Clinical effectiveness of golimumab in ulcerative colitis: a prospective multicentre study based on the Swedish IBD Quality Register, SWIBREG.

OBJECTIVES: Clinical trials demonstrated that golimumab is effective in anti-TNF naïve patients with ulcerative colitis. We aimed to assess the clinical effectiveness of golimumab in a real-world setting. MATERIALS AND METHODS: This was a prospective cohort study, conducted at 16 Swedish hospitals. Data were collected using an electronic case report form. Patients with active ulcerative colitis, defined as Mayo endoscopic subscore ≥2 were eligible for inclusion. The primary outcomes were clinical effectiveness at 12 weeks and 52 weeks, i.e. response (defined as a decrease in Mayo score by ≥3 points or 30% from baseline) and remission (defined as a Mayo score of ≤2 with no individual subscores >1). RESULTS: Fifty patients were included. At study entry, 70% were previously exposed to anti-TNF, 16% to vedolizumab, and 96% to immunomodulators. The 12 and 52-week drug continuation rates were 37/50 (74%) and 23/50 (46%), respectively. The 12-week response rate was 14/50 (28%), the remission rate, 8/50 (16%) and the corresponding figures at week 52 were 13/50 (26%) and 10/50 (20%). Among patients who continued golimumab, the median Mayo score decreased from 7 (6-9) at baseline to 1 (0-5) at 52 weeks (p < .01) and the faecal calprotectin decreased from 862 (335-1759) µg/g to 90 (34-169) µg/g (p < .01). Clinical response at week 12 was highly predictive of clinical remission at week 52 (adjusted OR: 73.1; 95% CI: 4.5‒1188.9). CONCLUSIONS: The majority of golimumab treated patients represented a treatment refractory patient-group. Despite this, our results confirm that golimumab is an effective therapy in ulcerative colitis.

Clinical effectiveness of golimumab in Crohn's disease: an observational study based on the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG).

OBJECTIVE: The effectiveness of golimumab in Crohn's disease (CD) is largely unknown as it is not approved for the treatment of the disease. We aimed to identify the population of CD patients treated with golimumab in Sweden, to assess the effectiveness of golimumab (defined as the drug retention rate), and to identify predictors of drug discontinuation. METHODS: Patients with CD who received at least one injection of golimumab were identified through the Swedish National Quality Registry for Inflammatory Bowel Disease, which includes prospectively collected clinical information. Cox regression models were used to identify predictors of golimumab discontinuation. RESULTS: The study cohort involved 94 patients of whom the majority (96.8%) had previously discontinued at least one anti-tumour necrosis factor (anti-TNF) agent. The drug retention rate at 12 weeks was 85.1%. Predictors of golimumab discontinuation at 12 weeks were previous surgery (adjusted HR = 7.52, 95% CI: 1.12-50.36), concomitant corticosteroid use at baseline (adjusted HR = 5.70, 95% CI: 1.13-28.68) and female sex (adjusted HR = 6.59; 95% CI: 1.04-41.62). The median duration of follow-up was 89 (IQR: 32-158) weeks. The drug retention at the most recent follow-up was 35.1%. Predictors of golimumab discontinuation at the most recent follow-up were corticosteroid use at baseline (adjusted HR = 2.60, 95% CI: 1.17-5.79) and female sex (adjusted HR = 2.24; 95% CI: 1.19-4.23). CONCLUSION: Patients with CD treated with golimumab were a treatment-refractory group. Despite this, more than one-third of the patients appeared to have had clinical benefit after a median follow-up of more than 1.5 years.

Nature and management of pancreatic mucinous cystic neoplasm (MCN): A systematic review of the literature.

BACKGROUND: The current management of pancreatic mucinous cystic neoplasms (MCN) is defined by the consensus European, International Association of Pancreatology and American College of Gastroenterology guidelines. However, the criterion for surgical resection remains uncertain and differs between these guidelines. Therefore through this systematic review of the existing literature we aimed to better define the natural history and prognosis of these lesions, in order to clarify recommendations for future management. METHODS: A systematic literature search was performed (PubMed, EMBASE, Cochrane Library) for studies published in the English language between 1970 and 2015. RESULTS: MCNs occur almost exclusively in women (female:male 20:1) and are mainly located in the pancreatic body or tail (93-95%). They are usually found incidentally at the age of 40-60 years. Cross-sectional imaging and endoscopic ultrasound are the most frequently used diagnostic tools, but often it is impossible to differentiate MCNs from branch duct intraductal papillary mucinous neoplasms (BD-IPMN) or oligocystic serous adenomas pre-operatively. In resected MCNs, 0-34% are malignant, but in those less than 4 cm only 0.03% were associated with invasive adenocarcinoma. No surgically resected benign MCNs were associated with a synchronous lesion or recurrence; therefore further follow-up is not required after resection. Five-year survival after surgical resection of a malignant MCN is approximately 60%. CONCLUSIONS: Compared to other pancreatic tumors, MCNs have a low aggressive behavior, with exceptionally low rates of malignant transformation when less than 4 cm in size, are asymptomatic and lack worrisome features on pre-operative imaging. This differs significantly from the natural history of small BD-IPMNs, supporting the need to differentiate mucinous cyst subtypes pre-operatively, where possible. The findings support the recommendations from the recent European Consensus Guidelines, for the more conservative management of MCNs.

Association between pancreatic intraductal papillary mucinous neoplasms and extrapancreatic malignancies.

BACKGROUND & AIMS: The association between pancreatic intraductal papillary mucinous neoplasms (IPMNs) and extrapancreatic neoplasms (EPNs) is controversial. We performed a multicenter observational study to assess the incidence of EPNs after an IPMN diagnosis. METHODS: 1340 patients with IPMNs were evaluated from 2000 through 2013 at 4 academic institutions in Europe for development of EPN. To estimate the actual incidence of EPN, we excluded patients with an EPN previous or synchronous to the IPMN, and patients who had been followed for less than 12 months, resulting in a study population of 816 patients. The incidence of EPN was compared with sex-specific, age-adjusted European cancer statistics; the standardized incidence ratio (SIR), and the 5- and 10-year cumulative incidence rates were calculated. RESULTS: A total of 290/1340 patients had a history of EPN (prevalence of 21.6%). In this subgroup of patients, the IPMN was discovered incidentally in 241. Among the 816 patients included in the incidence analysis, 50 developed an EPN after a median time of 46 months from study enrollment. The incidence of any EPN was not greater in patients with than without IPMN with a SIR of 1.48 (95% confidence interval, 0.94-2.22) in males and of 1.39 (95% CI 0.90-2.05) in females. The 5- and 10-year cumulative incidence rates for development of EPN in patients with IPMN were 7.9% and 16.6% in men, and 3.4% and 23.1% in women. CONCLUSIONS: Patients with IPMN do not have a significantly higher incidence of EPNs than the general European population. It might not be necessary to screen patients with IPMN for EPN.

Fetal haemoglobin and oxygen requirement in preterm infants: an observational study.

OBJECTIVE: To investigate the relationship between the fraction of fetal haemoglobin (HbF(%)) and oxygen requirement as determined by the fraction of inspired oxygen (FiO2) and alveolar-arterial gradient (A-a gradient). Increased alveolar exposure to oxygen may explain the association between decreased HbF(%) and the development of bronchopulmonary dysplasia (BPD). DESIGN: Longitudinal, retrospective, observational study. SETTING: Tertiary-level neonatal intensive care unit, referral centre for southern Sweden. PATIENTS: Four hundred forty very preterm infants born before gestational week 30, 2009-2015. INTERVENTION: Regular clinical practice. MAIN OUTCOME MEASURES: The FiO2 and A-a gradient were determined at the time-point of 10 015 arterial blood gas analyses obtained during postnatal days 1-7. The relationship between HbF(%) and FiO2 and A-a gradient and the modifying influence of other factors affecting haemoglobin oxygen affinity were evaluated. RESULTS: We found a significant relationship between a low fraction of HbF and an increase in FiO2 and A-a gradient, respectively. These relationships remained significant after adjusting for pH, pCO2, postnatal age, gestational age and sex. CONCLUSION: These high-resolution data show that decreased HbF(%) during the first postnatal week is associated with increased FiO2 and A-a gradient in very preterm infants. Increased alveolar exposure to oxygen and resulting oxidative stress may, at least partly, explain the previously reported associations between decreased HbF, blood transfusions and the development of BPD in preterm infants.

Cerebrospinal fluid kynurenic acid in male and female controls - correlation with monoamine metabolites and influences of confounding factors.

The concentrations of the tryptophan metabolite kynurenic acid (KYNA) and the monoamine metabolites homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA) and 4-hydroxy-3-methoxyphenylglycol (HMPG) were determined in the cerebrospinal fluid (CSF) from 43 healthy volunteers (30 males and 13 females). Healthy female controls displayed higher CSF concentration of KYNA (1.91nM+/-0.20) compared to healthy male controls (1.06nM+/-0.07) and lower CSF levels of HMPG (39.2nM+/-2.0 and 43.4+/-1.2, respectively). CSF levels of HVA and 5-HIAA did not differ between females (181.3nM+/-21.9 and 93.7nM+/-11.4, respectively) and males (138.9nM+/-12.6 and 74.8nM+/-5.9, respectively). Positive intercorrelations were found between CSF KYNA, HVA and 5-HIAA while CSF content of HMPG did not correlate with KYNA or the other monoamine metabolites in CSF. A negative correlation was found between back length and CSF concentrations of KYNA, HVA and 5-HIAA and also between CSF KYNA levels and body height. The results of the present study suggest that concentrations of KYNA and the monoamine metabolites in CSF from healthy controls are dependent on gender and back length, which must be taken in consideration when analysing mixed groups of men and women. The higher KYNA concentration found in female controls compared to male might be attributed to a shorter back in women compared to men. Furthermore, these findings suggest that increased KYNA formation is associated with an increased dopamine and serotonin turnover.

The kynurenic acid hypothesis of schizophrenia.

In recent years progress in the field of schizophrenia research has led to the suggestion that dopamine only plays an intermediary role in the pathophysiology of the disease and that the main abnormalities lie elsewhere. In particular, deficits in brain glutamatergic systems are suggested to play a prominent role in the pathophysiology of the disease. Kynurenic acid is an endogenous glutamate antagonist with a preferential action at the glycine-site of the N-methyl-D-aspartate-receptor. Mounting evidence indicates that the compound is significantly involved in basal neurophysiological processes in the brain. Thus, pharmacologically elevated levels of kynurenic acid, in similarity to systemic administration of phencyclidine or ketamine, were associated with increased firing rate and burst firing activity of midbrain dopamine neurons, indicating per se that elevated levels of brain kynurenic acid is associated with psychotomimetic effects. Indeed, cerebrospinal fluid level of kynurenic acid was elevated in schizophrenic patients as compared to healthy controls. The present paper also describes a prostaglandin-mediated regulation of kynurenic acid formation as well as a relationship between brain kynurenic acid concentration and the excitatory responses of ventral tegmental area dopamine neurons by clozapine and nicotine. Our results suggest that kynurenic acid contributes to the pathogenesis of schizophrenia and link the dopamine hypothesis of schizophrenia together with the idea of a deficiency in glutamatergic function in this disease.

3-Oxoisoindoline-1-carboxamides: potent, state-dependent blockers of voltage-gated sodium channel Na(V)1.7 with efficacy in rat pain models.

The voltage-gated sodium channel Na(V)1.7 is believed to be a critical mediator of pain sensation based on clinical genetic studies and pharmacological results. Clinical utility of nonselective sodium channel blockers is limited due to serious adverse drug effects. Here, we present the optimization, structure-activity relationships, and in vitro and in vivo characterization of a novel series of Na(V)1.7 inhibitors based on the oxoisoindoline core. Extensive studies with focus on optimization of Na(V)1.7 potency, selectivity over Na(V)1.5, and metabolic stability properties produced several interesting oxoisoindoline carboxamides (16A, 26B, 28, 51, 60, and 62) that were further characterized. The oxoisoindoline carboxamides interacted with the local anesthetics binding site. In spite of this, several compounds showed functional selectivity versus Na(V)1.5 of more than 100-fold. This appeared to be a combination of subtype and state-dependent selectivity. Compound 28 showed concentration-dependent inhibition of nerve injury-induced ectopic in an ex vivo DRG preparation from SNL rats. Compounds 16A and 26B demonstrated concentration-dependent efficacy in preclinical behavioral pain models. The oxoisoindoline carboxamides series described here may be valuable for further investigations for pain therapeutics.

Effects of COX-1 and COX-2 inhibitors on the firing of rat midbrain dopaminergic neurons--possible involvement of endogenous kynurenic acid.

Kynurenic acid (KYNA) is an endogenous glutamate-receptor antagonist with a preferential action at the glycine-site of the NMDA-receptor. In the present in vivo study, the importance of brain KYNA to modulate the activity of dopamine (DA) neurons in the ventral tegmental area (VTA) was analyzed by utilizing the decrease in brain KYNA formation induced by the cyclooxygenase (COX)-2 inhibitor parecoxib. A reduction in brain KYNA concentration (39-44%) by parecoxib (25 mg/kg, i.v., 1 h or, i.p., 3.5 h) was associated with a decreased firing rate and burst firing activity. In concordance, an increase in brain KYNA concentration (150-300%), induced by the COX-1 inhibitor indomethacin (50 mg/kg, i.v., 1 h or, i.p., 3.5 h), produced opposite effects, that is, increased firing rate and burst firing activity. The decrease and increase in neuronal firing of VTA DA neurons by the COX-inhibitors was reversed by L-701,324 (antagonist at the NMDA-glycine site; 0.06-2 mg/kg, i.v.) and by D-cycloserine (partial agonist at the NMDA-glycine site; 2-32 mg/kg, i.v.), respectively. In addition, the parecoxib-induced decrease in firing rate and burst firing activity was effectively blocked by pretreatment with kynurenine (5 mg/kg, i.p., 30 min), the immediate precursor of KYNA. Present results suggest that the action of COX-inhibitors on the firing of VTA DA neurons are linked to their effects on KYNA formation and that endogenous KYNA is tonically modulating the neuronal activity of VTA DA neurons. Such a modulatory action of KYNA should be of importance for the functioning of mesocorticolimbic DA pathway.

Activation of noradrenergic locus coeruleus neurons by clozapine and haloperidol: involvement of glutamatergic mechanisms.

The major brain noradrenergic nucleus locus coeruleus (LC) has long been thought to be involved in states of alertness and cognitive processes. These functional characteristics make this nucleus interesting with regard to the signs of schizophrenia, especially the negative symptoms of the disease. In the present in-vivo electrophysiological study we analyse a putative interaction between endogenous kynurenic acid (KYNA) and the antipsychotic drugs clozapine and haloperidol on noradrenergic LC neurons. Previous studies have shown that systemically administered antipsychotic drugs increase the neuronal activity of LC noradrenaline (NA) neurons. In line with these findings, our results show that clozapine (1.25-10 mg/kg i.v.) and haloperidol (0.05-0.08 mg/kg i.v.) increased the firing rate of LC NA neurons in anaesthetized rats. Pretreatment with PNU 156561A (40 mg/kg i.v., 3 h), a potent inhibitor of kynurenine 3-hydroxylase, produced a 2-fold increase in rat brain KYNA levels. This treatment prevented the increase in firing rate of LC NA neurons induced by haloperidol (0.05-0.08 mg/kg i.v.) and clozapine in high doses (2.5-10 mg/kg i.v.). However, the excitatory action of the lowest dose of clozapine (1.25 mg/kg i.v.) was not abolished by elevated levels of brain KYNA. Furthermore, pretreatment with L-701,324 (4 mg/kg i.v.) a selective antagonist at the glycine site of the NMDA receptor prevented the excitatory effects of both clozapine and haloperidol. The present results suggest that the excitation of LC NA neurons by haloperidol and clozapine involves a glutamatergic component.

Potential toxic effect on aquatic fauna by the dwarf shrub Empetrum hermaphroditum.

The common evergreen dwarf shrub Empetrum hermaphroditum has influence on the functioning of boreal terrestrial ecosystems in northern Sweden. The negative effects of E. hermaphroditum are partly attributed to the production of the dihydrostilbene, batatasin-III, which is released from leaves and litter by rain and snowmelt. In this study, we investigated whether batatasin-III is carried by runoff into streams and lakes during the snowmelt period and whether it is also potentially hazardous to aquatic fauna. Sampling of water from streams and a lake for which the surrounding terrestrial vegetation is dominated by E. hermaphroditum was done during the snowmelt period in May 1993 and in 1998, and analyzed for batatasin-III. Using 24- and 48-hr standard toxicity tests, we analyzed toxicity to brown trout (Salmo trutta) alevins and juvenile water fleas (Daphnia magna). Toxicity (proportion of dead individuals) to trout was tested at pH 6.5 and compared with that of a phenol within a range of concentrations. In the toxicity (proportion of immobilized individuals) test on D. magna, the interactive effect of pH (pH 5.5-7.0) was included. Concentration of batatasin-III was generally higher in 1998 than in 1993 and showed peak levels during snowmelt. Concentration in ephemeral runnels > the lake > streams running through clear-cuts dominated by E. hermaphroditum > control streams lacking adjacent E. hermaphroditum vegetation. The maximum concentration of batatasin-III found was 1.06 mg l(-1). The proportion of dead yolk sac alevins increased significantly (P < 0.001) with increasing concentrations of batatasin-III and time of exposure. After 24 hr, EC50 was 10 mg l(-1). It was 2 mg l(-1) after 48 hr. The effect of phenol was negligible, indicating a specific phytotoxic effect of the bibenzyl structure of batatasin-III. The proportion of mobile D. magna became significantly smaller (P < 0.001) with increasing concentrations of batatasin-III, with decreasing pH, and with increasing exposure time. EC50 varied between 7 and 17 mg l(-1) at pH 5.5 and 7.0, respectively. After 24 hr EC50 decreased and was 2.5 at pH 5.5 and 12 mg l(-1) at pH 7.0. The levels of batatasin-III found in the field samples were below the lowest EC50 in acute toxicity tests. However, in view of the interactive effect of pH and exposure time, this study suggests that this stable plant metabolite may impose a lethal effect on the aquatic fauna in small streams.

Autoradiography of opioid and ORL1 ligands in opioid receptor triple knockout mice.

Three genes for the opioid receptors ( micro, delta and kappa) and a gene coding for a related receptor (ORL1) have been cloned but pharmacological studies suggest that further subtypes exist that remain poorly understood. To determine if there are other classically defined opioid binding sites we have carried out homogenate binding and section autoradiography with [3H]naloxone in mice that lack all three opioid genes and are hyperalgesic in a thermal nociceptive test. We have also examined [3H]bremazocine labelling in triple knockout brain and spinal cord as this ligand has been proposed to label novel kappa-receptors. No receptor labelling for either ligand was detected in the brains or spinal cord of knockout mice demonstrating that all binding is the product of the three known receptors and that there is no cross-labelling of the ORL1 receptor. Nociceptin (1 micro m) caused marked displacement of [3H]bremazocine in wild-type brains indicating that nociceptin at high concentrations can displace classical opioid binding. As a number of studies have proposed a close association between the classical opioid receptors and the ORL1 system we also hypothesized that loss of all of the classical opioid receptors might lead to compensatory changes in ORL1 receptors. Labelling of the ORL1 receptor with [3H]nociceptin showed region-dependent quantitative increases in triple knockout brains indicating a close relationship between the two systems in specific brain areas.