tacrolimus and Irritable-Bowel-Syndrome

TRPV1 is phosphorylated and functionally upregulated by protein kinases, and negatively regulated by phosphatases including calcineurin. Since the clinical use of calcineurin-inhibiting immunosuppressants is commonly associated with chronic diarrhea, we examined if tacrolimus, a calcineurin inhibitor, promotes TRPV1-dependent colonic hypersensitivity in mice. Intracolonic administration of capsaicin, a TRPV1 agonist, caused referred hyperalgesia in the lower abdomen, an effect prevented by capsazepine, a TRPV1 blocker. Tacrolimus accelerated the intracolonic capsaicin-induced referred hyperalgesia. Similarly, intracolonic capsaicin caused spinal ERK phosphorylation, a marker for nociceptor excitation, an effect promoted by tacrolimus. Thus, tacrolimus may aggravate TRPV1-related colonic pain accompanying irritable bowel syndrome.

Topics: Animals; Calcineurin Inhibitors; Capsaicin; Colon; Hyperalgesia; Immunosuppressive Agents; Irritable Bowel Syndrome; Mice; Tacrolimus; TRPV Cation Channels

Diarrhea in kidney transplant recipients influences outcome of transplantation. Data from India in this regard are sparse and do not address the differential outcome of infective and non-infective diarrhea. We studied the demographic data, laboratory findings, treatment response, disease duration, and outcome of diarrhea in kidney transplant recipients, and the differential outcome between infective and non-infective diarrhea, if any.. All kidney transplant recipients who were referred to the Division of Gastroenterology with diarrhea between June 2015 and February 2017 were prospectively included. Demographic, clinical and laboratory data, graft function, treatment administered, and outcome were noted, and the patients were followed up for 3 months.. Forty-seven patients (median age 45 years, range 16-78; 34 men) with 64 episodes of diarrhea were studied. Thirty-three (51.5%) episodes were attributed to infections. Eleven (17%) were immunosuppressant-induced (mycophenolate 8, tacrolimus 2, cyclosporine 1). Twenty (31%) were due to other causes (antibiotics 6, laxatives 3, irritable bowel syndrome 3, sepsis 8). Fifty-three episodes (82%) had graft dysfunction during the diarrheal episodes. Mean increase in serum creatinine was 45% in the infectious diarrhea group and 95% in the non-infectious diarrhea group (p < 0.05). Median time to resolution of diarrhea was 3 days. With improvement in diarrhea, return to pre-diarrhea creatinine levels occurred in 87% of episodes at 3 months.. One-half of episodes of diarrhea in kidney transplant recipients were non-infectious in origin. Seventeen percent were attributed to immunosuppressants, requiring dose modification. More than 80% were associated with worsening of graft function. Recovery of graft function to baseline was seen in a majority of cases with the resolution of diarrhea.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Diarrhea; Female; Humans; Immunosuppressive Agents; Irritable Bowel Syndrome; Kidney Transplantation; Laxatives; Male; Middle Aged; Primary Graft Dysfunction; Prognosis; Prospective Studies; Retrospective Studies; Tacrolimus; Treatment Outcome; Young Adult

The pathogenesis of pain in irritable bowel syndrome (IBS) is poorly understood and treatment remains difficult. The present study was designed to investigate roles of adrenergic signaling and the endogenous hydrogen sulfide producing enzyme cystathionine β-synthetase (CBS) in a previously validated rat model of IBS induced by neonatal colonic inflammation (NCI). Here we showed that NCI-induced visceral hypersensitivity (VH) was significantly attenuated by β2 subunit inhibitor but not by β1 or β3 or α subunit inhibitor. NCI markedly elevated plasma norepinephrine (NE) concentration without alteration in expression of β2 subunit receptors in dorsal root ganglion (DRGs) innervating the colon. In addition, NCI markedly enhanced TRPV1 and CBS expression in the colon DRGs. CBS inhibitor AOAA reversed the upregulation of TRPV1 in NCI rats. In vitro experiments showed that incubation of DRG cells with NE markedly enhanced expression of TRPV1, which was reversed by application of AOAA. Incubation of DRG cells with the H2S donor NaHS greatly enhanced TRPV1 expression. Collectively, these data suggest that activation of adrenergic signaling by NCI sensitizes TRPV1 channel activity, which is likely mediated by upregulation of CBS expression in peripheral sensory neurons, thus contributing to chronic visceral hypersensitivity.

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Behavior, Animal; Cystathionine beta-Synthase; Disease Models, Animal; Ganglia, Spinal; Hypersensitivity; Irritable Bowel Syndrome; Male; Norepinephrine; Patch-Clamp Techniques; Propranolol; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta-2; Signal Transduction; Sulfites; Tacrolimus; TRPV Cation Channels; Up-Regulation

Tacrolimus proved its distinct mitigating potential in the treatment of inflammatory bowel disease (IBD). Due to the risk for severe adverse effects and to achieve increased efficiency and tolerability, a selective delivery to the site of inflammation is of interest. Tacrolimus nanoparticles (NP) were tested for their efficiency in local treatment of inflamed bowel tissue in IBD. Drug loaded NP were prepared from either biodegradable poly(lactide-co-glycolide) (PLGA) or pH-sensitive Eudragit P-4135F by using a simple oil/water emulsification method. Tests on the therapeutic effect were conducted using dextran sulfate model colitis in mice receiving tacrolimus formulations daily for 12 days. Clinical activity score and myeloperoxidase activity decreased while colon length increased significantly after administration of all tacrolimus containing formulations. Oral NP formulations were less efficient in mitigating the experimental colitis compared to subcutaneous drug solution (PLGA: 7.88 +/- 0.83; P-4135F: 7.48 +/- 0.42; subcutaneous: 5.27 +/- 0.68 U/mg) but superior to drug solution given by oral route (oral: 8.75 +/- 1.34; untreated colitis control: 9.95 +/- 0.92, all U/mg tissue). Tacrolimus solution groups (oral/subcutaneous) exhibited increased levels of adverse effects, whereas both NP groups demonstrated their potential to reduce nephrotoxicity. Both strategies showed similar mitigating effects while nephrotoxic adverse effects were slightly less expressed with pH-sensitive NP.

Topics: Administration, Oral; Animals; Biocompatible Materials; Blood Urea Nitrogen; Colon; Creatinine; Disease Models, Animal; Drug Delivery Systems; Hydrogen-Ion Concentration; Injections, Subcutaneous; Irritable Bowel Syndrome; Male; Mice; Nanostructures; Organ Size; Peroxidase; Tacrolimus