thiohydantoins and Pain

The present study aimed to indirectly compare apalutamide and enzalutamide with respect to tolerability and health-related quality of life (HRQoL) among men with non-metastatic castration-resistant prostate cancer (nmCRPC).. Patient-level data from the SPARTAN study [apalutamide + androgen deprivation therapy (ADT) versus placebo + ADT] and aggregate published data from the PROSPER study (enzalutamide + ADT versus placebo + ADT) were used. Anchored matching-adjusted indirect comparison (MAIC) was conducted by weighting patients' baseline characteristics from SPARTAN to match aggregated baseline characteristics in PROSPER. Odds ratios (ORs) of reported adverse events (AEs) and baseline-to-follow-up least squares mean differences in HRQoL [measured with Functional Assessment of Cancer Therapy-Prostate (FACT-P) score] with 95% credible intervals were re-estimated for SPARTAN arms using weighted population and indirectly compared with those in PROSPER through a Bayesian framework. Events of special interest included fatigue, hot flush, nausea, diarrhea, hypertension, falls, dizziness, decreased appetite, arthralgia, asthenia and headache. In addition, any AEs and serious AEs were explored.. Of 1207 SPARTAN patients, 1171 were matched to 1401 PROSPER patients. Relative to enzalutamide, apalutamide demonstrated better tolerability as evidenced by the highest probability of reduced occurrence of fatigue [p(OR < 1) = 99.5%], hypertension [p(OR < 1) = 99.2%], decreased appetite [p(OR < 1) = 98.3%], fall [p(OR < 1) = 90.3%], headaches [p(OR < 1) = 86.7%], and nausea [p(OR < 1) = 80.0%]. The probabilities of reduced occurrence of any AEs and SAEs with apalutamide versus enzalutamide were 66.9% and 90.9%, respectively. Relative to enzalutamide, apalutamide treatment was associated with a higher probability of a better HRQoL based on the FACT-P total score [p(diff > 0) = 73.1%]. The probability of a better HRQoL with apalutamide versus enzalutamide was highest for the physical [p(diff > 0) = 97.3%] and functional [p(diff > 0) = 86.7%] wellbeing subscales, and the pain-related subscale [p(diff > 0) = 90.1%].. Anchored MAIC suggests that treatment of men with nmCRPC with apalutamide is associated with a higher probability of better tolerability due to fewer AEs and better HRQoL than enzalutamide.

Topics: Androgen Receptor Antagonists; Bayes Theorem; Benzamides; Disease-Free Survival; Humans; Male; Middle Aged; Nitriles; Pain; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Thiohydantoins; Treatment Outcome

Some 2-substituted-(2'-aminophenyl)-4-thioxohydantoic acids (o-amino PTC-amino acids) have antinociceptive activity when administered (icv) alone (IC50 = 0.04-0.87 microM/animal) and show a striking prolongation of the antinociceptive action of (D-Ala-2 D-Leu5)-enkephalin (DADL) in combination. The effects are thought to be mediated via opioid receptors since they are naloxone-reversible. Although inhibitors of the enkephalin degrading puromycin-insensitive, bestatin-sensitive aminopeptidase (possibly aminopeptidase M) their action is weak (IC50 = 32 microM leucine, 536 microM, glycine) and they might be considered to have a direct antinociceptive effect on opioid receptors. The titled compounds constitute novel 'lead' compounds for the development of potent aminopeptidase M inhibitors.

Topics: Aminopeptidases; Analgesics; Animals; Glycine; Indicators and Reagents; Leucine; Mice; Naloxone; Neprilysin; Pain; Proline; Protease Inhibitors; Thiohydantoins; Thiorphan