Submitted by Cristiane Chim (cristiane.chim@ucpel.edu.br) on 2018-10-18T12:35:20Z No. of bitstreams: 1 Cristofer Magro.pdf: 1053801 bytes, checksum: db19d94f0fa23f19aebb5aacd7011af3 (MD5) / Made available in DSpace on 2018-10-18T12:35:21Z (GMT). No. of bitstreams: 1 Cristofer Magro.pdf: 1053801 bytes, checksum: db19d94f0fa23f19aebb5aacd7011af3 (MD5) Previous issue date: 2018-09-18 / The indiscriminate, and sometimes undue use of benzodiazepines is preponderant worldwide. In Brazil, surveys show that, year after year, there is a considerable increase in the use of this medication by an important part of the population. Older women often make greater use, as they also seek more health services. In primary care, both the prescription by the general practitioner, as well as the renewal requested by mental health specialists, are commonly performed. Chronic use of this medication causes various neurological damage to the patient, as well as the possibility of falls and loss of memory. The present study uses the cross-sectional methodology to evaluate the use of benzodiazepines by users of the Sanga Funda Basic Health Unit located in the Sanga Funda neighborhood of the city of Pelotas, Rio Grande do Sul. A questionnaire will be administered by a health professional. The study is relevant in the face of complications caused by benzodiazepines and the indiscriminate use of the medication, even with controlled prescriptions. / O uso indiscriminado, e por vezes, indevido de benzodiazepínicos é preponderante no mundo todo. No Brasil pesquisas demonstram que ano após ano existe um aumento considerável do uso desta medicação por parte importante da população. Mulheres na terceira idade costumam fazer maior uso, já que também procuram mais os serviços de saúde. Na atenção primária, comumente é realizada tanto a prescrição pelo médico generalista, assim como a renovação solicitada por especialistas em saúde mental. Uso crônico desta medicação causa diversos danos neurológicos ao paciente, assim como possibilidade de quedas e perda de memória. O presente estudo usa a metodologia transversal, para avaliar o uso de benzodiazepínicos por usuários da Unidade Básica de Saúde Sanga Funda, localizada no bairro Sanga Funda do município de Pelotas no Rio Grande do Sul. Será aplicado um questionário por um profissional da saúde. O estudo mostra-se relevante diante das complicações causadas pelos benzodiazepínicos e pelo uso, mesmo que com receitas controladas, indiscriminado da medicação.

The peripheral-type benzodiazepine receptor (PTBR) of trout brain was pharmacologically characterized and pyrethroid interaction with this site investigated. High-affinity binding sites for [³H]PK 11195 were detected in brain membranes of rainbow trout; these shared some of the characteristics of the PTBR of rodent brain (i.e., high affinity for PK 11195 and an endogenous ligand protoporphyrin IX) but were unique in the low affinity for Ro5-4864. Permethrin displaced [³H]PK 11195 binding with micromolar affinity while deltamethrin had less than 50% efficacy at displacement. Thus the PTBR appeared not to be relevant to pyrethroid toxicity in rainbow trout. Pyrethroid interaction with the GABA, receptor was investigated using [³⁵S]TBPS as a radioligand probe and by measurement of GABA-stimulated ³⁶c1- influx in vesicle preparations. At micromolar concentrations, deltamethrin, cypermethrin isomers and other pyrethroids inhibited [³⁵S]TBPS binding by 55- 95% with limited stereoselectivity. Pyrethroids were found to effect a GABAdependent inhibition of [³⁵S]TBPS binding. Ro5-4864, which showed micromolar affinity for the trout PTBR, produced a GABA-modulated interaction with [³⁵S]TBPS binding. These results delineate the reciprocal allosteric interactions between a pyrethroid binding site, a Ro5-4864 binding site, the GABA recognition moiety and the TBPS binding site in trout brain. However, pyrethroids exhibited a modest affinity for this binding site on the GABAA receptor. Pyrethroids indirectly inhibited the GABA-dependent influx of ³⁶Cl⁻into trout brain synaptoneurosomes by increasing the basal uptake of chloride, thereby compromising the ability of the vesicles to respond to applications of GABA. This pyrethroid effect was of nanomolar potency, stereospecific, tetrodotoxinsensitive and mimicked by veratridine. These results suggest that the primary effect of pyrethroids in trout brain, as measured by this assay, was due to an interaction with voltage-dependent sodium channels, increasing sodium conductance and thereby increasing the basal uptake of ³⁶Cl⁻ through a voltagesensitive channel. The convulsant activity of deltamethrin was tested in rainbow trout. The EC₅₀ for convulsant severity was 32 μg /kg body weight. By comparison, pyrethroids at these concentrations in rodents produce no overt toxicity but act as potent proconvulsants. / Graduation date: 1990

INTRODUCCIÓ: Les benzodiazepines figuraren entre els grups terapèutics de més consum (en import) del Sistema Nacional de Salud de l'estat Espanyol durant els anys 1999 i 2000 (Ministerio Sanidad y Consumo, 2000; 2001).L'administració d'aquests fàrmacs a l'organisme es realitza majoritàriament per via oral. Una alternativa a la via oral, per a fàrmacs idònis, és la via transdèrmica. Els avenços en tecnologia farmacèutica han cristal·litzat en l'obtenció, per a determinats fàrmacs, de sistemes d'alliberament transdèrmic (SAT) coneguts amb el nom de pegats transdèrmics.Les característiques de les benzodiazepines les fan estar dins del grup de fàrmacs candidats a ser potencialment usats per aquesta via.En aquest treball s'ha realitzat un estudi comparat del comportament transdèrmic d'una sèrie de benzodiazepines (alprazolam, clobazam, clonazepam, lorazepam, midazolam, pinazepam).OBJECTIUS DEL TREBALL·Realització d'un estudi comparatiu in vitro del pas de diferents benzodiazepines a través de pell humana.·Obtenció de correlacions entre paràmetres transdèrmics i físico-químics a fi i efecte de poder predir comportaments d'altres membres de la sèrie no sotmesos a experimentació.·Estudi preliminar de l'activitat superficial i les cinètiques de penetració de les benzodiazepines seleccionades en monocapes artificials com a metòdica ràpida i senzilla per a l'elecció de penetrants.PLA DE TREBALL I RESULTATS1. Posada a punt de les metòdiques analítiques per cromatografia líquida d'alta eficàcia (CLAE) i la seva validació corresponent dins l'àmbit de concentracions de treball.2. Es van determinar experimentalment paràmetres fisico-químics representatius del pas de fàrmac a través de la pell, com la solubilitat i el logaritme del coeficient de distribució (log D) per a intentar obtenir posteriorment correlacions matemàtiques amb paràmetres transdèrmics.3. A continuació es va procedir a determinar el perfil de permeació in vitro de totes les benzodiazepines estudiades a través de pell humana, amb ajust matemàtic.4. Es van fer estimacions dels paràmetres biofarmacèutics que caracteritzen el pas através de la pell (constant de permeabilitat, flux i període de latència) mitjançant l'ajustat de models representatius.5. A partir dels paràmetres físico-químics i transdèrmics es va intentar de trobar correlacions matemàtiques entre ambdós.6. Amb els fàrmacs de la sèrie seleccionats es va realitzar un estudi preliminar de l'activitat superficial i les cinètiques de penetració en monocapa artificial.7. Finalment es va intentar determinar una possible correlació in vitro pell humana / in vitro activitat superficial.CONCLUSIONSDel treball realitzat s'indiquen a continuació algunes de les conclusions més significatives :- En les condicions de treball emprades en els estudis transdèrmics la solubilitat de les benzodiazepines assajades, estan compreses entre 100.5 microgr·ml-1(Lorazepam) i 16 microgr·ml-1(Midazolam).- No s'ha trobat una relació inversament proporcional entre solubilitat i coeficient de repartiment pel conjunt de benzodiazepines estudiades.- Els valors de log P trobats experimentalment són majoritàriament del mateix ordre que els estimats a partir de les bases de dades KOWWIN i SciFInder 2001.- Les diferencies estadístiques trobades entre els paràmetres de permeació transdèrmica corresponents als fàrmacs assajats, no estan esbiaxades pel factor pell.- La constant de permeabilitat transdèrmica (kp) més elevada la presenta el Midazolam, amb un valor de 13.15·10-3 cm·h-1, i la kp més baixa la presenta l'Alprazolam.- El flux més elevat el presenta el Diazepam.- S'han predit les concentracions plasmàtiques en estat d'equilibri estacionari, a partir dels fluxos experimentals, en cap cas els valors estimats s'han situat dins de marge de concentracions terapèutiques.- S'han realitzat estudis d'activitat superficial amb Alprazolam i Diazepam per avaluar la utilitat de la tècnica com a metòdica predictiva de l'activitat intrínseca de la permeació transdèrmica.- L'increment de la pressió superficial de l'Alprazolam en presència de d-limonè està d'acord amb l'augment de kp que s'observa, en presència del mateix penetrant, en els estudis de penetració transdèrmica. Els increments de pressió estan directament relacionats amb els augments de la constant de permeabilitat.- De les correlacions lineals múltiples assajades per a les benzodiazepines entre log kp i paràmetres físico-químics, el log P, pes molecular i punt de fusió, influeixen significativament en la permeació transdèrmica.- El disseny d'un sistema d'administració transdèrmica d'una benzodiazepina comporta fer un estudi amb l'addició de penetrants a fi d'incrementar el flux transdèrmic d'aquesta sèrie de fàrmacs. / "RELATIONSHIP BETWEEN PREDICTED PERMEATION PARAMETERS BASED ON PHYSICOCHEMICAL PROPERTIES AND EXPERIMENTAL PERMEATION THROUGH HUMAN SKIN FOR A SERIES OF BENZODIAZEPINES. BEHAVIOUR IN PHOSPHOLIPIDS MONOLAYER".ABSTRACTTransdermal delivery of drugs is regarded as an alternative route to oral administration for certain drugs. The administration of drugs by this route overcomes the potential disadvantage of oral route, mainly presystemic elimination and side effects like digestive disturbances. Validated mathematical models represent an economically advantageous approach for the assessment of skin permeation, and their use is recommended before full-blown in vitro in vivo experiments are conducted. The transdermal permeation of the most important anxiolytics, namely, the benzodiazepines (alprazolam, clobazam, clonazepam, diazepam, lorazepam, midazolam and pinazepam) was studied in vitro with human skin. Permeation membrane consisted of abdominal human skin obtained from surplus of plastic surgery. The purpose of the study was to evaluate the physico-chemical suitability of these drugs for transdermal formulation, to predict the respectives permeation coefficients based on those values and to compare those results with experimental permeation parameters. Also it was studied benzodiazepines behaviour in phospholipids monolayer as a predictive and quickly method for determining skin permeability coefficients.Methods. Benzodiazepines were quantified by HPLC-UV. For permeation experiments we used Franz-type vertical diffusion cells from Crown Glass Company, (Sommerville, NY) with an effective permeation area of 2.54 cm2 and a receptor compartment volumeof approximately 13 mL were used. Among benzodiazepines assayed Midazolam showed the highest permeability coefficient (kp=11640 x 10-6 cm·h-1) while Lorazepam and Alprazolam exhibited the lowest values (kp=730 x 10-6 and 650 x 10-6 cm·h-1).By a mathematical multilineal method we propose an empirical equation to predict experimental human skin permeability coefficient values of a series of benzodiazepines based on respectives Partition coefficient, Molecular weight, Melting point and Solubility.The equation obtained to predict the permeability coefficient of benzodiazepines based on physicochemical properties gave a good correlation (R2=0.9851 and F=5.83%). Considering the whole transdermal permeation profile and required therapeutic plasma concentrations, none of the benzodiazepines reached therapeutic values, requiring to be formulated in the presence of suitable enhancers for reveal therapeutical usefulness.KEYWORDS: Benzodiazepines, Human skin, Transdermal permeation, Permeation parameters, phospholipids monolayers.

The purpose of this study is to evaluate the association between sustained-release morphine (Avinza®), and performance on neuropsychological tests assessing short term memory, information processing, and motor skills in chronic pain patients, while controlling for stages of pain model variables and the effects of benzodiazepines. A convenience sampling procedure was utilized to enroll a sample of patients who had a trial of short-acting narcotic analgesics for their chronic non-malignant pain. Enrolled patients were treated with long-acting morphine Avinza.® Patient interviews were conducted at enrollment and one-month follow-up. A total of 129 patients were enrolled in the study. Mean pain intensity ratings at the highest, lowest, and average levels in the previous week were lower at follow-up (10.90, 4.56. 7.64) than at baseline (12.71, 6.76, 10.01) respectively. Reduction in pain levels was associated with a corresponding reduction in levels of pain unpleasantness, pain suffering, and pain behaviors. The models evaluating the associations between the stages of pain model variables, morphine dose, benzodiazepine dose, and digit span test (chi square = 147.79, p = 0.76), digit symbol test (chi square = 128.06, p = 0.5), and paced auditory serial attention test fit the data well (chi square = 160.39, p = 0.85). There was a statistically significant inverse association between frequency of pain behaviors and digit span test scores at baseline (-0.49, p = 0.01). Although the association between pain behaviors and digit symbol test scores (- 17. 0 %, p = 0.09) and paced auditory serial addition test scores (-4.0%, p = .28) at baseline were not statistically significant, a large negative effect was found. At follow-up, the association between pain behaviors and digit span test was positive and not significant. The negative association between frequency of pain behaviors and digit symbol test scores (-4.4%, p = 0.67 ) and paced auditory serial addition test scores (-2.8%, p = 0.21) at follow-up were considerably weaker. There were no significant association between opioid dose and cognitive function test scores. Opioid therapy, particularly, sustained release morphine therapy (Avinza) does not contribute to cognitive impairment in chronic pain patients. / text