Granulation response and partial wound closure predict healing in clinical trials on advanced diabetes foot ulcers treated with recombinant human epidermal growth factor.

OBJECTIVE: To determine if partial wound closure surrogate markers proposed for neuropathic, small diabetic foot ulcers (DFUs) can be extended to advanced lesions and if the development of granulation tissue can be used to predict complete healing. RESEARCH DESIGN AND METHODS: Data from two multicenter, double-blind, randomized clinical trials (one of them placebo controlled) that used intralesional recombinant human epidermal growth factor (rhEGF) to promote granulation and healing were used. For confirmation in a larger sample from common clinical practice, the results of an active postmarketing surveillance of rhEGF treatment of DFUs in 60 healthcare units was included. The surrogates evaluated were percent area change, log healing rate, ratio of log areas, and percent of granulation tissue covering the wound area. The tests used were surrogate final end point correlation, receiver operating characteristic curves to discriminate healers from nonhealers, validation tests using logistic regression models, and the proportion-mediated estimation. RESULTS: Two weeks >50% granulation, end of treatment >75% granulation, and 16.1% area change showed significant predictive value (>70% correct classification) for final wound closure. The granulation-based variables fulfilled the criterion that the effect of rhEGF treatment on wound closure was mediated by the surrogate. CONCLUSIONS: This work provides the first evidence for the use of granulation tissue development as a predictor of wound healing in advanced DFUs. These results can be useful for clinical trial design, particularly during the exploratory phase of new products.

Aplicación Intralesional del Interferón alfa 2bHr cubano (Heberon Alfa R®) en el tratamiento de las verrugas genitales / Intralesion application of the Cuban 2bHr Alfa-Interferon (Heberon Alfa R®) in the treatment of genital warts

Introducción: la condilomatosis genital es la expresión clínica más frecuente de del virus del papiloma humano. De las alternativas de tratamiento existentes, no hay una de elección y absolutamente eficaz. Objetivo: describir la seguridad y el efecto del Interferón alfa recombinante, en el tratamiento de las verrugas genitales. meses mediante la curva de Kaplan-Meier. ..

Introduction: the genital condyloma is the more frequent clinical expression or the human papilloma virus. From the available alternative of treatment there is not one of election and totally effective. Objective: to describe the safety and the effect of recombinant alfa-Interferon in treatment of genital warts. Methods: a quasi-experimental study was conducted in 216 women and in 111 men. The above mentioned Interferon was applied in the basement of warts at a dose of 10 millions of international units weekly during 8-16 weeks...

Aplicación Intralesional del Interferón alfa 2bHr cubano (Heberon Alfa R®) en el tratamiento de las verrugas genitales / Intralesion application of the Cuban 2bHr Alfa-Interferon (Heberon Alfa R®) in the treatment of genital warts

Introducción: la condilomatosis genital es la expresión clínica más frecuente de del virus del papiloma humano. De las alternativas de tratamiento existentes, no hay una de elección y absolutamente eficaz. Objetivo: describir la seguridad y el efecto del Interferón alfa recombinante, en el tratamiento de las verrugas genitales. meses mediante la curva de Kaplan-Meier. ..

Introduction: the genital condyloma is the more frequent clinical expression or the human papilloma virus. From the available alternative of treatment there is not one of election and totally effective. Objective: to describe the safety and the effect of recombinant alfa-Interferon in treatment of genital warts. Methods: a quasi-experimental study was conducted in 216 women and in 111 men. The above mentioned Interferon was applied in the basement of warts at a dose of 10 millions of international units weekly during 8-16 weeks...

Pharmacokinetic and pharmacodynamic characterization of a new formulation containing synergistic proportions of interferons alpha-2b and gamma (HeberPAG) in patients with mycosis fungoides: an open-label trial.

BACKGROUND: The synergistic combination of interferon (IFN) alpha-2b and IFN gamma results in more potent in vitro biological effects mediated by both IFNs. The aim of this investigation was to evaluate by first time the pharmacokinetics and pharmacodynamics of this combination in patients with mycosis fungoides. METHODS: An exploratory, prospective, open-label clinical trial was conducted. Twelve patients, both genders, 18 to 75 years-old, with mycosis fungoides at stages IB to III, were eligible for the study. All of them received intramuscularly a single high dose (23 × 10(6) IU) of a novel synergistic IFN mixture (HeberPAG) for pharmacokinetic and pharmacodynamic studies. Serum IFN alpha-2b and IFN gamma concentrations were measured during 96 hours by commercial enzyme immunoassays (EIA) specific for each IFN. Other blood IFN-inducible markers and laboratory variables were used as pharmacodynamics and safety criteria. RESULTS: The pharmacokinetic evaluation by EIA yielded a similar pattern for both IFNs that are also in agreement with the well-known described profiles for these molecules when these are administered separately. The average values for main parameters were: Cmax: 263 and 9.3 pg/mL; Tmax: 9.5 and 6.9 h; AUC: 4483 and 87.5 pg.h/mL, half-life (t(1/2)): 4.9 and 13.4 h; mean residence time (MRT): 13.9 and 13.5 h, for serum IFN alpha-2b and IFN gamma, respectively. The pharmacodynamic variables were strongly stimulated by simultaneous administration of both IFNs: serum neopterin and beta-2 microglobulin levels (ß2M), and stimulation of 2'-5' oligoadenylate synthetase (OAS1) mRNA expression. The most encouraging data was the high increment of serum neopterin, 8.0 ng/mL at 48 h, not been described before for any unmodified or pegylated IFN. Additionally, ß2M concentration doubled the pre-dose value at 24-48 hours. For both variables the values remained clearly upper baseline levels at 96 hours. CONCLUSIONS: HeberPAG possesses improved pharmacodynamic properties that may be very useful in the oncologic setting. Efficacy trials can be carried out to confirm these findings. TRIAL REGISTRATION: Registro Público Cubano de Ensayos Clínicos RPCEC00000130.

Temporal trends of circulating nitric oxide and pro-inflammatory cytokine responses ex vivo in intra-abdominal sepsis: results from a cohort study.

OBJECTIVE AND DESIGN: To evaluate the association of pro-inflammatory mediators with organ dysfunction and adverse outcome in intra-abdominal sepsis patients. SUBJECTS: Twenty-one patients admitted to the Intensive Care Unit (ICU) were prospectively included in the study. Only patients with surgical diagnosis of intra-abdominal sepsis were enrolled. RESULTS: Tumor necrosis factor-α (TNFα) and interleukin (IL)-6 produced ex vivo were significantly lower in non-survivors on admission (p = 0.021) and day 2 (p = 0.013), respectively. Nitric oxide (NO(x)) levels were significantly higher in non-survivors from the onset of sepsis and until day 4 after diagnosis (p < 0.05). Circulating lymphocyte counts were lower in non-survivors after admission over time, but there was no association with impaired cytokine production in this group of patients during the entire follow-up. All non-survivors developed nosocomial pneumonia concomitantly with multiple organ dysfunction and septic shock. There was a significant correlation between nitric oxide (NO(x)) concentrations and the sequential organ failure assessment (SOFA) score at day 2 (r = 0.598, p = 0.009), and ICU stay (r = 0.605, p = 0.006). Continuously high NO(x) levels correlated with organ failure. The pro-inflammatory mediators TNFα, IL-6 and NO(x), and also the Simplified Acute Physiology Score II (SAPS-II), discriminate survivors from non-survivors. According to logistic regression models, although these parameters are independently associated with the outcome, they do not improve the predictive power of the SAPS-II score for mortality risk. CONCLUSIONS: Disturbances in inflammatory responses and increase in NO(x) generation seem to characterize early intra-abdominal sepsis, in which immune suppression is associated with an increased susceptibility to nosocomial infections. Sequential NO(x) determinations could be a useful approach for improving the management of patients with intra-abdominal sepsis.

Intralesional administration of epidermal growth factor-based formulation (Heberprot-P) in chronic diabetic foot ulcer: treatment up to complete wound closure.

Previous studies have shown that an epidermal growth factor-based formulation (Heberprot-P) can enhance granulation of high-grade diabetic foot ulcers (DFU). The aim of this study was to explore the clinical effects of this administration up to complete wound closure. A pilot study in 20 diabetic patients with full-thickness lower extremity ulcers of more than 4 weeks of evolution was performed. Mean ulcer size was 16.3 +/- 21.3 cm(2). Intralesional injections of 75 microg of Heberprot-P three times per week were given up to complete wound healing. Full granulation response was achieved in all 20 patients in 23.6 +/- 3.8 days. Complete wound closure was obtained in 17 (85%) cases in 44.3 +/- 8.9 days. Amputation was not necessary in any case and only one relapse was notified. The most frequent adverse events were tremors, chills, pain and odour at site of administration and local infection. The therapeutic scheme of intralesional Heberprot-P administration up to complete closure can be safe and suitable to improve the therapeutic goal in terms of healing of chronic DFU.

Intralesional injections of Citoprot-P (recombinant human epidermal growth factor) in advanced diabetic foot ulcers with risk of amputation.

To investigate the efficacy and safety of recombinant human epidermal growth factor (rhEGF) in advanced diabetic foot ulcers (DFU) A double-blind trial was carried out to test two rhEGF dose levels in type 1 or 2 diabetes patients with Wagner's grade 3 or 4 ulcers, with high risk of amputation. Subjects were randomised to receive 75 (group I) or 25 mug (group II) rhEGF through intralesional injections, three times per week for 5-8 weeks together with standardised good wound care. Endpoints were granulation tissue formation, complete healing and need of amputation. Safety was assessed by clinical adverse events (AEs) and laboratory evaluations. Forty-one patients were included. After 5-8 weeks of treatment, 83% patients in the higher dose group and 61% in group II achieved useful granulation tissue covering more than 98% of the wound area. At long-term assessment, 13 (56.5%) patients healed in group I and 9 (50%) in group II. The mean time to complete healing in group I was 20.6 weeks (95% CI: 17.0-24.2) and 19.5 weeks (16.3-22.7) in group II. After 1-year follow-up, only one patient relapsed. Amputation was not necessary in 65% and 66.7% of groups I and II, respectively. The AEs rates were similar. The most frequent were sepsis (33%), burning sensation (29%), tremors, chills and local pain (25% each). rhEGF local injection enhances advanced DFU healing and reduces the risk of major amputation. No dose dependency was observed.

Pharmacovigilance program to monitor adverse reactions of recombinant streptokinase in acute myocardial infarction.

BACKGROUND: Streptokinase (SK) is an effective fibrinolytic agent for the treatment of acute myocardial infarction (AMI). The objective of the present study was to assess the adverse drug reactions (ADRs) associated with intravenous recombinant SK in patients with AMI in routine clinical practice. METHODS: A national, prospective and spontaneous reporting-based pharmacovigilance program was conducted in Cuba. Patient demographics, suspected ADR description, elements to define causality, and outcomes were documented and analyzed. RESULTS: A total of 1496 suspected ADRs identified in 792 patients out of the 1660 (47.7 %) prescriptions reported in the program, were received from July 1995 to July 2002. Most of the patients (71.3%) were male, 67.2% were white and mean age was 61.6 +/- 13.0 years. The mean time interval between the onset of symptoms and the start of the SK infusion was 4.9 +/- 3.7 h. The most frequently reported ADRs were hypotension, arrhythmias, chills, tremors, vomiting, nauseas, allergy, bleeding and fever. ADR severity was 38% mild, 38% moderate, 10% severe, and 4% very severe. Only 3 patients with hemorrhagic stroke were reported. Seventy-two patients died in-hospital mainly because of cardiac causes associated with the patient's underlying clinical condition. Mortality was 3 times more likely in patients suffering arrhythmias than in those without this event (odds ratio 3.1, 95% CI: 1.8 to 5.1). Most of the reported ADRs were classified as possibly or probably associated with the study medication. CONCLUSION: Recombinant SK was associated with a similar post-marketing safety profile to those suggested in previous clinical trials.

Pharmacovigilance program to monitor adverse reactions of recombinant streptokinase in acute myocardial infarction

Background: Streptokinase (SK) is an effective fibrinolytic agent for the treatment of acute myocardial infarction (AMI). The objective of the present study was to assess the adverse drug reactions (ADRs) associated with intravenous recombinant SK in patients with AMI in routine clinical practice. Methods: A national, prospective and spontaneous reporting-based pharmacovigilance program was conducted in Cuba. Patient demographics, suspected ADR description, elements to define causality, and outcomes were documented and analyzed. ResultsA total of 1496 suspected ADRs identified in 792 patients out of the 1660 (47.7 percent) prescriptions reported in the program, were received from July 1995 to July 2002. Most of the patients (71.3percent) were male, 67.2percent were white and mean age was 61.6 ± 13.0 years. The mean time interval between the onset of symptoms and the start of the SK infusion was 4.9 ± 3.7 h. The most frequently reported ADRs were hypotension, arrhythmias, chills, tremors, vomiting, nauseas, allergy, bleeding and fever. ADR severity was 38percent mild, 38percent moderate, 10 percent severe, and 4percent very severe. Only 3 patients with hemorrhagic stroke were reported. Seventy-two patients died in-hospital mainly because of cardiac causes associated with the patient's underlying clinical condition. Mortality was 3 times more likely in patients suffering arrhythmias than in those without this event (odds ratio 3.1, 95percent CI: 1.8 to 5.1). Most of the reported ADRs were classified as possibly or probably associated with the study medication.Conclusion: Recombinant SK was associated with a similar post-marketing safety profile to those suggested in previous clinical trials(AU)

Antecedentes: la estreptoquinasa (SK) es un agente fibrinolítico eficaz para el tratamiento del infarto agudo de miocardio (IAM). El objetivo del presente estudio fue evaluar las reacciones adversas a medicamentos (RAM) se asocia con SK recombinante intravenoso en pacientes con IAM en la práctica clínica habitual. Métodos: Estudio nacional, prospectivo y notificaciones espontáneas de farmacovigilancia basado en el programa se llevó a cabo en Cuba. La demografía del paciente, presuntamente ADR descripción, los elementos para definir la causalidad, y los resultados fueron documentados y analizados. Resultados Un total de 1.496 sospechosos de RAM identificadas en 792 pacientes de los 1.660 (47,7 por ciento) informaron de las recetas en el programa, se recibieron entre julio de 1995 y julio de 2002. La mayoría de los pacientes (71.3percent) eran hombres, eran blancos y 67.2percent edad media fue de 61,6 ± 13,0 años. La media de intervalo de tiempo entre la aparición de los síntomas y el inicio de la infusión de SK fue de 4,9 ± 3,7 h. La RAM más frecuentes fueron hipotensión, arritmias, escalofríos, temblores, vómitos, náuseas, alergias, hemorragias y fiebre. ADR se 38percent gravedad leve, moderada 38percent, el 10 por ciento graves y muy graves 4percent. Sólo 3 pacientes con accidente cerebrovascular hemorrágico se informó. Setenta y dos pacientes fallecieron en el hospital debido principalmente a causas cardíacas asociadas con la del paciente condición clínica subyacente. La mortalidad fue 3 veces más probable en pacientes que sufren arritmias que en aquellos sin este evento (odds ratio: 3.1, 95percent IC: 1,8 a 5,1). La mayoría de los ADR fueron clasificados como posiblemente o probablemente relacionados con la medicación. Conclusión: SK recombinante se asoció con un puesto similar perfil de seguridad de la comercialización a los sugeridos en los ensayos clínicos previos