The effects of compound stimulus extinction and inhibition of noradrenaline reuptake on the renewal of alcohol seeking.

Alcohol-related stimuli can trigger relapse of alcohol-seeking behaviors even after extended periods of abstinence. Extinction of such stimuli can reduce their impact on relapse; however, the expression of extinction can be disrupted when testing occurs outside the context where extinction learning took place, an effect termed renewal. Behavioral and pharmacological methods have recently been shown to augment extinction learning; yet, it is not known whether the improved expression of extinction following these treatments remains context-dependent. Here we examined whether two methods, compound-stimulus extinction and treatment with the noradrenaline reuptake inhibitor atomoxetine, would reduce the vulnerability of extinction to a change in context. Following alcohol self-administration, responding was extinguished in a distinct context. After initial extinction, further extinction was given to a target stimulus presented in compound with another alcohol-predictive stimulus intended to augment prediction error (Experiment 1) or after a systemic injection of atomoxetine (1.0 mg kg(-1); Experiment 2). A stimulus extinguished as part of a compound elicited less responding than a stimulus receiving equal extinction alone regardless of whether animals were tested in the training or extinction context; however, reliable renewal was not observed in this paradigm. Importantly, atomoxetine enhanced extinction relative to controls even in the presence of a reliable renewal effect. Thus, extinction of alcohol-seeking behavior can be improved by extinguishing multiple alcohol-predictive stimuli or enhancing noradrenaline neurotransmission during extinction training. Importantly, both methods improve extinction even when the context is changed between extinction training and test, and thus could be utilized to enhance the outcome of extinction-based treatments for alcohol-use disorders.

Potential role of coenzyme Q10 in facilitating recovery from statin-induced rhabdomyolysis.

Rhabdomyolysis is a rare, but serious complication of statin therapy, and represents the most severe end of the spectrum of statin-induced myotoxicity. We report a case where coenzyme Q10 facilitated recovery from statin-induced rhabdomyolysis and acute renal failure, which had initially persisted despite statin cessation and haemodialysis. This observation is biologically plausible due to the recognised importance of coenzyme Q10 in mitochondrial bioenergetics within myocytes, and the fact that statins inhibit farnesyl pyrophosphate production, a biochemical step crucial for coenzyme Q10 synthesis. Coenzyme Q10 is generally well tolerated, and may potentially benefit patients with statin-induced rhabdomyolysis.

Acute tubulointerstitial nephritis following treatment with exenatide.

BACKGROUND: Acute tubulointerstitial nephritis, a cause of acute kidney injury, is seen occasionally following treatment with medications such as antibiotics and non-steroidal anti-inflammatory drugs. To date, the development of biopsy-proven acute tubulointerstitial nephritis after treatment with exenatide has not been reported. CASE REPORT: A 58-year-old man was prescribed exenatide for poorly controlled Type 2 diabetes mellitus. He subsequently developed deterioration in kidney function, with the estimated glomerular filtration rate declining from 59 to 39 ml min(-1) 1.73 m(-2) over 2 months. Despite cessation of exenatide, there was continued deterioration in estimated glomerular filtration rate to 16 ml min(-1) 1.73 m(-2). He underwent renal biopsy and the sections showed active diffuse tubulointerstitial nephritis with infiltration of eosinophils. He was treated with prednisolone over several months with incomplete recovery in kidney function. CONCLUSION: Acute tubulointerstitial nephritis should be suspected if there is deterioration in kidney function in a patient treated with exenatide in the absence of other causes of acute kidney injury such as dehydration or hypotension.

Metformin therapy in patients with chronic kidney disease.

Metformin therapy is limited in patients with chronic kidney disease (CKD) due to the potential risk of lactic acidosis. This open-label observational study investigated metformin and lactate concentrations in patients with CKD (n = 22; creatinine clearances 15-40 ml/min) and in two dialysed patients. Patients were prescribed a range of metformin doses (250-2000 mg daily) and metformin concentrations were compared with data from healthy subjects (scaled to 1500 mg twice daily). A subset of patients (n = 7) was controlled on low doses of metformin (250 or 500 mg daily). No correlation between metformin and lactate concentrations was observed. Three patients had high lactate concentrations (>2.7 mmol/l) and two had high metformin concentrations (3-5 mg/l), but none had any symptoms of lactic acidosis. Reducing metformin dosage and monitoring metformin concentrations will allow the safe use of metformin in CKD, provided that renal function is stable.

Online version of the food allergy quality of life questionnaire-adult form: validity, feasibility and cross-cultural comparison.

BACKGROUND: Food-allergic reactions occur in 3-4% of the adult population in Western countries. It has been shown that food allergy may impair health-related quality of life (HRQL). Food allergy quality of life questionnaires (FAQLQs) have been developed and validated, including an adult form (FAQLQ-AF). These questionnaires may be particularly useful for cross-cultural comparisons. OBJECTIVES: The aims of this study were to translate the FAQLQ-AF from Dutch into English and validate an online version in the United States. Additionally, HRQL of American and Dutch food-allergic adults was compared. METHODS: The Dutch FAQLQ-AF was translated into English as set out by the World Health Organization and converted to an electronic online format. Participants (food allergic American adults) were recruited through the 'Food Allergy and Anaphylaxis Network' website and completed the questionnaire online. Construct validity, internal consistency, discriminative ability and feasibility were analysed. A cross-cultural comparison was made using the Dutch FAQLQ-AF scores. RESULTS: Data from 180 American participants were analysed. The online FAQLQ-AF had a good construct validity (correlation with FAIM: ρ=0.72; P<0.001), internal consistency (Cronbach's α=0.95) and was discriminative for 'anaphylaxis' vs. 'no anaphylaxis' and 'number of food allergies'. The most striking finding was a significantly greater impairment in HRQL in the American participants, as compared with their Dutch counterparts (the total FAQLQ-AF scores were 4.3 vs. 3.5, respectively; P<0.001, where 1 signifies no impairment and 7 signifies extreme impairment in HRQL). CONCLUSIONS AND CLINICAL RELEVANCE: The online American FAQLQ-AF is a valid instrument to measure HRQL in food-allergic patients in the United States. Additionally, HRQL of American food-allergic adults may be more impaired than Dutch food-allergic adults. The FAQLQ-AF can now be used to determine the HRQL in American food-allergic adults and can assist clinicians in optimizing management strategies for food-allergic patients.

Therapy with mycophenolate mofetil for refractory acute and chronic GVHD.

We evaluated the pharmacokinetics and efficacy of oral mycophenolate mofetil (MMF) for treatment of refractory GVHD. In a prospective study of acute GVHD, 9 of 19 patients (47%) had a response and 10 (53%) had no improvement. Survival at 6 and 12 months after the start of MMF was 37 and 16%, respectively. In a retrospective study of acute GVHD, 14 of 29 patients (48%) had a response and 15 (52%) had no improvement. Survival at 6 and 12 months was 55 and 52%, respectively. In a prospective study of chronic GVHD, the cumulative incidence of disease resolution and withdrawal of all systemic immunosuppressive treatment was 9, 17 and 26% at 12, 24 and 36 months, respectively, after starting MMF. Thirteen patients (59%) required additional systemic immunosuppressive treatment for chronic GVHD. Nine of the 42 patients (21%) in the prospective studies discontinued MMF treatment because of toxicity. The area under the curve plasma concentrations of mycophenolic acid seemed to be suboptimal among patients with acute GVHD but not among those with chronic GVHD. MMF can be used effectively for treatment of GVHD.

Peanut and tree nut allergic reactions in restaurants and other food establishments.

BACKGROUND: The clinical features of food-allergic reactions in restaurants and other food establishments have not been studied. Of the registrants in the United States Peanut and Tree Nut Allergy Registry (PAR), 13.7% have reported reactions associated with such establishments. OBJECTIVE: The purpose of this study was to determine the features of allergic reactions to peanut and tree nut in restaurant foods and foods purchased at other private establishments (eg, ice cream shops and bakeries). METHODS: Telephone interviews were conducted through use of a structured questionnaire. Subjects/parental surrogates were randomly selected from among the 706 PAR registrants who reported a reaction in a restaurant or other food establishment. RESULTS: Details were obtained for 156 episodes (29 first-time reactions) from 129 subjects/parental surrogates. Most reactions were caused by peanut (67%) or tree nut (24%); for some reactions (9%), the cause was a combination of peanut and another nut or was unknown. Symptoms began at a median of 5 minutes after exposure and were severe in 27% of reactions. Overall, 86% of reactions were treated (antihistamines, 86%; epinephrine, 40%). Establishments commonly cited were Asian food restaurants (19%), ice cream shops (14%), and bakeries/doughnut shops (13%). Among meal courses, desserts were a common cause (43%). Of 106 registrants with previously diagnosed allergy who ordered food specifically for ingestion by the allergic individual, only 45% gave prior notification about the allergy to the establishment. For 83 (78%) of these 106 reactions, someone in the establishment knew that the food contained peanut or tree nut as an ingredient; in 50% of these incidents, the food item was "hidden" (in sauces, dressings, egg rolls, etc), visual identification being prevented. In 23 (22%) of the 106 cases, exposures were reported from contamination caused primarily by shared cooking/serving supplies. In the remaining 21 subjects with previously diagnosed allergy, reactions resulted from ingestion of food not intended for them, ingestion of food selected from buffet/food bars, or skin contact/inhalation (residual food on tables, 2; peanut shells covering floors, 2; being within 2 feet of the cooking of the food, 1). CONCLUSIONS: Restaurants and other food establishments pose a number of dangers for peanut- and tree nut-allergic individuals, particularly with respect to cross-contamination and unexpected ingredients in desserts and Asian food. Failure to establish a clear line of communication between patron and establishment is a frequent cause of errors.

A voluntary registry for peanut and tree nut allergy: characteristics of the first 5149 registrants.

BACKGROUND: A voluntary registry of individuals with peanut and/or tree nut allergy was established in 1997 to learn more about these food allergies. OBJECTIVE: The purpose of this study was to elucidate a variety of features of peanut and tree nut allergy among the first 5149 registry participants. METHODS: The registry was established through use of a structured questionnaire distributed to all members of the Food Allergy and Anaphylaxis Network and to patients by allergists. Parental surrogates completed the forms for children under the age of 18 years. RESULTS: Registrants were primarily children (89% of registrants were younger than 18 years of age; the median age was 5 years), reflecting the membership of the Network. Isolated peanut allergy was reported by 3482 registrants (68%), isolated tree nut allergy by 464 (9%), and allergy to both foods by 1203 (23%). Registrants were more likely to have been born in October, November, or December (odds ratio, 1.2; 95% CI, 1.18-1.23; P <.0001). The median age of reaction to peanut was 14 months, and the median age of reaction to tree nuts was 36 months; these represented the first known exposure for 74% and 68% of registrants, respectively. One half of the reactions involved more than 1 organ system, and more than 75% required treatment, frequently from medical personnel. Registrants with asthma were more likely than those without asthma to have severe reactions (33% vs 21%; P <.0001). In comparison with initial reactions, subsequent reactions due to accidental ingestion were more severe, more common outside the home, and more likely to be treated with epinephrine. CONCLUSIONS: Allergic reactions to peanut and tree nut are frequently severe, often occur on the first known exposure, and can become more severe over time.

The US Peanut and Tree Nut Allergy Registry: characteristics of reactions in schools and day care.

OBJECTIVE: Severe food-allergic reactions occur in schools, but the features have not been described. STUDY DESIGN: Participants in the US Peanut and Tree Nut Allergy Registry (PAR) who indicated that their child experienced an allergic reaction in school or day care were randomly selected for a telephone interview conducted with a structured questionnaire. RESULTS: Of 4586 participants in the PAR, 750 (16%) indicated a reaction in school or day care, and 100 subjects or parental surrogates described 124 reactions to peanut (115) or tree nuts (9); 64% of the reactions occurred in day care or preschool, and the remainder in elementary school or higher grades. Reactions were reported from ingestion (60%), skin contact/possible ingestion (24%), and inhalation/possible skin contact or ingestion (16%). In the majority of reactions caused by inhalation, concomitant ingestion/skin contact could not be ruled out. Various foods caused reactions by ingestion, but peanut butter craft projects were commonly responsible for the skin contact (44%) or inhalation (41%) reactions. For 90% of reactions, medications were given (86% antihistamines, 28% epinephrine). Epinephrine was given in school by teachers in 4 cases, nurses in 7, and parents or others in the remainder. Treatment delays were attributed to delayed recognition of reactions, calling parents, not following emergency plans, and an unsuccessful attempt to administer epinephrine. CONCLUSIONS: School personnel must be educated to recognize and treat food-allergic reactions. Awareness must be increased to avoid accidental exposures, including exposure from peanut butter craft projects.

Assessment of myocardial hypertrophy by echocardiography in adult patients receiving tacrolimus or cyclosporine therapy for prevention of acute GVHD.

The incidence of myocardial hypertrophy was determined in a comparative study of tacrolimus-based immunosuppression with cyclosporine-based immunosuppression for prevention of acute graft-versus-host disease (GVHD) after unrelated donor bone marrow transplantation. Patients were evaluated for clinical and echocardiographic abnormalities at baseline (prior to pretreatment conditioning and the first dose of study drug) and at 5-8 weeks after transplant when stable levels of oral tacrolimus or cyclosporine had been achieved. Left ventricular geometry and performance were assessed by echocardiography which included 2-D measurements and one Doppler measurement. Derived echocardiographic measurements and left ventricular mass index (LVMI) were also determined. A cut-off of <111 g/m(2) was used for the upper limit of normal for LVMI. Forty-four patients were included in this study (21 tacrolimus and 23 cyclosporine), of which 31 were evaluable for a comparison with both baseline and post-transplant values. There was no significant difference in the changes from baseline for mean left ventricular mass (LVM) or LVM index (LVMI) between treatment groups. Also, within the tacrolimus group there were no significant changes for these variables from baseline to post-transplant evaluations. Within the cyclosporine group there were significant increases from baseline for mean LVM (P = 0.011) and LVMI (P = 0.007). The incidence of myocardial hypertrophy (change of LVMI from <111 g/m(2) baseline to >111 g/m(2) post transplant) was 20% in the tacrolimus group and 56% in the cyclosporine group (P = 0.109). Changes in the LVMI from baseline to post baseline were greater with cyclosporine than with tacrolimus therapy, and there was no evidence that tacrolimus causes myocardial hypertrophy or significant clinical changes in adult bone marrow transplant patients. The increase in LVMI after transplant in the cyclosporine group was greater than in the tacrolimus group but was not associated with any significant clinical events.

Sirolimus (rapamycin) for the treatment of steroid-refractory acute graft-versus-host disease.

BACKGROUND: In a pilot trial we evaluated the toxicity and efficacy of sirolimus (rapamycin) as second-line therapy for the treatment of acute graft-versus-host disease (GVHD) in 21 patients (1-46 years of age) after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: All patients were treated with methylprednisolone at 2 mg/kg/day, but failed to respond satisfactorily. Sirolimus was started 19-78 (median 37) days after HSCT when 10 patients had grade III and 11 had grade IV GVHD. The first four patients received a loading dose (15 mg/m2) of oral sirolimus on day 1 followed by 5 mg/m2/day for 13 days. The next 17 patients received either 5 (n=7) or 4 (n=10) mg/m2/day for 14 days without a loading dose. Eleven patients completed the 14-day sirolimus course. Five patients were treated for 9-13 days, two for 6 days, and three for 1-3 days. RESULTS: Sirolimus was discontinued early in 10 patients because of lack of improvement in GVHD (n=5), myelosuppression (n=2), seizure (n=2), and attending physician preference (n=1). The most common and significant adverse events were thrombocytopenia (n=7) and neutropenia (n=4). Other side effects included increased blood triglycerides (n=8) and cholesterol (n=3). Five patients had evidence of a hemolytic uremic syndrome concurrently with or after sirolimus treatment. Eighteen of the 21 patients received 6 or more doses of sirolimus and 12 responded, 5 with complete and 7 with partial responses. Six of the 12 responders (28% of all patients enrolled) and 1 nonresponder are currently alive at 400-907 days after HSCT, 3 with chronic GVHD. Fourteen of the 21 patients (66%) died 40-263 days after transplant. CONCLUSION: These data suggest that sirolimus has activity in the treatment of steroid-refractory acute GVHD. However, there was considerable toxicity and further dose optimization studies seem warranted.

Clinical outcome after conversion to FK 506 (tacrolimus) therapy for acute graft-versus-host disease resistant to cyclosporine or for cyclosporine-associated toxicities.

This retrospective study describes the outcome in 53 patients who had immunosuppressive treatment changed from cyclosporine (CSP) to tacrolimus for resistant acute GVHD (n = 23), hemolytic uremic syndrome (HUS) (n = 13) or CSP-associated neurotoxicity (n = 17). Tacrolimus was administered at doses of 0.03 mg/kg/day intravenously or 0.12 mg/kg/day orally in divided doses, as tolerated. Median time of conversion to tacrolimus after transplant was day 47. Nineteen patients had treatment changed to tacrolimus for resistant acute GVHD grades III or IV, with the median day of conversion being day 49 after transplant. Two of 20 evaluable patients had a complete resolution of GVHD after changing treatment to tacrolimus, with 18 showing no improvement. Eleven evaluable patients had therapy changed to tacrolimus for CSP-associated neurotoxicity at a median of 36 days after transplant. Eight patients had resolution of neurotoxicity and three had partial improvement. Eleven evaluable patients had therapy changed to tacrolimus for HUS at a median of 46 days after transplant. One patient had complete resolution of HUS and 10 showed no response. Side-effects related to tacrolimus included renal toxicity (34%), neurotoxicity (15%) and HUS (9%). Nine (17%) patients remain alive, including six patients who had therapy changed to tacrolimus for CSP-associated neurotoxicity. While often successful for dealing with neurotoxicity, only a rare patient improved after therapy was changed from CSP to tacrolimus for HUS or resistant acute GVHD.

Changing from cyclosporine to tacrolimus as salvage therapy for chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) is the principal cause of transplantation-related morbidity and nonrelapse mortality late after allogeneic hematopoietic stem cell transplantation. The safety and potential efficacy of tacrolimus for the salvage treatment of chronic GVHD was evaluated in a single-arm, open-label phase 2 study. A total of 39 evaluable patients with chronic GVHD who failed previous immunosuppressive therapy with cyclosporine and prednisone were treated with tacrolimus starting at a median of 20 months (range, 3-68 months) after transplantation. At 3 years after the start of treatment, 5 patients (13%) had discontinued tacrolimus and were in complete remission, and 3 were considered clinically stable but not able to discontinue tacrolimus. A total of 31 patients (79%) experienced treatment failure; 22 (56%) who failed therapy had a change in immunosuppressive regimen because of progression (n = 18) or toxicity (n = 4). Nine patients (23%) died during continued treatment with tacrolimus. Two patients were lost to follow-up, at 11 and 19 months. The median duration of treatment with tacrolimus was 9 months (range, 1-29 months). Infections (144 episodes) were the most frequent adverse event. Nephrotoxicity occurred in 16 patients (41%); tacrolimus was discontinued in only 2 patients because of progressive deterioration in renal function. The Kaplan-Meier estimate of survival was 64% (95% confidence interval, 49%-79%) at 3 years posttransplantation. Seven patients had discontinued all immunosuppression at last contact, leading to an estimated 29% probability of stopping all immunosuppression by 3 years posttransplantation. Four patients died after relapse of malignancy. The response rate is consistent with previous reports of salvage treatment for chronic GVHD, indicating that a small group of patients failing cyclosporine may respond or stabilize with tacrolimus.

Genetics of peanut allergy: a twin study.

BACKGROUND: The role of genetics in the etiology of peanut allergy is unknown. For complex genetic traits, twin studies can provide information on the relative contribution of genetic factors to a disease, as the relative confounding effects of environmental factors are markedly decreased. OBJECTIVE: This study was performed to search for evidence that genetic factors influence peanut allergy by comparing the concordance rate for this allergy among monozygotic and dizygotic twins. METHODS: Twin pairs with at least one member with peanut allergy were ascertained through the Food Allergy Network by advertisements in the organization's newsletters and Web site. Individuals with peanut allergy or parental surrogates were interviewed by telephone. A full atopic history was obtained, and peanut allergy and zygosity were determined using previously validated questionnaires. Heritability of peanut allergy was determined using univariate genetic model fitting by maximum likelihood with the Mx statistical modeling software package. RESULTS: Seventy-five twin pairs were recruited. Seventeen pairs were excluded because of unconvincing peanut allergy histories (9 pairs, including 4 of uncertain zygosity) or because one twin had reportedly never ingested peanut (8 pairs). The median age of the 58 remaining twin pairs was 5 years (range 1 to 58 years). Seventy individuals had peanut allergy. In addition to convincing histories of peanut allergy, 52 (74%) had been tested (skin prick testing with or without radioallergosorbent assay) and all had positive reactions to peanut. Twenty-nine of the 70 had experienced >1 reaction to peanut; 29 of 70 had multisystem reactions. Among the monozygotic pairs (n = 14), 9 were concordant for peanut allergy (pairwise concordance, 64.3%) and among dizygotic pairs (n = 44), 3 were concordant for peanut allergy (pairwise concordance, 6.8%; chi(2) = 21.38, P <.0001). Heritability of peanut allergy was estimated at 81. 6% (95% confidence interval 41.6% to 99.7%) with model fitting using a population prevalence of peanut allergy of 0.4%. CONCLUSIONS: The significantly higher concordance rate of peanut allergy among monozygotic twins suggests strongly that there is a significant genetic influence on peanut allergy.

Self-reported allergic reactions to peanut on commercial airliners.

BACKGROUND: Allergic reactions to food occurring on commercial airlines have not been systematically characterized. OBJECTIVE: We sought to describe the clinical characteristics of allergic reactions to peanuts on airplanes. METHODS: Participants in the National Registry of Peanut and Tree Nut Allergy who indicated an allergic reaction while on a commercial airliner were interviewed by telephone. RESULTS: Sixty-two of 3704 National Registry of Peanut and Tree Nut Allergy participants indicated a reaction on an airplane; 42 of 48 patients or parental surrogates contacted confirmed the reaction began on the airplane (median age of affected subject, 2 years; range, 6 months to 50 years). Of these, 35 reacted to peanuts (4 were uncertain of exposure) and 7 to tree nuts, although 3 of these 7 reacted to substances that may have also contained peanut. Exposures occurred by ingestion (20 subjects), skin contact (8 subjects), and inhalation (14 subjects). Reactions generally occurred within 10 minutes of exposure (32 of 42 subjects), and reaction severity correlated with exposure route (ingestion > inhalation > skin). The causal food was generally served by the airline (37 of 42 subjects). Medications were given in flight to 19 patients (epinephrine to 5) and to an additional 14 at landing/gate return (including epinephrine to 1 and intravenous medication to 2), totaling 79% treated. Flight crews were notified in 33% of reactions. During inhalation reactions as a result of peanut allergy, greater than 25 passengers were estimated to be eating peanuts at the time of the reaction. Initial symptoms generally involved the upper airway, with progression to the skin or further lower respiratory reactions (no gastrointestinal symptoms). CONCLUSIONS: Allergic reactions to peanuts and tree nuts caused by accidental ingestion, skin contact, or inhalation occur during commercial flights, but airline personnel are usually not notified. Reactions can be severe, requiring medications, including epinephrine.

FK506 in combination with methotrexate for the prevention of graft-versus-host disease after marrow transplantation from matched unrelated donors.

The safety and potential efficacy of FK506 in combination with a short course of methotrexate (MTX) for the prevention of acute graft-versus-host disease (GVHD) after marrow transplantation from HLA-matched unrelated donors was evaluated in a single-arm Phase II study conducted at two centers. Forty-three patients, 15 to 54 (median 41) years of age, were transplanted for hematologic malignancies. Thirty-seven of 43 evaluable patients had evidence of sustained marrow engraftment. Five patients died before day 17 after transplantation. The median time to an absolute neutrophil count of > 0.5 x 10(5)/L was 21 (range, 14 to 30) days. Nephrotoxicity (serum creatinine concentration > 2 mg/dL or doubling of baseline) occurred in 32 patients (74% cumulative incidence during the first 100 days after transplant). Other adverse effects included hypertension (n = 27), hyperglycemia (n = 27), neurotoxicity (n = 9) and thrombotic thrombocytopenic purpura (n = 2). Severe veno-occlusive disease of the liver occurred in 9 (21%) of the 43 patients. Eighteen patients (42%) developed grades II to IV acute GVHD and five (12%) developed grades III to IV acute GVHD. Twelve of 25 evaluable patients developed extensive chronic GVHD within 1 year of marrow transplantation resulting in an estimate of the probability of developing this complication of 48%. The cumulative incidence of transplant-related mortality during the first 100 days was 37%. Kaplan-Meier estimates of disease-free survival at 2 years for good-risk, poor-risk, and all patients were 65%, 4%, and 32%, respectively. FK506 in combination with a short course of MTX appears active in preventing acute GVHD after marrow transplantation from unrelated donors. Further studies comparing the combination of FK506 and MTX with cyclosporine and MTX for the prevention of acute GVHD are warranted.

Tacrolimus (FK506) alone or in combination with methotrexate or methylprednisolone for the prevention of acute graft-versus-host disease after marrow transplantation from HLA-matched siblings: a single-center study.

The pharmacokinetics, safety, and efficacy in marrow transplantation of FK506-based immunosuppression for graft-versus-host disease (GVHD) prophylaxis was evaluated in an open label pilot study of 18 patients. Patients more than 12 years of age (median, 35 years; range, 15 to 50 years) with advanced hematologic malignancies receiving HLA-matched sibling marrow grafts were randomized to receive FK506 alone, FK506 and methotrexate (MTX), or FK506 and methyl-prednisolone. Of 17 evaluable patients, all had evidence of sustained marrow engraftment. The median time to an absolute neutrophil count of greater than 500/microL was 15 days for patients receiving FK506 alone or FK506 plus methylprednisolone and 23 days for FK506 plus short MTX. Pharmacokinetic studies did not show any significant difference in clearance of FK506 when administered alone or in combination with methylprednisolone or MTX. The mean bioavailability after oral administration in these same three groups was 0.49 +/- 0.1, 0.27 +/- 0.12, and 0.16 +/- 0.08, respectively (P = .003). The decrease in bioavailability may have resulted from an exacerbation of radiation-induced gastroenteritis by MTX. The most significant adverse effect associated with the administration of FK506 was nephrotoxicity, which occurred in 14 of 18 patients (78%). The mean glomerular filtration rate, determined by clearance of (99MTc)DTPA, decreased to 56% (+/- 18%) of the pretransplant baseline level by week 8 (P = .002). Eight of 18 patients (44%) developed grades II-IV acute GVHD, predominantly of the skin and gastrointestinal tract. The actuarial probability of transplant-related mortality during the first 100 days was 24%. The actuarial probability of 1-year disease-free survival was 39%. In conclusion, although bioavailability of FK506 may be affected in patients receiving MTX, this study suggests that FK506 may have a role in the management of patients after allogeneic marrow transplantation.