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Janus kinase inhibitors (JAKi) have been approved for use in various immune-mediated inflammatory diseases. With five agents licensed, it was timely to summarise the current understanding of JAKi use based on a systematic literature review (SLR) on efficacy and safety. more...

Alectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system (CNS) efficacy in the treatment of ALK-positive non-small-cell lung cancer (NSCLC). We investigated alectinib as compared with crizotinib in patients with previously untreated, advanced ALK-positive NSCLC, including those with asymptomatic CNS disease. In a randomized, open-label, phase 3 trial, we randomly assigned 303 patients with previously untreated, advanced ALK-positive NSCLC to receive either alectinib (600 mg twice daily) or crizotinib (250 mg twice daily). The primary end point was investigator-assessed progression-free survival. Secondary end points were independent review committee-assessed progression-free survival, time to CNS progression, objective response rate, and overall survival. During a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression or death occurred in 62 of 152 patients (41%) in the alectinib group and 102 of 151 patients (68%) in the crizotinib group. The rate of investigator-assessed progression-free survival was significantly higher with alectinib than with crizotinib (12-month event-free survival rate, 68.4% [95% confidence interval (CI), 61.0 to 75.9] with alectinib vs. 48.7% [95% CI, 40.4 to 56.9] with crizotinib; hazard ratio for disease progression or death, 0.47 [95% CI, 0.34 to 0.65]; P more...

BackgroundMultiple biologic and targeted synthetic disease-modifying rheumatic drugs (b/tsDMARDs) are approved for the management of rheumatoid arthritis (RA), including TNF inhibitors (TNFi), bDMARDs with other modes of action (bDMARD-OMA) and Janus kinase inhibitors (JAKi). Combination of b/tsDMARDs with conventional synthetic DMARDs (csDMARDs) is recommended, yet monotherapy is common in practice.ObjectiveTo compare drug maintenance and clinical effectiveness of three alternative treatment options for RA management.MethodsThis observational cohort study was nested within the Swiss RA Registry. TNFi, bDMARD-OMA (abatacept or anti-IL6 agents) or the JAKi tofacitinib (Tofa) initiated in adult RA patients were included. The primary outcome was overall drug retention. We further analysed secondary effectiveness outcomes and whether concomitant csDMARDs modified effectiveness, adjusting for potential confounding factors.Results4023 treatment courses of 2600 patients were included, 1862 on TNFi, 1355 on bDMARD-OMA and 806 on Tofa. TNFi was more frequently used as a first b/tsDMARDs, at a younger age and with shorter disease duration. Overall drug maintenance was significantly lower with TNFi compared with Tofa [HR 1.29 (95% CI 1.14 to 1.47)], but similar between bDMARD-OMA and Tofa [HR 1.09 (95% CI 0.96 to 1.24)]. TNFi maintenance was decreased when prescribed without concomitant csDMARDs [HR: 1.27 (95% CI 1.08 to 1.49)], while no difference was observed for bDMARD-OMA or Tofa maintenance with respect to concomitant csDMARDs.ConclusionTofa drug maintenance was comparable with bDMARDs-OMA and somewhat higher than TNFi. Concomitant csDMARDs appear to be required for optimal effectiveness of TNFi, but not for bDMARD-OMA or Tofa. more...

BACKGROUND: Substance P and the neurokinin-1 (NK-1) receptor are implicated in chronic refractory cough pathophysiology. We assessed the efficacy and safety of orvepitant, a brain-penetrant NK-1 antagonist, in an open-label study in CRC patients with chronic refractory cough.METHODS: Thirteen patients with daytime cough frequency >3 to RESULTS: All patients completed the study. Mean baseline cough frequency was 71.4/h. A statistically and clinically significant improvement in objective daytime cough frequency was observed at week 4: reduction from baseline of 18.9 (26%) coughs/h (95% CI, 9.6-28.3; P < .001). This effect was apparent at week 1 (reduction from baseline of 27.0 [38%] coughs/h [95% CI, 11.4-42.7; P = .001]) and sustained after drug discontinuation at week 8 (reduction from baseline of 20.4 [29%] coughs/h [95% CI, 3.2-37.5; P = .020]). Statistically significant improvements were seen for severity VAS and quality of life. Orvepitant was safe and well-tolerated.CONCLUSIONS: Orvepitant resulted in a significant and sustained improvement in objective cough frequency, severity VAS, and quality of life; appeared safe; and merits further clinical investigation.TRIAL REGISTRY: EU Clinical Trials Register; No.: 2014-003947-36; URL: www.clinicaltrialsregister.eu. more...

The phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK+) non-small-cell lung cancer (NSCLC) met its primary end point of improved progression-free survival (PFS) with alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX. Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression. In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib, n = 64; crizotinib, n = 58), 43 had measurable lesions (alectinib, n = 21; crizotinib, n = 22), and 46 had received prior radiotherapy (alectinib, n = 25; crizotinib, n = 21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25-0.64] and those without (HR 0.51, 95% CI: 0.33-0.80, P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus crizotinib and comparable between patients with and without baseline CNS metastases (P < 0.0001). CNS ORR was 85.7% with alectinib versus 71.4% with crizotinib in patients who received prior radiotherapy and 78.6% versus 40.0%, respectively, in those who had not. Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advanced ALK+ NSCLC, irrespective of prior CNS disease or radiotherapy. ClinicalTrials.gov NCT02075840. more...

RATIONALE: Tardive dyskinesia is a syndrome of abnormal, involuntary movements, which occurs as a complication of long-term neuroleptic therapy. The pathophysiology of this potentially irreversible syndrome is still an enigma. OBJECTIVE: The objective of the present study was to elucidate the role of N-methyl-D-aspartate (NMDA) receptor involvement in neuroleptic-induced orofacial dyskinesia in rats. METHODS: Animals chronically treated with haloperidol for a period of 40 weeks exhibited significantly more vacuous chewing movements (VCMs), as compared to vehicle-treated controls. In a series of acute experiments, rats received: amantadine (10, 20, and 40 mg/kg i.p.), a low-affinity, uncompetitive NMDA-receptor antagonist (open channel blocker); dextrorphan (5, 10, and 20 mg/kg i.p.), an NMDA receptor channel antagonist; ifenprodil (2.5, 5, and 10 mg/kg i.p.), a noncompetitive allosteric NMDA receptor antagonist acting at the polyamine site; and Ro 25-6981 (2.5, 5, and 10 mg/kg i.p.), a potent and selective blocker of NMDA receptors which contain the NR2B subunit. RESULTS: All the drugs tested, except dextrorphan, reduced VCMs and tongue protrusions with varying efficacies and side effects profiles. Ro 25-6981 was found significantly more potent than amantadine and ifenprodil in reducing VCMs and tongue protrusions at all doses tested, and at the higher dose, it completely eliminated orofacial dyskinesia (p more...

We investigated the association between retinol-binding protein 4 (RBP(4)) and apolipoprotein B (ApoB)-containing lipoproteins. Obese or overweight, hypertriglyceridemic patients underwent the following interventions for 3 months: (1) Diet (n = 20), (2) Diet + fenofibrate (n = 18), (3) Diet + rimonabant (n = 8). Circulating RBP4 decreased during dietary treatment. The percentage change in RBP(4) was positively correlated with the percentage changes in very-low density lipoprotein cholesterol (r = .570, P = .02), low-density lipoprotein cholesterol ([LDL-C]; r = .605, P = .01), ApoB (r = .705, P = .007), and small dense LDL-C ([sdLDL-C]; r = .872, P < .001). The percentage change in RBP4 was the best predictor of the percentage changes in sdLDL-C and ApoB. Rimonabant treatment reduced RBP4, whereas fenofibrate increased RBP4 during the first month of therapy followed by a subsequent decrease. In conclusion, RBP4 may significantly influence the metabolic pathways responsible for changes in ApoB lipoprotein subspecies, thus RBP4 may be associated with cardiovascular disease risk. Angiology more...

A double blind study was made on rifampicin (RFP) and cephaloglycin (CEG) for 55 nonspecific urinary tract infections. RFP was administered 900 mg/day (b. i. d.) and CEG 2 g/day (q. i. d.), each for three days. Of 42 acute cystitis, 23 were treated with RPF and a11 responded, whereas 19 were treated with CEG and 17 responded (Table 2). There was, however, no statistically significant difference between the effectiveness rate of both drugs (p=O.1988). Out of 13 cases of urinary tract infection other than acute cystitis, 6 were treated with RFP and 3 were cured while 7 with CEG and 4 cured (Table 3). MIC of RFP for the isolated organisms from the cases above mostly ranged between 6.25 and 25 mcg/ml (Table 5). Disappearance rate of urinary microorganism after drug administration for acute cystitis was 96 % CZZ/Z3) in RFP-group and 63 % (12/19) in CEG-group. This shows superiority of RFP (p=O.0098). Even after three days' administration, increased RFP-resistance was proved in 4 strains (Table 7). No side-effects were encountered. more...

ROWAPRAXIN (BR-18), a newly developed analgesic of Rowa-Wagner Co., was administered to 28 patients complaining of various type of pain. They were 19 patients of upper urinary diseases, 5 patients after retrograde pyelography, and 4 patients of lower urinary diseases. Analgesic effect was proved in 24 patients (85.7%). No serious side effect was observed. more...

BR-18, a newly developed analgesic of Rowa-Wagner Co., was administered to 30 patients complaining various type of pain due to urolithiasis. The clinical trial was carried out at the outpatients clinic of Kitano Hospital. Remarkable analgesic effect , was proved in 24 patients in which disappearance or relief of pain was noted. Six patients were lost for follow-up. Spontaneous discharge of the stone was noted in 26 %. This rather low rate is explained by short period of administration and the fact that the cases were not selected as to the size of stone. No serious side effect was observed. more...

ROWAPRAXIN (BR-18), a newly developed analgesic of Rowa-Wagner Co., was administered to 28 patients complaining of various type of pain. They were 19 patients of upper urinary diseases, 5 patients after retrograde pyelography, and 4 patients of lower urinary diseases. Analgesic effect was proved in 24 patients (85.7%). No serious side effect was observed. more...

A double blind study was made on rifampicin (RFP) and cephaloglycin (CEG) for 55 nonspecific urinary tract infections. RFP was administered 900 mg/day (b. i. d.) and CEG 2 g/day (q. i. d.), each for three days. Of 42 acute cystitis, 23 were treated with RPF and a11 responded, whereas 19 were treated with CEG and 17 responded (Table 2). There was, however, no statistically significant difference between the effectiveness rate of both drugs (p=O.1988). Out of 13 cases of urinary tract infection other than acute cystitis, 6 were treated with RFP and 3 were cured while 7 with CEG and 4 cured (Table 3). MIC of RFP for the isolated organisms from the cases above mostly ranged between 6.25 and 25 mcg/ml (Table 5). Disappearance rate of urinary microorganism after drug administration for acute cystitis was 96 % CZZ/Z3) in RFP-group and 63 % (12/19) in CEG-group. This shows superiority of RFP (p=O.0098). Even after three days' administration, increased RFP-resistance was proved in 4 strains (Table 7). No side-effects were encountered. more...

BR-18, a newly developed analgesic of Rowa-Wagner Co., was administered to 30 patients complaining various type of pain due to urolithiasis. The clinical trial was carried out at the outpatients clinic of Kitano Hospital. Remarkable analgesic effect , was proved in 24 patients in which disappearance or relief of pain was noted. Six patients were lost for follow-up. Spontaneous discharge of the stone was noted in 26 %. This rather low rate is explained by short period of administration and the fact that the cases were not selected as to the size of stone. No serious side effect was observed. more...

CG-201, a new antispasmodic as well as analgesic, was administered to thirty-three patients having pain mainly due to urolithiasis. Twenty-two patients responded well. Six patients complained of thurst, but this side effect disappeared quickly after discontinuing the drug. more...