Journal of Pharmacology and Experimental Therapeutics最新文献

This study examined the effects of intravenous injection of isobutyric tropine ester (Ibutropin) on ventilation in freely-moving sham-operated (SHAM) male Sprague Dawley rats and those with bilateral carotid sinus nerve transection (CSNX). This study also examined the effects of a subsequent injection of fentanyl on ventilatory parameters in both groups of rats. Ibutropin (200 μmol/kg, i.v.) elicited rapid and pronounced increases in breathing frequency, tidal volume, minute ventilation, peak inspiratory and expiratory flows, and inspiratory and expiratory drives in SHAM rats, but substantially smaller responses in CSNX rats. The subsequent injection of fentanyl (75 μg/kg, i.v.) elicited similar ventilatory responses in Ibutropin-treated SHAM and CSNX rats with markedly different changes in end-inspiratory and end-expiratory pauses, expiratory delay, and apneic pause. Moreover, the fentanyl-induced responses in Ibutropin-treated SHAM and CSNX rats were substantially smaller than in rats that were pre-injected with vehicle (saline) rather than Ibutropin. These novel findings suggest that Ibutropin acts at the carotid body-chemoafferent complex to drive ventilation by mechanisms that may involve the rapid entry of this cell-permeant tropine ester into chemoafferent nerve terminals and/or primary glomus cells. A key finding was that the ability of Ibutropin to blunt the adverse effects of fentanyl on breathing does not require functional carotid body chemoreceptor afferent input to brainstem structures controlling breathing. As such, the ability of Ibutropin to greatly diminish the adverse effects of fentanyl on breathing may involve the actions of Ibutropin within central respiratory control centers and/or peripheral structures other than the carotid bodies. SIGNIFICANCE STATEMENT: This study revealed that the ability of Ibutropin to blunt the respiratory depressant effects of fentanyl may involve mechanisms present in central respiratory control centers and/or peripheral structures other than the carotid bodies.

Aclaris Therapeutics Inc (ATI)-2138 is a novel investigational covalent inhibitor of interleukin-2-inducible T cell kinase (ITK), resting lymphocyte kinase, and Janus kinase 3 (JAK3) in development for the treatment of autoimmune and inflammatory diseases. In this study, we evaluated the inhibitory effects of ATI-2138 on ITK and JAK3 signaling in cells and preclinical animal models and assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of ATI-2138 in healthy human participants. ATI-2138 potently, selectively, and irreversibly inhibited ITK, resting lymphocyte kinase, and JAK3 kinases with similar potency observed against ITK and JAK3 in biochemical and immune cell signaling assays. Translation from cellular and whole blood studies to in vivo models was observed, wherein ATI-2138 demonstrated disease-modifying activity in 2 rodent models of arthritis and an adoptive T cell model of colitis. In single and multiple ascending dose studies in healthy human participants, ATI-2138 had a favorable safety profile with linear pharmacokinetics. Biomarkers linked to both ITK and JAK3 activity were inhibited with ATI-2138 in an exposure-, dose-, and time-dependent manner and correlated with enzyme, cellular, whole blood, and rodent studies, thereby demonstrating predictive translational properties. As a potential first-in-class dual inhibitor of ITK and JAK3, ATI-2138 may be useful in the treatment of immunoinflammatory diseases. SIGNIFICANCE STATEMENT: Aclaris Therapeutics Inc (ATI)-2138 is a novel covalent inhibitor of interleukin-2-inducible T cell kinase (ITK)/resting lymphocyte kinase and Janus kinase 3 (JAK3). ATI-2138 inhibits JAK3 and ITK in enzyme and functional cellular assays, demonstrates disease-modifying activity in rodent models of arthritis and colitis, and inhibits biomarkers linked to both ITK and JAK3 activity in healthy human participants. With this dual kinase activity against components of these inflammatory signaling pathway, ATI-2138 has the potential for enhanced therapeutic efficacy in the treatment of autoimmune and chronic inflammatory disease.

Interorgan crosstalk contributes to the pathogenesis of various disorders, and drug development based on interorgan crosstalk is attracting attention. The roles of nitric oxide (NO) derived from the NO synthases system (NOSs) in interorgan crosstalk remain unclear. We have investigated this issue by using our mice deficient in all 3 NOSs (triple n/i/eNOSs^-/- mice). We reported that 2/3 nephrectomized triple n/i/eNOSs^-/- mice die suddenly because of the early onset of myocardial infarction, suggesting the protective role of NO derived from NOSs in the crosstalk between the kidney and the heart. We studied the role of NO derived from NOSs expressed in the bone marrow in vascular lesion formation. Constrictive arterial remodeling and neointimal formation following unilateral carotid artery ligation were prominently aggravated in wild-type mice transplanted with triple n/i/eNOSs^-/- bone marrow cells as compared with those with wild-type bone marrow cells, suggesting the protective role of NO derived from NOSs in the crosstalk between the bone marrow and the blood vessel. We further investigated the role of NO derived from NOSs expressed in the bone marrow in pulmonary hypertension. The extent of pulmonary hypertension after chronic hypoxic exposure was markedly exacerbated in wild-type mice that underwent triple n/i/eNOSs^-/- bone marrow transplantation as compared with those that underwent wild-type bone marrow transplantation, suggesting the protective role of NO derived from NOSs in the crosstalk between the bone marrow and the lung. These lines of evidence demonstrate that systemic and myelocytic NOSs could be novel therapeutic targets for myocardial infarction, vascular disease, and pulmonary hypertension. SIGNIFICANCE STATEMENT: This study demonstrated partial nephrectomy accelerates the occurrence of myocardial infarction induced by systemic NOSs deficiency in triple n/i/eNOSs^-/- mice, that myelocytic NOSs deficiency aggravates vascular lesion formation after unilateral carotid artery ligation, and that myelocytic NOSs deficiency exacerbates chronic hypoxia-induced pulmonary hypertension. These results suggest that NO derived from NOSs plays a protective role in cardiovascular interorgan crosstalk, indicating that systemic and myelocytic NOSs could be important therapeutic targets for myocardial infarction, vascular disease, and pulmonary hypertension.

Chronic intestinal inflammation significantly contributes to the development of colorectal cancer and remains a pertinent clinical challenge, necessitating novel therapeutic approaches. Indole-based microbial metabolite mimics Felix Kopp Kortagere 6 (FKK6), which is a ligand and agonist of the pregnane X receptor (PXR), was recently demonstrated to have PXR-dependent anti-inflammatory and protective effects in a mouse model of dextran sodium sulfate (DSS)-induced acute colitis. Here, we examined the therapeutic potential of FKK6 in a mouse model (C57BL/6 FVB humanized PXR mice) of colitis-associated colon cancer (CAC) induced by azoxymethane and DSS. FKK6 (2 mg/kg) displayed substantial antitumor activity, as revealed by reduced size and number of colon tumors, improved colon histopathology, and decreased expression of tumor markers (c-MYC, β-catenin, Ki-67, and cyclin D) in the colon. In addition, we carried out a chronic toxicity (30 days) assessment of FKK6 (1 mg/kg and 2 mg/kg) in C57BL/6 mice. Histological examination of tissues, biochemical blood analyses, and immunohistochemical staining for Ki-67 and γ-H2AX showed no difference between FKK6-treated and control mice. Comparative metabolomic analyses in mice exposed for 5 days to DSS and administered with FKK6 (0.4 mg/kg) revealed no significant effects on several classes of metabolites in the mouse fecal metabolome. Ames and micronucleus tests showed no genotoxic and mutagenic potential of FKK6 in vitro. In conclusion, anticancer effects of FKK6 in azoxymethane/DSS-induced CAC, together with FKK6 safety data from in vitro tests and in vivo chronic toxicity study, and comparative metabolomic study, are supportive of the potential therapeutic use of FKK6 in the treatment of CAC. SIGNIFICANCE STATEMENT: Microbial metabolite mimicry proposes that chemical mimics of microbial metabolites that serve to protect hosts against aberrant inflammation in the gut could serve as a new paradigm for the development of drugs targeting inflammatory bowel disease if, like the parent metabolite, is devoid of toxicity but more potent against the microbial metabolite receptor. We identified a chemical mimic of Felix Kopp Kortagere 6, and we propose that Felix Kopp Kortagere 6 is devoid of toxicity yet significantly reduces tumor formation in an azoxymethane-dextran sodium sulfate model of murine colitis-induced colon cancer.

Several large-scale clinical trials have shown that long-term use of antimuscarinic agents for overactive bladder treatment increases the risk of dementia and that this risk varies between agents. Fesoterodine, an overactive bladder antimuscarinic, reportedly has no significant effect on cognitive function. Differences in the brain distribution of antimuscarinic agents and blockade of muscarinic receptors could be the reasons for the differences in central side effects among antimuscarinics. In this study, we assessed the brain distribution of antimuscarinic agents and muscarinic receptor occupancy using brain microdialysis and in vivo receptor-binding analysis in rats. The test drugs were 5-hydroxymethyl tolterodine (5-HMT), an active metabolite of fesoterodine, oxybutynin, and trihexyphenidyl, a central antimuscarinic agent. The brain/plasma unbound concentration ratio at steady state (K_puu) of 5-HMT was much lower than that of oxybutynin and trihexyphenidyl, indicating very low 5-HMT distribution in the brain. The muscarinic receptor occupancy in the rat brain at clinical plasma concentrations of 5-HMT was rarely observed, whereas the occupancy by oxybutynin and trihexyphenidyl was 20% and 67%, respectively. The brain muscarinic receptor occupancy, reconstituted using K_puu values and muscarinic receptor affinity retrieved from literature, revealed a significant correlation between the calculated and measured values. These results indicate that 5-HMT has low brain distribution and muscarinic receptor occupancy, which might be the reasons for the insignificant effect of fesoterodine on cognitive function. SIGNIFICANCE STATEMENT: This study reports that 5-hydroxymethyl tolterodine, the active metabolite of fesoterodine, has much lower brain distribution and muscarinic receptor occupancy compared with oxybutynin and trihexyphenidyl based on brain microdialysis and in vivo receptor-binding analysis with unlabeled muscarinic tracer in rats. The low brain distribution and muscarinic receptor occupancy of 5-hydroxymethyl tolterodine might be the reasons for the insignificant effect of fesoterodine on cognitive function.

With the current pressure to reduce opioid usage in the clinical setting, there is a call for the development of adjunct therapies. Although opioids remain the primary analgesic used in the treatment of moderate to severe pain, these drugs come with negative side effects, such as increased potential for abuse. The overlap in expression of opioid and GABA receptors suggests that the 2 systems may interact. Therefore, to investigate this interaction, our study used the GABA_B receptor agonist, baclofen, because it has previously been used as a treatment for spasticity and addiction and has demonstrated weak analgesic properties. Our study focused on the interaction between baclofen and opioid analgesics regarding analgesic efficacy and abuse potential. Analgesia was assessed through hot plate testing and reward was assessed through conditioned place preference testing in outbred CD1 mice. These interactions were examined with morphine, methadone, oxycodone, and fentanyl using isobolographic analyses. All opioids tested with baclofen demonstrate synergism in analgesia and no consistent significant interactions in place preference conditioning. Together these data support the use of baclofen coupled with opioids to enhance the analgesia, with no concomitant increase in abuse liability and associated common side effects of opioid drugs. SIGNIFICANCE STATEMENT: The combination of the commonly prescribed drug, baclofen, and a variety of opioids exhibits a synergistic analgesic effect allowing for lower doses of opioids to be used for equivalent analgesic effect. Synergistic analgesia was seen without concomitant enhanced tolerance, constipation, or reward, and across species, suggesting a beneficial interaction for pain relief.

Cisplatin causes permanent hearing loss or cisplatin-induced ototoxicity in over 50% of treated patients with cancer, leading to significant social and functional limitations. Interindividual variability in developing hearing loss suggests the role of genetic predispositions to cisplatin-induced hearing loss. We investigated genetic associations between cisplatin-induced ototoxicity and toll-like receptor 4 (TLR4), an immune receptor known to mediate inflammatory responses to cisplatin. Using a case-control candidate gene approach, we identified 20 single nucleotide polymorphisms at the TLR4 locus with significant protection against ototoxicity in a cohort of 213 adult patients, followed by an independent pediatric patient cohort (n = 357). Combined cohort analysis demonstrated a significant association between cisplatin-induced ototoxicity protection and a single variant in the TLR4 promoter, rs10759932. We showed that rs10759932 downregulated TLR4 expression that is normally induced by cisplatin. This work provides pharmacogenetic and functional evidence to implicate TLR4 with cisplatin-induced hearing loss in patients. SIGNIFICANCE STATEMENT: Adult and pediatric patients carrying toll-like receptor 4 (TLR4) genetic variants were protected against developing cisplatin-induced hearing loss following cisplatin treatment. Important variants in the TLR4 promoter disrupted a drug-gene interaction between cisplatin and TLR4, mirroring the protective effect conferred by genetic inhibition of TLR4. These variants have the potential to improve the prediction of cisplatin toxicity, allowing for more precise chemotherapy treatment.