tacrolimus and Cystitis

Given that more cancers are being diagnosed earlier and that treatment of cancer is improving, health issues of cancer survivors are becoming more common and apparent. Pelvic radiation therapy for the treatment of gynecological cancers can lead to long-term collateral damage to the bladder, a condition termed radiation cystitis (RC). Late sequelae may take many years to develop and include incontinence and pain as well as hematuria. RC is a rare but potentially life-threatening condition for which there are few management and treatment options.. There are limited data in the literature regarding the effects of radiation on the bladder after gynecological cancer therapy and we hereby review the literature on cancer survivorship issues of pelvic radiation for gynecology literature.. Treatment options are available for patients with radiation-induced hemorrhagic cystitis. However, most treatments are risky or only effective for a short timeframe and no therapy is currently available to reverse the disease progress. Furthermore, no standardized guidelines exist describing preferred management options. Common therapies include hyperbaric oxygen therapy, clot evacuation, fulguration, intravesical instillation of astringent agents, and surgery. Novel developing strategies include Botulinum Toxin injections and liposomal-tacrolimus instillations. These treatments and strategies are discussed.. In this review, we will present current and advanced therapeutic strategies for RC to help cancer survivors deal with long-term bladder health issues.

Topics: Administration, Intravesical; Astringents; Botulinum Toxins; Cancer Survivors; Cystitis; Female; Genital Neoplasms, Female; Hematuria; Humans; Hyperbaric Oxygenation; Immunosuppressive Agents; Radiation Injuries; Survivorship; Tacrolimus; Urinary Bladder

Polyomaviruses are increasingly recognized as important human pathogens. Among those, BK virus has been identified as the main cause of polyomavirus-associated nephropathy (PVAN), a major cause of renal allograft failure. PVAN has also been well described in the setting of non-renal solid organ transplantation. The reports of PVAN after hematopoietic stem cell transplantation (HCT) are surprisingly very few. Here, we describe a patient with treatment-related myelodysplastic syndrome who received an unrelated donor HCT after ablative conditioning and in vivo T cell depletion with alemtuzumab. He developed a biopsy-proven BK nephropathy, which contributed to his renal failure. Leflunomide as well as cidofovir were given at different times, both in combination with intravenous immunoglobulin. Both treatments were effective in reducing the BK viral load, the cystitis symptoms and both stabilized but did not really improved the renal function. The patient was still dialysis-dependent when he died from Pseudomonas sepsis 13 months after HCT. A critical review of the literature and the treatment modalities for post-HCT PVAN are provided.

Topics: Antiviral Agents; BK Virus; Cystitis; Cytomegalovirus Infections; Fatal Outcome; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hepatorenal Syndrome; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kidney Failure, Chronic; Lymphoma, Follicular; Male; Middle Aged; Myelodysplastic Syndromes; Nephritis, Interstitial; Polyomavirus Infections; Postoperative Complications; Reoperation; Tacrolimus; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous

We primarily determined whether the small animal radiation research platform could create a rat radiation cystitis model via targeted bladder irradiation (phase I). The response to treating early phase radiation cystitis in rats with transurethral catheter instillation of liposomal tacrolimus was also examined (phase II).. In phase I 16 adult female Sprague Dawley® rats were used. Metabolic urination patterns were analyzed before and after exposure to 20, 30 or 40 Gy radiation. In phase II irradiated rats were randomly assigned to receive a single instillation of saline or liposomal tacrolimus.. The 40 Gy radiation dose induced statistically significant reductions in the intermicturition interval compared to the lower radiation doses. By approximately 20 minutes 40 Gy radiation caused a significant decrease in the mean intermicturition interval (p < 0.0001). Histological analysis revealed degenerative epithelial changes and urothelial swelling with evidence of pseudocarcinomatous epithelial hyperplasia. Therefore, 40 Gy were chosen for the phase II efficacy study. There was no measurable change in total voided urine volume after irradiation, or after liposomal tacrolimus or saline instillation. Liposomal tacrolimus significantly increased the post-irradiation intermicturition interval by approximately 30 minutes back to baseline (p < 0.001).. The radiation cystitis rat model showed a dose dependent decrease in the intermicturition interval without inducing short-term skin or gastrointestinal damage. This study demonstrates that liposomal tacrolimus may be a promising new intravesical therapy for the rare, serious condition of radiation cystitis.

Topics: Administration, Intravesical; Animals; Cystitis; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Female; Immunosuppressive Agents; Instillation, Drug; Neoplasms, Experimental; Pelvic Neoplasms; Protective Agents; Radiation Injuries, Experimental; Rats; Rats, Sprague-Dawley; Tacrolimus; Treatment Outcome; Urinary Bladder; Urothelium

Hemorrhagic cystitis is a rare and severe late complication of pelvic radiation, and there is no regulatory-approved drug treatment. We present an 81-year-old man with a history of localized prostate cancer, which was treated with external beam radiation therapy and subsequently developed severe hemorrhagic radiation cystitis for which he has failed several treatments. We present the novel use of intravesical tacrolimus for the treatment of refractory radiation cystitis and gross hematuria. The patient tolerated the treatment well, and it resulted in the resolution of his gross hematuria without further consideration for formalin instillation or cystectomy and diversion. Intravesical tacrolimus is a safe, minimally invasive, and promising treatment option for radiation hemorrhagic cystitis.

Topics: Administration, Intravesical; Aged, 80 and over; Calcineurin Inhibitors; Cystitis; Hematuria; Humans; Male; Prostatic Neoplasms; Radiation Injuries; Radiotherapy; Tacrolimus

The potent immunosuppressive effect of systemic tacrolimus is limited by the high incidence of severe adverse effects, including nephrotoxicity and hypertension. Intravesical application of tacrolimus is hindered by its poor aqueous solubility, justifying the search for novel delivery platforms such as liposomes. We evaluated the pharmacokinetics of tacrolimus encapsulated in liposomes (lipo-tacrolimus), which is being developed as a potential orphan drug indication for hemorrhagic cystitis.. A single dose of lipo-tacrolimus was instilled in the bladder with the rat under anesthesia. Also, tacrolimus was instilled intravesically or injected intraperitoneally in other rat groups. The tacrolimus dose was constant in all formulations at 200 μg/ml. At different times blood, urine and bladder samples were collected and stored at -80C until analysis. Tacrolimus levels in samples were analyzed using microparticle enzyme immunoassay II.. The AUC of lipo-tacrolimus in serum at 0 to 24 hours was significantly lower than that of tacrolimus instillation or injection. Noncompartmental pharmacokinetic data analysis revealed maximum concentration of lipo-tacrolimus and tacrolimus in serum and urine at 1 and at 2 hours, respectively. Urine AUC(0-24) after intravesical administration was significantly higher than in the intraperitoneal group (p <0.05). Bladder tacrolimus AUC(0-24) did not differ significantly between the groups.. Single dose pharmacokinetics revealed that bladder instillation of liposome encapsulated tacrolimus significantly decreased systemic exposure to instilled tacrolimus as well as vehicle related toxicity. Intravesical liposomal tacrolimus may be a promising approach as an orphan drug indication for hemorrhagic cystitis.

Topics: Administration, Intravesical; Animals; Cystitis; Hemorrhage; Immunosuppressive Agents; Liposomes; Orphan Drug Production; Rats; Tacrolimus

Potent immunosuppressive effect of tacrolimus has encouraged its topical application for achieving local anti-inflammatory effect. However, its poor aqueous solubility presents challenges in formulating biocompatible instillations to justify the investigation of liposomes as vehicle for tacrolimus.. Adult female Sprague-Dawley rats (N=52) divided into 4 groups were injected with cyclophosphamide (CYP) (200 mg/kg, ip) except for sham (saline injection, ip). Other three groups were instilled with either saline (1 cc, retained for 1 hr), liposome (LP- 1 cc) or liposomal encapsulated tacrolimus (LFK- 0.2 mg tacrolimus/1 ml LP). Baseline cystometrogram was performed on day 1 and day 3 prior to bladder harvest for histological staining (N=24) in all groups except sham. In addition, 4-hr baseline urine on day 1 and day 3 was collected from all groups for urine PGE2 assay and bladder harvested for PGE2 and IL2 assay on day 3 (N=28).. Rats treated with LFK demonstrated suppression of CYP induced inflammatory reaction with reduced EP4 staining and bladder overactivity (intercontraction interval 61.0% decrease in untreated animals) as well as normalized the several fold elevation of IL 2 and PGE2 levels in tissue and urine. CYP induced effects were not suppressed in rats left untreated with tacrolimus.. This is the first report of immunosuppression in bladder by intravesical delivery of tacrolimus using liposomes. LFK significantly inhibited CYP induced inflammatory cystitis through the modulation of IL2, PGE2, and EP4 function. These findings support investigation of local tacrolimus in cases of inflammatory cystitis refractory to conventional therapy.

Topics: Administration, Intravesical; Animals; Cyclophosphamide; Cystitis; Dinoprostone; Disease Models, Animal; Female; Immunosuppressive Agents; Interleukin-2; Liposomes; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E, EP4 Subtype; Tacrolimus; Time Factors; Urinary Bladder; Urination

A 23-year-old woman presented with recurrence of lupus cystitis, which had been in remission under daily administration of a single corticosteroid over a period of 8 years. She was treated with increased doses of corticosteroid and immunosuppressants, i.e., cyclosporin, cyclophosphamide, azathioprine, and salazosulfapyridine, but the cystitis remained active. Since her condition became critical by the complication of intestinal pseudo-obstruction, tacrolimus was administered. This agent induced a remission promptly without significant adverse events in this patient, suggesting an efficacy to lupus cystitis refractory to corticosteroid and other immunosuppressants.

Topics: Adrenal Cortex Hormones; Adult; Cystitis; Female; Humans; Hydronephrosis; Immunosuppressive Agents; Intestinal Pseudo-Obstruction; Lupus Erythematosus, Systemic; Radiography; Tacrolimus; Ultrasonography

We present a case of adenovirus (ADV) infection in a patient who had undergone nonmyeloablative stem cell transplantation (NST). A 50-year-old man with chronic myelogenous leukemia in the second chronic phase underwent NST from an HLA 2-loci-mismatched sibling. ADV hemorrhagic cystitis developed and progressed to lethal pneumonia. ADV was isolated from urine, bronchoalveolar lavage fluid, and postmortem specimens of kidney and liver. Because there are few reports of lethal pneumonia associated with ADV in Japan, we present the case and discuss the cause of and therapy for the infection.

Topics: Adenoviridae Infections; Adenoviruses, Human; Antilymphocyte Serum; Bronchoalveolar Lavage Fluid; Busulfan; Cystitis; Fatal Outcome; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Leukemia, Myeloid, Chronic-Phase; Lymphocyte Count; Lymphocyte Subsets; Male; Methylprednisolone; Middle Aged; Pneumonia, Viral; T-Lymphocytes; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Vidarabine