A randomized, double-blind phase I clinical trial of two recombinant dimeric RBD COVID-19 vaccine candidates: Safety, reactogenicity and immunogenicity.

BACKGROUND: The Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein is the target for many COVID-19 vaccines. Here we report results for phase I clinical trial of two COVID-19 vaccine candidates based on recombinant dimeric RBD (d-RBD). METHODS: We performed a randomized, double-blind, phase I clinical trial in the National Centre of Toxicology in Havana. Sixty Cuban volunteers aged 19-59 years were randomized into three groups (20 subjects each): 1) FINLAY-FR-1 (50 µg d-RBD plus outer membrane vesicles from N. meningitidis); 2) FINLAY-FR-1A-50 (50 µg d-RBD, three doses); 3) FINLAY-FR-1A-25 (25 µg d-RDB, three doses). The FINLAY-FR-1 group was randomly divided to receive a third dose of the same vaccine candidate (homologous schedule) or FINLAY-FR-1A-50 (heterologous schedule). The primary outcomes were safety and reactogenicity. The secondary outcome was vaccine immunogenicity. Humoral response at baseline and following each vaccination was evaluated using live-virus neutralization test, anti-RBD IgG ELISA and in-vitro neutralization test of RBD:hACE2 interaction. RESULTS: Most adverse events were of mild intensity (63.5%), solicited (58.8%), and local (61.8%); 69.4% with causal association with vaccination. Serious adverse events were not found. The FINLAY-FR-1 group reported more subjects with adverse events than the other two groups. After the third dose, anti-RBD seroconversion was 100%, 94.4% and 90% for the FINLAY-FR-1, FINLAY-FR-1A-50 and FINLAY-FR-1A-25 respectively. The in-vitro inhibition of RBD:hACE2 interaction increased after the second dose in all formulations. The geometric mean neutralizing titres after the third dose rose significantly in the group vaccinated with FINLAY-FR-1 with respect to the other formulations and the COVID-19 Convalescent Serum Panel. No differences were found between FINLAY-FR-1 homologous or heterologous schedules. CONCLUSIONS: Vaccine candidates were safe and immunogenic, and induced live-virus neutralizing antibodies against SARS-CoV-2. The highest values were obtained when outer membrane vesicles were used as adjuvant. TRIAL REGISTRY: https://rpcec.sld.cu/en/trials/RPCEC00000338-En.

Nivel de conocimientos sobre los daños del consumo de drogas en adolescentes / Level of knowledge about the harms of drug use in adolescents

Introducción: El consumo de sustancias de abuso por adolescentes y jóvenes, es un problema de salud que preocupa a profesionales de la salud, padres y educadores. Objetivo: Identificar el nivel de conocimientos sobre los daños del consumo de drogas en los adolescentes de la secundaria básica "Martín Klein" de Varadero. Método: Estudio descriptivo transversal en 228 estudiantes. Se recogieron las variables: nivel de conocimientos, nivel de escolaridad, lugar y frecuencia de consumo. Para medir el nivel de conocimientos se utilizó un cuestionario de seis preguntas, tres cerradas y tres mixtas. Resultados: El 64,9 por ciento de los estudiantes resultó con conocimientos medianos sobre los daños que ocasionan las drogas; el 98,2 por ciento reconoce como drogas al tabaco/cigarro, cocaína y marihuana. El 85,1 por ciento ha obtenido información sobre el tema a través de la televisión, la familia y profesor; el 94,7 por ciento reconoce que el consumo de sustancias es perjudicial para la salud. Predominan los no consumidores de sustancias (66,7 por ciento), y los que consumen, alcohol y cigarros, los fines de semana. Conclusiones: Poseen conocimientos medianos sobre los daños que para la salud ocasionan las drogas; reconocen al tabaco, la cocaína y la marihuana, como drogas. Las mayores fuentes de información fueron la televisión, la familia y el profesor. Identifican que el consumo de drogas deteriora la salud física y mental. Predominan los abstemios, seguido de los que usan alcohol y fuman cigarros en centros recreativos, los fines de semana(AU)

ABSTRACT Introduction: The abuse of substances by adolescents and young people is a health problem that worries health professionals, parents and educators. Objective: To identify the level of knowledge about the harms of drug use in adolescents of the "Martín Klein" secondary school in Varadero. Method: Cross-sectional descriptive study in 228 students. The variables were collected; level of knowledge, level of schooling, place and frequency of consumption. To measure the level of knowledge, a questionnaire of six questions, three closed and three mixed, was used. Results: 64.9 percent of the students were found with medium knowledge about the damage caused by drugs; 98.2 percent recognize tobacco / cigar, cocaine and marijuana as drugs. 85, 1 percent have obtained information on the subject through television, family and teacher; 94.7 percent acknowledge that the consumption of substances is harmful to health. Predominant non-consumers of substances (66.7 percent), and those who consume, alcohol and cigars, on weekends. Conclusions: They have medium knowledge about the damages caused by drugs to health; they recognize tobacco / cigar, cocaine and marijuana as drugs. The main sources of information were television, the family and the teacher. They identify that drug use impairs physical and mental health. The abstainers predominate, followed by those who use alcohol and smoke cigars in recreational centers, on weekends(AU)

Intoxicaciones agudas por medicamentos consumidos con fines de abuso / Acute poisoning due to medications used for abuse purposes

Introducción: El consumo de sustancias con fines de abuso y entre ellas los medicamentos, se ha incrementado a nivel mundial. Objetivo: Caracterizar a los pacientes atendidos por intoxicaciones agudas debido a medicamentos consumidos con fines de abuso. Métodos: El universo estuvo constituido por consultas de 961 pacientes, realizadas al servicio de información toxicológica de urgencia del Centro Nacional de Toxicología, durante el período 2010 al 2014. Fueron todas las intoxicaciones agudas por consumo de sustancias con fines de abuso. La serie incluyó 578 pacientes con intoxicaciones agudas con fines de abuso, donde el agente causal fueron los medicamentos. Se recopilaron los datos sociales y biológicos, formas de consumo, grupos farmacológicos, manifestaciones clínicas, aspectos de la toxicocinética y la toxicodinamia. Resultados: Los consumidores de medicamentos con fines de abuso, representaron el 60,14 por ciento de las consultas por consumo de sustancias con fines de abuso. El grupo etario de hasta 20 años fue el de mayor consumo (360 consultas; 62,28 por ciento) y el sexo masculino el más frecuente (447 pacientes; 77,3 por ciento). La combinación de medicamentos más alcohol fue la forma de consumo más empleada (292 consultas; 50,5 por ciento). La carbamazepina fue el medicamento más consumido (305 consultas; 52,7 por ciento). Conclusiones: Predominó la intoxicación aguda en el grupo etario de 10-20 años y del sexo masculino. La ingestión de medicamentos más alcohol, fue la forma de consumo más empleada. El grupo farmacológico más utilizado con fines no médicos, fue el de los anticonvulsivantes (carbamazepina), seguido de las benzodiacepinas y los opiáceos. Las manifestaciones clínicas que predominaron fueron del sistema neurológico, seguido del cardiovascular y el digestivo(AU)

ABSTRACT Introduction: The consumption of substances for the purpose of abuse, including drugs, has increased worldwide. Objective: To characterize patients treated for acute intoxications due to drugs consumed for abuse purposes. Methods: The universe was constituted by consultations of 961 patients, made to the emergency toxicology information service of the National Center of Toxicology, during the period from 2010 to 2014. They were all acute intoxications due to the consumption of substances for the purpose of abuse. The series included 578 patients with acute intoxications for abuse, where the causative agent was medication. We collected social and biological data, forms of consumption, pharmacological groups, clinical manifestations, aspects of toxicokinetics and toxicodynamics. Results: Consumers of medications for the purpose of abuse accounted for 60.14 percent of consultations for the consumption of substances for the purpose of abuse. The age group of up to 20 years consumed the most (360 consultations, 62.28 percent) and the most frequent was the male sex (447 patients, 77.3 percent). The combination of drugs plus alcohol was the most used form of consumption (292 consultations, 50.5 percent). Carbamazepine was the most commonly used medication (305 consultations, 52.7 percent). Conclusions: Acute intoxication predominated in the age group of 10-20 years and of the male sex. The ingestion of drugs plus alcohol was the most used form of consumption. The most used pharmacological group for non-medical purposes was the anticonvulsant group (carbamazepine), followed by benzodiazepines and opiates. The clinical manifestations that predominated were of the neurological system, followed by cardiovascular and digestive(AU)

Nasal administration of the neuroprotective candidate NeuroEPO to healthy volunteers: a randomized, parallel, open-label safety study.

BACKGROUND: Delivery of therapeutic agents as erythropoietin (EPO) into Central Nervous System through intranasal route could benefit patients with neurological disorders. A new nasal formulation containing a non-hematopoietic recombinant EPO (NeuroEPO) has shown neuroprotective actions in preclinical models. In the current study, the safety of NeuroEPO was evaluated for the first time in humans. METHODS: A phase I, randomized, parallel, open-label study was carried out in healthy volunteers. They received, intranasally, 1 mg of NeuroEPO every 8 h during 4 days (Group A) or 0.5 mg of NeuroEPO (Group B) with the same schedule. The working hypothesis was that intranasal NeuroEPO produce <10% of severe adverse reactions in the evaluated groups. Therefore, a rigorous assessment of possible adverse events was carried out, which included tolerance of the nasal mucosa and the effect on hematopoietic activity. Clinical safety evaluation was daily during treatment and laboratory tests were done before and on days 5 and 14 after starting treatment. RESULTS: Twenty-five volunteers, 56% women, with a mean age of 27 yrs. were included. Twelve of them received the highest NeuroEPO dose. Twenty types of adverse events occurred, with headache (20%) and increase of hepatic enzymes (20%) as the most reported ones. Nasopharyngeal itching was the most common local event but only observed in four patients (16%), all of them from the lowest dose group. About half of the events were very probably or probably caused by the studied product. Most of the events were mild (95.5%), did not require treatment (88.6%) and were completely resolved (81.8%). No severe adverse events were reported. During the study the hematopoietic variables were kept within reference values. CONCLUSIONS: NeuroEPO was a safe product, well tolerated at the nasal mucosa level and did not stimulate erythropoiesis in healthy volunteers. TRIAL REGISTRATION: Cuban Public Registry of Clinical Trials RPCEC00000157 , June 10, 2013.

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.

Crecimiento bacteriano en la úlcera del pie diabético previo al uso de Heberprot-P / Bacterial growth in diabetic foot ulcer prior to Heberprot-P

Objetivo: determinar el comportamiento del crecimiento microbiológico en las úlceras de pie diabético, previo al uso del Heberprot-P. Métodos: estudio descriptivo mediante la revisión de las historias clínicas de 52 pacientes, incluidos en los ensayos clínicos fase I y II del Heberprot-P en la úlcera de pie diabético. Se tomaron 63 muestras y se consideró el estudio microbiológico realizado en cualquier momento de su evolución, en el período de estudio.Resultados: cuatro muestras resultaron negativas y 29 positivas a Staphylococcus aureus meticillin resistente, que fue el germen más frecuentemente cultivado, por lo que un tercio de los pacientes requirió tratamiento antimicrobiano. Conclusiones: se recomienda realizar estudio microbiológico a todos los pacientes con úlcera de pie diabético, previo al uso de Heberprot-P aun cuando no existan evidencias clínicas de infección local.(AU)

Objective: to determine the microbiological growth behavior in diabetic foot ulcers, pre Heberprot-P. Methods: descriptive study was conducted by reviewing the medical records of 52 patients enrolled in Heberprot-P clinical trials phase I and II of diabetic foot ulcer. 63 samples were taken and microbiological study was considered at any point in its evolution in the study period. Results: four samples were negative and 29 positive to Staphylococcus aureus meticillin resistant, which was the most frequently cultivated germ, so that one third of the patients required antibiotic treatment. Conclusions: microbiological study is recommended to all patients with diabetic foot ulcer, prior to the use of Heberprot-P even when there is no clinical evidence of local infection(AU)

Crecimiento bacteriano en la úlcera del pie diabético previo al uso de Heberprot-P / Bacterial growth in diabetic foot ulcer prior to Heberprot-P

OBJETIVO: determinar el comportamiento del crecimiento microbiológico en las úlceras de pie diabético, previo al uso del Heberprot-P. MÉTODOS: estudio descriptivo mediante la revisión de las historias clínicas de 52 pacientes, incluidos en los ensayos clínicos fase I y II del Heberprot-P en la úlcera de pie diabético. Se tomaron 63 muestras y se consideró el estudio microbiológico realizado en cualquier momento de su evolución, en el período de estudio. RESULTADOS: cuatro muestras resultaron negativas y 29 positivas a Staphylococcus aureus meticillin resistente, que fue el germen más frecuentemente cultivado, por lo que un tercio de los pacientes requirió tratamiento antimicrobiano. CONCLUSIONES: se recomienda realizar estudio microbiológico a todos los pacientes con úlcera de pie diabético, previo al uso de Heberprot-P aun cuando no existan evidencias clínicas de infección local.

OBJECTIVE: to determine the microbiological growth behavior in diabetic foot ulcers, pre Heberprot-P. METHODS: descriptive study was conducted by reviewing the medical records of 52 patients enrolled in Heberprot-P clinical trials phase I and II of diabetic foot ulcer. 63 samples were taken and microbiological study was considered at any point in its evolution in the study period. RESULTS: four samples were negative and 29 positive to Staphylococcus aureus meticillin resistant, which was the most frequently cultivated germ, so that one third of the patients required antibiotic treatment. CONCLUSIONS: microbiological study is recommended to all patients with diabetic foot ulcer, prior to the use of Heberprot-P even when there is no clinical evidence of local infection.

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.

Bioequivalencia de una formulación cubana de carbamazepina con el producto líder / Bioequivalent of a Cuban formula of Carbamazepine with the leader product

Se demostró la intercambiabilidad terapéutica mediante un estudio de bioequivalencia en 25 voluntarios sanos de una formulación cubana de carbamazepina de 200 mg con respecto al producto innovador (Tegretol®), en condiciones de administración a dosis única; el diseño experimental fue cruzado a doble ciegas y aleatorizado; el periodo de lavado fue de 15 días. Las extracciones para la obtención del plasma, se realizaron a las 0; 0,5; 1; 1,5; 2; 3; 4; 6; 8; 10; 12; 16; 20; 24; 48; 72; 96 y 120 h. Para el análisis se empleó un método analítico por cromatografía líquida de alta eficiencia, isocrático en fase reversa con detección ultravioleta. Se estimaron mediante técnicas no compartimentales los parámetros farmacocinéticos (AUC0-t, AUCt-¥, Cmax, Tmax y T1/2) representativos de la biodisponibilidad en magnitud y velocidad. Sobre la base de los resultados estadísticos, ambas formulaciones resultaron bioequivalentes(AU)

It was possible to demonstrate the therapeutic interchange level by means of a bioequivalence study in 25 healthy volunteers of a Cuban formula of Carbamazepine(200 mg) according to the innovative product (Tegretol®) for a administration of unique dose; the experimental design was of crossed, double-blind and random type; washing period was of 15 days. Extractions for plasma obtaining were performed at 0, 0,5, 1, 1,5, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 and 120 hours. In analysis we used an analytical method by high performance liquid chromatography, isocratic type in reverse phase with UV detection. By means of non-compartment techniques pharmacokinetic parameters (AUC0-t, AUC t-¥, Cmax, Tmax, and T½) were estimated, which are representative of bioavailability in magnitude and speed. On the base of statistical results, both formulae were bioequivalent(AU)

Bioequivalencia de una formulación cubana de carbamazepina con el producto líder / Bioequivalent of a Cuban formula of Carbamazepine with the leader product

Se demostró la intercambiabilidad terapéutica mediante un estudio de bioequivalencia en 25 voluntarios sanos de una formulación cubana de carbamazepina de 200 mg con respecto al producto innovador (Tegretol®), en condiciones de administración a dosis única; el diseño experimental fue cruzado a doble ciegas y aleatorizado; el periodo de lavado fue de 15 días. Las extracciones para la obtención del plasma, se realizaron a las 0; 0,5; 1; 1,5; 2; 3; 4; 6; 8; 10; 12; 16; 20; 24; 48; 72; 96 y 120 h. Para el análisis se empleó un método analítico por cromatografía líquida de alta eficiencia, isocrático en fase reversa con detección ultravioleta. Se estimaron mediante técnicas no compartimentales los parámetros farmacocinéticos (AUC0-t, AUCt-¥, Cmax, Tmax y T1/2) representativos de la biodisponibilidad en magnitud y velocidad. Sobre la base de los resultados estadísticos, ambas formulaciones resultaron bioequivalentes.

It was possible to demonstrate the therapeutic interchange level by means of a bioequivalence study in 25 healthy volunteers of a Cuban formula of Carbamazepine(200 mg) according to the innovative product (Tegretol®) for a administration of unique dose; the experimental design was of crossed, double-blind and random type; washing period was of 15 days. Extractions for plasma obtaining were performed at 0, 0,5, 1, 1,5, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 and 120 hours. In analysis we used an analytical method by high performance liquid chromatography, isocratic type in reverse phase with UV detection. By means of non-compartment techniques pharmacokinetic parameters (AUC0-t, AUC t-¥, Cmax, Tmax, and T½) were estimated, which are representative of bioavailability in magnitude and speed. On the base of statistical results, both formulae were bioequivalent.