ABSTRACT
AIM: The aim of this study was to add robustness and provide further evidence on the bioequivalence, safety and immunogenicity between MB02 and reference bevacizumab. No similar study has been performed before with a biosimilar monoclonal antibody. METHODS: Population analysis by pooling data from three independent pharmacokinetic (PK) studies was performed. The studies had a single-dose, double-blind, three-arm, parallel-group design and two studies, MB02-A-02-17 and MB02-A-05-18, compared MB02 to EU- and US-bevacizumab in Caucasian subjects, while study MB02-A-04-18 compared MB02 and EU-bevacizumab in Japanese participants. Primary endpoints included maximum observed serum concentration (Cmax ), area under the serum concentration-time curve (AUC) from time zero and extrapolated to infinity (AUC0-∞ ) and AUC from time zero to the time of last quantifiable concentration (AUC0-t ). Secondary endpoints included other PK parameters, safety and immunogenicity. A sensitivity analysis using actual protein concentration as a correction factor was applied to primary PK parameters. RESULTS: Point estimates and 90% confidence intervals for the geometric mean ratios of primary PK parameters for MB02, EU- and US-bevacizumab were all contained within the predefined bioequivalence margins (80%-125%) for all pairwise comparisons. The same results for all pairwise comparisons were observed when protein-corrected primary PK parameters were analyzed. Safety and immunogenicity were similar between MB02 and the EU- and US-reference bevacizumab in healthy subjects. CONCLUSIONS: This pooled analysis of three comparable PK studies further supports the bioequivalence of biosimilar MB02 to EU- and US-reference bevacizumab. No clinically meaningful differences in safety or immunogenicity were observed.
Subject(s)
Biosimilar Pharmaceuticals , Humans , Antibodies, Monoclonal , Area Under Curve , Bevacizumab/adverse effects , Bevacizumab/pharmacokinetics , Biosimilar Pharmaceuticals/adverse effects , Biosimilar Pharmaceuticals/pharmacokinetics , Therapeutic EquivalencyABSTRACT
During the Late Cretaceous and early Cenozoic the Earth experienced prolonged climatic cooling most likely caused by decreasing volcanic activity and atmospheric CO2 levels. However, the causes and mechanisms of subsequent major global warming culminating in the late Paleocene to Eocene greenhouse climate remain enigmatic. We present deep and intermediate water Nd-isotope records from the North and South Atlantic to decipher the control of the opening Atlantic Ocean on ocean circulation and its linkages to the evolution of global climate. The marked convergence of Nd-isotope signatures 59 million years ago indicates a major intensification of deep-water exchange between the North and South Atlantic, which coincided with the turning point of deep-water temperatures towards early Paleogene warming. We propose that this intensification of Atlantic overturning circulation in concert with increased atmospheric CO2 from continental rifting marked a climatic tipping point contributing to a more efficient distribution of heat over the planet.
Subject(s)
Cefotaxime/therapeutic use , Cephalosporin Resistance , Cephalosporins/therapeutic use , Meningitis, Pneumococcal/drug therapy , Streptococcus pneumoniae/drug effects , Anti-Bacterial Agents/therapeutic use , Cefotaxime/adverse effects , Cefotaxime/pharmacology , Cephalosporins/adverse effects , Cephalosporins/pharmacology , Drug Therapy, Combination/therapeutic use , Humans , Infant , Male , Vancomycin/therapeutic useABSTRACT
Three cases of dilated cardiomyopathy manifested at 2, 5, and 13 months of age are reported. The clinical, radiographic, electrocardiographic, echocardiographic and angiocardiographic findings are analyzed. The follow up during 11, 14 and 16 years is described. After several years of the onset, 2 patients recovered a normal cardiac function. The third patient required a cardiac transplant when he was 9 years old, and now, after 2 and a half years, he is healthy, without congestive heart failure. Current references about indications of cardiac transplant in this disease are reviewed. We got the following conclusion: In patients with dilated cardiomyopathy, at least in those who begin before 2 years, the indication and the time of the cardiac transplant have to be established by individual valuation of each case, considering the follow up of the risk's criteria, mainly the congestive heart failure.
Subject(s)
Cardiomyopathy, Dilated/physiopathology , Cardiomyopathy, Dilated/therapy , Cardiomyopathy, Dilated/surgery , Child , Follow-Up Studies , Heart Transplantation , Humans , InfantABSTRACT
The cases of tuberculosis in the Pediatric Units of the Basque Autonomous Community during the period of 1980-89 were studied. The annual incidence rate in the 0-4 year old age group was 5.8 per 100.00 in Biscay (95% confidence interval: 4.0-7.6), 5.9 (2.3-9.5) in Alava and 16.7 (12.7-20.7) in Guipúzcoa. Out of the 263 registered cases, 55 (21%) corresponded to meningitis and/or miliaria, 194 (74%) to respiratory tuberculosis and 14 (5%) to other clinical forms. Of these cases, the diagnosis in 83 (32%) was based on results from microbiological cultures, in 8 (3%) on histological examinations and in the remaining 172 (65%) on other diagnostic criteria. In 226 cases (86%) no scars were found nor were there any antecedents of BCG vaccination. In 32 patients (12%), there were scars or antecedents of BCG vaccinations and in 5 cases no information was available. The estimated protective effect of the BCG vaccination in the 0-4 year old group was 88% and in the 5-14 year old group 63%. We recommend that the efficiency of the BCG vaccination program be studied in order to assess the need of this program.
Subject(s)
BCG Vaccine/administration & dosage , Tuberculosis/epidemiology , Child , Child, Preschool , Humans , Infant , Infant, Newborn , Spain/epidemiology , Tuberculosis/immunology , Tuberculosis/mortality , VaccinationABSTRACT
A new simple micro-erythrocyte sedimentation rate method in newborns and infants is proposed. The results on 300 determinations are exposed. Results of the classic method and this micro-method for erythrocyte sedimentation rate as far as 20 mm. per hour, may differ in +/- 3.72 in 68.27% and in +/- 7.44 in 95.45% of the cases.
Subject(s)
Blood Sedimentation , Infant, Newborn, Diseases/blood , Citrates , Female , Humans , Infant, Newborn , Male , Time FactorsABSTRACT
Clinical, hemodynamic and pathologic findings of three patients with total anomalous pulmonary venous drainage to the portal vein system are presented. Some of the findings are emphasized because of its rarity in previous reports. These are: 1) Cyanosis was mild. 2) There was some obstruction of the foramen ovale, besides the obstruction at the portal system level. In two patients gastrointestinal bleeding and analitical evidence of renal failure, were found, both findings not previously reported to our knowledge.
Subject(s)
Arteriovenous Malformations/diagnosis , Pulmonary Veins/abnormalities , Angiocardiography , Arteriovenous Malformations/diagnostic imaging , Electrocardiography , Female , Hemodynamics , Humans , Infant, Newborn , Male , Pulmonary Veins/diagnostic imagingABSTRACT
One case of anomalous origin of the right pulmonary artery from ascending aorta is reported. The anomalies in the origin of the main pulmonary branches are classified in Type A: Anomalous origin of a pulmonary artery from ascending aorta; Type B: Anomalous origin of a pulmonary artery from the aortic arch through a ductus arteriosus, and Type C: Absence of a pulmonary artery with pulmonary vasculariation through systemic arteries arising from descending aorta. The normal embryology of the 6th. aortic arch and the pulmonary branches and the differents theories postulated about the embryopathogenesis of these malformations are reviewed. The outstanding clinical, hemodynamic, angiocardiographic and surgical features are also discussed.
Subject(s)
Aorta/abnormalities , Pulmonary Artery/abnormalities , Aorta, Thoracic/diagnostic imaging , Female , Humans , Infant, Newborn , Pulmonary Artery/diagnostic imaging , RadiographyABSTRACT
The morphologic changes of the atrio-ventricular valve in 30 cases of lone ventricle or similar anomalies have been: 1. Common atrio-ventricular valve (8 cases); 2. Abnormally small left atrio-ventricular valve (15 cases) 3. Parachute-like left atrio-ventricular valve (5 cases); 4. Atresia of one of the atrio-ventricular valves (2 cases); 5. Atrio-ventricular valves corresponding to a tricuspid valve which were bicuspid (6 cases); 6. Accessory valvular orifices (5 cases); 7. Valvular clefts (3 cases); 8. Insufficient valvular tissue (4 cases); 9. Accessory valvular tissue (7 cases); 10. Anomalies of orientation of the anterior in relation with the posterior mitral valve leaflet (7 cases); 11. Peculiar orientation of the valve in relation with the outflow tract, resulting in a "functional overlap" (1 case); 12. Muscle column on the posterior wall of the main ventricular chamber (18 cases); 13. Papillary muscle distribution alterations (29 cases). The embryologic, diagnostic and surgical signification of all these anomalies were considered.
