Tachykinin Antagonists Reverse Ischemia/Reperfusion Gastrointestinal Motility Impairment in Rats.

BACKGROUND: Supraceliac aortic clamping and unclamping produces ischemia-reperfusion (I/R) injury of the splanchnic organs. The protective effects of tachykinin receptor antagonists, SR140333 (NK1 receptor), SR48968 (NK2 receptor), and SB222200 (NK3 receptor), against I/R-induced inhibition of intestinal motility were tested in rats. MATERIAL AND METHODS: The intestinal transit of Evans blue was measured in untreated rats and animals subjected to skin incision, I/R (1 h superior mesenteric artery occlusion followed by 24 h reperfusion) or sham operation. Surgical procedures were conducted under diethyl ether anesthesia. RESULTS: The gastrointestinal transit has not been markedly affected in rats, which were anesthetized or subjected to skin incision in comparison with untreated animals. In contrast, a sham operation and I/R have significantly reduced the intestinal motility. Pretreatment with NK1-3 blockers (SR140333 [3-30 µg/kg]; SR48968 [3-100 µg/kg]; and SB222200 [10-100 µg/kg]) reversed dose dependently the effects of I/R to the level observed after sham operation only. A combination of NK1+NK2+NK3 inhibitors exerted an additive effect compared with NK1 and NK2 antagonists used as single agents. Similarly, combined NK1+NK2 were more effective than NK2 alone. Sham operation and I/R have shifted the in vitro carbachol concentration-response curves to the right in comparison with untreated animals, a phenomenon partially reversed by NK1-NK3 pretreatment. CONCLUSIONS: Single-agent and combined treatment with NK1-3 antagonists markedly attenuated the gastrointestinal dysmotility evoked by I/R injury. The pretreatment with NK3 blocker proved to be the most active in this experimental setting.

MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial.

OBJECTIVES: To determine the safety, tolerability and signs of efficacy of MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF), in patients with rheumatoid arthritis (RA). METHODS: Patients with active, moderate RA were enrolled in a randomised, multicentre, double-blind, placebo-controlled, dose-escalation trial of intravenous MOR103 (0.3, 1.0 or 1.5 mg/kg) once a week for 4 weeks, with follow-up to 16 weeks. The primary outcome was safety. RESULTS: Of the 96 randomised and treated subjects, 85 completed the trial (n=27, 24, 22 and 23 for pooled placebo and MOR103 0.3, 1.0 and 1.5 mg/kg, respectively). Treatment emergent adverse events (AEs) in the MOR103 groups were mild or moderate in intensity and generally reported at frequencies similar to those in the placebo group. The most common AE was nasopharyngitis. In two cases, AEs were classified as serious because of hospitalisation: paronychia in a placebo subject and pleurisy in a MOR103 0.3 mg/kg subject. Both patients recovered fully. In exploratory efficacy analyses, subjects in the MOR103 1.0 and 1.5 mg/kg groups showed significant improvements in Disease Activity Score-28 scores and joint counts and significantly higher European League Against Rheumatism response rates than subjects receiving placebo. MOR103 1.0 mg/kg was associated with the largest reductions in disease activity parameters. CONCLUSIONS: MOR103 was well tolerated and showed preliminary evidence of efficacy in patients with active RA. The data support further investigation of this monoclonal antibody to GM-CSF in RA patients and potentially in those with other immune-mediated inflammatory diseases. TRIAL REGISTRATION NUMBER: NCT01023256.

Efficacy and Safety of Autologous Dendritic Cell-Based Immunotherapy, Docetaxel, and Prednisone vs Placebo in Patients With Metastatic Castration-Resistant Prostate Cancer: The VIABLE Phase 3 Randomized Clinical Trial.

IMPORTANCE: DCVAC/PCa is an active cellular immunotherapy designed to initiate an immune response against prostate cancer. OBJECTIVE: To evaluate the efficacy and safety of DCVAC/PCa plus chemotherapy followed by DCVAC/PCa maintenance treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). DESIGN, SETTING, AND PARTICIPANTS: The VIABLE double-blind, parallel-group, placebo-controlled, phase 3 randomized clinical trial enrolled patients with mCRPC among 177 hospital clinics in the US and Europe between June 2014 and November 2017. Data analyses were performed from December 2019 to July 2020. INTERVENTIONS: Eligible patients were randomized (2:1) to receive DCVAC/PCa (add-on and maintenance) or placebo, both in combination with chemotherapy (docetaxel plus prednisone). The stratification was applied according to geographical region (US or non-US), prior therapy (abiraterone, enzalutamide, or neither), and Eastern Cooperative Oncology Group performance status (0-1 or 2). DCVAC/PCa or placebo was administered subcutaneously every 3 to 4 weeks (up to 15 doses). MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival (OS), defined as the time from randomization until death due to any cause, in all randomized patients. Survival was compared using 2-sided log-rank test stratified by geographical region, prior therapy with abiraterone and/or enzalutamide, and Eastern Cooperative Oncology Group performance status. RESULTS: A total of 1182 men with mCRPC (median [range] age, 68 [46-89] years) were randomized to receive DCVAC/PCa (n = 787) or placebo (n = 395). Of these, 610 (81.8%) started DCVAC/PCa, and 376 (98.4%) started placebo. There was no difference in OS between the DCVAC/PCa and placebo groups in all randomized patients (median OS, 23.9 months [95% CI, 21.6-25.3] vs 24.3 months [95% CI, 22.6-26.0]; hazard ratio, 1.04; 95% CI, 0.90-1.21; P = .60). No differences in the secondary efficacy end points (radiological progression-free survival, time to prostate-specific antigen progression, or skeletal-related events) were observed. Treatment-emergent adverse events related to DCVAC/PCa or placebo occurred in 69 of 749 (9.2%) and 48 of 379 (12.7%) patients, respectively. The most common treatment-emergent adverse events (DCVAC/PCa [n = 749] vs placebo [n = 379]) were fatigue (271 [36.2%] vs 152 [40.1%]), alopecia (222 [29.6%] vs 130 [34.3%]), and diarrhea (206 [27.5%] vs 117 [30.9%]). CONCLUSIONS AND RELEVANCE: In this phase 3 randomized clinical trial, DCVAC/PCa combined with docetaxel plus prednisone and continued as maintenance treatment did not extend OS in patients with mCRPC and was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02111577.

Tachykinin antagonists ameliorate surgically induced impairment of gastrointestinal motility in rats.

The protective effects of tachykinin receptor antagonists: SR140333 (NK1 receptor), SR48968 (NK2 receptor), and SB222200 (NK3 receptor) were tested in rats against a surgically induced postoperative inhibition of gut motility, a common complication of abdominal surgery. The small intestinal transit of Evans blue was measured 24-h post-surgery in untreated rats and animals subjected to skin incision, laparotomy, or laparotomy followed by gut evisceration and manipulation. Surgical procedures were conducted under diethyl ether anesthesia. In comparison to untreated and ether-anesthetized rats, animals undergoing skin incision, laparotomy, or laparotomy with gut evisceration and manipulation showed a significant decrease in the intestinal transit of Evans blue. The pretreatment with NK1 (3-100 µg/kg), NK2 (3-30 µg/kg), and NK3 (10-300 µg/kg) blockers before surgery ameliorated the inhibitory effects of gut manipulation in a dose-dependent manner. Moreover, the submaximal and maximal doses of NK3 antagonists showed a trend toward reversing not only the inhibition caused by gut manipulation but also laparotomy. An additive effect of combining submaximal doses of NK1-3 blockers was observed in animals pretreated with NK1  + NK2 compared to single-agent NK1 and NK2 . Additionally, doublets: NK1  + NK3 or NK2  + NK3 and a triplet: NK1  + NK2  + NK3 proved to be more effective than NK2 antagonist alone. In contrast, NK1-3 blockers have not markedly affected the intestinal propulsion in untreated rats or animals subjected to skin incision or laparotomy. NK1-3 blockers ameliorated the suppressed small-bowel gut motility 24 post-surgery. Combined pretreatment with NK1-3 antagonists provided selective, additive benefits compared to single agents.

Autologous dendritic cell-based immunotherapy (DCVAC/LuCa) and carboplatin/paclitaxel in advanced non-small cell lung cancer: A randomized, open-label, phase I/II trial.

PURPOSE: To investigate the efficacy and safety of an active cellular immunotherapy (DCVAC/LuCa) and chemotherapy in patients with stage IV non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: SLU01 was a multicenter, open-label, parallel-group, randomized, phase I/II trial. NSCLC patients were randomized in a ratio of 1:1:1 to receive: DCVAC/LuCa and chemotherapy (carboplatin and paclitaxel; Group A); DCVAC/LuCa, chemotherapy, pegylated interferon-α2b, and hydroxychloroquine (Group B); or chemotherapy alone (Group C). DCVAC/LuCa was administered subcutaneously every 3-6 weeks (up to 15 doses). The primary endpoint was overall survival (OS). During the study, enrollment into Group B was discontinued for strategic reasons. RESULTS: Forty-five patients were randomized to Group A, 29 patients to Group B, and 38 patients to Group C. The median OS in the modified intention-to-treat (mITT) population was 3.7 months longer in Group A than in Group C (15.5 vs. 11.8 months; p = 0.0179; hazard ratio = 0.54; 95% confidence interval: 0.32-0.91). This OS effect was consistent across subgroups of the mITT population (females, males, current smokers, former smokers, and patients with non-squamous and squamous cell histology). The most common treatment-emergent adverse events of any grade reported in Groups A, B, and C, respectively, were neutropenia (50.0%, 29.6%, and 20.6%), fatigue (40.0%, 18.5%, and 20.6%), anemia (35.0%, 44.4%, and 32.4%), paresthesia (27.5%, 25.9%, and 17.6%), and alopecia (25.0%, 29.6%, and 41.2%). CONCLUSION: DCVAC/LuCa in combination with carboplatin and paclitaxel extended OS and was well tolerated.

The protective effect of endothelin receptor antagonists against surgically induced impairment of gastrointestinal motility in rats.

Endothelin (ET) receptor antagonists: BQ-123 (ETA), BQ-788 (ETB), tezosentan (dual ET receptor antagonist) protect against the development of postoperative ileus (POI) evoked by ischemia-reperfusion (I/R). The current experiments explored whether ET antagonists prevent the occurrence of POI evoked by surgical gut manipulation. Intestinal transit was assessed by measuring the rate of dye migration subsequent to skin incision (SI), laparotomy (L), or laparotomy and surgical gut handling (L+M) in diethyl ether anaesthesized rats (E). Experimental animals were randomly sub-divided into two groups depending on the time of recovery following surgery: viz. either 2 or 24 h (early or late phase POI). E and SI did not affect the gastrointestinal (GI) transit. In contrast, L and L+M significantly reduced GI motility in comparison to untreated group (UN). Tezosentan (10 mg/kg), BQ-123 and BQ-788 (1 mg/kg) protected against development of L+M evoked inhibition of intestinal motility in the course of late phase, but not early phase POI. Furthermore, tezosentan alleviated the decrease in the contractile response of the longitudinal jejunal smooth muscle strips to carbachol in vitro induced by L+M. The serum ET(1-21) concentration was not increased in either the early or the late phase POI groups after surgery compared to control animals. This study indicates that delay in the intestinal transit in late phase of surgically induced POI involves an ET-dependent mechanism.

Heat stroke complicated by liver failure and hyperbilirubinaemia--a case report.

Heat stroke may appear as a result of exposure to high environmental temperature or strenuous exercise. It represents a medical emergency characterized by an elevated core body temperature and multi-organ failure. We have described a case of a 41 year-old female after sun exposure, who was admitted to the hospital with the temperature of 42 degrees C. Because of high plasma bilirubin level the Molecular Adsorbent Recirculating System (MARS) was started. Three sessions of MARS, which lasted for eight hours each, were conducted on 15h, 18th, and 23rd day of hospitalization. The procedure was well tolerated by the patient and resulted in a sustained decline of plasma bilirubin from 33.5 to 14.7 mg/dl. The female was discharged from the hospital in good general condition. The two months follow up showed that the patient felt very well, and the plasma bilirubin was reduced to 2.2 mg/dl.

Randomized phase 1b trial of MOR103, a human antibody to GM-CSF, in multiple sclerosis.

OBJECTIVES: To determine the safety, pharmacokinetics (PK), and immunogenicity of the recombinant human monoclonal antibody MOR103 to granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with multiple sclerosis (MS) with clinical or MRI activity. METHODS: In this 20-week, randomized, double-blind, placebo-controlled phase 1b dose-escalation trial (registration number NCT01517282), adults with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) received an IV infusion of placebo (n = 6) or MOR103 0.5 (n = 8), 1.0 (n = 8), or 2.0 (n = 9) mg/kg every 2 weeks for 10 weeks. Patients had to have ≤10 gadolinium (Gd)-enhancing brain lesions on T1-weighted MRI at baseline. The primary objective was safety. RESULTS: Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity. The most frequent was nasopharyngitis. Between-group differences in TEAE numbers were small. There were no TEAE-related trial discontinuations, infusion-related reactions, or deaths. Nine patients experienced MS exacerbations: 3, 5, 1, and 0 patient(s) in the placebo, 0.5, 1.0, and 2.0 mg/kg groups, respectively. A few T1 Gd-enhancing lesions and/or new or enlarging T2 lesions indicative of inflammation were observed in all treatment groups. No clinically significant changes were observed in other clinical assessments or laboratory safety assessments. No anti-MOR103 antibodies were detected. PK evaluations indicated dose linearity with low/no drug accumulation over time. CONCLUSIONS: MOR103 was generally well-tolerated in patients with RRMS or SPMS. No evidence of immunogenicity was found. CLASSIFICATION OF EVIDENCE: This phase 1b study provides Class I evidence that MOR103 has acceptable tolerability in patients with MS.

Differential salutary effects of nonselective and selective COX-2 inhibitors in postoperative ileus in rats.

BACKGROUND: Postoperative ileus (PI) is a common surgical complication, the treatment of which consists of supportive measures. AIM: The effects of several cyclooxygenase (COX) inhibitors and their interaction with L-arginine/nitric oxide synthase (NOS) pathway were tested in a rat PI model. METHODS: Intestinal transit was measured as Evans blue migration after skin incision, laparotomy, or laparotomy followed by evisceration and gut handling. RESULTS: In contrast to a selective inducible NOS (iNOS) blocker, L-N(6)-(1-iminoethyl)lysine hydrochloride (L-NIL), N(omega)-nitro-L-arginine methyl ester (L-NAME) reversed the additional inhibitory effects of gut manipulation after laparotomy on the gastrointestinal transit (GI) in a dose-dependent, L-arginine-sensitive manner. Laparotomy and manipulations of small intestine increased blood plasma nitrites and nitrates level (NOx), an effect preventable by L-NAME. Indomethacin, resveratrol (selective COX-1 blocker), and COX-2 antagonists, nimesulide, NS-398, DuP-697, and L-752860, attenuated the additional inhibitory effects of gut manipulation following laparotomy in a dose-dependent manner. In contrast, only nimesulide, NS-398, DuP-697, and L-752860 partly, but significantly, reversed the effects of laparotomy on the intestinal transit. Administration of L-NAME subsequent to COX inhibitors abolished the salutary effects of the latter, implying that at least the synthesis of either NO or prostanoids must remain unaffected to enable a return of GI transit during the postoperative period. CONCLUSION: In addition to NO synthesized by constitutive NOS (cNOS), prostaglandins produced by both COX-1 and COX-2 participate in the pathogenesis of PI, albeit in different pathological mechanisms. Thus laparotomy stimulated COX-2 activity, whereas gut manipulation led to an excessive cNOS activity and prostaglandin synthesis by COX-1.

Mechanism of the contractile effects of galantide and Galanin(1-14) [alpha-aminobutyric acid]scyliorhinin-I in rat isolated fundus strips.

BACKGROUND: The study was undertaken to establish the pharmacological basis of the stimulatory activity of galantide (M15) and galanin(1-14)-(a-aminobutyric acid8-[Abu8])scyliorhinin-I [Scy-I] in gastric smooth muscle. MATERIAL/METHODS: Isotonic contractions of the isolated, longitudinal rat gastric fundus strips were recorded. RESULTS: Galanin, galanin(1-15)-NH2, M15 and galanin(1-14)-[Abu8]Scy-I elicited concentration-dependent contractions. Their EC50s equaled 12.95, 174, 70.06 and 187 nM respectively. Hill's coefficients for galanin and galanin(1-15)-NH2 were not different from unity, indicating an interaction of one peptide molecule with one receptor according to the principles of classical receptor theory. Hill's coefficients were 0.73 and 1.56 for M15 and galanin (1-14)-[Abu8]Scy-I, respectively, a value significantly different from unity. Cold-storage denervation, tetrodotoxin-TTX (1 mM), spantide (100 mM) and NK1-3 receptor antagonists SR140333, 48968, 142801 (up to 10 mM) notably diminished M15, galanin(1-14)-[Abu8]Scy-I, SP(5-11) and [Abu8]-Scy-I evoked contractions without affecting activities of galanin and galanin(1-15)-NH2. Additionally, cross-desensitization experiments attenuated activity of M15 and galanin(1-14)-[Abu8]Scy-I without any noticeable action on galanin or galanin(1-15)-NH2. CONCLUSIONS: The action of chimeric peptides on the smooth muscle of the rat gastrointestinal tract depended not only on the myogenic interaction of those peptides with galanin binding sites, but also on the activation of tachykinin receptors or the release of endogenous mediators from the presynaptic terminals.