Repifermin (keratinocyte growth factor-2) for the treatment of active ulcerative colitis: a randomized, double-blind, placebo-controlled, dose-escalation trial.

BACKGROUND: Repifermin (keratinocyte growth factor-2) has been shown to reduce inflammation in animal models of colitis. AIM: To evaluate repifermin for the treatment of active ulcerative colitis. METHODS: Eighty-eight patients with active ulcerative colitis were enrolled in a 6-week, double-blind trial. Patients were randomized to receive treatment for five consecutive days with intravenous repifermin at a dose of 1, 5, 10, 25 or 50 microg/kg, or placebo. The primary objective of the study was to evaluate the safety of repifermin. The primary efficacy outcome was clinical remission at week 4, defined as a score of zero on the endoscopic appearance and stool blood components of the Mayo score and a score of zero or unity on the stool frequency and physician's global assessment components. RESULTS: At week 4, the rates of clinical remission in the 1, 5, 10, 25 and 50 microg/kg repifermin groups were 19%, 9%, 0%, 0% and 0%, respectively, and 11% for the placebo group (P = 0.32 for repifermin vs. placebo). The frequencies of commonly occurring adverse events and severe adverse events were similar in both groups. CONCLUSIONS: Intravenous repifermin at a dose of 1-50 microg/kg was very well tolerated, but there was no evidence that repifermin was effective for the treatment of active ulcerative colitis at these doses. An additional study to determine the efficacy of repifermin at doses of > 50 microg/kg or for a longer treatment duration may be warranted, as the maximally tolerated dose was not reached in the present study.

Randomized trial of topically applied repifermin (recombinant human keratinocyte growth factor-2) to accelerate wound healing in venous ulcers.

About 600,000 people in the United States are estimated to be affected by venous ulcers. The cornerstone of care of chronic venous ulcers involves the application of compression bandages. Other therapies include treatment of associated infection, treatment for edema and inflammation, and debridement when necessary. Repifermin, a recombinant human KGF-2 (fibroblast growth factor-10), exerts a proliferative effect on epithelial cells, in vitro and in vivo, and has been shown to accelerate wound healing in several experimental animal models. A randomized, double-blind, parallel-group, placebo-controlled, multicenter study was conducted to evaluate the safety and efficacy of topical repifermin treatment, for 12 weeks, in the healing of chronic venous ulcers in 94 patients. Repifermin was shown to accelerate wound healing, with significantly more patients achieving 75% wound closure with repifermin than with placebo. The treatment effect appeared more marked for a subgroup of patients with initial wound areas < or = 15 cm2 and wound ages of < or = 18 months. A longer duration of treatment (e.g., 26 weeks) may allow better differentiation of the benefit of repifermin compared with placebo, particularly with respect to complete wound closure. The safety assessment showed that repifermin was well tolerated.

The relationship between fetal hemoglobin and disease severity in children with sickle cell anemia.

A study was conducted in a sample of 140 children with sickle cell anemia to evaluate the relationship between hematological variables (%HbF, %HbA2, %Hb, and mean cell volume) and disease severity. A patient's severity status was determined by whether he/she was hospitalized, had a transfusion, and/or had a pain crisis at 2 evaluation periods; the first was based on a patient's history taken at the initial assessment visit to the Wayne State Comprehensive Sickle Cell Center, and the second was based on a 1-3 year follow-up at the center. Fetal hemoglobin was a strong predictor of a patient's hospitalization and transfusion status. A decrease in %HbF of 4.76% (one SD of %HbF) was associated with a 3.58 fold (95% confidence interval, 1.18-7.28) greater odds of being hospitalized both prior to initial assessment and on follow-up, compared to not being hospitalized at either evaluation. Similarly, a decrease in %HbF of 4.76% was associated with a 5.56 fold (95% confidence interval, 1.67-18.96) greater odds of having a transfusion both prior to initial assessment and on follow-up compared to not having a transfusion at either evaluation. Patients who were both hospitalized and transfused at initial assessment and on follow-up (n = 12) had a mean %HbF of 7.59%, while patients who were not hospitalized or transfused at either evaluation (n = 19) had a mean %HbF of 13.61%. Fetal hemoglobin was not a significant predictor of pain crises in this sample of patients. None of the other hematological variables were significant predictors of disease severity in this study. The strong relationship between %HbF and disease severity identified in this study suggests that a single %HbF measurement may be useful in predicting important aspects of the clinical course of children with sickle cell anemia.

HLA antigens, phytohemagglutinin stimulation, and corticosteroid response.

Although it is clear that the major histocompatibility complex is associated with lymphocyte glucocorticoid sensitivity in mice, there has been less evidence for a similar relationship in man. We have typed 158 individuals for: (1) 13 A locus and 16 B locus antigens, (2) degree of stimulation of their purified lymphocytes by phytohemagglutinin A (PHA), and (3) degree of inhibition of the PHA stimulation by prednisolone and prednisolone-21-hemisuccinate. In contrasts of individuals with a particular antigen (homozygous or heterozygous) with all remaining individuals, HLA-B7 was found to be associated with an enhancing effect on the log stimulation by PHA while other antigens of these series did not have significant associations. In similar contrasts, A10 was associated with a decrease in sensitivity to glucocorticoid inhibition of PHA stimulation as measured by the log I50 of the suppression of PHA stimulation. Other antigens of these series were not found to have significant associations with the glucocorticoid sensitivity of lymphocytes in this assay.

HLA-B18 is associated with decreased levels of isoproterenol-stimulated cAMP in lymphocytes.

One hundred fifty-nine individuals were typed for HLA-A and B antigens and levels of isoproterenol-stimulated, lymphocyte cAMP. No significant age, sex, or caffeine effects on the natural log of the lymphocyte cAMP variable (ln cAMP) were found. A comparison of mean ln cAMP levels between individuals who carried a particular antigen (homozygous or heterozygous) and individuals who did not carry the antigen identified a highly significant decrease in ln cAMP levels associated with the HLA-B18 antigen. We estimated that 18.9% of the variability in ln cAMP was attributable to the HLA-B18 antigen. In addition, 38% of the variability in ln cAMP was attributable to factors that aggregate in families that were independent of the HLA-B18 effect. A weaker association of A10 with lymphocyte cAMP might be due to linkage disequilibrium between A10 and B18.

Risk factors for benign breast disease: a case-control study of discordant twins.

The influences of potential risk factors for benign breast disease were assessed using women twins in a matched pair design. Two groups of cases from the Kaiser-Permanente Twin Registry were considered: 1) 90 pairs of female twins in which one twin reported a history of benign breast disease confirmed by biopsy and her twin reported no history of benign breast disease, and 2) 48 pairs of female twins in which the case had clinically diagnosed fibrocystic benign breast disease and her twin was free of disease at examination and reported no history of the disease. Results were similar in these two samples. A significant positive association was found between benign breast disease and coffee consumption. Oral contraceptive use and greater body mass were inversely associated with benign breast disease after controlling for possible confounding variables by matched-pairs multiple logistic analysis. All associations were stronger for monozygotic than for dizygotic pairs. Twin pairs discordant for disease provide an excellent sample in which to assess the importance of potential risk factors while controlling for early environmental and genetic backgrounds.

PIP: The influences of potential risk factors for benign breast disease (BBD) were assessed using women twins in a matched pair design. 2 groups of cases from the Kaiser Permanente Twin Registry were considered: 90 pairs of female twins in which 1 twin reported a history of BBD confirmed by biopsy and her twin reported no such history, and 48 pairs of female twins in which the case had clinically diagnosed fibrocystic BBD and the twin was free of disease at examination and reported no history of the disease. Results were similar in those 2 samples. A significantly positive association was found between BBD and coffee consumption. Oral contraceptive use and greater body mass were inversely associated with BBD after controlling for possible confounding variables by matched pairs multiple logistic analysis. All associations were stronger for monozygotic than dizygotic pairs. Twin pairs discordant for disease provide an excellent sample in which to assess the importance for potential risk factors while controlling for early environmental and genetic backgrounds.

Stability over time of hematological variables in 197 children with sickle cell anemia.

One hundred ninety-seven children with sickle cell anemia were followed for 4 years at the Wayne State Comprehensive Sickle Cell Center to evaluate the stability of the hematological variables (Hb, Hct, RBC count, MCV, %HbF and %HBA2) over time. The mean values of the hematological measurements taken during three separate 16-month intervals were used to represent an individual's values. The correlations of the hematological variables between intervals ranged from a low of 0.46 for %HBA2 to a high of 0.91 for %HbF. Correlations that spanned two intervals (an average of 32 months) were of the same magnitude as those that spanned only one interval (an average of 16 months), suggesting that there was no decrease in the degree of stability of these variables as the time between measurements increased. The stability of the correlations between variables within intervals, and the stability of the coefficients of the first two principal components of the six hematological variables over time suggested that the relationships among variables were also stable. In a recent report [Odenheimer et al, 1983], we used the values of the six hematological variables collected at an individual's first visit to the sickle cell center to identify four hematologically distinct subgroups of children. In the current report, we found that as many as 83% of the individuals remained in the same subgroup in at least two of the three follow-up intervals, suggesting that the factors that contributed to this classification were the result of stable, rather than transient phenomena.

Cerebral infarction after middle cerebral artery occlusion in progenies of spontaneously stroke-prone and normal rats.

A differential outcome results from rapid middle cerebral artery (MCA) occlusion in young normotensive Wistar (NW) rats as compared to the spontaneously hypertensive stroke-prone (SHRSP) rat. The SHRSP invariably infarcts; the NW usually does not. To determine if segregation at a single autosomal locus explains the difference between strains, a NW male was crossed with several SHRSP females to produce F1 rats. The segregation of the strain difference was studied in the F2 and backcrosses to the NW and SHRSP parental strains. The relative frequency of infarcting and noninfarcting animals in the segregating progenies supported a single locus recessive model of inheritance for susceptibility to infarction after sudden occlusion of the MCA. Mean infarct size was largest for SHRSP and proportional to the SHRSP gene dosage in the segregating progenies. Variation in the size of the infarct within segregating classes may be attributable to the segregation of polygenes and/or environmental influences during the initial formation of the cerebral anastomoses.

Heterogeneity of sickle-cell anemia based on a profile of hematological variables.

Factors that influence the heterogeneity of the disease expression of sickle-cell anemia are not well understood. This study examines the ability of a profile of six hematological variables (HB, HCT, RBC, %Hb F, MCV, and %HBA2) to predict the severity of disease measured on 225 patients ranging from 0.2 to 18 years of age. Four subgroups of patients were identified separately in each sex using cluster analysis techniques. In each sex, mean hemoglobin concentration and percent Hb F increased across the four clusters from 7 to 10 gm/dl and from 7% to 16%, respectively. Mean cell volumes were approximately 90, 80, 90, and 75 in groups 1, 2, 3, and 4, respectively; thus MCV did not increase in an orderly progression along with HB and %Hb F. We studied the distribution of four anthropometric, five physical examination, and seven clinical measures of disease severity among clusters. In each sex, subgroups differed significantly (P less than .05) for percent ever hospitalized for sickle-cell anemia, percent ever transfused, and percent with bone-age delays greater than 1 year. In addition, male clusters differed significantly for percent ever having had pneumonia, priapism, or dactylitis, and females differed significantly for height and weight. %Hb F and its inverse relationship with %HBA2 was more highly associated with the measures of severity than the degree of anemia or MCV. This study establishes the utility of a vector of hematological variables as a predictor of heterogeneity of measures of clinical manifestations among young patients with sickle-cell anemia. The role of alpha-thalassemia and genetic factors that affect Hb F levels were considered as possible explanations for the observed heterogeneity.