Metabolism and Disposition of a Novel B-Cell Lymphoma-2 Inhibitor Venetoclax in Humans and Characterization of Its Unusual Metabolites.

Venetoclax (ABT-199), a B-cell lymphoma-2 (Bcl-2) protein inhibitor, is currently in clinical development for the treatment of hematologic malignancies. We characterized the absorption, metabolism, and excretion of venetoclax in humans. After a single oral dose of [14C]venetoclax to healthy volunteers, the recovery of total radioactive dose was 100%, with feces being the major route of elimination of the administered dose, whereas urinary excretion was minimal (<0.1%). The extent of absorption was estimated to be at least 65%. Venetoclax was primarily cleared by hepatic metabolism (∼66% of the administered dose). ∼33% of the administered dose was recovered as the parent drug and its nitro reduction metabolite M30 [2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-amino-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide] (13%) in feces. Biotransformation of venetoclax in humans primarily involves enzymatic oxidation on the dimethyl cyclohexenyl moiety, followed by sulfation and/or nitro reduction. Nitro reduction metabolites were likely formed by gut bacteria. Unchanged venetoclax was the major drug-related material in circulation, representing 72.8% of total plasma radioactivity. M27 (oxidation at the 6 position of cyclohexenyl ring followed by cyclization at the α-carbon of piperazine ring; 4-[(10aR,11aS)-7-(4-chlorophenyl)-9,9-dimethyl-1,3,4,6,8,10,10a,11a-octahydropyrazino[2,1-b][1,3]benzoxazin-2-yl]-N-[3-nitro-4-(tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide) was identified as a major metabolite, representing 12% of total drug-related material. M27 was primarily formed by cytochrome P450 isoform 3A4 (CYP3A4). Steady-state plasma concentrations of M27 in human and preclinical species used for safety testing suggested that M27 is a disproportionate human metabolite. M27 is not expected to have clinically relevant on- or off-target pharmacologic activities.

Metabolism and Disposition of the Hepatitis C Protease Inhibitor Paritaprevir in Humans.

Paritaprevir (also known as ABT-450), a potent NS3-4A serine protease inhibitor [identified by AbbVie (North Chicago, IL) and Enanta Pharmaceuticals (Watertown, MA)] of the hepatitis C virus (HCV), has been developed in combination with ombitasvir and dasabuvir in a three-direct-acting antiviral agent (DAA) oral regimen for the treatment of patients infected with HCV genotype 1. This article describes the mass balance, metabolism, and disposition of paritaprevir in humans. After the administration of a single 200-mg oral dose of [(14)C]paritaprevir coadministered with 100 mg of ritonavir to four male healthy volunteers, the mean total percentage of the administered radioactive dose recovered was 96.5%, with recovery in individual subjects ranging from 96.0% to 96.9%. Radioactivity derived from [(14)C]paritaprevir was primarily eliminated in feces (87.8% of the dose). Radioactivity recovered in urine accounted for 8.8% of the dose. The biotransformation of paritaprevir in humans involves: 1) P450-mediated oxidation on the olefinic linker, the phenanthridine group, the methylpyrazinyl group, or combinations thereof; and 2) amide hydrolysis at the acyl cyclopropane-sulfonamide moiety and the pyrazine-2-carboxamide moiety. Paritaprevir was the major component in plasma [90.1% of total radioactivity in plasma, AUC from time 0 to 12 hours (AUC0-12hours) pool]. Five minor metabolites were identified in plasma, including the metabolites M2, M29, M3, M13, and M6; none of the metabolites accounted for greater than 10% of the total radioactivity. Paritaprevir was primarily eliminated through the biliary-fecal route followed by microflora-mediated sulfonamide hydrolysis to M29 as a major component in feces (approximately 60% of dose). In summary, the biotransformation and clearance pathways of paritaprevir were characterized, and the structures of metabolites in circulation and excreta were elucidated.

Metabolism and Disposition of Hepatitis C Polymerase Inhibitor Dasabuvir in Humans.

Dasabuvir [also known as ABT-333 or N-(6-(3-(tert-butyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide] is a potent non-nucleoside NS protein 5B polymerase inhibitor of the hepatitis C virus (HCV) and is being developed in combination with paritaprevir/ritonavir and ombitasvir in an oral regimen with three direct-acting antivirals for the treatment of patients infected with HCV genotype 1. This article describes the mass balance, metabolism, and disposition of dasabuvir in humans. After administration of a single oral dose of 400-mg [(14)C]dasabuvir (without coadministration of paritaprevir/ritonavir and ombitasvir) to four healthy male volunteers, the mean total percentage of the administered radioactive dose recovered was 96.6%. The recovery from the individual subjects ranged from 90.8% to 103%. Dasabuvir and corresponding metabolites were predominantly eliminated in feces (94.4% of the dose) and minimally through renal excretion (2.2% of the dose). The biotransformation of dasabuvir primarily involves hydroxylation of the tert-butyl group to form active metabolite M1 [N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide], followed by glucuronidation and sulfation of M1 and subsequent secondary oxidation. Dasabuvir was the major circulating component (58% of total radioactivity) in plasma, followed by metabolite M1 (21%). Other minor metabolites represented < 10% each of total circulating radioactivity. Dasabuvir was cleared mainly through cytochrome P450-mediated oxidation metabolism to M1. M1 and its glucuronide and sulfate conjugates were primarily eliminated in feces. Subsequent oxidation of M1 to the tert-butyl acid, followed by formation of the corresponding glucuronide conjugate, plays a secondary role in elimination. Cytochrome P450 profiling indicated that dasabuvir was mainly metabolized by CYP2C8, followed by CYP3A4. In summary, the biotransformation pathway and clearance routes of dasabuvir were characterized, and the structures of metabolites in circulation and excreta were elucidated.

Metabolism and Disposition of Pan-Genotypic Inhibitor of Hepatitis C Virus NS5A Ombitasvir in Humans.

Ombitasvir (also known as ABT-267) is a potent inhibitor of hepatitis C virus (HCV) nonstructural protein 5A (NS5A), which has been developed in combination with paritaprevir/ritonavir and dasabuvir in a three direct-acting antiviral oral regimens for the treatment of patients infected with HCV genotype 1. This article describes the mass balance, metabolism, and disposition of ombitasvir in humans without coadministration of paritaprevir/ritonavir and dasabuvir. Following the administration of a single 25-mg oral dose of [(14)C]ombitasvir to four healthy male volunteers, the mean total percentage of the administered radioactive dose recovered was 92.1% over the 192-hour sample collection in the study. The recovery from the individual subjects ranged from 91.4 to 93.1%. Ombitasvir and corresponding metabolites were primarily eliminated in feces (90.2% of dose), mainly as unchanged parent drug (87.8% of dose), but minimally through renal excretion (1.9% of dose). Biotransformation of ombitasvir in human involves enzymatic amide hydrolysis to form M23 (dianiline), which is further metabolized through cytochrome P450-mediated oxidative metabolism (primarily by CYP2C8) at the tert-butyl group to generate oxidative and/or C-desmethyl metabolites. [(14)C]Ombitasvir, M23, M29, M36, and M37 are the main components in plasma, representing about 93% of total plasma radioactivity. The steady-state concentration measurement of ombitasvir metabolites by liquid chromatography-mass spectrometry analysis in human plasma following multiple doses of ombitasvir, in combination with paritaprevir/ritonavir and dasabuvir, confirmed that ombitasvir is the main component (51.9% of all measured drug-related components), whereas M29 (19.9%) and M36 (13.1%) are the major circulating metabolites. In summary, the study characterized ombitasvir metabolites in circulation, the metabolic pathways, and the elimination routes of the drug.

Frequency of reporting of adverse events in randomized controlled trials of psychotherapy vs. psychopharmacotherapy.

BACKGROUND: Psychopharmacology and psychotherapy are the two main therapies in mental health. It is common practice to consider adverse events (AEs) of medications, but it's not clear this occurs with psychotherapy. AIM: This study investigates the frequency with which reports of AEs occur in clinical trials using either psychopharmacology alone, psychotherapy alone, or combined approaches. METHODS: Forty-five articles of randomized trials published in high-impact journals were chosen from a Medline search, and separated into three groups of 15 articles: pharmacotherapy alone (M), psychotherapy alone (T) and combined studies that looked at the effect of both a psychotherapeutic (CT) and psychopharmacologic (CM) intervention. Criteria for what defines an AE were established and the papers were rated for mentions of AEs in papers as a whole and by each section. RESULTS: The χ(2)-analysis of AE mentions showed significant differences between the four study conditions in terms of each paper as a whole (χ(2):10.1,p<0.018), and by section. Medication (M+CM) and psychotherapy papers (T+CT) were then combined into two groups to compare the odds that one was more likely to mention AEs than the other. Bivariate logistic regression yielded statistically significant odds ratios ranging from 9.33 to 20.99, with medications being far more likely to mention AEs. CONCLUSION: We believe the difference in reports of AEs mirrors the attitudes researchers and providers. It's critical to consider, and standardize the definition of, AEs in psychotherapy, and imperative to identify and address potential AEs in psychotherapy research.

Musical hallucinations associated with pontine lacunar lesions.

Three elderly patients experienced musical hallucinations (MH) in the context of hearing loss. In at least two of the cases, the onset was sudden. All three patients had pontine T2/FLAIR hyperintense foci on MR scan after the onset of the MH.

Treatment of memory loss with herbal remedies.

OPINION STATEMENT: Increased rates of dementia throughout the world are creating an emergent need for successful preventive and treatment strategies. Despite a lack of any significant scientific basis, herbal remedies and other types of "complementary and alternative medicine" (CAM) are being aggressively marketed for both prophylactic and therapeutic effects in regard to memory disorders. In the past few years, a small number of controlled studies have explored the effectiveness of some of the more popular herbal and CAM remedies, including gingko biloba, phosphatidylcholine, phosphatidylserine, and omega-3 fatty acids. To date, the bulk of evidence suggests that such approaches are not successful in preventing or delaying cognitive decline or dementia, and there is little reason to prescribe these remedies for the treatment of established cognitive impairment. Some very preliminary evidence suggests that Gingko biloba may be useful in treating behavioral problems in demented people. It is likely that the absence of regulatory controls on the sale of herbal and CAM preparations will foster continued use of these agents and perhaps even accelerated use as the dementia epidemic increases, assuming no imminent breakthroughs in pharmacotherapy.

A study of herbal remedies for memory complaints.

This study explored the approach to marketing herbal substances and the specific remedies being sold for the treatment of memory complaints. Gingko and phosphatidylcholine/phosphatidylserine were most frequently recommended, often in combinations with many other substances. Counseling regarding toxicity is nil.

Takotsubo cardiomyopathy and electroconvulsive treatments: a case study and review.

A 90-year-old woman who had received more than 100 electroconvulsive treatments (ECT) over many years requested another course for depression. After the third ECT, an electrocardiogram showed new T-wave inversion (V2-V6) and ST elevation (V2). Catheterization revealed severe left ventricular dysfunction but no coronary obstruction, leading to a diagnosis of Takotsubo cardiomyopathy (stress-related). The patient's recovery was uneventful. Recent literature cites three other cases post-ECT. It appears that elderly women are at greatest risk, repeated stress is generally required, and recovery is achieved quickly. Elevated levels of catecholamines and of vasopressin may be implicated.

Weekend prescribing practices and subsequent seclusion and restraint in a psychiatric inpatient setting.

OBJECTIVE: This case-control study examined the role of early medication management in preventing seclusion and restraint. METHODS: Data were extracted from the medical records, including whether standing medication was increased, decreased, or left unchanged during the first 48 hours of hospitalization. RESULTS: Compared with inpatients who did not experience seclusion or restraint (N=39), those who did (N=39) were younger (p=.01) and more likely to be male (p=.023) and to have a primary discharge diagnosis of bipolar disorder, mixed or manic episode, schizophrenia, or schizoaffective disorder (p<.001). Patients whose standing medication was not changed during the first 48 hours of hospitalization had 5.5 times as many restraints as patients whose dose was increased or who received new prescriptions (p=.027). CONCLUSIONS: Early use of medication can reduce the incidence of seclusion and restraint among high-risk patients early in their hospitalization.

The effects of testosterone on cognition in elderly men: a review.

In this article, the literature examining the relationship between testosterone and various cognitive domains in elderly men is reviewed. The review focuses on the role of endogenous testosterone levels and the effects of androgen depletion and replacement. The cognitive domains most commonly linked to testosterone include memory and visuospatial function. Indeed, the literature suggests that in certain conditions (ie, hypogonadism, cognitive impairment) testosterone levels may be significantly associated with memory and visuospatial function, but not other cognitive functions. Studies with larger sample sizes and more sensitive cognitive measures are indicated, as questions remain about the potential role of testosterone as a cognitive enhancer.

Discovery of piperidine-aryl urea-based stearoyl-CoA desaturase 1 inhibitors.

A series of structurally novel stearoyl-CoA desaturase1 (SCD1) inhibitors has been identified via molecular scaffold manipulation. Preliminary structure-activity relationship (SAR) studies led to the discovery of potent, and orally bioavailable piperidine-aryl urea-based SCD1 inhibitors. 4-(2-Chlorophenoxy)-N-[3-(methyl carbamoyl)phenyl]piperidine-1-carboxamide 4c exhibited robust in vivo activity with dose-dependent desaturation index lowering effects.

Discovery of potent, selective, orally bioavailable stearoyl-CoA desaturase 1 inhibitors.

Stearoyl-CoA desaturase 1 (SCD1) catalyzes the committed step in the biosynthesis of monounsaturated fatty acids from saturated, long-chain fatty acids. Studies with SCD1 knockout mice have established that these animals are lean and protected from leptin deficiency-induced and diet-induced obesity, with greater whole body insulin sensitivity than wild-type animals. In this work, we have discovered a series of potent, selective, orally bioavailable SCD1 inhibitors based on a known pyridazine carboxamide template. The representative lead inhibitor 28c also demonstrates excellent cellular activity in blocking the conversion of saturated long-chain fatty acid-CoAs (LCFA-CoAs) to monounsaturated LCFA-CoAs in HepG2 cells.

Discovery of 1-(4-phenoxypiperidin-1-yl)-2-arylaminoethanone stearoyl-CoA desaturase 1 inhibitors.

A series of novel stearoyl-CoA desaturase 1 (SCD1) inhibitors were identified by scaffold design based on known SCD1 inhibitors. Large structural changes were made leading to multiple analogs with comparable or improved potency. This approach is valuable for generation of proprietary compounds without conducting a costly high-throughput screening.

Hemodynamic effects of potent and selective JNK inhibitors in anesthetized rats: implication for targeting protein kinases in metabolic diseases.

The hemodynamic effects of a series of potent and selective 4-aminopyridine carboxamide-based pan-JNK inhibitors were assessed in an anesthetized rat model. The effects of these agents on mean arterial pressure, heart rate, cardiac contractility, and peripheral vascular resistance are described, and the implication for targeting protein kinases in metabolic diseases is discussed.

Discovery of potent, highly selective, and orally bioavailable pyridine carboxamide c-Jun NH2-terminal kinase inhibitors.

C-Jun NH2 terminal kinases (JNKs) are important cell signaling enzymes. JNK1 plays a central role in linking obesity and insulin resistance. JNK2 and JNK3 may be involved in inflammatory and neurological disorders, respectively. Small-molecule JNK inhibitors could be valuable tools to study the therapeutic benefits of inhibiting these enzymes and as leads for potential drugs targeting JNKs. In this report, we disclose a series of potent and highly selective JNK inhibitors with good pharmacokinetic profiles.

Discovery and pharmacological evaluation of growth hormone secretagogue receptor antagonists.

The discovery and pharmacological evaluation of potent, selective, and orally bioavailable growth hormone secretagogue receptor (GHS-R) antagonists are reported. Previously, 2,4-diaminopyrimidine-based GHS-R antagonists reported from our laboratories have been shown to be dihydrofolate reductase (DHFR) inhibitors. By comparing the X-ray crystal structure of DHFR docked with our GHS-R antagonists and GHS-R modeling, we designed and synthesized a series of potent and DHFR selective GHS-R antagonists with good pharmacokinetic (PK) profiles. An amide derivative 13d (Ca2+ flux IC50 = 188 nM, [brain]/[plasma] = 0.97 @ 8 h in rat) showed a 10% decrease in 24 h food intake in rats, and over 5% body weight reduction after 14-day oral treatment in diet-induced obese (DIO) mice. In comparison, a urea derivative 14c (Ca2+ flux IC50 = 7 nM, [brain]/[plasma] = 0.0 in DIO) failed to show significant effect on food intake in the acute feeding DIO model. These observations demonstrated for the first time that peripheral GHS-R blockage with small molecule GHS-R antagonists might not be sufficient for suppressing appetite and inducing body weight reduction.