Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal. / La grossesse s'accompagne d'une réponse pressive diminuée aux stimuli d'agents vasoactifs. Les mécanismes responsables de ce changement demeurent peu connus. Afin de mieux les comprendre, nous avons évalué la dépendance du muscle lisse vasculaire au calcium extracellulaire lors de sa contraction. Plus spécifiquement, nous avons mesuré la fonction des canaux calciques dépendants du voltage, voie d'entrée importante de calcium extracellulaire, sur des anneaux aortiques de rates gestantes à terme et des rates vierges servant de témoins. Dans un premier temps, différentes concentrations de calcium extracellulaire ont été utilisées afin de mesurer les réponses contractiles à la phényléphrine, un agoniste a-adrénergique. L'effet maximal de la phényléphrine diminue significativement en présence de 0.5 mM et 0.25 mM de calcium dans la solution physiologique chez les témoins. Par contre, chez les gestantes, cette diminution n'apparaît qu'en présence de 0.25 mM de calcium. Ces résultats suggèrent une sensibilité diminuée des vaisseaux sanguins au calcium extracellulaire au cours de la grossesse. Les contractions des anneaux à la phényléphrine, mesurées en l'absence de calcium dans la solution physiologique, s'avèrent plus importantes chez la rate gestante que chez la rate vierge. Ces réponses sont pratiquement absentes chez les deux groupes d'animaux lorsque le KC1, un agent dépolarisant, est utilisé comme stimulant. Dans un deuxième temps, l'effet de différents bloqueurs de canaux calciques a été étudié sur des anneaux aortiques de rates gestantes et vierges. Le D-600, un bloqueur de canaux calciques de la famille des phénylalkylamines, inhibe les réponses au CaC12 dans les deux groupes d'anneaux étudiés. 11 induit une inhibition de la réponse à la phényléphrine et au KC1 proportionnellement à sa concentration dans le milieu physiologique. Cependant, son effet est moins prononcé sur les tissus provenant des rates gestantes que ceux des vierges et ce pour les deux agonistes. La cinnarizine, un bloqueur de canaux calciques, de type pipérazine, est, pour sa part, plus efficace pour bloquer les réponses contractiles au KC1 et à la phényléphrine sur les anneaux aortiques provenant de rates vierges par rapport aux anneaux de rates gestantes. Troisièmement, l'effet de bloqueurs de la phosphodiestérase a été évaluée. L'amrinone, décrite comme un bloqueur des canaux calciques opérés par un récepteur, bloque aussi la phosphodiestérase et engendre une réduction similaire de la contraction maximale à la phényléphrine et au KC1 dans les deux groupes étudiés. L'IBMX (1-methy1-3-isobutylxanthine), un inhibiteur non-spécifique de la phosphodiestérase, s'avère moins apte à diminuer la contraction à la PhE sur les anneaux aortiques de rates gestantes que de rates vierges. Finalement, les taux de captation de 45Ca2+ont été investigués. La captation de 45Ca2+, lorsque mesurée à différents temps, en absence ou en présence d'une stimulation, montre une diminution sur les anneaux aortiques de rates gestantes en comparaison à ceux des rates vierges. Par ailleurs, quand les compartiments intracellulaires de calcium sensibles à la phényléphrine sont vidés, leur remplissage est retardé dans les aortes de rates gestantes. Enfin, la captation de 45Ca2+des deux groupes de tissus, avec ou sans AVP (8arg-vasopressine), n'est pas significativement diminuée. Par contre, l'amrinone induit une diminution de captation de 45Ca2+sur les tissus de rates vierges mais non sur ceux de rates gestantes lorsque la phényléphrine (1 mon) est utilisée. L'ensemble de ces résultats démontre une diminution de l'influx de calcium extracellulaire dans la cellule musculaire lisse vasculaire; résultat d'une possible diminution de l'activité des canaux calciques dépendants du voltage. De plus, nos résultats suggèrent que des mécanismes contrevenants à la contraction semblent inhibés lors de la gestation chez la rate.

Introdução: O tratamento hormonal para amenizar sintomas do climatério é bem conhecido, mas nem sempre pode ser indicado para grande parte das mulheres. Por estes motivos, tem-se testado várias opções de tratamento não hormonal, cujos resultados nem sempre são satisfatórios e conclusivos. Objetivo: Avaliar a eficácia da cinarizina no tratamento dos sintomas climatéricos. Casuística e método: Foram estudadas prospectivamente 62 mulheres climatéricas sintomáticas com predomínio de ondas de calor que preencheram os critérios de inclusão e exclusão com idade variando de 45 a 60 anos, as quais foram avaliadas pelo Índice Menopausal de Kupperman (IMK), e atendidas no Setor de Ginecologia Endócrina e Climatério do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Foram divididas aleatoriamente em dois grupos: S com 27 pacientes (25 mg de Cinarizina a cada 12 hs, v.o., por 6 meses) e M com 35 pacientes (1 comprimido de placebo a cada 12hs, v.o., por 6 meses). Resultados: No grupo S a média etária foi 53,9 anos; 51,9% brancas e 48,1% negras; e no grupo M a média etária foi de 54,7 anos; 51,4% brancas e 48,6% negras. Os níveis pressóricos e o índice de massa corpórea foram semelhantes, entre os grupos. A análise do IMK e suas variantes comparativamente nos grupos S e M nos tempos 0 e 1 foi p=0,235 e p=0,406, respectivamente. Conclusões: A cinarizina foi semelhante ao placebo no alívio dos sintomas do climatério avaliados pelo IMK. Houve melhora significante do sintoma vertigem nas pacientes que receberam cinarizina. / Introduction: The hormonal treatment for relief of climateric symptoms is well-known but most women can not be treated with homones. For this reason several treatments without hormones has been evaluated with no conclusive results yet. Objective: Evaluate the efficacy of cinnarizine in the treatment of climacteric symptoms. Casuistry and Method: Were prospectively studied 62 symptomatic climacteric women with prevalence of hot flashes who met the inclusion and exclusion criteria aged from 45 to 60 years, evaluated by Kupperman\'s Menopause Index (KMI) attended at the Sector of Endocrinology Gynecology and Climacteric from the Medical School of the Hospital das Clinicas of the University of São Paulo. The subjects were divided alleatory in two: 27 patients Group S (Cinnarizine 25mg every 12h) and Group M with 35 (1 Placebo each 12h). Results: In group S the mean age was 53.9 years; 51.9% white and 48.1% black; and in group M the mean age was 54.7 years; 51.4% white and 48.6% black. Blood pressure levels and body mass index were similar in both groups. The analysis of the KMI and their variables comparision betwen groups (S and M) at time 0 and 1 was p=0.235 and p=0.406 respectively. Conclusions: Cinnarizine was similar to placebo for recipe of climacteric symptoms evaluated by KMI. There was significant improvement of symptom vertigo in patients treated with cinnarizine.

Introdução: O tratamento hormonal para amenizar sintomas do climatério é bem conhecido, mas nem sempre pode ser indicado para grande parte das mulheres. Por estes motivos, tem-se testado várias opções de tratamento não hormonal, cujos resultados nem sempre são satisfatórios e conclusivos. Objetivo: Avaliar a eficácia da cinarizina no tratamento dos sintomas climatéricos. Casuística e método: Foram estudadas prospectivamente 62 mulheres climatéricas sintomáticas com predomínio de ondas de calor que preencheram os critérios de inclusão e exclusão com idade variando de 45 a 60 anos, as quais foram avaliadas pelo Índice Menopausal de Kupperman (IMK), e atendidas no Setor de Ginecologia Endócrina e Climatério do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Foram divididas aleatoriamente em dois grupos: S com 27 pacientes (25 mg de Cinarizina a cada 12 hs, v.o., por 6 meses) e M com 35 pacientes (1 comprimido de placebo a cada 12hs, v.o., por 6 meses). Resultados: No grupo S a média etária foi 53,9 anos; 51,9% brancas e 48,1% negras; e no grupo M a média etária foi de 54,7 anos; 51,4% brancas e 48,6% negras. Os níveis pressóricos e o índice de massa corpórea foram semelhantes, entre os grupos. A análise do IMK e suas variantes comparativamente nos grupos S e M nos tempos 0 e 1 foi p=0,235 e p=0,406, respectivamente. Conclusões: A cinarizina foi semelhante ao placebo no alívio dos sintomas do climatério avaliados pelo IMK. Houve melhora significante do sintoma vertigem nas pacientes que receberam cinarizina. / Introduction: The hormonal treatment for relief of climateric symptoms is well-known but most women can not be treated with homones. For this reason several treatments without hormones has been evaluated with no conclusive results yet. Objective: Evaluate the efficacy of cinnarizine in the treatment of climacteric symptoms. Casuistry and Method: Were prospectively studied 62 symptomatic climacteric women with prevalence of hot flashes who met the inclusion and exclusion criteria aged from 45 to 60 years, evaluated by Kupperman\'s Menopause Index (KMI) attended at the Sector of Endocrinology Gynecology and Climacteric from the Medical School of the Hospital das Clinicas of the University of São Paulo. The subjects were divided alleatory in two: 27 patients Group S (Cinnarizine 25mg every 12h) and Group M with 35 (1 Placebo each 12h). Results: In group S the mean age was 53.9 years; 51.9% white and 48.1% black; and in group M the mean age was 54.7 years; 51.4% white and 48.6% black. Blood pressure levels and body mass index were similar in both groups. The analysis of the KMI and their variables comparision betwen groups (S and M) at time 0 and 1 was p=0.235 and p=0.406 respectively. Conclusions: Cinnarizine was similar to placebo for recipe of climacteric symptoms evaluated by KMI. There was significant improvement of symptom vertigo in patients treated with cinnarizine.

In this thesis, the incorporation of drug loaded mesoporous magnesium carbonate as an excipient for the additive manufacturing of oral tablets by fused deposition modeling was investigated. Cinnarizine, a BCS class II drug, was loaded into the pores of the mesoporous material via a soaking method, corresponding to a drug loading of 8.68 wt%. DSC measurements on the loaded material suggested that the drug was partially crystallized after incorporation, meanwhile the XRD diffractogram implied that the drug was in a state lacking long range order. The drug loaded material was combined with two pharmaceutical polymers, Aquasolve LG and Klucel ELF, and extruded into filaments with a single screw extruder. Filaments of Klucel ELF and drug loaded Upsalite (30:70 wt% ratio) were successfully implemented for the printing oral tablets, in contrast to the Aquasolve LG based filaments which were difficult to print due to thickness variations and non-uniform material distributions. The drug content obtained by TGA suggested drug loadings of 7.71 wt% and 2.23 wt% in the drug loaded Upsalite and tablets respectively. Dissolution studies using an USP II apparatus showed a slower API-release from the tablets in comparison to the crystalline drug, most probably due to slow diffusion of drug species through the polymeric matrix. For future studies, pharmaceutical polymers with higher aqueous solubility should be investigated in order to thoroughly examine the potential of utilizing the immediate release property of Upsalite.