Pharmacokinetic and pharmacodynamic characterization of a novel formulation containing co-formulated interferons alpha-2b and gamma in healthy male volunteers.

BACKGROUND: More potent antitumor activity is desired in Interferon (IFN)-treated cancer patients. This could be achieved by combining IFN alpha and IFN gamma. The aim of this work was to characterize the pharmacokinetics and pharmacodynamics of a novel formulation containing a co-formulated combination of IFNs alpha-2b and gamma (CIGB-128-A). METHODS: A group of nine healthy male subjects received intramuscularly 24.5 × 106 IU of CIGB-128-A. IFN concentrations were evaluated for 48 h. Serum neopterin, beta2-microglobulin (ß2M) and 2'-5' oligoadenylate synthetase (2'-5' OAS), classical IFN-inducible serum markers, were measured during 192 h by enzyme immunoassay and body temperature was used as pharmacodynamic variable as well. RESULTS: Concerning pharmacokinetics, serum IFNs' profiles were better fitted to a mono-compartmental model with consecutive zero order and first order absorption, one bioavailability value. No interferences by simultaneous administered IFNs were observed in their typical similar systemic profiles. Neopterin and ß2M time profiles showed a delay that was efficiently linked to pharmacokinetics by means of a zero order absorption rate constant. Neopterin level was nine-fold higher than initial values, 48 h post-administration, an increment not described before. At this time, mean serum ß2M peaked around the double from baseline. Serum concentrations of the enzyme 2'-5' OAS was still elevated on the 8 day post-injection. The formulation was well tolerated. Most frequent adverse reactions were fever, headache, arthralgia and lymphopenia, mostly mild. CONCLUSIONS: The administration of co-formulated IFN alpha-2b and IFN gamma likely provides improved pharmacodynamic properties that may be beneficial to treat several malignancies. TRIAL REGISTRATION: Cuban Public Registry of Clinical Trials RPCEC00000118 , May 24, 2011.

Caracterización clínica, epidemiológica y terapéutica de pacientes con condiloma acuminado / Clinical, epidemiological and therapeutics characteristics of patients with condyloma acuminatum

OBJETIVO. Caracterizar desde el punto de vista epidemiológico, clínico y de respuesta terapéutica a los pacientes con condiloma acuminado (CA) en la consulta protocolizada del Hospital Clínico Quirúrgico Hermanos Ameijeiras (HCQHA) PACIENTES y MÉTODO. Estudio descriptivo, longitudinal, ambispectivo, en 2/9 pacientes con CA del Servicio de Dermatología del HCQHA en el período 2009-2013, para su caracterización clínico, epidemiológica y de los tratamientos recibidos. Se determinaron variables epidemiológicas (edad, sexo, color de la piel, estado civil, grado escolaridad, ocupación, hábitos tóxicos, orientación y conducta sexual), características clínicas de las lesiones y tratamientos y respuesta a estos. RESULTADOS. Predominaron los pacientes menores de 20 años, trabajadores, solteros, heterosexuales, del sexo masculino, piel blanca, de nivel escolar preuniversitario, con conducta sexual muy promiscua y prolongado tiempo de evolución de la enfermedad asociado a gran área de afectación y a elevado número y tamaño de las lesiones. Los tratamientos utilizados fueron radiocirugía, podofilina al 25 %, ácido tricloroacético al 80 %, 5-fluorouracilo (crema), criocirugía, interferón-a2b humano recombinante (3 x 10 UI) por vía intramuscular e interferón-a2b humano recombinante (3 x 10 Ul) por vía subcutánea más criocirugía. Significativa mayor respuesta y significativo menor porcentaje de recidivas (p < 0,001) se observó en los pacientes tratados con el interferón asociado a la criocirugía. CONCLUSIONES. El CA predominó en adolescentes y adultos jóvenes, solteros, heterosexuales, del sexo masculino, nivel escolar, preuniversitario, con conducta sexual promiscua. Los mayores porcentajes de respuesta al tratamiento y los menores porcentajes de recidiva se lograron con el interferón alfa adyuvante a la criocirugía.

BACKGROUND. A literature review revealed few studies witli clinical, epidemiological and therapeutics characteristics of patients witli condyloma acuminate. PATlENTS AND METHOD. We performed a descriptive, ambispective study in 219 with condyloma acuminate, attended in the dermatology department of the Hermanos Ameijeiras Hospital between January 2009 and December 2013. The aim was to obtain the patients' clinical and epidemiological characteristics and to know the received treatment and their therapeutic efficacy. Were determined different epidemiological variables, such as: age, sex, skin color, civil state, schooling, occupation, toxic habits, behavior and orientation sexual; the clinical characteristics of the lesions; and were evaluated the received treatments and their response. RESULTS. The most frequents clinical and epidemiological characteristics of patients were masculine, single, workers, white skin color, younger than 20 years old, heterosexual orientation and promiscuous behavior with very large evolution s time of the illness associated to big affected area and high number and site of the lesions. The received treatments were: radiosurgery, 25 % podophyllin resin, 80 % trichloroacetic acid, topical 5-fluorouracil (5 % cream], cryosurgery, intramuscular interferon-a2b (3 x 10 lU) and subcutaneous application of interferon-a2b (3 x 10 lU) three times a week plus fortnightly application of cryosurgery. Statistically significant better response and lower relapse rates (p<0,001) were found in the patients who received subcutaneous application of interferon- a2b (3x10 IU) 3 three times a week the therapeutic efficacy and the patientsÆ clinical, epidemiological characteristics allow improved patient management.

Caracterización epidemiológica de la enfermedad hemorroidal aguda en hospitales seleccionados en Cuba (noviembre de 2011 a enero 2012) / Epidemiological characterization of acute hemorrhoidal disease in selected hospitals in Cuba (November 2011 to January 2012)

Introducción: la enfermedad hemorroidal constituye un problema de salud mundial y Cuba; sin embargo, la literatura no recoge información epidemiológica sobre la población cubana. Por lo que este trabajo caracteriza la enfermedad hemorroidal aguda en hospitales cubanos seleccionados, con particular énfasis en los factores de riesgo que favorecen su aparición. Objetivos: identificar los principales factores de riesgo, sus características demográficas y de base; hábitos tóxicos y alimenticios, así como modos y estilos de vida, que favorecen la aparición de una enfermedad hemorroidal aguda. Métodos: se realizó un estudio observacional descriptivo en 11 servicios cubanos de Coloproctología. Se incluyeron 510 pacientes con diagnóstico de enfermedad hemorroidal aguda, con edades comprendidas entre 18 y 75 años, que dieron su consentimiento de participación en el estudio. A todos los pacientes se les aplicó una encuesta epidemiológica que indagaba acerca de los hábitos tóxicos y alimenticios, así como modos y estilos de vida, los cuales son reconocidos como factores de riesgo para la aparición de la enfermedad. Resultados: casi el 75 por ciento de los pacientes comenzó con la enfermedad. Predominaron las hemorroides externas y los signos y síntomas más frecuentes fueron el dolor anal, la sensación de masa, el edema y el sangramiento rectal. La mitad de los pacientes ingiere bebidas alcohólicas y la mayoría consume café, alimentos condimentados y requiere una posición erecta o permanecer sentado durante largos períodos de tiempo, para sus actividades cotidianas. Pocos pacientes consumen altos contenidos de fibras en la dieta, así como abundante agua. Conclusiones: se corrobora la presencia de factores de riesgo e inadecuados modos y estilos de vida en la población cubana que facilitan o propician la aparición de un episodio agudo hemorroidal(AU)

Introduction: hemorrhoidal disease is a global health problem. In Cuba, however, epidemiological data about the population is not available in the literature on the subject. That is the reason why the present paper is aimed at characterizing acute hemorrhoidal disease in selected Cuban hospitals, with particular emphasis on the risk factors leading to its appearance. Objectives: identify the main risk factors, demographic and base features, toxic and eating habits, and life styles and modes, leading to the appearance of acute hemorrhoidal disease. Methods: an observational descriptive study was conducted in 11 Cuban coloproctology services. The sample consisted of 510 patients aged 18-75 diagnosed with acute hemorrhoidal disease, who gave their consent to participate in the study. All patients were given an epidemiological survey about toxic and eating habits, and life styles and modes perceived as risk factors for the disease. Results: almost 75 percent of the patients developed the disease. There was a predominance of external hemorrhoids, and the most common signs and symptoms were anal pain, mass sensation, edema and rectal bleeding. Half the patients consume alcohol and most drink coffee, eat spicy foods and must remain in a standing or sitting position for long periods during their daily activities. Few patients consume a fiber-rich diet and abundant water. Conclusions: corroboration was made of the presence of risk factors and inadequate life styles and modes among the Cuban population which lead to the occurrence of acute hemorrhoidal episodes(AU)

Recombinant streptokinase vs phenylephrine-based suppositories in acute hemorrhoids, randomized, controlled trial (THERESA-3).

AIM: To compare the efficacy and safety of recombinant streptokinase (rSK) and phenylephrine-based suppositories in acute hemorrhoidal disease. METHODS: A multicenter (14 sites), randomized (1:1), open, parallel groups, active controlled trial was done. After inclusion, subjects with acute symptoms of hemorrhoids, who gave their written, informed consent to participate, were centrally randomized to receive, as outpatients, rSK (200000 IU) or 0.25% phenylephrine suppositories, which had different organoleptic characteristics. Treatment was administered by the rectal route, one unit every 6 h during 48 h for rSK, and up to a maximum of 5 d (20 suppositories) for phenylephrine. Evaluations were performed at 3, 5 and 10 d post-inclusion. The main end-point was the 5(th)-day complete clinical response (disappearance of pain and edema, and ≥ 70% reduction of the lesion size). Time to response and need for thrombectomy were secondary efficacy variables. Adverse events were evaluated too. RESULTS: 5(th) day complete response rates were 83/110 (75.5%) and 36/110 (32.7%) with rSK and phenylephrine suppositories, respectively. This 42.7% difference (95%CI: 30.5-54.2) was highly significant (P < 0.001). The advantage was detected since the early 3(rd) day evaluation (37.3% vs 6.4% for the rSK and active control groups, respectively; P < 0.001) and was kept even at the late 10(th) day assessment (83.6% vs 58.2% for rSK and phenylephrine, respectively; P < 0.001). Time for complete response was significantly shorter (P = 0.031; log-rank test) in the rSK group (median: 4.9 d; 95%CI: 4.8-5.0) with respect to the active control (median: 9.8 d; 95%CI: 9.8-10.0). Thrombectomy was necessary in 1/59 and 8/57 patients with baseline thrombosis in the rSK and phenylephrine groups, respectively (P = 0.016). There were no adverse events attributable to the experimental treatment. CONCLUSION: rSK suppositories showed a significant advantage over a widely used over-the-counter phenylephrine preparation for the treatment of acute hemorrhoidal illness, with an adequate safety profile.

Active post-marketing surveillance of the intralesional administration of human recombinant epidermal growth factor in diabetic foot ulcers.

BACKGROUND: After several exploratory and confirmatory clinical trials, the intralesional administration of human recombinant epidermal growth factor (hrEGF) has been approved for the treatment of advanced diabetic foot ulcers (DFU). The aim of this work was to evaluate the effectiveness and safety of this procedure in medical practice. METHODS: A prospective, post-marketing active pharmacosurveillance was conducted in 41 hospitals and 19 primary care polyclinics. Patients with DFU received hrEGF, 25 or 75 µg, intralesionally 3 times per week until complete granulation of the ulcer or 8 weeks maximum, adjuvant to standard wound care. Outcomes measured were complete granulation, amputations, and adverse events (AE) during treatment; complete lesion re-epithelization and relapses in follow-up (median: 1.2; maximum 4.2 years). RESULTS: The study included 1788 patients with 1835 DFU (81% Wagner's grades 3 or 4; 43% ischemic) treated from May 2007 to April 2010. Complete granulation was observed in 76% of the ulcers in 5 weeks (median). Ulcer non-ischemic etiology (OR: 3.6; 95% CI: 2.8-4.7) and age (1.02; 1.01-1.03, for each younger year) were the main variables with influence on this outcome. During treatment, 220 (12%) amputations (171 major) were required in 214 patients, mostly in ischemic or Wagner's grade 3 to 5 ulcers. Re-epithelization was documented in 61% of the 1659 followed-up cases; 5% relapsed per year. AE (4171) were reported in 47% of the subjects. Mild or moderate local pain and burning sensation, shivering and chills, were 87% of the events. Serious events, not related to treatment, occurred in 1.7% of the patients. CONCLUSIONS: The favorable benefit/risk balance, confirms the beneficial clinical profile of intralesional hrEGF in the treatment of DFUs.

Enemas de factor de crecimiento epidérmico para inducir la remisión de la colitis ulcerosa izquierda / Epidermal growth factor enemas for induction of remission in left-sided ulcerative colitis

Introducción: la colitis ulcerosa es una enfermedad inflamatoria crónica de etiología poco conocida, que afecta la mucosa del colon. El efecto positivo del factor de crecimiento epidérmico fue reportado en estudio previo con uso de enema para tratamiento de la manifestación izquierda leve o moderada de la enfermedad. Este antecedente sirvió de base para evaluar la eficacia y perfil de seguridad de una solución viscosa del producto.Métodos: fueron aleatorizados 31 pacientes hacia tres grupos de tratamiento diario durante 14 días. Doce recibieron enemas de 10 mg de factor de crecimiento epidérmico en 100 mL de solución viscosa, mientras nueve fueron tratados con enemas placebo conteniendo solamente solución viscosa. Ambos grupos recibieron además 1,2 g diarios de mesalacina oral. El tercer grupo incluyó 10 pacientes con mesalacina en enemas de 3g / 100 mL. La variable principal de eficacia fue la respuesta clínica al finalizar las dos semanas de tratamiento, definida como la disminución de, al menos tres puntos, el índice basal de actividad de la enfermedad acompañada de mejoría endoscópica o histológica.Resultados: se alcanzó remisión de la enfermedad en todos los pacientes que recibieron factor de crecimiento epidérmico y en seis de los grupos mesalacina enema y placebo. Todas las comparaciones entre grupos mostraron superioridad estadísticamente significativa para el factor de crecimiento epidérmico, único producto que logró la reducción significativa del índice de actividad de la enfermedad y de la presencia e intensidad de los síntomas digestivos en los pacientes luego del tratamiento. Ningún evento adverso fue reportado.Conclusiones: estos resultados son consistentes con las anteriores evidencias moleculares y clínicas que señalan al factor de crecimiento...

Introduction: ulcerative colitis is a little known chronic inflammatory disease in colonic mucosa. The positive effect of epidermal growth factor was shown in a previous report, with enema use for treatment of mild to moderate left-sided manifestation of the disease. This evidence provided the basis for evaluating the efficacy and safety profile of a viscous solution of this product. Methods: thirty-one patients were randomized to three groups for daily medications during 14 days. Twelve received one 10 mg enema of epidermal growth factor dissolved in 100 mL of viscous solution whereas nine were treated with placebo enema; both groups also received 1.2 g of oral mesalamine per day. The other group included ten patients with 3 g / 100 mL of mesalamine enema. Primary end point was clinical responses after two weeks of treatment, defined as a decreased of, at least three points from baseline, the Disease Activity Index and endoscopic or histological evidences of improvement. Results: remission of disease was observed in all patients in the epidermal growth factor group, and six in both, mesalamine enema and placebo group. All the comparisons between groups showed statistically significant superiority for epidermal growth factor, the only product with significant reduction in disease activity index as well as the presence and intensity of digestive symptoms in patients after treatment. None adverse event was reported. Conclusions: the results agree with previous molecular and clinical evidences, indicating that the epidermal growth factor is effective to reduce disease activity and to induce remission. A new study involving more patients should be conducted to confirm the efficacy of the epidermal growth factor enemas

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.

CIGB-300, a synthetic peptide-based drug that targets the CK2 phosphoaceptor domain. Translational and clinical research.

CK2 represents an oncology target scientifically validated. However, clinical research with inhibitors of the CK2-mediated phosphorylation event is still insufficient to recognize it as a clinically validated target. CIGB-300, an investigational peptide-based drug that targets the phosphoaceptor site, binds to a CK2 substrate array in vitro but mainly to B23/nucleophosmin in vivo. The CIGB-300 proapoptotic effect is preceded by its nucleolar localization, inhibition of the CK2-mediated phosphorylation on B23/nucleophosmin and nucleolar disassembly. Importantly, CIGB-300 shifted a protein array linked to apoptosis, ribosome biogenesis, cell proliferation, glycolisis, and cell motility in proteomic studies which helped to understand its mechanism of action. In the clinical ground, CIGB-300 has proved to be safe and well tolerated in a First-in-Human trial in women with cervical malignancies who also experienced signs of clinical benefit. In a second Phase 1 clinical trial in women with cervical cancer stage IB2/II, the MTD and DLT have been also identified in the clinical setting. Interestingly, in cervical tumors the B23/nucleophosmin protein levels were significantly reduced after CIGB-300 treatment at the nucleus compartment. In addition, expanded use of CIGB-300 in case studies has evidenced antitumor activity when administered as compassional option. Collectively, our data outline important clues on translational and clinical research from this novel peptide-based drug reinforcing its perspectives to treat cancer and paving the way to validate CK2 as a promising target in oncology.

Safety and Immunogenicity of a Human Papillomavirus Peptide Vaccine (CIGB-228) in Women with High-Grade Cervical Intraepithelial Neoplasia: First-in-Human, Proof-of-Concept Trial.

Objective. CIGB-228 is a novel therapeutic vaccine consisting of HLA-restricted HPV16 E7 epitope adjuvated with VSSP. This trial was designed to evaluate the toxicity, safety, immunogenicity, HPV clearance, and lesion regression. Methods. Seven women were entered. All were HLA-A2 positive, had biopsy-proven high-grade CIN, histologically positive for HPV16, and beared persistent postbiopsy lesions visible by digital colposcopy. HLA-A2 women with biopsy-proven high-grade CIN, HPV16-positive, and beared persistent postbiopsy lesions visible by digital colposcopy were vaccinated. One weekly injections of CIGB-228 vaccine was given for four weeks. Then, loop electrosurgical excision procedure (LEEP) of the transformation zone was performed. Study subjects were followed for 1 year after LEEP. Results. No toxicity beyond grade 1 was observed during and after the four vaccinations. Five of seven women had complete and partial regression. Cellular immune response was seen in all patients. HPV was cleared in three of the patients with complete response. Conclusion. CIGB-228 vaccination was well tolerated and capable to induce IFNγ-associated T-cell response in women with high-grade CIN. In several patients, lesion regression and HPV clearance were observed.

C-Phycocyanin is neuroprotective against global cerebral ischemia/reperfusion injury in gerbils.

Although the huge economic and social impact and the predicted incidence increase, neuroprotection for ischemic stroke remains as a therapeutically empty niche. In the present study, we investigated the rationale of the C-Phycocyanin (C-PC) treatment on global cerebral ischemia/reperfusion (I/R) injury in gerbils. We demonstrated that C-PC given either prophylactically or therapeutically was able to significantly reduce the infarct volume as assessed by triphenyltetrazolium chloride (TTC) staining and the neurological deficit score 24h post-stroke. In addition, C-PC exhibited a protective effect against hippocampus neuronal cell death, and significantly improved the functional outcome (locomotor behavior) and gerbil survival after 7 days of reperfusion. Malondialdehyde (MDA), peroxidation potential (PP) and ferric reducing ability of plasma (FRAP) were assayed in serum and brain homogenates to evaluate the redox status 24h post-stroke. The treatment with C-PC prevented the lipid peroxidation and the increase of FRAP in both tissue compartments. These results suggest that the protective effects of C-PC are most likely due to its antioxidant activity, although its anti-inflammatory and immuno-modulatory properties reported elsewhere could also contribute to neuroprotection. To our knowledge, this is the first report of the neuroprotective effect of C-PC in an experimental model of global cerebral I/R damage, and strongly indicates that C-PC may represent a potential preventive and acute disease modifying pharmacological agent for stroke therapy.

Seguridad de la terapia de interferón alfa 2b recombinante más ribavirina en la hepatitis crónica C / Safety of recombinant interferon alpha 2b plus ribavirin in chronic hepatitis C

La hepatitis crónica C ha adquirido rango de pandemia. El virus de la hepatitis C se ha convertido en la causa principal de hepatitis crónica, cirrosis hepática, hepatocarcinoma, y trasplante de hígado a nivel mundial. OBJETIVO: identificar los efectos adversos asociados a la terapia combinada interferón alfa 2b recombinante más ribavirina durante la evolución del tratamiento y hasta 8 semanas después de finalizado, así como los principales efectos asociados a salidas temporales o definitivas de esta terapia. MÉTODOS: estudio de farmacovigilancia cuya serie estuvo conformada por 122 pacientes con hepatitis crónica C atendidos en el Instituto de Gastroenterología desde mayo de 2001 hasta mayo de 2006. Se utilizó interferón alfa 2b recombinante (3 millones de unidades 3 veces por semana) más ribavirina (1 000 o 1 200 mg diarios en dependencia del peso corporal) durante 48 semanas. RESULTADOS: el 88,5 por ciento del total de casos presentó efectos adversos; de ellos el 79,5 por ciento correspondió al síndrome seudogripal, seguido de manifestaciones hematológicas, neuropsiquiátricas, gastrointestinales, entre otras menos frecuentes. El 6,6 por ciento de la serie presentó salidas temporales del tratamiento por efecto adverso distinto de la anemia y 4 pacientes, salidas definitivas del estudio, tres por anemia hemolítica severa y uno con hipertiroidismo no controlable. CONCLUSIONES: la terapia combinada interferón alfa 2b recombinante más ribavirina resulta segura, donde el mayor número de casos presentó síndrome seudogripal como efecto adverso más frecuente. Las manifestaciones hematológicas asociadas a las salidas definitivas del estudio permitieron recomendar seguimiento estricto de la hemoglobina y profundizar en el diagnóstico y tratamiento de los principales efectos adversos presentes en otros sistemas y asociados a esta terapia

Chronic hepatitis C has reached the category of pandemic. The hepatitis C virus is the main cause of chronic hepatitis, hepatic cirrhosis, hepatocarcinoma and liver transplantation worldwide. OBJECTIVE: to identify the side effects of a combined therapy of recombinant interpheron alpha 2b plus ribavirin during the treatment and up to 8 weeks afterwards, as well as the main effects related to temporary or definitive withdrawal. METHODS: a pharmacological surveillance study was performed in which 122 patients with chronic hepatitis C, who had been seen at the Institute of Gastroenterology from May 2001 to May 2006, were included. Recombinant interferon alpha 2b (3 million units administered 3 times a week) plus ribavirin (1 000 or 1 200 mg daily depending on the body weight) was the therapy used for 48 weeks. RESULTS: of the total number of cases, 88,5 percent had side effects; 79,5 percent of which corresponded to pseudocold syndrome followed by hematological, neuropsychiatric and gastrointestinal manifestations, and other less frequent ailments. In the studied group, 6,6 percent had to interrupt their treatment temporarily due to some side effect different from anemia whereas 4 patients gave up the study, three affected by severe hemolytic anemia and one with uncontrollable hyperthyroidism. CONCLUSIONS: the combined therapy of recombinant interferon alpha 2b plus ribavirin proved to be safe; the most frequent side effect was pseudocold syndrome in the majority of cases. The hematological manifestations that made the patients to give up the study led to recommend a strict follow-up of hemoglobin levels and thorough diagnosis and treatment of the main side effects found in other systems and associated to this combined therapy

C-Phycocyanin ameliorates experimental autoimmune encephalomyelitis and induces regulatory T cells.

For decades Experimental Autoimmune Encephalitis (EAE) has remained as an unsurpassed multiple sclerosis (MS) animal model. C-Phycocyanin (C-Pc) has been reported to exhibit pharmacological properties that may be expected to symptomatically improve EAE and MS. However, in this paper we reveal a basic underlying mechanism that may provide a new approach to the rationale of the overall beneficial effect of this natural antioxidant. We demonstrate that C-Pc is able to trigger mechanisms preventing or downgrading EAE expression and induces a regulatory T cell (Treg) response, in peripheral blood mononuclear cells (PBMC) from MS patients. These results agree with reports suggesting that Treg limit acute MS attacks and that C-Pc may act as a neuroprotector and thereby reverts the organic and functional damage in neurodegenerative disorders of the central nervous system (CNS). Moreover, evidence is provided on the antioxidant activity of C-Pc within the CNS, intended to improve the myelin and axonal damage of EAE induced Lewis rats. Our results indicate that specific Treg activation may represent a central and essential mechanism in supporting the therapeutic potential of C-Pc for MS and may lead to new and more effective therapies; this property would then complement and enhance other proven active principles such as interferons (IFN), giving rise to combined therapies.

Pharmacokinetic and pharmacodynamic comparison of two "pegylated" interferon alpha-2 formulations in healthy male volunteers: a randomized, crossover, double-blind study.

BACKGROUND: Interferon (IFN) alpha conjugation to polyethylene glycol (PEG) results in a better pharmacokinetic profile and efficacy. The aim of this study was to compare the pharmacokinetic, pharmacodynamic and safety properties of a new, locally developed, 40-kDa PEG-IFN alpha-2b preparation with a reference, commercially available PEG-IFN alpha-2a in healthy male volunteers. METHODS: A randomized, crossover, double-blind study with a 3-weeks washout period, was done. A single 180 micrograms PEG-IFN alpha-2 dose was administered subcutaneously in both groups. Sixteen apparently healthy male subjects were included. Serum PEG-IFN concentration was measured during 336 hours by an enzyme immunoassay (EIA). Other clinical and laboratory variables were used as pharmacodynamic and safety criteria. RESULTS: The pharmacokinetic comparison by EIA yielded a high similitude between the formulations. In spite of a high subject variability, the parameters' mean were very close (in all cases p > 0.05): AUC: 53623 vs. 44311 pg.h/mL; Cmax: 333 vs. 271 pg/mL; Tmax: 54 vs. 55 h; half-life (t1/2): 72.4 vs. 64.8 h; terminal elimination rate (lambda): 0.011 vs. 0.014 h(-1); mean residence time (MRT): 135 vs. 123 h for reference and study preparations, respectively. There were no significant differences with respect to the pharmacodynamic variables either: serum neopterin and beta-2 microglobulin levels, stimulation of 2'5' oligoadenylate synthetase expression, and serum IFN antiviral activity. A strong Spearman's rank order correlation (p < 0.01) between the pharmacokinetic and pharmacodynamic concentration-time curves was observed. Both products caused similar leukocyte counts diminution and had similar safety profiles. The most frequent adverse reactions were leukopenia, fever, thrombocytopenia, transaminases increase and asthenia, mostly mild. CONCLUSIONS: Both formulations are fully comparable from the pharmacokinetic, pharmacodynamic, and safety profiles. Efficacy trials can be carried out to confirm clinical similarity.

Interferón alfa 2b recombinante más ribavirina en el tratamiento de la hepatitis crónica C / Recombinant Interferon alfa-2b plus Ribavirin in treatment of chronic hepatitis C

El virus de la hepatitis C se ha convertido en la causa principal de hepatitis crónica, cirrosis hepática, hepatocarcinoma, y trasplante de hígado a nivel mundial. OBJETIVO: El presente estudio estuvo dirigido a determinar la evolución virológica, bioquímica e histológica de los pacientes con hepatitis crónica C bajo terapia combinada Interferón a 2b recombinante más ribavirina e identifica los principales factores asociados a las tasas obtenidas de respuesta virológica sostenida. MÉTODOS: Ensayo clínico-terapéutico fase IV, abierto, no controlado y multicéntrico rectorado por el Instituto de Gastroenterología y el Centro de Ingeniería Genética y Biotecnología en el período comprendido de mayo de 2001 a mayo de 2006. La muestra estuvo conformada por 122 pacientes con hepatitis crónica C que cumplieron con criterios de inclusión y exclusión predeterminados. Se utilizó interferón a 2b recombinante (3 millones de unidades 3 veces por semana) más ribavirina (1 000 o 1 200 mg diarios en dependencia del peso corporal) durante 48 sem. RESULTADOS: Se obtuvo una tasa de respuesta virológica y bioquímica sostenida a la semana 72 de 32,8 y 50,8 por ciento respectivamente. Un 41,3 por ciento del total de pacientes experimentó mejoría histológica a expensas de la reducción de la fibrosis y pocos cambios en la inflamación. CONCLUSIONES: Teniendo en cuenta la tasa de respuesta global obtenida, se consideró como tratamiento eficaz para la hepatitis crónica C y se recomendó profundizar en el conocimiento de las características de la infección en Cuba así como en opciones de tratamiento más eficaces para esta enfermedad

The hepatitis C virus becomes in leading cause of chronic hepatitis, hepatic cirrhosis, hepatocarcinoma and liver transplant at world level. OBJECTIVE: The aim of present study is to determine the virological, biochemical and histological course of patients presenting with Chronic hepatitis C under a combination of recombinant Interferon alfa-2b plus Ribavirin and to identify the main factors associated with the rates obtained of virological response. METHODS: A non-controlled and multicenter phase IV clinical-therapeutical trial was sponsored by the Institute of Gastroenterology and the Genetics and Biotechnology Engineering Center from May, 2002 to May, 2006. Sample included 122 patients diagnosed with chronic hepatitis C fulfilling the predetermined inclusion and exclusion criteria. Recombinant Interferon alfa-2b (3 millions of t.i.d units) was used plus Ribavirin (1000 or 1200 mg daily depending on the body weight) during 48 weeks. RESULTS: We achieved a sustained biochemical and virological response rate of 32,8 and 50,8 percent, respectively at week 72. A 41,3, percent from the total of patients had a histological improvement at the expense of reduction of fibrosis and a few changes in inflammation level. CONCLUSIONS: Raking into account the global response rate achieved this combined treatment was considered effectiveness for chronic hepatitis C and we recommended to deepen in the knowledge of infection in Cuba, as well as in more efficient treatment options for this disease

Interferón gamma recombinante como alternativa terapéutica en niños con artritis idiopática juvenil / Recombinant gamma Interferon as a therapeutical alternative in children with juvenile idiopathic arthritis

INTRODUCCIÓN. La artritis idiopática juvenil (AIJ) es una enfermedad del colágeno caracterizada por sinovitis crónica y síntomas extraarticulares, de inicio antes de los 16 años de edad. El interferón gamma (INFγ) mostró eficacia en un ensayo anterior con pacientes resistentes o intolerantes a las otras terapias disponibles, por lo que se decidió evaluar su eficacia y seguridad como medicamento modificador de la evolución de esta enfermedad. MÉTODOS. Se realizó un ensayo clínico abierto, no controlado, en el que se administró INFγ por vía intramuscular en dosis de 50 000 UI/kg (hasta 1 x 10(6) UI) durante 2 años. En el ensayo se incluyeron 20 pacientes con AIJ: 5 tenían la forma pauciarticular; 9, la poliarticular y 6, la sistémica. RESULTADOS. Al final del tratamiento, 13 pacientes (65 por ciento) se evaluaron como respondedores. El número de articulaciones afectadas, los síntomas sistémicos y los valores de eritrosedimentación y del cuestionario de calidad se redujeron significativamente. Igualmente disminuyó el número de pacientes que continuó consumiendo esteroides, así como la dosis de éstos. El tratamiento fue bien tolerado, excepto en 2 pacientes. CONCLUSIONES. El INFγ disminuye la expresión de la quimiocina CCR-4 en los niños, pero no en los adultos con la enfermedad. Es posible concluir que esta citocina puede ser una alternativa terapéutica eficaz en pacientes con AIJ; para confirmarlo se necesitan estudios controlados más extensos

INTRODUCTION: The juvenile idiopathic arthritis (JIA) is a collagen entity characterized by chronic synovitis and extra-articulation symptoms appearing before the 16 years old. Gamma Interferon (gamma-INF) showed its effectiveness in a prior trial with resistant and intolerant patients to other available gamma-INF therapies, thus authors assessed its effectiveness and safety as a modifier drug of the course of this entity. METHODS: An open clinical, no-controlled trial was carried out administering gammaINF by intramuscular route in doses of 50 000 IU/kg (up to 1 x 10(6) IU) during two years. Trial included 20 patients with JIA: five had the pauciarticular type; nine had the polyarticular one and six had the systemic one. RESULTS: At treatment termination, 13 patients (65 percent) were assessed as respondents. Figure of involved joints, the systemic symptoms and the erythrosedimentation values, and the quality questionnaire significantly decreased, as well as the figure of patients to continue consuming steroids and its dosage. Treatment was well tolerated, except 2 patients. CONCLUSIONS: Gamma-INF decrease the expression of CCR-4 chemokine in children, but not in adults ones presenting this entity. We conclude that this cytokine may be an efficient therapeutical alternative in patients with JIA; for its confirmation it is necessary more extent controlled studies

Epidermal growth factor in clinical practice - a review of its biological actions, clinical indications and safety implications.

Chemotaxis, mitogenesis, motogenesis and cytoprotection are common cellular events involved in both tumourigenesis and tissue repair, which appear amplified upon growth factors exposure. Epidermal growth factor (EGF) promotes these events in epithelial and mesenchymal cells through the binding to a specific tyrosine kinase receptor. In experimental oncology settings, EGF does not initiate malignant transformation but exhibits 'tumour promotion'. These observations have raised doubts on the clinical use of EGF despite solid demonstrations of efficacy in experimental conditions and clinical trials. The results of a Pubmed and Bioline investigation on EGF clinical uses and preclinical safety data are presented here. EGF topical administration has been used since 1989 to enhance the healing process of a variety of peripheral tissues wounds (16 clinical reports), as well as its intravenous, oral and rectal administration for gastrointestinal damages (11 clinical reports). EGF therapeutic efficacy and excellent tolerability seem demonstrated. Lack of long-term adverse effects is highlighted in those studies with 6, 12 and 24 months of patients follow-up. Although post-treatment follow-up may fall short for malignant growth, there are no reports on evidences linking EGF clinical use with cancer. A multicentre, nationwide survey in Cuba, 15 years after randomly using silver sulphadiazine with EGF or not in burn victims yielded that cancer incidence was comparable between EGF-treated and control subjects and that such incidence rate does not differ from the age-matched national incidence for those 15-year period. All the animal species subjected to long-term EGF systemic administration exhibit dose-dependent and reversible epithelial organs hyperplasia with no changes in cells phenotypic differentiation. Histotypic pre-malignant markers were not identified. The results emerged from co-carcinogenesis studies and from transgenic mice over-expressing EGF are conflicting and indicate that EGF overexposure, either innate or postnatal, may not be sufficient to transform cells. The ability of EGF to heal injured tissues in life-threatening scenarios or to assist in preventing physical and social disability advocates for its clinical use under a rational medical risk/benefit balance.

Treatment of advanced, recurrent, resistant to previous treatments basal and squamous cell skin carcinomas with a synergistic formulation of interferons. Open, prospective study.

BACKGROUND: Aggressive non-melanoma skin cancer (deeply infiltrating, recurrent, and morphea form lesions) are therapeutically challenging because they require considerable tissue loss and may demand radical disfiguring surgery. Interferons (IFN) may provide a non-surgical approach to the management of these tumors. The aim of this work was to evaluate the effect of a formulation containing IFNs-alpha and -gamma in synergistic proportions on patients with recurrent, advanced basal cell (BCC) or squamous cell skin carcinomas (SCSC). METHODS: Patients with extensive, recurrent, resistant to other procedures BCC or SCSC received the IFN formulation peri- and intralesionally, three times per week for 3 weeks. They had been previously treated with surgery and/or radiotherapy or chemotherapy. Thirteen weeks after the end of treatment, the original lesion sites were examined for histological evidence of remaining tumor. RESULTS: Sixteen elder (median 70 years-old) patients were included. They beared 12 BCC and 4 SCSC ranging from 1.5 to 12.5 cm in the longest dimension. At the end of treatment 47% CR (complete tumor elimination), 40% PR (>30% tumor reduction), and 13% stable disease were obtained. None of the patients relapsed during the treatment period. The median duration of the response was 38 months. Only one patient with complete response had relapsed until today. Principal adverse reactions were influenza-like symptoms well known to occur with interferon therapy, which were well tolerated. CONCLUSION: The peri- and intralesional combination of IFNs-alpha and -gamma was safe and showed effect for the treatment of advanced, recurrent and resistant to previous treatments of BCC and SCSC in elder patients. This is the first report of such treatment in patients with advance non-melanoma skin cancer. The encouraging result justifies further confirmatory trials. TRIAL REGISTRATION: Current Controlled Trials RPCEC00000052.

TNF-alpha and IL-10 downregulation and marked oxidative stress in Neuromyelitis Optica.

BACKGROUND: Neuromyelitis optica is a central nervous system demyelinating and inflammatory syndrome. The objective of this study is to identify cytokines related to the cellular immune response as well as blood brain barrier integrity and oxidative stress. METHODS: We performed a molecular characterization of cellular immune response and oxidative stress in serum from relapsing-NMO (R-NMO) patients and established the correlations between the clinical measurements and molecular parameters using the Bayesian approach.Serum samples from 11 patients with R-NMO diagnosed according to Wingerchuk criteria and matched in terms of age, gender and ethnicity with the healthy controls were analyzed. The levels of TNF-alpha, IFN-gamma, IL-10, MMP-9, TIMP-1 and oxidative stress markers: malondialdehyde, advanced oxidation protein products, peroxidation potential, superoxide dismutase, catalase, and total hydroperoxides were measured. RESULTS: We found almost undetectable levels of TNF-alpha, a decreased production of IL-10 and a significant up-regulation of every oxidative stress biomarker studied. The insufficient production of TNF-alpha and IL-10 in R-NMO patients, which are two important players of T cell mediated immunoregulation, suggest an effector - regulator imbalance. The overproduction of oxygen reactive species as a consequence of the chronic inflammatory milieu is reflected on the excess of oxidative damage mediators detected. Furthermore, Multidimensional Scaling and a Bayesian linear regression model revealed a significant linear dependence between Expanded Disability Status Scale Kurtzke and TIMP-1; pointing to a possible predictive or prognostic value of this clinical-molecular relationship. CONCLUSION: These results suggest that there is a breakdown in immunoregulatory mechanisms and noteworthy pro-oxidant environment contributing to NMO pathogenesis.

Safety and preliminary efficacy data of a novel casein kinase 2 (CK2) peptide inhibitor administered intralesionally at four dose levels in patients with cervical malignancies.

BACKGROUND: Cervical cancer is now considered the second leading cause of death among women worldwide, and its incidence has reached alarming levels, especially in developing countries. Similarly, high grade squamous intraepithelial lesion (HSIL), the precursor stage for cervical cancer, represents a growing health problem among younger women as the HSIL management regimes that have been developed are not fully effective. From the etiological point of view, the presence of Human Papillomavirus (HPV) has been demonstrated to play a crucial role for developing cervical malignancies, and viral DNA has been detected in 99.7% of cervical tumors at the later stages. CIGB-300 is a novel cyclic synthetic peptide that induces apoptosis in malignant cells and elicits antitumor activity in cancer animal models. CIGB-300 impairs the Casein Kinase (CK2) phosphorylation, by targeting the substrate's phosphoaceptor domain. Based on the perspectives of CIGB-300 to treat cancer, this "first-in-human" study investigated its safety and tolerability in patients with cervical malignancies. METHODS: Thirty-one women with colposcopically and histologically diagnosed microinvasive or pre-invasive cervical cancer were enrolled in a dose escalating study. CIGB-300 was administered sequentially at 14, 70, 245 and 490 mg by intralesional injections during 5 consecutive days to groups of 7 - 10 patients. Toxicity was monitored daily until fifteen days after the end of treatment, when patients underwent conization. Digital colposcopy, histology, and HPV status were also evaluated. RESULTS: No maximum-tolerated dose or dose-limiting toxicity was achieved. The most frequent local events were pain, bleeding, hematoma and erythema at the injection site. The systemic adverse events were rash, facial edema, itching, hot flashes, and localized cramps. 75% of the patients experienced a significant lesion reduction at colposcopy and 19% exhibited full histological regression. HPV DNA was negative in 48% of the previously positive patients. Long term follow-up did not reveal recurrences or adverse events. CONCLUSION: CIGB 300 was safe and well tolerated. This is the first clinical trial where a drug has been used to target the CK2 phosphoaceptor domain providing an early proof-of-principle of a possible clinical benefit.

Intra-lesional injections of recombinant human epidermal growth factor promote granulation and healing in advanced diabetic foot ulcers: multicenter, randomised, placebo-controlled, double-blind study.

A multicenter, double-blind, placebo-controlled trial was carried out to evaluate the intra-lesional infiltration of recombinant epidermal growth factor (EGF) in Wagner's grade 3 or 4 diabetic foot ulcers (DFUs). Subjects (149) were randomised to receive EGF (75 or 25 microg) or placebo, three times per week for 8 weeks and standard good wound care. The main endpoint was granulation tissue covering > or = 50% of the ulcer at 2 weeks. It was achieved by 19/48 controls versus 44/53 in the 75 microg group [odds ratio (OR): 7.5; 95% confidence interval (CI): 2.9-18.9] and 34/48 in the 25 microg group (OR: 3.7; 1.6-8.7). Secondary outcome variables such as end-of-treatment complete granulation response (28/48 controls, 46/53 with 75 microg and 34/48 with 25 microg EGF), time-to-complete response (controls: 5 weeks; both EGF dose groups: 3 weeks), and wound closure after follow-up (25/48 controls, 40/53 with 75 microg and 25/48 with 25 microg EGF) were also treatment dependent. Multivariate analyses yielded that they were significantly enhanced by 75 microg EGF treatment and neuropathic versus ischemic ulcers. Most adverse events were mild and no drug-related severe adverse reactions were reported. It was concluded that recombinant human EGF (rhEGF) local injections offer a favourable risk-benefit balance in patients with advanced DFU.