Design, Synthesis, and Pharmacological Evaluation of Spiro[carbazole-3,3'-pyrrolidine] Derivatives as cGAS Inhibitors for Treatment of Acute Lung Injury.

Overactivation of cyclic GMP-AMP synthase (cGAS) is implicated in the occurrence of many inflammatory and autoimmune diseases, and inhibition of cGAS with a specific inhibitor has been proposed as a potential therapeutic strategy. However, only a few low-potency cGAS inhibitors have been reported, and few are suitable for clinical investigation. As a continuation of our structural optimization on the reported cGAS inhibitor 6 (G140), we developed a series of spiro[carbazole-3,3'-pyrrolidine] derivatives bearing a unique 2-azaspiro[4.5]decane structural motif, among which compound 30d-S was identified with high cellular effects against cGAS. This compound showed improved plasma exposure, lower clearance, and an oral bioavailability of 35% in rats. Moreover, in the LPS-induced acute lung injury (ALI) mice model, oral administration of compound 30d-S at 30 mg/kg markedly reduced lung inflammation and alleviated histopathological changes. These results confirm that 30d-S is a new efficacious cGAS inhibitor and is worthy of further investigation.

Novel Spirocyclic Dimer, SpiD3, Targets Chronic Lymphocytic Leukemia Survival Pathways with Potent Preclinical Effects.

Chronic lymphocytic leukemia (CLL) cell survival and growth is fueled by the induction of B-cell receptor (BCR) signaling within the tumor microenvironment (TME) driving activation of NFκB signaling and the unfolded protein response (UPR). Malignant cells have higher basal levels of UPR posing a unique therapeutic window to combat CLL cell growth using pharmacologic agents that induce accumulation of misfolded proteins. Frontline CLL therapeutics that directly target BCR signaling such as Bruton tyrosine kinase (BTK) inhibitors (e.g., ibrutinib) have enhanced patient survival. However, resistance mechanisms wherein tumor cells bypass BTK inhibition through acquired BTK mutations, and/or activation of alternative survival mechanisms have rendered ibrutinib ineffective, imposing the need for novel therapeutics. We evaluated SpiD3, a novel spirocyclic dimer, in CLL cell lines, patient-derived CLL samples, ibrutinib-resistant CLL cells, and in the Eµ-TCL1 mouse model. Our integrated multi-omics and functional analyses revealed BCR signaling, NFκB signaling, and endoplasmic reticulum stress among the top pathways modulated by SpiD3. This was accompanied by marked upregulation of the UPR and inhibition of global protein synthesis in CLL cell lines and patient-derived CLL cells. In ibrutinib-resistant CLL cells, SpiD3 retained its antileukemic effects, mirrored in reduced activation of key proliferative pathways (e.g., PRAS, ERK, MYC). Translationally, we observed reduced tumor burden in SpiD3-treated Eµ-TCL1 mice. Our findings reveal that SpiD3 exploits critical vulnerabilities in CLL cells including NFκB signaling and the UPR, culminating in profound antitumor properties independent of TME stimuli. SIGNIFICANCE: SpiD3 demonstrates cytotoxicity in CLL partially through inhibition of NFκB signaling independent of tumor-supportive stimuli. By inducing the accumulation of unfolded proteins, SpiD3 activates the UPR and hinders protein synthesis in CLL cells. Overall, SpiD3 exploits critical CLL vulnerabilities (i.e., the NFκB pathway and UPR) highlighting its use in drug-resistant CLL.

'Damning' FDA inspection report undermines Alzheimer's drug.

Inspectors faulted analyses of clinical trial samples by Hoau-Yan Wang for drug developer Cassava Sciences.

Efficacy, safety, and side effects of oliceridine in acute postoperative pain, a protocol for a systematic review and meta-analysis.

This will be the first meta-analysis on the efficacy, safety, and side effects of oliceridine on postoperative pain. Our aim with this work is to evaluate the clinical utility of this relatively new substance in a broad postoperative context. Oliceridine is a new so-called bias opioid that is approved for severe pain requiring an opioid. Due to its biased agonism, it is said to have fewer side effects than conventional opioids. This systematic review and meta-analysis will analyze the efficacy, safety, and side effects of oliceridine compared to placebo or morphine in acute postoperative pain for up to 72 hours. In January 2024, an extensive search in various databases will be performed without restrictions for randomized controlled trials with at least single blinding. After data extraction, data will be pooled and meta-analytic calculations performed. A random-effects model will be used. Dichotomous data will be presented as risk ratio and continuous data as standardized mean difference. Dose-dependent side effects will be evaluated with meta-regression. Heterogeneity will be assessed via the Q statistic and prediction interval in case of a sufficient number of included studies. Publication bias will be examined using funnel plot and Duval and Tweedie's trim and fill method.

Patient-reported migraine-specific quality of life, activity impairment and headache impact with once-daily atogepant for preventive treatment of migraine in a randomized, 52-week trial.

BACKGROUND: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist for the preventive treatment of episodic migraine. METHODS: In this 52-week, multicenter, randomized, open-label trial, adults with 4-14 monthly migraine days received atogepant 60 mg once-daily or standard care. Health outcome endpoints collected from participants randomized to atogepant included change from baseline in Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) Role Function-Restrictive (RFR), Role Function-Preventive (RFP) and Emotional Function (EF) domain scores, change in Activity Impairment in Migraine-Diary (AIM-D) Performance of Daily Activities (PDA) and Physical Impairment (PI) domain scores, and change in Headache Impact Test-6 (HIT-6) total score. RESULTS: Of 744 randomized participants, 521 received atogepant 60 mg in the modified intent-to-treat population. Least-squares mean changes from baseline in MSQ-RFR score were 30.02 (95% confidence interval = 28.16-31.87) at week 12 and 34.70 (95% confidence interval = 32.74-36.66) at week 52. Improvements were also observed in other MSQ domains, AIM-D PDA, PI and HIT-6 total scores. A ≥5-point improvement from baseline in HIT-6 score was observed in 59.9% of participants at week 4 and 80.8% of participants at week 52. CONCLUSION: Over 52 weeks, atogepant 60 mg once-daily was associated with sustained improvements in quality of life and reductions in activity impairment and headache impact.Trial Registration: NCT03700320.

Cebranopadol as a Novel Promising Agent for the Treatment of Pain.

Opioids are used to treat pain, but despite their effectiveness, they possess several side effects such as respiratory depression, tolerance and physical dependence. Cebranopadol has been evaluated as a solution to this problem. The compound acts on the mu opioid receptor and the nociceptin/orphanin receptor and these receptors co-activation can reduce opioid side-effects without compromising analgesia. In the present review, we have compiled information on the effects of cebranopadol, its pharmacokinetics, and clinical trials involving cebranopadol, to further explore its promise in pain management.

Shorter pruritus period and milder disease stage are associated with response to nalfurafine hydrochloride in patients with chronic liver disease.

Nalfurafine hydrochloride, a selective κ-opioid receptor agonist has been approved for pruritus in patients with chronic liver disease. However, not all patients respond to nalfurafine hydrochloride. The aim of this study was to clarify the efficacy of nalfurafine hydrochloride. The subjects were patients with chronic liver disease complicated by pruritus who were treated with nalfurafine hydrochloride between May, 2015, and May, 2021. The degree of pruritus was evaluated based on the Visual Analog Scale (VAS) score and the Kawashima's pruritus score. Nalfurafine hydrochloride 2.5 µg was orally administered once a day for 12 weeks. A decrease in the VAS score of ≥ 25 mm or the Kawashima's pruritus score of ≥ 1 scores was designated as relevant response. The former of ≥ 50 mm or the latter of ≥ 2 scores as remarkable response. The 326 patients who were evaluated the efficacy at 12 weeks. The median time suffering from pruritus to administration of nalfurafine hydrochloride was 4 months. The median VAS score improved from 70.0 mm before administration to 40.0 and 30.0 mm at 4 and 12 weeks of treatment, respectively. On multivariate analysis, shorter itching period and lower FIB-4 index value were extracted as the independent factors related to remarkable responder. On multivariate analysis, shorter itching period was extracted as the only independent factor related to relevant responder. In conclusion, this study suggested nalfurafine hydrochloride treatment markedly improves pruritus in patients with chronic liver disease. A short pruritus period and less-advanced fibrosis were associated with response to nalfurafine hydrochloride.

Clinical Profiles of Nalfurafine Hydrochloride for the Treatment of Pruritus Patients.

Nalfurafine hydrochloride is a selective kappa-opioid agonist that has antipruritic effects. Here we describe the clinical trials for treatment of uremic pruritus in dialysis patients and on hepatic pruritus in patients with chronic liver disease. Among cytochrome P-450 (CYP) isoforms in humans, CYP3A4 is the major isoform involved in metabolic decyclopropylmethylation of nalfurafine hydrochloride. Nalfurafine hydrochloride was found to be a substrate for P-glycoprotein (P-gp), but had no inhibitory effects on P-gp-mediated transport. The efficacy of oral nalfurafine hydrochloride at 2.5 and 5 µg for refractory pruritus in hemodialysis patients was observed within the first 7 days of treatment, and the effects persisted for the 52-week treatment period. Nalfurafine hydrochloride is also effective in the treatment of conventional refractory pruritus in peritoneal dialysis patients. Moreover, nalfurafine hydrochloride at 2.5 and 5 µg is effective for the treatment of refractory pruritus in chronic liver disease patients within the first 7 days of drug administration. In all the clinical trials, most adverse drug reactions (ADRs) were mild and resolved quickly and there was no clinical safety problem. Following 52 weeks of treatment, hemodialysis patients did not develop physical or psychological dependence, indicating no addiction risks. In summary, nalfurafine hydrochloride administered orally at doses of 2.5 and 5 µg was safe and effective for treatment of refractory pruritus in patients undergoing hemodialysis or peritoneal dialysis and in chronic liver disease patients.

Hepatic safety and tolerability of cipargamin (KAE609), in adult patients with Plasmodium falciparum malaria: a randomized, phase II, controlled, dose-escalation trial in sub-Saharan Africa.

BACKGROUND: The novel anti-malarial cipargamin (KAE609) has potent, rapid activity against Plasmodium falciparum. Transient asymptomatic liver function test elevations were previously observed in cipargamin-treated subjects in two trials: one in malaria patients in Asia and one in volunteers with experimentally induced malaria. In this study, the hepatic safety of cipargamin given as single doses of 10 to 150 mg and 10 to 50 mg once daily for 3 days was assessed. Efficacy results, frequency of treatment-emerging mutations in the atp4 gene and pharmacokinetics have been published elsewhere. Further, the R561H mutation in the k13 gene, which confers artemisinin-resistance, was associated with delayed parasite clearance following treatment with artemether-lumefantrine in Rwanda in this study. This was also the first study with cipargamin to be conducted in patients in sub-Saharan Africa. METHODS: This was a Phase II, multicentre, randomized, open-label, dose-escalation trial in adults with uncomplicated falciparum malaria in five sub-Saharan countries, using artemether-lumefantrine as control. The primary endpoint was ≥ 2 Common Terminology Criteria for Adverse Events (CTCAE) Grade increase from baseline in alanine aminotransferase (ALT) or aspartate transaminase (AST) during the 4-week trial. RESULTS: Overall, 2/135 patients treated with cipargamin had ≥ 2 CTCAE Grade increases from baseline in ALT or AST compared to 2/51 artemether-lumefantrine patients, with no significant difference between any cipargamin treatment group and the control group. Cipargamin exposure was comparable to or higher than those in previous studies. Hepatic adverse events and general safety and tolerability were similar for all cipargamin doses and artemether-lumefantrine. Cipargamin was well tolerated with no safety concerns. CONCLUSIONS: This active-controlled, dose escalation study was a detailed assessment of the hepatic safety of cipargamin, across a wide range of doses, in patients with uncomplicated falciparum malaria. Comparison with previous cipargamin trials requires caution as no clear conclusion can be drawn as to whether hepatic safety and potential immunity to malaria would differ with ethnicity, patient age and or geography. Previous concerns regarding hepatic safety may have been confounded by factors including malaria itself, whether natural or experimental infection, and should not limit the further development of cipargamin. Trial registration ClinicalTrials.gov number: NCT03334747 (7 Nov 2017), other study ID CKAE609A2202.

Liproxstatin-1 attenuates unilateral ureteral obstruction-induced renal fibrosis by inhibiting renal tubular epithelial cells ferroptosis.

Renal fibrosis is a common pathological process that occurs with diverse etiologies in chronic kidney disease. However, its regulatory mechanisms have not yet been fully elucidated. Ferroptosis is a form of non-apoptotic regulated cell death driven by iron-dependent lipid peroxidation. It is currently unknown whether ferroptosis is initiated during unilateral ureteral obstruction (UUO)-induced renal fibrosis and its role has not been determined. In this study, we demonstrated that ureteral obstruction induced ferroptosis in renal tubular epithelial cells (TECs) in vivo. The ferroptosis inhibitor liproxstatin-1 (Lip-1) reduced iron deposition, cell death, lipid peroxidation, and inhibited the downregulation of GPX4 expression induced by UUO, ultimately inhibiting ferroptosis in TECs. We found that Lip-1 significantly attenuated UUO-induced morphological and pathological changes and collagen deposition of renal fibrosis in mice. In addition, Lip-1 attenuated the expression of profibrotic factors in the UUO model. In vitro, we used RSL3 treatment and knocked down of GPX4 level by RNAi in HK2 cells to induce ferroptosis. Our results indicated HK2 cells secreted various profibrotic factors during ferroptosis. Lip-1 was able to inhibit ferroptosis and thereby inhibit the secretion of the profibrotic factors during the process. Incubation of kidney fibroblasts with culture medium from RSL3-induced HK2 cells promoted fibroblast proliferation and activation, whereas Lip-1 impeded the profibrotic effects. Our study found that Lip-1 may relieve renal fibrosis by inhibiting ferroptosis in TECs. Mechanistically, Lip-1 could reduce the activation of surrounding fibroblasts by inhibiting the paracrine of profibrotic factors in HK2 cells. Lip-1 may potentially be used as a therapeutic approach for the treatment of UUO-induced renal fibrosis.

New Drugs 2021, Part 2.

ABSTRACT: The second of a two-part series, this article describes eight recently approved drugs, including the first drug approved for the treatment of SARS-CoV-2, a first-in-class HIV attachment inhibitor, and a new intravenous injection indicated for the treatment of acute pain in adults for whom other treatments are ineffective.

Effectiveness of sarolaner in the clinical management of furuncular myiasis in dogs naturally infested with Dermatobia hominis (Diptera: Cuterebridae).

BACKGROUND: The human botfly, Dermatobia hominis, is a common cause of furuncular myiasis in dogs in Latin America. Lesions can be single or multiple, each harboring an individual larva, presented as an erythematous nodule that causes pruritus and pain. Typical treatment consists of sedation for removal of larvae by surgical incision or manual pressure. Medications to kill the larva before its extraction can reduce inflammation and discomfort and provide a less traumatic larval removal. Isoxazolines are broad-spectrum ectoparasiticides with larvicidal activity previously reported in the treatment of screwworm myiasis in companion animals. The aim of this study was to evaluate the effectiveness of sarolaner as part of the clinical management of furuncular myiasis in dogs caused by D. hominis larvae. METHODS: Ten short-haired mixed breed dogs naturally infested with D. hominis were enrolled. Clinical diagnosis was achieved by observation of skin nodules and visualization of larval motility through the lesion orifice. Sarolaner was administered at manufacturer recommended dose for fleas and ticks. Lesions were reexamined 24 h post-treatment and assessed for viability of larvae. Larvae were removed by digital compression and identified as D. hominis. RESULTS: Seventy-five D. hominis larvae were retrieved from ten dogs. No live larvae were observed, demonstrating 100% larvicidal efficacy of sarolaner. Skin lesions were healed 30 days post-treatment and new lesions were not observed. CONCLUSIONS: Sarolaner seems to be effective as larvicidal treatment for dogs with furuncular myiasis, reducing discomfort caused by the presence of the larva in the skin and facilitating its safe removal.

Atogepant for the Preventive Treatment of Migraine.

BACKGROUND: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist that is being investigated for the preventive treatment of migraine. METHODS: In a phase 3, double-blind trial, we randomly assigned adults with 4 to 14 migraine days per month in a 1:1:1:1 ratio to receive a once-daily dose of oral atogepant (10 mg, 30 mg, or 60 mg) or placebo for 12 weeks. The primary end point was the change from baseline in the mean number of migraine days per month across the 12 weeks. Secondary end points included headache days per month, a reduction from baseline of at least 50% in the 3-month average of migraine days per month, quality of life, and scores on the Activity Impairment in Migraine-Diary (AIM-D). RESULTS: A total of 2270 participants were screened, 910 were enrolled, and 873 were included in the efficacy analysis; 214 were assigned to the 10-mg atogepant group, 223 to the 30-mg atogepant group, 222 to the 60-mg atogepant group, and 214 to the placebo group. The mean number of migraine days per month at baseline ranged from 7.5 to 7.9 in the four groups. The changes from baseline across 12 weeks were -3.7 days with 10-mg atogepant, -3.9 days with 30-mg atogepant, -4.2 days with 60-mg atogepant, and -2.5 days with placebo. The mean differences from placebo in the change from baseline were -1.2 days with 10-mg atogepant (95% confidence interval [CI], -1.8 to -0.6), -1.4 days with 30-mg atogepant (95% CI, -1.9 to -0.8), and -1.7 days with 60-mg atogepant (95% CI, -2.3 to -1.2) (P<0.001 for all comparisons with placebo). Results for the secondary end points favored atogepant over placebo with the exceptions of the AIM-D Performance of Daily Activities score and the AIM-D Physical Impairment score for the 10-mg dose. The most common adverse events were constipation (6.9 to 7.7% across atogepant doses) and nausea (4.4 to 6.1% across atogepant doses). Serious adverse events included one case each of asthma and optic neuritis in the 10-mg atogepant group. CONCLUSIONS: Oral atogepant once daily was effective in reducing the number of migraine days and headache days over a period of 12 weeks. Adverse events included constipation and nausea. Longer and larger trials are needed to determine the effect and safety of atogepant for migraine prevention. (Funded by Allergan; ADVANCE ClinicalTrials.gov number, NCT03777059.).

Involvement of GRK2 in modulating nalfurafine-induced reduction of excessive alcohol drinking in mice.

Though it is well known that G protein-coupled receptor kinase 2 [GRK2] is involved in regulation of mu opioid receptor [MOR] desensitization and morphine-related behaviors, the potential role of GRK2 in regulation of kappa opioid receptor [KOR] functions in vivo has not been established yet. A couple of recent studies have found that GRK2 activity desensitizes KOR functions via decreasing G protein-coupled signaling with sensitizing arrestin-coupled signaling. Nalfurafine, a G protein-biased KOR full agonist, produces an inhibitory effect on alcohol intake in mice, with fewer side effects (sedation, aversion, or anxiety/depression-like behaviors). Using RNA sequencing (RNA-seq) analysis, we first identified that nuclear transcript level of grk2 [adrbk1] (but not other grks) was significantly up-regulated in mouse nucleus accumbens shell (NAcs) after chronic excessive alcohol drinking, suggesting alcohol specifically increased NAcs grk2 expression. We then tested whether selective GRK2/3 inhibitor CMPD101 could alter alcohol intake and found that CMPD101 alone had no effect on alcohol drinking. Therefore, we hypothesized that the grk2 increase in the NAcs could modulate the nalfurafine effect on alcohol intake via interacting with the G protein-mediated KOR signaling. Nalfurafine decreased alcohol drinking in a dose-related manner, and pretreatment with CMPD101 enhanced the reduction in alcohol intake induced by nalfurafine, indicating an involvement of GRK2/3 blockade in modulating G protein-biased KOR agonism of nalfurafine. Together, our study provides initial evidence relevant to the transcriptional change of grk2 gene in the NAc shell after excessive alcohol drinking. Pharmacological GRK2/3 blockade enhanced nalfurafine's efficacy, suggesting a GRK2/3-mediated mechanism, probably through the G protein-mediated KOR signaling.

Case series: Efficacy of a formulation containing selamectin and sarolaner against naturally acquired mite infestations (Demodex sp., Ornithonyssus bacoti) in degus (Octodon degus).

Ectoparasite infestations are not common in degus. Two cases are presented here where use of Stronghold® Plus/Revolution® Plus (selamectin and sarolaner topical solution) was successfully administered to a degu (Octodon degus) for treatment of naturally-occurring mite infesations. Selamectin (Stronghold®/Revolution®) has been demonstrated to be effective against naturally-occurring mite infections in dogs and selamectin is approved for use in dogs for the treatment of sarcoptic mange (caused by Sarcoptes scabiei) at a dose of 6 mg/kg. In the first case, a 2.6-years-old female degu housed in a group with four other degus was presented with pruritic skin reactions, restlessness and hairloss. Mites morphologically similar to Demodex sp. were detected in the deep skin scrapings. All four degus were treated with Stronghold® Plus/Revolution® Plus (30 mg/kg selamectin and 5 mg/kg sarolaner) once a week for a total of six treatments. The spot-on was administered topically on the dorsal cervical region. Following treatment the degu presenting with clinical signs showed a rapid improvement with the pruritus and overall dermatitis resolving within 2 weeks of treatment. Skin scrapes and microscopic examination of epidermal debris collected from the affected degu were negative for mites from day 14 onwards. In the second case, a group of four 4-6.5-years-old female and male degus that were housed together were infested with Ornithonyssus bacoti. All animals were treated with 30 mg/kg selamectin and 5 mg/kg sarolaner in four total weekly doses. One week later no living mites were found on the patients or in their environment. The four degus improved visibly, and within three weeks of treatment the skin lesions associated with the infestation subsided. The antiparasiticides showed a satisfactory efficacy and were well tolerated (n = 9 animals treated in a total).