Continuous infusions of barbiturates in artificially-respired animals result in profound cardiovascular depression with terminal cardiac arrest. In an attempt to elucidate the nature of this cardiac depression at a cellular level, tissue electrolyte analyses were performed on mammalian hearts in failure following infusion of the intact animal with sodium pentobarbital. The patterns of electrolyte distribution encountered were compared to those in animals receiving control saline infusions, and to those in cats subjected to partial myocardial ischemia through ligation of the left coronary-artery. Significant species differences in resistance to the cardiolethal effect of pentobarbital were observed. On the basis of differences in effects on electrolyte distribution and pattern of failure, the conclusion was reached that myocardial ischemia was probably not responsible for pentobarbital failure in the cat and the dog. In cat auricles, pentobarbital exerted a selective action on electrolyte metabolism which may have been related to depression of atrial electrical activity. In addition, evidence was found of a direct action of pentobarbital on cardiac contractility independent of Na and K distribution. Control electrolyte values provided support for the hypothesis that electrolyte distribution is related to cardiac automaticity. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

No description available.

No description available.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1970. / Typescript. Vita. Description based on print version record. Includes bibliographical references.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Ternatina (5,4â-dihidroxi-3, 7, 8, 3â-tetrametoxi-flavona), um bioflavonÃide isolado de Egletes viscosa, Less (Compositae), foi estudado frente a vÃrios efeitos farmacolÃgicos em animais experimentais. O composto (15 e 30 mg/kg, i.p.) demonstrou de forma dose-dependente um efeito antiinflamatÃrio significante no edema de pata induzido por carragenina. Neste modelo, a indometacina (5 mg/kg, v.o.), uma conhecida droga antiinflamatÃria nÃo esterÃide, demonstrou maior potÃncia que a Ternatina. Com doses semelhantes Ãs anteriores, o bioflavonÃide reduziu efetivamente o aumento da permeabilidade capilar provocada por Ãcido acÃtico em camundongos, propriedade comum para muitos flavonÃides. Nesses mesmos animais, a Ternatina (15 e 30 mg/kg, i.p.) nÃo demonstrou atividade sobre o tempo de reaÃÃo no modelo da placa quente de Eddy (55Â1ÂC). PorÃm, no teste de âWRITHINGâ induzido por Ãcido acÃtico, o composto reduziu significativamente o nÃmero de contorÃÃes abdominais de maneira dose-dependente, indicando ter uma possÃvel propriedade analgÃsica perifÃrica. A substÃncia em estudo tambÃm mostrou atividade antipirÃtica em ratos no modelo de pirexia provocada por leveduras de cerveja. Este efeito, com dose de 30 mg/kg, via intraperitoneal, foi quase equivalente ao produzido por paracetamol (250 mg/kg, v.o.). A propriedade gastroprotetora da Ternatina foi evidenciada no modelo experimental de hipertermia gÃstrica aguda provocada por etanol 99% em camundongos. A Ternatina, nas doses de 30 e 60 mg/kg, via intraperitoneal, reduziu significativamente o desenvolvimento das mudanÃas hiperÃmicas induzidas por etanol no estÃmago. Essa droga (30 mg/kg, i.p.) tambÃm demonstrou um possÃvel efeito hepatoprotetor ao diminuir de forma significativa a atividade da alanina-aminotransferase (ALT) sÃrica nas lesÃes do fÃgado provocadas por tetracloreto de carbono (CCl4) em ratos. Nos animais tratados com Ternatina (30 mg/kg, i.p.) durante 8 dias consecutivos, o tempo de sono induzido por pentobarbital sÃdico foi significativamente maior que o do grupo controle, mostrando um provÃvel efeito depressor do flavonÃide sobre o metabolismo enzimÃtico de drogas no fÃgado e/ou em outros sistemas orgÃnicos. A Ternatina (15 e 30 mg/kg, i.p.) inibiu de forma dose-dependente o trÃnsito gastrointestinal em camundongos. AlÃm disso, o composto (10 e 40 Âg/mL no banho) produziu uma eficaz e reversÃvel inibiÃÃo das respostas contrÃteis causadas por diversos agonistas (acetilcolina, histamina, serotonina e cloreto de bÃrio) em Ãleo isolado de cobaio. A inibiÃÃo mostrou-se inespecÃfica e foi revertida por um aumento da concentraÃÃo de cÃlcio no banho, implicando que a Ternatina afeta os processos celulares dependentes desse Ãon. Em cÃlulas KBr, a substÃncia estudada evidenciou baixa citotoxicidade. A concentraÃÃo efetiva da droga necessÃria para inibir o crescimento celular (CyED50) foi de 100 Âg/mL. A Ternatina e o extrato bruto de Egletes viscosa, tambÃm exibiram baixa toxicidade geral. Os resultados obtidos no presente estudo como os compostos, juntamente com a atividade antiviral descrita contra poliovÃrus e adenovÃrus, sugerem que ela deve ser um dos principais componentes ativos de Egletes viscosa e, portanto, a base cientÃfica para comprovar o intensivo uso do extrato bruto da planta em medicina popular no tratamento dos distÃrbios gastrointestinais / Ternatin (5, 4â-dihydroxy-3, 7, 8, 3â-tetrametoxy-flavone), a flavonoid which was extracted and purified from Egletes viscosa, Less. (Compositae), was screened for various pharmacological effects in experimental animals. The compound (15 and 30 mg/kg, i.p.) demonstrated a dose-related significant anti- inflammatory effect in the carrageenan-induced rat hind paw test. In this model, indomethacin (5 mg/kg, p.o.), a known nonsteroidal anti-inflammatory drug (NASID), evidenced a much greater potency than to Ternatin. At similar doses, Ternatin effectively reduced the increase in vascular permeability induced by acetic acid in mice, a property common to many of the flavonoids. In mice, Ternatin (15 and 30 mg/kg, i.p.) failed to modify the reaction time in Eddyâs hot plate (55Â1ÂC) test, but in writhing test induced by acetic acid, it significantly reduced the number of abdominal contractions (writhes) in a dose-dependent manner indicating a possible peripheral analgesic property. Ternatin also showed antipyretic activity in the rat model of pyrexia induced by Brewerâs Yeast. Its activity at 30 mg/kg, i.p., was almost equivalent to that produced by paracetamol (250 mg/kg, p.o.). The gastroprotective effect of Ternatin was evident in the model of acute gastric hyperemia provoked by ethanol 99% in mice. Ternatin at doses of 30 and 60 mg/kg, i.p., significantly reduced the development of ethanol induced hyperemic changes in the stomach. Besides, Ternatin (30 mg/kg, i.p.) demonstrated hepatoprotective property by causing significant inhibition of carbon tetrachloride (CCl4) â induced increases in serum alanina-aminotransferase (ALT) in rats. In rats treated with Ternatin (30 mg/kg, i.p.) for eight consecutive days, the pentobarbital-induced sleeping times was found to be significantly higher than vehicle treated controls what means signifies the possible depressant effect of the compound on drug metabolizable enzymes in liver and/or other organ systems. Ternatin (15 and 30 mg/kg, i.p.) inhibited, in a dose-dependent manner the gastrointestinal propulsion in mice. In addition, Ternatin (10 to 40 Âg/mL in bath fluid) produced an effective reversible inhibition of contractile responses evoked by various agonists (acetylcholine, histamine, serotonin and barium chloride) in isolated guinea pig ileum. The inhibition was observed to be inespecific and could be overcome by an increase in the Ca++ concentration of bathing fluid implying that Ternatin affects cellular calcium dependent processes. In KB-cell lines, Ternatin evidenced low cytotoxicity. The effective drug concentration required to inhibit the growth of KB-cells (CyED50) was found to be 100 Âg/mL. Ternatin and the crude extrats of Egletes viscosa evidenced low order of general toxicity. The present findings on Ternatin, together with the reported antiviral activity against polioviruses and adenoviruses suggest that it might be the unique active compound present in Egletes viscose and this may be the scientific basis for the extensive use of plant crude extracts in popular medicine for treating gastrointestinal disturbances

Despite the advances made in our understanding of the molecular mechanistic actions of general anesthetics very little is known about the in vivo neural circuits involved in creating the state of general anesthesia. To date the common consensus is that general anesthetics act ubiquitously within the CNS. Recently, (Devor and Zalkind, 2001) have reported that microinjections of pentobarbital (PB) into a discrete brainstem focal area of conscious rats induced a classical, reversible general anesthesia-like behavioral state. The authors concluded that this area, termed the mesopontine tegmental anesthesia area (MPTA), may be important for the induction of general anesthesia. The purpose of the present project was to study the neurophysiological basis of the analgesia, which accompanied the state of general anesthesia induced by PB microinjections into the MPTA that was reported by (Devor and Zalkind, 2001). Here, sensory inflow via the spinothalamic tract (STT), a classical spinal nociceptive pathway in the rat, was assessed using single neuron extracellular recording techniques before, during and after microinjections of PB into the MPTA. Spontaneous firing rate (SFR), antidromic firing index (FI) and sciatic as well as sural nerve-evoked responses (Sc-, Su-ER) of STT neurons in isoflurane-anesthetized rats were quantified before as well as 2, 15, 30 and 60 min following bilateral microinjections of either PB (200 micrograms/side) or vehicle control solution (Vh, 1 microliter/side) into the MPTA. The group mean SFR, FI as well as magnitudes of Sc-, Su-ER of STT neurons were significantly and reversibly reduced following PB microinjections compared to corresponding baseline measurements. There were no significant changes in any of the three parameters following microinjections of Vh compared to the pre-microinjection baseline responses. The results from this study indicate that analgesia, which occurs during the anesthesia-like state following microinjections of PB into the MPTA, may be due to attenuation of sensory inflow through the STT. The suppression of STT neurons likely occurs via direct and/or indirect descending pathways from the MPTA to the spinal cord. This study provides the first direct electrophysiological evidence for the analgesia caused by PB microinjections into the rat MPTA.

Despite the advances made in our understanding of the molecular mechanistic actions of general anesthetics very little is known about the in vivo neural circuits involved in creating the state of general anesthesia. To date the common consensus is that general anesthetics act ubiquitously within the CNS. Recently, (Devor and Zalkind, 2001) have reported that microinjections of pentobarbital (PB) into a discrete brainstem focal area of conscious rats induced a classical, reversible general anesthesia-like behavioral state. The authors concluded that this area, termed the mesopontine tegmental anesthesia area (MPTA), may be important for the induction of general anesthesia. The purpose of the present project was to study the neurophysiological basis of the analgesia, which accompanied the state of general anesthesia induced by PB microinjections into the MPTA that was reported by (Devor and Zalkind, 2001). Here, sensory inflow via the spinothalamic tract (STT), a classical spinal nociceptive pathway in the rat, was assessed using single neuron extracellular recording techniques before, during and after microinjections of PB into the MPTA. Spontaneous firing rate (SFR), antidromic firing index (FI) and sciatic as well as sural nerve-evoked responses (Sc-, Su-ER) of STT neurons in isoflurane-anesthetized rats were quantified before as well as 2, 15, 30 and 60 min following bilateral microinjections of either PB (200 micrograms/side) or vehicle control solution (Vh, 1 microliter/side) into the MPTA. The group mean SFR, FI as well as magnitudes of Sc-, Su-ER of STT neurons were significantly and reversibly reduced following PB microinjections compared to corresponding baseline measurements. There were no significant changes in any of the three parameters following microinjections of Vh compared to the pre-microinjection baseline responses. The results from this study indicate that analgesia, which occurs during the anesthesia-like state following microinjections of PB into the MPTA, may be due to attenuation of sensory inflow through the STT. The suppression of STT neurons likely occurs via direct and/or indirect descending pathways from the MPTA to the spinal cord. This study provides the first direct electrophysiological evidence for the analgesia caused by PB microinjections into the rat MPTA.

Despite the advances made in our understanding of the molecular mechanistic actions of general anesthetics very little is known about the in vivo neural circuits involved in creating the state of general anesthesia. To date the common consensus is that general anesthetics act ubiquitously within the CNS. Recently, (Devor and Zalkind, 2001) have reported that microinjections of pentobarbital (PB) into a discrete brainstem focal area of conscious rats induced a classical, reversible general anesthesia-like behavioral state. The authors concluded that this area, termed the mesopontine tegmental anesthesia area (MPTA), may be important for the induction of general anesthesia. The purpose of the present project was to study the neurophysiological basis of the analgesia, which accompanied the state of general anesthesia induced by PB microinjections into the MPTA that was reported by (Devor and Zalkind, 2001). Here, sensory inflow via the spinothalamic tract (STT), a classical spinal nociceptive pathway in the rat, was assessed using single neuron extracellular recording techniques before, during and after microinjections of PB into the MPTA. Spontaneous firing rate (SFR), antidromic firing index (FI) and sciatic as well as sural nerve-evoked responses (Sc-, Su-ER) of STT neurons in isoflurane-anesthetized rats were quantified before as well as 2, 15, 30 and 60 min following bilateral microinjections of either PB (200 micrograms/side) or vehicle control solution (Vh, 1 microliter/side) into the MPTA. The group mean SFR, FI as well as magnitudes of Sc-, Su-ER of STT neurons were significantly and reversibly reduced following PB microinjections compared to corresponding baseline measurements. There were no significant changes in any of the three parameters following microinjections of Vh compared to the pre-microinjection baseline responses. The results from this study indicate that analgesia, which occurs during the anesthesia-like state following microinjections of PB into the MPTA, may be due to attenuation of sensory inflow through the STT. The suppression of STT neurons likely occurs via direct and/or indirect descending pathways from the MPTA to the spinal cord. This study provides the first direct electrophysiological evidence for the analgesia caused by PB microinjections into the rat MPTA. / Pharmaceutical Sciences, Faculty of / Graduate

The Food, Drug, and Cosmetic Act of 1938 required a producer of a new drug to substantiate the safety of the drug product when used as recommended; however, the introduction of the Kefauver-Harris Amendments of 1962 considerably strengthened this act. These amendments intensified the controls on quality, labeling, and safety, while adding a new requirement that all NDA's should be able to present substantial evidence of the effectiveness of the drug product for its indicated use of uses (4). The procedure used to determine the efficacy of a drug included identification of the product, copies of the labeling, and a bibliography of publications substantiating the claims made for the drug. The manufacturers were also requested to submit any unpublished information to further substantiate the claims made for the drug product (5,6). Bioavailability is a complex problem due to the many variables associated with the development of drug dosage form design. The bioavailability of a drug product can be influenced by pharmaceutical formulation factors as well as by the physiological factors of the patient taking that drug product. Compressed tablets are the mostly widely used of all the dosage forms, and they present the most problems in regard to the bioavailability of the active component. This is especially true for those compressed tablets that contain drugs with a low solubility, a low rate of solution, drugs which exhibit poor absorption characteristics, drugs which are unstable in the gastrointestinal environment or drugs that are used in large dosage (25). The significance of a bioavailability study is established when a correlation is demonstrated between the blood levels achieved using a drug already shown to be clinically effective and the drug product being tested (34). This type of relationship tends to indicate that the drug product being tested would be therapeutically equivalent to the reference drug product (35). Bioavailability data is necessary for the establishment of therapeutic equivalency among drug products. Consequently, bioavailability data is necessary for the establishment of therapeutic equivalency among drug products; particularly for those drug products most often prescribed. Phenobarbital tablets have been listed among the top 5 generic products, by new prescription volume, for the last 4 years. In addition, phenobarbital tablets have been the leading drug product amon the top 20 generic products by refill prescription volume over the last 4 years. Of the top 20 generic products by new and refill prescription volume, phenobarbital products have ranked among the top 3 for the past 4 years. Furthermore, phenobarbital tablets have been listed among the top 4 drug products in a list of the average retail new prescription prices for the top 20 generic products in the last 4 years (36). From a physiochemical basis, the bioavailability of phenobarbital tablets has been suspect. The incomplete data available on phenobarbital tablets indicated the necessity for determining the physical properties and the bioavailability of these products. Therefore, Phenobarbital Tablets, USP, 100 mg, were obtained from 7 manufactures to characterized the physical properties of tablet weight, hardness, disintegration time , and dissolution rate; to determine the bioequivalency, bioavailability studies were conducted employing 5 normal, healthy human adult male subjects.

Signal averaging of visually evoked cortical potentials was done on Wistar strain rats during recovery from nembutal (sodium pentobarbital) anesthesia. Several studies (Dafny, 1978; Gines et al., 1963; Roig et al., 1961) have shown significant differences between recordings from unanesthetized rats and from rats anesthetized with various agents. The purpose of this study was to evaluate changes in the cortical response throughout an eight hour nembutal recovery period in order to determine the feasibility of using a signal averaging technique for classification of anesthetic depth. The results of this study show that the recovery from nembutal anesthesia is characterized by three major changes in the cortical response: the presence or absence of the secondary response component, the appearance of desynchronized cortical firing and a change in the latency of the individual component peaks. Using these neurophysiological signs, the rate of recovery from nembutal anesthesia can be described and quantified. The characterization of these changes will provide future researchers with a tool to evaluate electrophysiologically the usefulness of various treatments at altering the rate of recovery from anesthesia.