Comparative dissolution profiles of two anti-emetic delayed release dosage forms of doxylamine and pyridoxine: Xonvea® tablets vs. Cariban® capsules.

OBJECTIVE: Nausea and vomiting of pregnancy is a common disease that affects many women suffering from mild to severe symptoms. Amongst the different treatments, a fixed dose combination of doxylamine and pyridoxine has been proven safe and effective although the mechanism of action is not well established. There are different pharmaceutical dosage forms in the European market. The objective of this study was to compare the characteristics of a capsule formulation, Cariban® and a tablet formulation, Xonvea® to evaluate the potential impact of their release profiles on their onset of action. MATERIALS AND METHODS: 10 mg/10 mg of doxylamine succinate/pyridoxine hydrochloride capsules (Cariban®) and tablets (Xonvea®) were used as reference materials. Appearance, mass, composition, and in vitro dissolution profiles were compared. Bibliographic data from 4 pharmacokinetic studies of Xonvea® and 1 pharmacokinetic study of Cariban® was reviewed. RESULTS: In vitro dissolution studies showed significant differences in dissolution profiles of tablets and capsules. The later exhibiting some release of both drug substances in acid conditions followed by a non-complete release after a total of 3 hours while the tablets demonstrated gastro-resistant properties and rapid API release in about 20-30 minutes after the acid stage. Comparison of PK data showed greater Cmax for pyridoxine. CONCLUSIONS: At pH 6.8, complete and faster release of the fixed dose combination for Xonvea® gastro-resistant tablets compared to Cariban® capsules could possibly explain the greater Cmax observed in vivo for the tablet's formulation. This could translate into faster onset of action and relief of nausea for pregnant women taking the tablets vs. the capsules.

Development of a new method for the quantitation of metabolites in the absence of chemically synthetized authentic standards.

A new method for the quantification of metabolites in the absence of a chemically synthetized authentic standard is described herein. Metabolites to be used as reference standards were obtained biologically from microsomes incubation. The method is a stepwise process in which, only the radiolabeled (14C) and non-radiolabeled parent compound are required. Briefly, the separation and principles of equimolar detection of LC-radioactivity were applied and, a calibration curve of the 14C-parent compound was used to quantify the formation of its 14C-metabolite. In turn, serial dilutions of this 14C-metabolite were the base for the calibration curve that allowed the quantification of the non-radiolabeled metabolite. This method was applied in plasma samples obtained from a dog pharmacokinetic study in which, a PharmaMar compound (lurbinectedin) and its N-desmethylated metabolite were quantified and, the results compared to those obtained by the classical approach (with the chemically synthetized N-desmethylated metabolite). Plasma concentrations obtained with the two methods were very similar, with standard relative errors between -11% to -4%. Similar, main pharmacokinetic parameters were calculated with the concentrations obtained either thru this method or by using a chemically synthetized authentic standard.

Biocompatibility of alendronate-loaded acrylic cement for vertebroplasty.

This paper reports a biological evaluation of a non-resorbable acrylic cement loaded with alendronate for the treatment of osteoporotic vertebral compression fractures. The cement formulation was based on polymethyl methacrylate and acrylic monomers; one of these had covalently linked vitamin E residues. The same cement in the absence of alendronate was used as a control. The setting of the charged cement presented a maximum polymerization temperature of 44°C, a setting time of 24 min, a residual monomer content lower than 3 wt.%, a compressive strength of 99±10 MPa and an elastic modulus of 1.2±0.2 GPa. Cytotoxicity studies using human osteoblast cultures revealed that the leachable substances of the alendronate loaded cement collected between 1 and 7 days decreased cell viability to values lower than 80%. However, morphological changes and cellular damage in cells produced by the extracts decreased with the leak time. Cell adhesion and growth on charged cement was significantly lower than on the control. Implantation of the cement paste in the intra-femoral cavity of rabbits showed that initially the osteogenic activity was evident for the cement charged with alendronate, and the osteosynthesis process took place mainly in the trabeculae and was manifested by the presence of a non-mineralised osseous spicule. The interface between material and adjacent bone tissue was initially characterized by a variable fibrous response that in many cases it appeared reduced to thin connective tissue after a 24-week-period.

Estudio de la regeneración ósea mediante la implantación endomedular de biomateriales / Study of bone regeneration by endomedullar implantation of biomaterials

Ante una pérdida ósea en la clínica tras un accidente, un tumor ouna infección se plantean diferentes posibilidades de reconstrucción.Un modelo experimental válido para el estudio de la osteorregeneraciónse basa en la resección de un defecto diafisario suficiente para impedirla reparación espontánea. La originalidad del tema elegido se cimentaen la utilización, in vivo en un animal de talla media (conejo),de un biomaterial que está compuesto de una base estructural de poli(metacrilato de metilo) (PMMA) (serie 1), al que se añade hidroxiapatita(HA) como material osteoconductor (serie 2) y además, un factor decrecimiento fibroblástico (FGF) como osteoinductor. (serie 3). Tras 2, 4y 8 semanas después de la resección (20mm) e implantación endomedularde los tres tipos de barras (25mm de longitud), se procede al análisisradiológico e histológico. Parece que la reparación esta influida porpropiedades mecánicas de estabilidad, fuerza y carga. La regeneraciónósea en el presente modelo sigue un patrón de desarrollo que va desdelos extremos de resección diafisario a la zona media y siempre a expensasde la cortical radial. De los tres modelos de barras utilizados, losformados por PMMA, HA y bFGF, presentan un proceso de reparaciónmás avanzado, hecho observado tanto radiológica como histológicamente

Faced with bone loss after an accident, different possibilities for reconstructioncan be considered dependent on presence of a tumour orinfection. A valid experimental model for the study of osteoregenerationis based on the resectioning of a faulty diaphyseal, sufficientlydamaged to impede spontaneous healing. The origins of the chosen topicare founded in vivo in an animal of average size (a rabbit); of biomaterialthat is composed of a structured basis polymethyl methacrylate(PMMA) (series 1), to which hidroxyapatite (HA) is added asosteoconductor material (series 2) and also a fibroblast growth factor(FGF) as osteoinductor. (Series 3). 2, 4 and 8 weeks after the resection(20mm) and endomedular implants of the three types of bars (25mm oflength), radiological and histological analysis is carried out. This analysisis done without decalcification. The histological technique ‘Von Kossaand Goldner’ is used for this histological study. It seems that healingis influenced by mechanical properties of stability, force and load. Inthe present model, the osseous regeneration follows a definite path thatgoes from the extremities of diaphyseal resection to the middle areaand is always at the expense of the radial cortical. Of the three types ofbars used, those formed by PMMA, HA and FGF, show a more advancedrepair process, visible as much in radiological analysis as histological

Response of GABAergic cells in the deep mesencephalic nucleus to dopaminergic cell degeneration: an electrophysiological and in situ hybridization study.

The deep mesencephalic nucleus (DMN) is a large midbrain reticular region located between the substantia nigra compacta and the superior colliculus. It contains GABAergic cells that share striatal afferents, thalamic and collicular efferents, as well as neurochemical and electrophysiological similarities, with those of the substantia nigra reticulata. In the present paper we used electrophysiological (firing rate and firing pattern) and morphological (densitometric analysis of in situ hybridization histochemical labeling for glutamic acid decarboxylase (GAD)65 and GAD67 mRNA) techniques, to study the response of DMN GABAergic cells to the degeneration of nigral dopaminergic cells. Our results showed that unilateral dopaminergic cell loss (after injection of 6-hydroxydopamine in the medial forebrain bundle) induces a bilateral and symmetrical increase in both firing rate and GAD67 mRNA levels and a decrease in GAD65 mRNA levels. These findings support the involvement of DMN GABAergic cells in the basal ganglia modifications that follow dopaminergic cell loss, also suggesting its participation in the pathophysiology of Parkinson's disease. The symmetry of effects, together with its recently reported bilateral projections to the thalamus and superior colliculus, suggest that unlike substantia nigra reticulata, DMN is involved in the interhemispheric regulation of basal ganglia, probably keeping their functional symmetry even after asymmetric lesions.

Chronopharmacokinetics and calcium in the prevention of gentamicin-induced nephrotoxicity in rabbits.

The study used 36 New Zealand white rabbits organized into three groups of 12 animals each. Group I received gentamicin; Group II received joint administration of gentamicin and calcium chloride and Group III received gentamicin, calcium chloride and verapamil. All the drugs were administered over 16 day periods. Groups I and II were divided in two subgroups, one subgroup receiving the treatment in winter and the other in summer. The results obtained for Group I indicate that there is an influence of the seasonal period on the gentamicin elimination and/or distribution. Mean plasma levels of the antibiotic at steady-state as well as the amounts of gentamicin accumulated in renal tissue are higher in winter than in summer. On the other hand, when calcium was administrated with the antibiotic, no significant circannual variations were observed in the renal toxicity of gentamicin. Under our study conditions the presence of calcium diminishes gentamicin plasma levels and the amount accumulated in kidney. Calcium, probably, generated a diminution in renal damage and consequently gentamicin renal excretion increases. The differences between Group II and Group III are due to the effect of verapamil. This agent blocks the calcium channels reducing the calcium protective effect on the nephrotoxicity of gentamicin.

Histochemical and immunohistochemical detection of neurons that produce nitric oxide: effect of different fixative parameters and immunoreactivity against non-neuronal NOS antisera.

This study focused on two points concerning the histochemical and immunohistochemical detection of neurons that produce nitric oxide (NO): (a) the effect of fixation and other methodological parameters on the staining pattern of both NADPH-diaphorase (NADPH-d) histochemistry and nitric oxide synthase (NOS) immunohistochemistry, and (b) the possibility that neurons display immunoreactivity against NOS antisera obtained from non-neuronal sources. Frontal sections of rat brains, fixed with 4% paraformaldehyde according to different protocols, were processed for single and double labeling using NADPH-d histochemistry and neuronal (nNOS), macrophagic (macNOS), and endothelial (eNOS) NOS immunohistochemistry. Our results show that variations in the fixative schedule, even within standard parameters, produce qualitative and quantitative changes in NADPH-d labeling. The effect of fixative on weakly stained neurons is different from that on heavily stained neurons. In subfixed brains, a large number of NOS-positive neurons lose their NADPH-d activity, whereas NOS immunolabeling remains unaltered. This finding may be particularly interesting in morphological studies that compare NADPH-d activity under experimental conditions that can affect brain perfusion. On the other hand, many cortical and subcortical neurons show macNOS immunoreactivity, most of it colocalized with nNOS.

High pressure liquid chromatographic determination of the new non-steroidal anti-inflammatory agent butibufen.

High performance liquid chromatography (HPLC) method for the determination and validation of a new non-steroidal anti-inflammatory agent, butibufen (CAS 55837-18-8), microencapsulated butibufen and its pharmaceutical forms--tablets, sachets (microencapsulated butibufen with excipients), microemulsion and cream--is described. Acetonitrile proved to be the best solvent for the extraction of butibufen from its pharmaceutical forms. The results submitted in this paper suggest that the HPLC method for the quantitative determination of butibufen is linear, accurate, precise and sensitive.