Ileocolonic-Targeted JAK Inhibitor: A Safer and More Effective Treatment for Inflammatory Bowel Disease.

Janus kinase (JAK) inhibitors, such as tofacitinib (Xeljanz) and filgotinib (Jyseleca), have been approved for treatment of ulcerative colitis with several other JAK inhibitors in late-stage clinical trials for inflammatory bowel disease (IBD). Despite their impressive efficacy, the risk of adverse effects accompanying the use of JAK inhibitors has brought the entire class under scrutiny, leading to them receiving an FDA black box warning. In this study we investigated whether ileocolonic-targeted delivery of a pan-JAK inhibitor, tofacitinib, can lead to increased tissue exposure and reduced systemic exposure compared to untargeted formulations. The stability of tofacitinib in the presence of rat colonic microbiota was first confirmed. Next, in vivo computed tomography imaging was performed in rats to determine the transit time and disintegration site of ileocolonic-targeted capsules compared to gastric release capsules. Pharmacokinetic studies demonstrated that systemic drug exposure was significantly decreased, and colonic tissue exposure increased at 10 mg/kg tofacitinib dosed in ileocolonic-targeted capsules compared to gastric release capsules and an oral solution. Finally, in a rat model of LPS-induced colonic inflammation, targeted tofacitinib capsules significantly reduced concentrations of proinflammatory interleukin 6 in colonic tissue compared to a vehicle-treated control (p = 0.0408), unlike gastric release tofacitinib capsules and orally administered dexamethasone. Overall, these results support further development of ileocolonic-targeted tofacitinib, and potentially other specific JAK inhibitors in pre-clinical and clinical development, for the treatment of IBD.

Patients with extra-adrenal malignancies and adrenal lesions have similar rates of subclinical hypercortisolism compared with patients with true adrenal incidentalomas.

OBJECTIVE: During follow-up in cancer patients, adrenal lesions are frequently found by computer tomography imaging. In these patients, the frequency of subclinical Cushing's syndrome (SCS) has not been fully explored. The aim of the present study was to investigate the presence of SCS in cancer patients with adrenal lesions in comparison to patients with true adrenal incidentalomas. DESIGN: We studied 95 patients with adrenal lesions: 57 patients (group A, 20 males and 37 females) had a history of extra-adrenal malignancy and adrenal lesions were discovered during staging of the primary cancer, and 38 patients (group B, 6 males and 32 females) had adrenal incidentalomas. The two groups had similar BMI. All patients had unenhanced HU < 10 in computed tomography to ensure low risk of adrenal metastatic disease. Patients' morning plasma cortisol levels and ACTH were measured. An overnight 1 mg dexamethasone suppression test (ODST) was performed in all participants; in case of abnormal results, 24-h urine cortisol and the low-dose dexamethasone suppression test were additionally conducted. The cutoffs of morning cortisol values used for ODST were 1.8 and 5 µg/dl. RESULTS: When the cutoff of 1.8 µg/dl for suppressed morning cortisol was used, 42.1% of group A and 39.5% of group B had abnormal results (p = 0.95). By using the threshold of 5 µg/dl after ODST, 5.3% of group A and 13.2% of group B did not have suppressed cortisol levels with the 1 mg ODST (p = 0.18). The main factors found to influence suppressed cortisol levels after ODST in both groups were BMI and size of the adrenal lesion. CONCLUSIONS: Patients with extra-adrenal malignancies and adrenal lesions had similar rates of subclinical hypercortisolemia compared to patients with true adrenal incidentalomas.

Total Antioxidant Capacity, Haematological and Coagulation Parameters after Orthodox Christian Fast.

BACKGROUND: Orthodox Christian believers fast abstaining from meat, eggs, dairy products or even fish and oil in certain days of the fasting period, three times a year. AIM: The present study aimed to investigate the impact of a 48-day fast before Easter in blood count parameters, coagulation and antioxidant status. MATERIAL AND METHODS: A total of 35 healthy volunteers, 19-66 years old, were included in the study. White blood cells (WBC), lymphocytes (Lymph), granulocytes (Gran), haemoglobin (Hb), hematocrit (Ht), red blood cells (RBC), mean erythrocyte volume (MCV), platelets (Plt), were measured. Blood coagulation parameters, such as PT, aPTT, fibrinogen concentration, factor VII activity were also determined, and INR (PTsample/PTcontrol) and aPTT ratio (aPTTsample/aPTTcontrol) were calculated. Total antioxidant capacity (TAC) was assayed. RESULTS: Levels of all parameters remained within normal. By the end of the fasting period, lymphocytes and TAC levels were significantly increased (p = 0.011), whereas all the other parameters, except fibrinogen, were significantly decreased. CONCLUSION: Orthodox Christian fast impairs all haematological and coagulation parameters and seems to be beneficial in the body antioxidant protection.