

Anemia is a frequently observed adverse effect in cancer patients who receive chemotherapy or drugs designed to block specific oncogenic signaling pathways, although the underlying mechanisms are poorly understood. An article first published online (Zhu HH, Luo X, Zhang K, et al. Proc Natl Acad Sci USA 2015;112:13342-13347) presented data indicating that cell type-specific pathway cross-talk is likely an important mechanism to consider. Shp2 and Pten, two master regulators of central cytoplasmic signaling pathways, oppose each other in myeloproliferation and leukemogenesis, but cooperate in promoting erythropoiesis. Thus, genetic ablation or pharmacologic inhibition of Shp2 suppresses the leukemogenic effect of Pten loss, yet simultaneously induces severe anemia in mice with Pten deficiency in blood cells.

Topics: Anemia; Animals; Enzyme Inhibitors; Erythropoiesis; Leukemia; Mice; Mice, Knockout; Models, Genetic; Mutation; Protein Tyrosine Phosphatase, Non-Receptor Type 11; PTEN Phosphohydrolase; Pyridones; Pyrimidinones; Risk Factors; Signal Transduction