Surveillance pouchoscopy for dysplasia: Cleveland Clinic Ileoanal Pouch Anastomosis Database.

BACKGROUND: No formal guidelines exist for surveillance pouchoscopy following ileal pouch-anal anastomosis (IPAA) for ulcerative colitis. METHODS: All adults who had previously had IPAA for ulcerative colitis, and underwent a pouchoscopy between 1 January 2010 and 1 January 2020, were included. RESULTS: A total of 9398 pouchoscopy procedures were performed in 3672 patients. The majority of the examinations were diagnostic (8082, 86·0 per cent; 3260 patients) and the remainder were for routine surveillance (1316, 14·0 per cent; 412 patients). Thirteen patients (0·14 per cent of procedures) were found to have biopsy-proven neoplasia at the time of pouchoscopy; seven had low-grade dysplasia (LGD) (0·07 per cent; all located in the anal transition zone), none had high-grade dysplasia (HGD) and six (0·06 per cent) had invasive adenocarcinoma (4 in anal transition zone and 6 in pouch). Of the six patients with adenocarcinoma, four had neoplasia at the time of proctocolectomy (2 adenocarcinoma, 1 LGD, 1 HGD); all six were symptomatic with anal bleeding or pelvic pain at the time of pouchoscopy, had a negative surveillance pouchoscopy examination within 2 years of diagnosis of adenocarcinoma, had palpable masses on digital rectal examination, and had visible lesions at the time of pouchoscopy. CONCLUSION: Surveillance pouchoscopy is not recommended in asymptomatic patients because significant neoplasia following IPAA for ulcerative colitis is rare.

ANTECEDENTES: No existen unas recomendaciones formales para vigilancia endoscópica en pacientes a los que se les ha realizado un reservorio ileoanal (ileal pouch anal anastomosis, IPAA) por una colitis ulcerosa (ulcerative colitis, UC). MÉTODOS: Se incluyeron todos los pacientes adultos a los que se les había realizado previamente un IPAA por UC y se sometieron a una endoscopia del reservorio. RESULTADOS: Se realizaron un total de 9.398 procedimientos endoscópicos en 3.672 pacientes entre el 1/1/2010 y el 1/1/2020. La mayoría de las exploraciones fueron diagnósticas (n = 8.082; 86%; 3.260 pacientes) y el resto fueron de seguimiento (n = 1.316; 14%; 412 pacientes). Se descubrió que 13 pacientes tenían una neoplasia demostrada por biopsia (0,14%) en el momento de la endoscopia; siete pacientes tenían displasia de bajo grado (low-grade displasia, LGD) (0,074%; localizada en todos los casos en la zona de transición anal), ninguno tenía displasia de alto grado (high-grade displasia, HGD) y seis (0,064%) tenían un adenocarcinoma invasivo (cuatro en la zona de transición anal) y dos en el reservorio). De los seis pacientes con adenocarcinoma, 4 tenían neoplasia en el momento de la proctocolectomía (2 adenocarcinoma, uno LGD, uno HGD). Todos estos pacientes tenían síntomas de hemorragia anal o dolor pélvico en el momento de la endoscopia, se les había practicado una endoscopia previa reciente del reservorio en los dos años anteriores, presentaban una masa palpable en la exploración digital rectal, así como lesiones visibles en la endoscopia del reservorio. CONCLUSIÓN: La vigilancia endoscópica del reservorio no se recomienda en pacientes asintomáticos porque es raro que aparezca una neoplasia después del IPAA por UC.

Surma eye cosmetic in Afghanistan: a potential source of lead toxicity in children.

Surma is a traditional eye cosmetic used as an eyeliner for infants in Afghanistan, as well as in many other countries in Asia, the Middle East, and Africa. Surma has been reported to contain lead and to be a potential source of lead toxicity in children, which can lead to permanent damage to multiple organ systems. To our knowledge, assessment for lead in surma found in Afghanistan has not been performed. We determined the quantitative lead content of a convenience sample of 10 surma products acquired in Afghanistan. Analysis revealed that 70% of surma samples contained high levels of lead (range 35-83%). The remaining samples contained low levels of lead (range 0.04-0.17%). CONCLUSION: The majority of surma samples contained very high levels of lead, a troubling finding that could potentially correlate with lead toxicity in Afghan children. Making available lead-free surma alternatives and providing health education, for both healthcare professionals and the general population, in locations where surma use is prevalent and for those involved in care of refugees and immigrants from Afghanistan, may be strategies to prevent lead poisoning in children. What is Known: • Surma is a traditional cosmetic used as an eyeliner for infants in Afghanistan as well as in many countries in Asia, the Middle East, and Africa. • Surma has been reported to contain lead and to be a source of lead toxicity in children. What is New: • Assessment for lead content in surma found in Afghanistan has not been performed. • In this convenience sample of 10 surma products acquired in Afghanistan, 70% contained very high levels of lead.

Utility of international store-and-forward teledermatopathology among a cohort of mostly female patients at a tertiary referral center in Afghanistan.

BACKGROUND: The variety and complexity of dermatologic diseases in Afghanistan and the associated diagnostic resource constraints have not been previously studied. Moreover, the utility of store-and-forward teledermatopathology in this resource-limited setting has not been investigated. METHODS: A retrospective analysis was conducted of 150 store-and-forward teledermatopathology cases that were composed of a clinical history, clinical images, and histologic images that were sent from an academic teaching hospital in Kabul to a dermatology-trained dermatopathologist at Emory University in the United States between November 2013 and June 2017. For each case, the histologic impression of the Emory dermatopathologist was compared with that of the Kabul-based general pathologist and the clinical differential diagnosis and histologic impression of the Kabul-based dermatologist. RESULTS: Eighty-one of the cases that were analyzed were from female patients. The diagnosis after telepathology consultation differed from the first entity in the clinical differential diagnosis in 34.7% of cases. The telepathology consultation refined the Afghan general pathologist's histologic impression 45.5% of the time and the Kabul-based dermatologist's histologic impression 24.3% of the time. A clinically significant difference in care was made in 19.3% of cases for which an analysis could take place between the histologic impressions of the Emory dermatopathologist and U.S.-trained dermatologist. The most common resource constraints that limited a definitive diagnosis were the inability to perform infectious stains and cultures to identify specific pathogens (19.3% of cases) and immunofluorescence studies to confirm autoimmune bullous disease (6.7% of cases). CONCLUSIONS: These results highlight the important diagnostic role that teledermatopathology can serve in resource-limited settings such as in Afghanistan.

In vitro effects and clinical evaluation of a human chorionic gonadotrophin preparation in acute leukemia.

Commercial human chorionic gonadotrophin (HCG) preparations decrease the tumorigenicity of human tumors in immunodeficient mice and induce apoptotic cell death in animal tumor models. Preliminary studies in humans have demonstrated tumor regression in patients with Kaposi's sarcoma given intralesional injections of HCG. To further evaluate HCG's antitumor activity we conducted in vitro and clinical evaluations of HCG in acute myeloid leukemia (AML). In HL-60 leukemic cell lines, a 20-40% inhibition of cell density was demonstrated by trypan blue exclusion method at low concentrations of an HCG preparation (2 x 10(-3)-2 x 10(-2)). Similar concentrations also resulted in a reduction in the proportion of cells in G2M phase of the cell cycle, as well as enhanced differentiation compared to control cells. Fifteen patients with advanced AML with marrow blast counts >30%, and five with marrow blast counts between 10 and 26% were given daily subcutaneous injections of HCG 2-4 IU and oral levamisole 50 mg weekly. Five patients with absolute blast counts in the blood ranging from 0 to 3500/microl and percent blasts in the marrow ranging from 16 to 81% were observed to have no progressive increase in either marrow or peripheral blast counts for 70-121 days. One patient with a pretreatment blast count of 10% in the marrow, no circulating blasts and minor cytopenias had a decrease in marrow blasts to less than 5% which has persisted at 550 days. No significant improvement from baseline levels of neutrophils, hemoglobin or platelets were observed in any nl the patients treated. Increases in apoptotic cell death were observed in over 50% of patients' cells with some demonstrating peak levels similar to experiences in patients treated with DNA-damaging chemotherapy. A decreased expression of bcl-2 was seen in the majority of patients ranging from 6 to 62%. These new observations suggest that HCG preparations may inhibit leukemic cell growth through enhancement of cell death mechanisms and could be used in judicious combinations with other approaches. The results confirm the pro-apoptotic effects of HCG preparations reported in patients with Kaposi's sarcoma. Identification of the active component of HCG preparations and further understanding of its growth modulatory action will be important in its development as a clinically useful agent.

Progress toward the development of a vaccine to prevent Moraxella (Branhamella) catarrhalis infections.

Moraxella catarrhalis is a major cause of otitis media and respiratory disease. Vaccine development is at the antigen identification stage. This review examines the more promising antigens, including the 200K protein, the hemagglutinins, the lactoferrin-binding proteins, the UspA proteins, the CopB protein, the transferrin-binding proteins, the CD protein, the E protein and lipooligosaccharide conjugates. Clinical testing of some of these antigens should begin soon.

Antimicrobial peptides: mediators of innate immunity as templates for the development of novel anti-infective and immune therapeutics.

Antimicrobial molecules are ancient and essential small cationic molecules of the host defence system which are found in a wide variety of species. They display antimicrobial activity against a wide range of bacteria, fungi and viruses, an activity that has been mostly attributed to the disruption of microbial membranes. In this article, we will review the "classical" functions of 3 classes of antimicrobial molecules, namely defensins, cathelicidins, and the four-disulfide core proteins secretory leukocyte proteinase inhibitor (SLPI) and elafin. In addition to the study of their expression in a variety of cell types and the regulation of their production, we will also describe novel properties of these molecules that have been highlighted by recent studies. These include their ability to chemoattract a variety of inflammatory, immune and other cell types (neutrophils, macrophages, monocytes, lymphocytes, mast cells, epithelial cells) in vitro and in vivo. In addition, we will discuss the potential use of these newly discovered properties for therapeutic or vaccination purposes, using protein- or gene-transfer based methodologies. Finally, we will examine in an extensive fashion the strategies used by microorganisms to circumvent and subvert host defence mechanisms, such as the modifications of cell membranes and walls, the secretion of inactivating proteins and proteases and the down-regulation of expression of antimicrobial molecules. Increased understanding of the mechanisms used by both the host and the microbes to 'win the battle' may ultimately lead to new therapeutic strategies aimed to treat infectious diseases.

The use of nitrocellulose blotting for the study of hepatitis B surface antigen electrophoresed in agarose gels.

Nitrocellulose-protein blotting of serum electrophoresed in agarose gels has been adapted for the study of hepatitis B surface antigen (HBsAg). 125I-labeled anti-HBs was used as the antigen probe, and the electrophoretic migration was monitored by autoradiography. The method required 3 microliter or less of serum and could detect as little as 1 pg of purified HBsAg. Typically, we observed two bands of HbsAg; a moving band which migrated about one-third the distance moved by human serum albumin and a non-migratory band which remained at the loading site. Some examples of the use of the method include: (1) empirical methods for correlating HBsAg concentration in serum to film darkness; (2) observations of mobility changes in serial sera from dialysis patients with chronic HBsAg antigenemia; and (3) detection of related antigens such as antigen from the PLC/PRF/5 hepatoma tissue culture line and the cross-reacting woodchuck patients hepatitis virus surface antigen (WHsAg).

Weaning of immunosuppression in liver transplant recipients.

Immunosuppression has been sporadically discontinued by noncompliant liver allograft recipients for whom an additional 4 1/2 years of follow-up is provided. These anecdotal observations prompted a previously reported prospective drug withdrawal program in 59 liver recipients. This prospective series has been increased to 95 patients whose weaning was begun between June 1992 and March 1996, 8.4+/-4.4 (SD) years after liver replacement. A further 4 1/2 years follow-up was obtained of the 5 self-weaned patients. The prospectively weaned recipients (93 livers; 2 liver/kidney) had undergone transplantation under immunosuppression based on azathioprine (AZA, through 1979), cyclosporine (CsA, 1980-1989), or tacrolimus (TAC, 1989-1994). In patients on CsA or TAC based cocktails, the adjunct drugs were weaned first in the early part of the trial. Since 1994, the T cell-directed drugs were weaned first. Three of the 5 original self-weaned recipients remain well after drug-free intervals of 14 to 17 years. A fourth patient died in a vehicular accident after 11 years off immunosuppression, and the fifth patient underwent retransplantation because of hepatitis C infection after 9 drug-free years; their allografts had no histopathologic evidence of rejection. Eighteen (19%) of the 95 patients in the prospective series have been drug free for from 10 months to 4.8 years. In the total group, 18 (19%) have had biopsy proved acute rejection; 7 (7%) had a presumed acute rejection without biopsy; 37 (39%) are still weaning; and 12 (13%, all well) were withdrawn from the protocol at reduced immunosuppression because of noncompliance (n=8), recurrent PBC (n=2), pregnancy (n=1), and renal failure necessitating kidney transplantation (n=1). No patients were formally diagnosed with chronic rejection, but 3 (3%) were placed back on preexisting immunosuppression or switched from cyclosporine (CsA) to tacrolimus (TAC) because of histopathologic evidence of duct injury. Two patients with normal liver function died during the trial, both from complications of prior chronic immunosuppression. No grafts suffered permanent functional impairment and only one patient developed temporary jaundice. Long surviving liver transplant recipients are systematically overimmunosuppressed. Consequently, drug weaning, whether incomplete or complete, is an important management strategy providing it is done slowly under careful physician surveillance. Complete weaning from CsA-based regimens has been difficult. Disease recurrence during drug withdrawal was documented in 2 of 13 patients with PBC and could be a risk with other autoimmune disorders.

Early death or retransplantation in adults after orthotopic liver transplantation. Can outcome be predicted?

Early, reliable outcome prediction after a liver transplant would help improve organ use by minimizing unnecessary retransplantations. At the same time, early intervention in those cases destined to fail may ameliorate the high morbidity and mortality associated with retransplantation. The purpose of this study was to analyze several parameters that have been identified in the past as being associated with patient and graft outcome, and to try to develop a model that would allow us to make predictions based on data available in the early postoperative period. A total of 148 patients were followed in a prospective, observational study. Graft failure was defined as patient death or retransplantation within 3 months of surgery. Preoperative variables studied included patient demographics, need for life support, presence of ascites, serum bilirubin, serum albumin, prothrombin time, serum creatinine, and the results of the cytotoxic crossmatch. During the first 5 postoperative days, standard measurements included serum transaminases, serum bilirubin, ketone body ratio, prothrombin time, factor V, and serum lactate. Oxygen consumption was measured shortly after surgery, once the patients had rewarmed to 36 degrees C. There were 131 successful transplants (88.5%) and 17 failures (11.5%). Most of the variables studied were found to be associated with outcome (by univariate analysis) at different points in the early postoperative period. However, receiver operating characteristic curve analysis showed that the predictive ability of even the best parameter was not adequate to make decisions on individual patients. Multivariate analysis, using stepwise logistic regression, yielded a model with an overall accuracy of 92.7%. Again, receiver operating characteristic curve analysis suggested that this model did not achieve the discriminating power needed for routine clinical use. We are still not able to accurately predict outcome in the early posttransplant period. We must be very careful when evaluating parameters, or scoring systems, that are said to accomplish this. It is especially important in this era of cost containment, with its renewed pressures to guide therapy based on our perceived understanding of a patient's future clinical course.

Screening donors for xenotransplantation. The potential for xenozoonoses.

Xenotransplantation is a potential solution to the current donor shortage for solid organ transplantation. The transmission of infectious agents from donor organs or bone marrow to the recipient is a well-recognized phenomenon following allotransplantation. Thus the prospect of xenotransplantation raises the issue of xenozoonoses--i.e., the transmission of animal infections to the human host. Anticipating an increasing number of baboon to human transplants, 31 adult male baboons (Papio cynocephalus) from a single colony in the United States were screened for the presence of antibody to microbial agents (principally viral) that may pose a significant risk of infection. Antibody to simian cytomegalovirus, simian agent 8 and Epstein-Barr virus, was found in 97% of animals tested. Antibody to simian retroviruses and Toxoplasma gondii was found in 30% and 32% respectively. Discordant results were found when paired samples were examined by two primate laboratories. This was particularly noted when methodologies were based on cross-reaction with human viral antigens. These results highlight the need to develop specific antibody tests against the species used for xenotransplantation.

HLA and cross-reactive antigen group matching for cadaver kidney allocation.

BACKGROUND: Allocation of cadaver kidneys by graded human leukocyte antigen (HLA) compatibility scoring arguably has had little effect on overall survival while prejudicing the transplant candidacy of African-American and other hard to match populations. Consequently, matching has been proposed of deduced amino acid residues of the individual HLA molecules shared by cross-reactive antigen groups (CREGs). We have examined the circumstances under which compatibility with either method impacted graft survival. METHODS: Using Cox proportional hazards regression modeling, we studied the relationship between levels of conventional HLA mismatch and other donor and recipient factors on primary cadaver kidney survival between 1981 and 1995 at the University of Pittsburgh (n=1,780) and in the United Network for Organ Sharing (UNOS) Scientific Registry during 1991-1995 (n=31,291). The results were compared with those obtained by the matching of amino acid residues that identified CREG-compatible cases with as many as four (but not five and six) HLA mismatches. RESULTS: With more than one HLA mismatch (> 85% of patients in both series), most of the survival advantage of a zero mismatch was lost. None of the HLA loci were "weak." In the UNOS (but not Pittsburgh) category of one-HLA mismatch (n=1334), a subgroup of CREG-matched recipients (35.3%) had better graft survival than the remaining 64.7%, who were CREG-mismatched. There was no advantage of a CREG match in the two- to four-HLA incompatibility tiers. Better graft survival with tacrolimus was observed in both the Pittsburgh and UNOS series. CONCLUSIONS: Obligatory national sharing of cadaver kidneys is justifiable only for zero-HLA-mismatched kidneys. The potential value of CREG matching observed in the one-HLA-mismatched recipients of the UNOS (but not the Pittsburgh) experience deserves further study.

Stimulated response of peripheral lymphocytes may distinguish cyclosporine effect in renal transplant recipients receiving a cyclosporine+rapamycin regimen.

BACKGROUND: Clinically, cyclosporine (CSA, Neoral) is titrated to concentrations, and not to pharmacological effect. METHODS: Intracellular interleukin- (IL) 2 was measured in phorbol myristic acid-ionomycin-stimulated peripheral lymphocytes by flow cytometry, after isolation from 14 renal transplant recipients receiving CSA+prednisone, and double-blind rapamycin (rapamycin:placebo=4:1). RESULTS: The proportion (%) of CD4+IL-2+ lymphocytes corresponding to CSA levels (mean+/-SD ng/ml) measured preoperatively (TO=O), and on postoperative day 8, before (356+/-63), and 2 hr after the morning dose (Cmax=1567+/-669), decreased from 39+/-16 to 15+/-8 and 3+/-1.6, respectively. Reciprocally, unresponsive lymphocytes (%CD4+IL-2-) increased with increasing CSA levels and predicted an EC50 of 249 ng/ml (CSA concentration at which CD4+IL-2- cells increased by 50% over baseline) in an Emax pharmacodynamic model. CONCLUSIONS: Clinically, the pharmacological effect of CSA is quantifiable, and lies in the upper end of the predicted range. In our Neoral-treated sample population, Cmax was associated with the least variable "cyclosporine effect." Such information could potentially individualize immunosuppression, and lead to rational dosing strategies.

Hepatic Retransplantation--an analysis of risk factors associated with outcome.

Hepatic retransplantation is controversial because the results are inferior to primary transplants and organs are so scarce. To determine the factors that are associated with poor outcome within the first year following retransplantation, we performed a multivariate analysis, using stepwise logistic regression, of 418 hepatic retransplantations performed at a single institution from November 1987 to December 1993. The minimum follow-up was 1 year. Seven variables were found to be independently associated with subsequent graft failure (defined as either patient death or retransplantation): donor age (odds ratio 2.2 for each 10-year increase over age 45, 95% CI 1.3 to 3.7), female donor sex (odds ratio 1.7, 95% CI 1.05 to 2.7), recipient age (odds ratio 1.6 for each 10-year increase over age 45,95% CI 1.2 to 2.8), need for preoperative mechanical ventilation (odds ratio 1.8, 95% CI 1.1 to 2.9), pretransplant serum creatinine (odds ratio 1.24 for each increase of 1 mg/dl, 95% CI 1.1 to 1.4), pretransplant total serum bilirubin (odds ratio 1.4 for each 10-mg/dl increase over 15 mg/dl, 95% CI 1.1 to 1.8), and the primary immunosuppressant, using tacrolimus as the reference category (odds ratio for cyclosporine-based immunosuppression 3.9, 95% CI 2.3 to 6.8). Although not part of the logistic regression model, the timing of retransplantation was also found to be important, with the overall probability of failure increasing from 0.58 on day 0 to a peak of 0.8 on day 38 and decreasing slowly after that. The implications of these results regarding the appropriateness of retransplantation are discussed.

Weaning of immunosuppression in long-term liver transplant recipients.

Seventy-two long-surviving liver transplant recipients were evaluated prospectively, including a baseline allograft biopsy for weaning off of immunosuppression. Thirteen were removed from candidacy because of chronic rejection (n = 4), hepatitis (n = 2), patient anxiety (n = 5), or lack of cooperation by the local physician (n = 2). The other 59, aged 12-68 years, had stepwise drug weaning with weekly or biweekly monitoring of liver function tests. Their original diagnoses were PBC (n = 9), HCC (n = 1), Wilson's disease (n = 4), hepatitides (n = 15), Laennec's cirrhosis (n = 1), biliary atresia (n = 16), cystic fibrosis (n = 1), hemochromatosis (n = 1), hepatic trauma (n = 1), alpha-1-antitrypsin deficiency (n = 9), and secondary biliary cirrhosis (n = 1). Most of the patients had complications of long-term immunosuppression, of which the most significant were renal dysfunction (n = 8), squamous cell carcinoma (n = 2) or verruca vulgaris of skin (n = 9), osteoporosis and/or arthritis (n = 12), obesity (n = 3), hypertension (n = 11), and opportunistic infections (n = 2). When azathioprine was a third drug, it was stopped first. Otherwise, weaning began with prednisone, using the results of corticotropin stimulation testing as a guide. If adrenal insufficiency was diagnosed, patients reduced to < 5 mg/day prednisone were considered off of steroids. The baseline agents (azathioprine, cyclosporine, or FK506) were then gradually reduced in monthly decrements. Complete weaning was accomplished in 16 patients (27.1%) with 3-19 months drug-free follow-up, is progressing in 28 (47.4%), and failed in 15 (25.4%) without graft losses or demonstrable loss of graft function from the rejections. This and our previous experience with self-weaned and other patients off of immunosuppression indicate that a significant percentage of appropriately selected long-surviving liver recipients can unknowingly achieve drug-free graft acceptance. Such attempts should not be contemplated until 5-10 years posttransplantation and then only with careful case selection, close monitoring, and prompt reinstitution of immunosuppression when necessary.

A prospective randomized trial of tacrolimus and prednisone versus tacrolimus, prednisone, and mycophenolate mofetil in primary adult liver transplant recipients: an interim report.

BACKGROUND: Tacrolimus (Tac) and mycophenolate mofetil (MMF) are newly approved immunosuppressive agents. However, the safety and efficacy of the combination of MMF and Tac in primary liver transplantation has not been determined. METHODS: An Institutional Review Board-approved, open-label prospective randomized protocol was initiated to study the efficacy and toxicity of Tac and steroids (double-drug therapy) versus Tac, steroids, and MMF (triple-drug therapy) in primary adult liver transplant recipients. Both groups of patients began on the same doses of Tac and steroids. Patients randomized to triple-drug therapy also received 1 g of MMF twice a day. RESULTS: Between August 1995 and January 1997, 200 patients were enrolled, 99 in double-drug therapy and 101 in triple-drug therapy. All patients were followed until May 1997, with a mean follow-up of 12.7 months. During the study period, 28 of 99 patients in double-drug therapy received MMF to control ongoing acute rejection, nephrotoxicity, and/or neurotoxicity. On the other hand, 61 patients in triple-drug therapy discontinued MMF for infection, myelosuppression, and/or gastrointestinal disturbances. By an "intention-to-treat analysis," the actuarial 1-year patient survival rate was 85.1% in double-drug therapy and 83.1% in triple-drug therapy (P=0.77). The actuarial 1-year graft survival rate was 80.2% for double-drug therapy and 79.2% for triple-drug therapy (P=0.77). Forty-one patients (41.4%) in double-drug therapy and 32 (31.7%) in triple-drug therapy had at least one episode of rejection, but this was not statistically significant (P=0.15). The mean maintenance dose of corticosteroids was slightly lower in triple-drug compared with double-drug therapy. CONCLUSION: Patient and graft survival rates were similar in both groups. There was a trend to a lower incidence of rejection, reduced nephrotoxicity, and a lesser amount of maintenance corticosteroids in triple-drug therapy compared with double-drug therapy.

Tacrolimus rescue therapy for renal allograft rejection--five-year experience.

Over the 5 year period from 7/14/1989 until 5/24/1994, we have attempted graft salvage with tacrolimus conversion in a total of 169 patients (median age 33 years, range 2-75 years) with ongoing rejection on baseline CsA immunosuppression after failure of high dose corticosteroids and/or antilymphocyte preparations to reverse rejection. The indications for conversion to tacrolimus were ongoing, biopsy confirmed rejection in all patients. The median interval to tacrolimus conversion was 2 months (range 2 days to 55 months; mean 4.3+/-2.6 months) after transplantation. All patients had failed high dose corticosteroid therapy and 144 (85%) of the 169 patients had received at least one course of an antilymphocyte preparation plus high dose corticosteroid therapy prior to conversion. Twenty-eight patients (17%) were dialysis-dependent at the time of conversion owing to the severity of rejection. With a mean follow-up of 30.0+/-2.4 months (median 36.5 months, range 12-62 months), 125 of 169 patients (74%) have been successfully rescued and still have functioning grafts with a mean serum creatinine (SCR) of 2.3+/-1.1 mg/dl. Of the 144 patients previously treated with antilymphocyte preparations, 117 (81%) were salvaged. Of the 28 patients on dialysis at the time of conversion to tacrolimus, 13 (46%) continue to have functioning grafts (mean SCR 2.15+/-0.37 mg/dl) at a mean follow-up of 37.3+/-16.7 months. In the 125 patients salvaged, prednisone doses have been lowered from 28.0+/-9.0 mg/d (median 32, range 4-60 mg/d) preconversion to 8.5+/-4.1 mg/d (median 12 mg/d, range 2.5-20 mg/d) postconversion. Twenty-eight patients (22.4%) are currently receiving no steroids. This 5 year experience demonstrates that tacrolimus has sustained efficacy as a rescue agent for ongoing renal allograft rejection. Based on these data, we recommend that tacrolimus be used as an alternative to the conventional drugs used for antirejection therapy in renal transplantation.

Clinical pharmacokinetics of tacrolimus.

Tacrolimus, a novel macrocyclic lactone with potent immunosuppressive properties, is currently available as an intravenous formulation and as a capsule for oral use, although other formulations are under investigation. Tacrolimus concentrations in biological fluids have been measured using a number of methods, which are reviewed and compared in the present article. The development of a simple, specific and sensitive assay method for measuring concentrations of tacrolimus is limited by the low absorptivity of the drug, low plasma and blood concentrations, and the presence of metabolites and other drugs which may interfere with the determination of tacrolimus concentrations. Currently, most of the pharmacokinetic data available for tacrolimus are based on an enzyme-linked immunosorbent assay method, which does not distinguish tacrolimus from its metabolites. The rate of absorption of tacrolimus is variable with peak blood or plasma concentrations being reached in 0.5 to 6 hours; approximately 25% of the oral dose is bioavailable. Tacrolimus is extensively bound to red blood cells, with a mean blood to plasma ratio of about 15; albumin and alpha 1-acid glycoprotein appear to primarily bind tacrolimus in plasma. Tacrolimus is completely metabolised prior to elimination. The mean disposition half-life is 12 hours and the total body clearance based on blood concentration is approximately 0.06 L/h/kg. The elimination of tacrolimus is decreased in the presence of liver impairment and in the presence of several drugs. Various factors that contribute to the large inter- and interindividual variability in the pharmacokinetics of tacrolimus are reviewed here. Because of this variability, the narrow therapeutic index of tacrolimus, and the potential for several drug interactions, monitoring of tacrolimus blood concentrations is useful for optimisation of therapy and dosage regimen design.

A randomised prospective comparison of cefotaxime versus netilmicin/penicillin for treatment of suspected neonatal sepsis.

In an open prospective study performed in 2 neonatal units, infants with suspected neonatal sepsis (SNS) of unknown microbial cause were randomly allocated to receive treatment with either cefotaxime (CTX) or netilmicin plus penicillin (N + P). 236 patients were entered into the trial, of whom 222 were evaluable. The number of 'definitely' and 'probably' infected babies was similar in both groups. There was no difference in clinical outcome between patients in the 2 treatment groups and no side effects were recorded for either of the antibiotic regimens. Antibiotic sensitivity testing of bacterial isolates from peripheral sites showed almost universal sensitivity of potential pathogens to both antibiotic regimens at the start of treatment in all infants. Thereafter, organisms resistant to CTX were isolated from patients in both treatment groups, possibly reflecting the antibiotic sensitivity profile of the colonising bacteria in both neonatal units. The results of this study indicate that either CTX or N + P are suitable, in our units, for the 'blind' treatment of early SNS. In units where listerial infections are prevalent, specific cover should be added to CTX. For SNS developing after admission, the choice of antibiotics will depend upon the background antibiotic sensitivity profile of the colonising bacteria.

An intelligent and cost-effective computer dosing system for individualizing FK506 therapy in transplantation and autoimmune disorders.

The accuracy and precision of an intelligent dosing system (IDS) for FK506 in predicting doses to achieve target drug levels has been prospectively evaluated in transplant and autoimmune patients. For dose individualization, the knowledge base is updated with patient-specific feedback including the current dose, drug level, and the new target level. The study population of 147 patients consisted of 97 transplant patients (liver and kidney) and 50 patients with autoimmune disorders. Patients in the transplant study group were entered sequentially and followed as a cohort. Patients in the autoimmune study group were randomly assigned to one of three predefined FK506 concentration windows (low, 0.1-.3; medium, 0.4-.7; and high, 0.8-1.3 ng/mL) as part of a concentration controlled clinical trial. Predictions of steady-state plasma drug levels were made throughout the clinical course of autoimmune patients and during the first 6 weeks post-transplant in liver and kidney recipients. FK506 concentration in plasma was measured by a monoclonal antibody based ELISA assay. Accuracy was computed as the mean prediction error (mpe). Precision was computed as the root mean squared prediction error (rmspe). The accuracy of the IDS in each study group was as follows: 0.016 ng/mL (liver), -0.034 ng/mL (kidney), and -0.022 ng/mL (autoimmune). Because the 95% confidence interval included zero in each case, the IDS showed no bias. The precision of the IDS in each study group was as follows: 0.133 ng mL (liver), 0.1903 ng/mL (kidney), and 0.1188 ng/mL (autoimmune). These results indicate that the FK506 IDS is both accurate and very precise (reproducible) in transplant and autoimmune patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The Pittsburgh randomized trial of tacrolimus compared to cyclosporine for hepatic transplantation.

BACKGROUND: Tacrolimus (formerly FK506) was first used clinically in 1989 to successfully replace cyclosporine in hepatic transplant recipients who were experiencing intractable rejection or as the baseline drug from the time of operation. After extensive pilot experience, an institutional review board-mandated clinical trial comparing cyclosporine with tacrolimus was performed. STUDY DESIGN: From February 16, 1990 to December 26, 1991, 154 patients were recruited. The competing drugs were combined with equal induction doses of prednisone in both arms of the study for the first 81 patients and with subsequently higher doses of prednisone in the remaining 35 patients who received cyclosporine and were entered into the trial. Drug crossover was permitted for lack of efficacy or adverse events. End points were rejection confirmed by biopsy and treatment failure leading to retransplantation or death. RESULTS: Seventy-nine patients were randomized to the tacrolimus arm and 75 to the cyclosporine arm during 1990 and 1991. All patients were available for follow-up throughout the trial, which terminated on May 30, 1995. The mean duration of follow-up was four years. Patients randomized to the tacrolimus arm were less likely to experience acute rejection than were those receiving cyclosporine, with 36.2 percent of the patients receiving tacrolimus and 16.8 percent of the patients receiving cyclosporine showing freedom from rejection at one year (p = 0.003, likelihood ratio test). Survival of patients over the course of the study was virtually the same in the two groups.