Timna Naftali

Cannabis Induces a Clinical Response in Patients With Crohn's Disease: A Prospective Placebo-Controlled Study

BACKGROUND & AIMS The marijuana plant Cannabis sativa has been reported to produce beneficial effects for patients with inflammatory bowel diseases, but this has not been investigated in controlled trials. We performed a prospective trial to determine whether cannabis can induce remission in patients with Crohns disease. METHODS We studied 21 patients (mean age, 40 ± 14 y; 13 men) with Crohns Disease Activity Index (CDAI) scores greater than 200 who did not respond to therapy with steroids, immunomodulators, or anti-tumor necrosis factor-α agents. Patients were assigned randomly to groups given cannabis, twice daily, in the form of cigarettes containing 115 mg of Δ9-tetrahydrocannabinol (THC) or placebo containing cannabis flowers from which the THC had been extracted. Disease activity and laboratory tests were assessed during 8 weeks of treatment and 2 weeks thereafter. RESULTS Complete remission (CDAI score, <150) was achieved by 5 of 11 subjects in the cannabis group (45%) and 1 of 10 in the placebo group (10%; P = .43). A clinical response (decrease in CDAI score of >100) was observed in 10 of 11 subjects in the cannabis group (90%; from 330 ± 105 to 152 ± 109) and 4 of 10 in the placebo group (40%; from 373 ± 94 to 306 ± 143; P = .028). Three patients in the cannabis group were weaned from steroid dependency. Subjects receiving cannabis reported improved appetite and sleep, with no significant side effects. CONCLUSIONS Although the primary end point of the study (induction of remission) was not achieved, a short course (8 weeks) of THC-rich cannabis produced significant clinical, steroid-free benefits to 10 of 11 patients with active Crohns disease, compared with placebo, without side effects. Further studies, with larger patient groups and a nonsmoking mode of intake, are warranted. ClinicalTrials.gov, NCT01040910.

Cannabis for Inflammatory Bowel Disease

The marijuana plant Cannabis sativa has been used for centuries as a treatment for a variety of ailments. It contains over 60 different cannabinoid compounds. Studies have revealed that the endocannabinoid system is involved in almost all major immune events. Cannabinoids may, therefore, be beneficial in inflammatory disorders. In murine colitis, cannabinoids decrease histologic and microscopic inflammation. In humans, cannabis has been used to treat a plethora of gastrointestinal problems, including anorexia, emesis, abdominal pain, diarrhea, and diabetic gastroparesis. Despite anecdotal reports on medical cannabis in inflammatory bowel disease (IBD), there are few controlled studies. In an observational study in 30 patients with Crohns disease (CD), we found that medical cannabis was associated with improvement in disease activity and reduction in the use of other medications. In a more recent placebo-controlled study in 21 chronic CD patients, we showed a decrease in the CD activity index >100 in 10 of 11 subjects on cannabis compared to 4 of 10 on placebo. Complete remission was achieved in 5 of 11 subjects in the cannabis group and 1 of 10 in the placebo group. Yet, in an additional study, low-dose cannabidiol did not have an effect on CD activity. In summary, evidence is gathering that manipulating the endocannabinoid system can have beneficial effects in IBD, but further research is required to declare cannabinoids a medicine. We need to establish the specific cannabinoids, as well as appropriate medical conditions, optimal dose, and mode of administration, to maximize the beneficial effects while avoiding any potential harmful effects of cannabinoid use.

Ziziphus jujuba Extract for the Treatment of Chronic Idiopathic Constipation: A Controlled Clinical Trial

Purpose: To investigate the safety and efficacy of an extract of Ziziphus jujuba for chronic constipation.Constipated patients received liquid Z. jujuba or placebo for 12 weeks. Subjects completed questionnaires, a visual analog scale and transit time (TT) tests before and after treatment. Results: Of 37 patients with a prolonged TT, 18 received the study drug and 19 a placebo. Two (12%) of the study and 16 (84%) of the control group dropped out due to severe constipation. The TT decreased from 12.2 particles for the study group to 3 particles at week 11. Symptom severity ratings decreased from 6 and 6.2 to 2 and 5, and the quality of life score improved from 1.9 and 2.3 to 1.3 and 1.4 in the study and control groups, respectively. Conclusion:Z. jujuba extract is an effective and safe treatment for chronic constipation.

Maternal inflammatory bowel disease has short and long-term effects on the health of their offspring: A multicenter study in Israel

BACKGROUND There are concerns about the effect of inflammatory bowel diseases (IBD) on fertility, pregnancy and pregnancy outcomes, but no long-term data on the health of offspring born to IBD mothers. The aims were to assess the short- and long-term effects of maternal IBD on the morbidity and development of their offspring. METHODS Female IBD patients and controls completed questionnaires on their pregnancy outcome, and their offsprings short- and long-term health and development. RESULTS IBD and control mothers (159 and 175, respectively) were recruited. Medical data of 412 IBD and 417 control offspring were recorded. IBD mothers had significantly more singleton pregnancies, their offsprings birth weight was significantly lower, and they breastfed significantly less compared to controls (P=0.028, 0.007, and <0.0001, respectively). There were significantly more congenital anomalies (mainly limb deformities) among the IBD offspring (P<0.035). Offspring born post-maternal IBD diagnosis, compared to pre-diagnosis, tended to have more neurodevelopmental problems (e.g., gross motor delay, P=0.03). IBD was significantly more prevalent in the offspring of IBD mothers, while allergies and atopic dermatitis were more frequent in offspring of control mothers. More offspring of IBD mothers taking medications during pregnancy were born preterm and had lower birth weights compared to offspring of IBD mothers not taking medications during pregnancy. Children of mothers taking steroids had the lowest birth weights, compared to those of IBD mothers taking 5ASAs or immunomodulators. CONCLUSIONS Maternal IBD affects pregnancy and the offsprings immediate and long-term morbidity, specifically, congenital anomalies and neurodevelopmental problems.

Original articleVery early feeding in stable small for gestational age preterm infants: a randomized clinical trialNutrição precoce de neonatos prematuros estáveis e pequenos para a idade gestacional: um ensaio clínico randomizado☆

Objective To examine the effect of initiating very early feeding on time-to-reach full feeding in stable, small for gestational age (SGA) preterm infants.OBJECTIVE To examine the effect of initiating very early feeding on time-to-reach full feeding in stable, small for gestational age (SGA) preterm infants. METHOD Preterm infants with gestational age below 37 weeks and birth weight below the 10(th) percentile were randomly allocated to a very early (within 24 hours of birth) feeding regimen or delayed (after 24 hours of birth) feeding. All infants had in utero evidence of absent or reverse diastolic flow. Infants unable to start early feeding were excluded. Time-to-reach full feeding, feeding progression, and related morbidity were compared. Electrogastrography (EGG) was used to measure pre- and postprandial gastric motility on the second and seventh day after feeding initiation. RESULTS Sixty infants were included in the study, 30 in each group. Infants included in the very early feeding regimen achieved full enteral feeding sooner than controls (98±80-157 vs. 172±123-261 hours of age, respectively; p= 0.004) and were discharged home earlier (p=0.04). No necrotizing enterocolitis (NEC) was documented in both study groups. Gastric motility was improved at day seven after feeding initiation in both study groups, with no difference between groups. CONCLUSIONS Stable SGA preterm infants on a very early feeding regimen achieved full enteral feeding and were discharged home significantly earlier than those on a delayed regimen, with no excess morbidity.

Very early feeding in stable small for gestational age preterm infants: a randomized clinical trial

Objective To examine the effect of initiating very early feeding on time-to-reach full feeding in stable, small for gestational age (SGA) preterm infants.OBJECTIVE To examine the effect of initiating very early feeding on time-to-reach full feeding in stable, small for gestational age (SGA) preterm infants. METHOD Preterm infants with gestational age below 37 weeks and birth weight below the 10(th) percentile were randomly allocated to a very early (within 24 hours of birth) feeding regimen or delayed (after 24 hours of birth) feeding. All infants had in utero evidence of absent or reverse diastolic flow. Infants unable to start early feeding were excluded. Time-to-reach full feeding, feeding progression, and related morbidity were compared. Electrogastrography (EGG) was used to measure pre- and postprandial gastric motility on the second and seventh day after feeding initiation. RESULTS Sixty infants were included in the study, 30 in each group. Infants included in the very early feeding regimen achieved full enteral feeding sooner than controls (98±80-157 vs. 172±123-261 hours of age, respectively; p= 0.004) and were discharged home earlier (p=0.04). No necrotizing enterocolitis (NEC) was documented in both study groups. Gastric motility was improved at day seven after feeding initiation in both study groups, with no difference between groups. CONCLUSIONS Stable SGA preterm infants on a very early feeding regimen achieved full enteral feeding and were discharged home significantly earlier than those on a delayed regimen, with no excess morbidity.

Increased TERC gene copy number and cells in senescence in primary sclerosing cholangitis compared to colitis and control patients

OBJECTIVE Primary sclerosing cholangitis (PSC) is a chronic cholestatic disorder that involves inflammatory and fibrotic changes in the bile ducts. Up to 80% of patients have concomitant inflammatory bowel disease (IBD) with colitis. PSC patients are predisposed to develop hepatobiliary, colonic and other extrahepatic malignancies, probably related to inflammatory processes that might promote carcinogenesis. Telomerase is an enzyme complex that lengthens telomeres and has enhanced expression in numerous malignancies. In this study, we evaluated the TERC gene copy number, the proportion of cells in senescence and the amount of fragmentation in the senescent state. METHODS Fluorescence in situ hybridization (FISH) for the TERC gene was applied to lymphocytes retrieved from PSC (N=19), colitis (N=20) and healthy control patients (N=20) to determine the TERC copy number. On the same FISH slides, cells stained with DAPI were also analyzed for senescence-associated heterochromatin foci (SAHF) status, including the number of cells with fragments and the number of SAHF fragments in each cell. RESULTS A higher TERC gene copy number was observed in cells from PSC patients compared to colitis and control group patients. It was also higher in the colitis than in the control group. Significantly more cells in the senescent state and more fragmentation in each cell were observed in the PSC group compared to colitis and control groups. CONCLUSION The TERC gene copy number and the number of cells in the senescent state were increased in PSC patients compared to the colitis and control groups. These findings are probably related to the genetic instability parameters that reflect the higher tendency of this patient group to develop malignancies.

Vedolizumab Levels in Breast Milk of Nursing Mothers With Inflammatory Bowel Disease

Introduction There are no data on the transfer of vedolizumab in breast milk of nursing mothers. We aimed to assess the presence of vedolizumab in breast milk of nursing inflammatory bowel disease [IBD] patients. Methods This was a prospective observational study of vedolizumab-treated breastfeeding patients with IBD. Serum and breast milk samples were obtained at pre-defined tim -points. The in-house developed enzyme-linked immunosorbent assay [ELISA] for measuring vedolizumab in blood was adapted and validated for measurement of the drug in breast milk. The level of vedolizumab was also measured in breast milk of a control group of nursing healthy mothers. Results Vedolizumab was undetectable in breast milk in IBD patients before the first infusion of vedolizumab [n = 3] and in all of the healthy controls [n = 5]. Vedolizumab was measurable in all lactating women who received vedolizumab [n = 5]. However, on serial measurements in breast milk after an infusion, drug levels did not surpass 480 ng/ml, which was roughly 1/100 of the comparable serum levels. Conclusions Vedolizumab can be detected in the breast milk of nursing mothers. Although more data are imperative, the concentrations of vedolizumab in breast milk are minute and are therefore unlikely to result in systemic or gastro-intestinal immune-suppression of the infant.

Telomere dysfunction in peripheral blood lymphocytes from patients with primary sclerosing cholangitis and inflammatory bowel disease

BACKGROUND AND AIMS Primary sclerosing cholangitis and inflammatory bowel disease are two associated, chronic inflammatory, pre-malignant conditions. We hypothesized that patients with these disorders may harbour telomere dysfunction as a marker of chromosomal instability. The aim of our study was to compare parameters of the telomere-telomerase system in these cohorts. METHODS In this prospective study, peripheral blood was withdrawn from patients with primary sclerosing cholangitis (N=20), inflammatory bowel disease (N=20) and healthy controls (N=20), and lymphocytes were isolated. Telomere length was quantified as a function of the signal intensity and telomere number. Random aneuploidy and telomere capture were determined by fluorescence in situ hybridization technique with specific probes. RESULTS Patients with inflammatory bowel disease had higher measures of intestinal disease activity than patients with primary sclerosing cholangitis. Despite this, shorter telomere length and telomere aggregates, especially the fusion of 2-5 telomeres, were observed at significantly higher rate in patients with primary sclerosing cholangitis relative to inflammatory bowel disease or healthy controls. Rates of aneuploidy and telomere capture were higher in the two probes in both diseases compared to controls (p<0.001). CONCLUSION Dysfunction of telomeres was demonstrated in primary sclerosing cholangitis patients more than inflammatory bowel disease and healthy controls patients, which attests to genetic instability and immunosenescence. TRIAL REGISTRATION NUMBER NCT02247622.

Prospective Observational Evaluation of Time-Dependency of Adalimumab Immunogenicity and Drug Concentrations: The Poetic Study

OBJECTIVES: Adalimumab is usually self‐injected at home, making prospective serial‐sampling studies challenging and scarce. This has led to a gap in knowledge about evolution of anti‐adalimumab antibodies (AAAs) over time and its correlation with clinical and inflammatory outcomes. METHODS: A program for home visits by physicians at induction, every 3 months and at event of relapse, was established prospectively for Crohns disease (CD) patients. At each visit, patients’ clinical scores were determined and sera were obtained for C‐reactive protein, drug, and AAA levels. This cohort was compared to a parallel prospective cohort of infliximab‐treated CD patients. In a subgroup of 29 patients, trough and in‐between‐trough levels were compared, to elucidate the importance of timing of sampling during the injection cycle. RESULTS: Ninety‐eight CD patients starting adalimumab were prospectively followed (median follow‐up 44 weeks) and 621 serum samples were analyzed. Thirty‐three patients (32%) developed AAA; 18/33 (55%) of them as early as week 2, and 26/33 (79%) by week 14. Induction period AAAs were strongly associated with primary non‐response (odds ratio (OR) = 5.4, 95% confidence interval (CI): 1.6–17.8, p = 0.005). As compared to antibodies‐to‐infliximab (ATI), AAA formation rate over time was significantly lower (p = 0.01) and AAA were much more specific—85% of AAA events were associated with loss‐of‐response compared with 58% rate for ATI (p = 0.01). In 29 patients sampled serially during an injection cycle, levels of drug and AAA seemed comparable between four time‐points during a single cycle both in patients with or without AAA (n = 8, n = 21, respectively). CONCLUSIONS: When followed prospectively and serially, AAAs are found to arise earlier than previously appreciated and their impact may be more pronounced for primary rather than secondary, non‐response. Drug and AAA levels were similar both at trough and in‐between injections, enabling to simplify therapeutic drug monitoring of adalimumab.