CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / A Alpinia zerumbet à uma planta da famÃlia Zingiberaceae, denominada popularmente âcolÃniaâ no Nordeste do Brasil. à utilizada com fins medicinais no tratamento de hipertensÃo e tem sido estudada em relaÃÃo as suas propriedades farmacolÃgicas. Esta pesquisa teve por objetivo analisar o efeito farmacolÃgico das fraÃÃes hexÃnica (FHOEAz), clorofÃrmica (FCOEAz) e metanÃlica (FMOEAz) do Ãleo essencial da Alpinia zerumbet (OEAz) na reatividade vascular in vitro e nos parÃmetros cardiovasculares in vivo. O projeto de pesquisa foi aprovado pela ComissÃo de Ãtica em Pesquisa Animal, da Universidade Federal do CearÃ, sob os protocolos n 55/10 e n 18/2011, de acordo com as normas de boas prÃticas que envolvem o uso de animais experimentais. Para todos os experimentos foram utilizados ratos Wistar machos. Realizaram-se experimentos de reatividade vascular no banho de ÃrgÃos, com preparaÃÃes de aorta isolada de rato, com endotÃlio Ãntegro e desnudo, mantidos em carbogÃnio e soluÃÃo de Krebs-Henseleit com concentraÃÃo em mmol/L: NaCl: 118,0; KCl: 4,7; KH2PO4: 1,2; MgSO4.7H2O; 1,2; NaHCO3: 15,0; CaCl2: 2,5 e Glicose: 5,5. Foi observada a variaÃÃo da tensÃo isomÃtrica e utilizados diferentes fÃrmacos inibidores especÃficos para anÃlise do mecanismo de aÃÃo do efeito vasodilatador. Analisou-se a pressÃo arterial indireta por pletismografia de cauda em ratos submetidos ao modelo de hipertensÃo por inibiÃÃo crÃnica do Ãxido nÃtrico, atravÃs da administraÃÃo do L-NAME, obtendo-se a pressÃo arterial sistÃlica, diastÃlica e mÃdia, frequÃncia cardÃaca, alÃm da variaÃÃo do peso corporal. Constatou-se que o OEAz, FHOEAz, FCOEAz e FMOEAz induzem relaxamento de anÃis aÃrticos prÃ-contraÃdos com Fenilefrina (1 mol/L), de forma dependente da dose, sendo a menor CE50 a da FMOEAz (150,45 g/mL). A administraÃÃo por gavagem de 100 mg/kg de OEAz, FHOEAz, FCOEAz e FMOEAz reduziu a pressÃo arterial em ratos hipertensos pelo modelo de inibiÃÃo crÃnica do Ãxido nÃtrico, um efeito que foi superior ao controle negativo com Ãgua destilada e inferior aos controles positivos com Captopril e Nifedipina. A FMOEAz (0,1 - 3000 g/mL) induz relaxamento dependente da dose em anÃis aÃrticos prÃ-contraÃdos com Fenilefrina (1 mol/L) ou KCl (80 mmol/L), com endotÃlio intacto ou desnudo. Os estudos de mobilizaÃÃo de cÃlcio mostraram que a FMOEAz inibe o influxo de Ca2+ do meio extracelular, bem como interfere na contraÃÃo induzida pela liberaÃÃo de Ca2+ dos estoques intracelulares pela Fenilefrina (1 mol/L) ou CafeÃna (30 mmol/L). A 4-aminopiridina (1 mmol/L) e a Iberiotoxina (30 nmol/L) aumentam a CE50 da FMOEAz, mas nÃo interferem no seu efeito vasodilatador final. A prÃ-incubaÃÃo com L-NAME (100 mol/L), ODQ (10 mol/L); Indometacina (10 mol/L), Atropina (1 mol/L), Catalase (500 U/ml), SOD (300 U/mL); Wortmannina (0,5 mol/L), TetraetilamÃnio (10 mmol/L), Apamina (1 mol/L); Caribdotoxina (15 nmol/L) e Glibenclamida (10 mol/L) nÃo interferiram no relaxamento induzido pela FMOEAz. Concluiu-se que o OEAz, FHOEAz, FCOEAz e FMOEAz possuem efeito hipotensor in vivo e vasodilatador in vitro, e que o mecanismo de aÃÃo da FMOEAz, provavelmente, envolve o antagonismo aos canais de cÃlcio dependentes de voltagem, aos canais de cÃlcio operados por receptor, interferindo tambÃm na liberaÃÃo de cÃlcio dos estoques intracelulares. / The Alpinia zerumbet is a plant of the family Zingiberaceae, popularly called "colÃnia" in Northeastern Brazil. It is used for medicinal purposes to treat hypertension and has been studied in relation to its pharmacological properties. This study aimed to analyze the pharmacological effect of hexanic (HFEOAz), chloroformic (CFEOAz), and methanolic (MFEOAz) fractions of the essential oil of Alpinia zerumbet (EOAz) in the vascular reactivity in vitro and cardiovascular parameters in vivo. The research project was approved by the Ethics Committee on Animal Research, of the Federal University of CearÃ, under protocol numbers 55/10 and 18/2011, according to the standards of good laboratory practice involving the use of experimental animals. For all experiments male Wistar rats were used. Experiments of vascular reactivity were conducted in organ bath, with preparations of isolated rat aorta with intact endothelium and desnuded, kept in carbogen and Krebs-Henseleit solution with a concentration in mmol/L: NaCl: 118,0; KCl: 4,7; KH2PO4: 1,2; MgSO4.7H2O; 1,2; NaHCO3: 15,0; CaCl2: 2,5 e Glicose: 5,5. Was observed variation in isometric tension and used different specific inhibitors to analyze the mechanism of action of the vasodilator effect. We analyzed blood pressure indirectly by tail plethysmography in rats submitted to chronic hypertension by inhibition of nitric oxide by the administration of L-NAME, obtaining the systolic, diastolic and mean blood pressure, heart rate, beyond variation in body weight. It was found that the EOAz, HFEOAz, CFEOAz MFEOAz induced relaxation of aortic rings pre-contracted with Phenylephrine (1 mol/L), of dose-dependent manner, with the smallest of the EC50 MFEOAz (150.45 mg/mL). The administration by gavage of 100 mg/kg EOAz, HFEOAz, CFEOAz MFEOAz reduced blood pressure in hypertensive rats by the model of chronic inhibition of nitric oxide, an effect that was greater than the negative control with distilled water and less than the positive controls with Captopril and Nifedipine. The MFEOAz (0.1 - 3000 Âg/mL) concentration dependently relaxed Phenylephrine (1 mol/L) and KCl (80 mmol/L) contracted rings with intact or denuded endothelium. Studies of calcium mobilization showed that FMOEAz inhibits the influx of Ca2+ from the extracellular environment and interferes with the contraction-induced Ca2+ release from intracellular stocks by Phenylephrine (1 mol/L) or Caffeine (30 mmol/L). The 4-aminopyridine (1 mmol/L) and Iberiotoxina (30 nmol/L) increased the EC50 of MFEOAz but do not interfere in its final vasodilator effect. The pre-incubation with L-NAME (100 mol/L), ODQ (10 mol/L), Indomethacin (10 mol/L), Atropine (1 mol/L), Catalase (500 U/mL), SOD (300 U/mL), Wortmannin (0.5 mol/L), Tetraethylammonium (10 mmol/L), Apamin (1 mol/L); Caribdotoxin (15 nmol/L) and Glibenclamide (10 mol/L) did not interfere with the relaxation induced by MFEOAz. It was concluded that the EOAz, HFEOAz, CFEOAz and MFEOAz have hypotensive effect in vivo and vasodilator effect in vitro, and that the mechanism of action of MFEOAz probably involves the antagonism of calcium channels voltage-dependent, the calcium channel operated by receptor, also interfering in the release of calcium from intracellular stores.

Infantile hemangiomas (IHs), benign vascular lesions present on the surface of the skin of children, are treated with systemic or topical beta-adrenergic antagonists (known as “beta-blockers”). However, systemic beta-blocker therapy is associated with serious adverse events in pediatric patients, and there are currently no topical formulations optimized for the skin. The objectives of this work were to 1) evaluate the local skin concentrations and drug permeation through the skin using novel beta-blocker formulations, and 2) characterize the epidermal properties and skin surface inflammatory mediators of IH skin. Skin concentrations and drug permeation through the skin from current topical treatment options were quantified in vitro; these data served as benchmarks to which other treatment paradigms in later studies were compared. Microneedle (MN)-mediated delivery of two beta-blockers, propranolol and timolol, was evaluated in vitro using solid MNs and two dissolving MN array formulations. Solid MNs increased skin concentrations of timolol compared to intact skin, while producing similar skin concentrations of propranolol. Drug permeation through the skin was increased for both drugs after MN pretreatment. Both formulations of dissolving MN arrays were ineffective at increasing local skin concentrations compared to intact skin. This was likely due to the small loading capacity of drug into the array. Drug-loaded microemulsions (ME) of varying composition were formulated and characterized. All ME formulations had solubilization properties, and water rich MEs had the greatest cumulative release through a homogenous membrane compared to surfactant rich MEs. Drug-loaded MEs did not increase local skin concentrations in vitro compared to a drug solution; however, water rich ME formulations produced greater skin-to-receiver ratio of drug concentration, indicating their potential for skin accumulation. MN pretreatment increased the skin-to-receiver ratios for surfactant rich formulations but not for water rich formulations, indicating this enhancement in skin retention after MN pretreatment is formulation dependent. These results demonstrate the potential for topical treatment of IHs upon further optimization of delivery and formulation parameters. The epidermal properties and skin surface mediators of IH skin were compared to normal, unaffected skin. Significant differences in barrier function and color, as well as chemokine and growth factor concentrations, were observed between the two sites. These results provide a greater understanding of the IH properties that have previously not been quantified. Similar changes in lesion color, which correlate to efficacy, were observed after beginning treatment with oral propranolol or topical timolol, while changes in barrier function were similar between the two treatment groups. These results indicate topical timolol may be a safe alternative for systemic treatment for superficial IHs without a loss of efficacy.

Les potentiels daction neuronaux sont suivis dune post-hyperpolarisation qui est médiée par les canaux K+ Ca2+-dépendant de faible conductance (canaux SK). Cette post-hyperpolarisation joue un rôle important dans la régulation de lexcitabilité neuronale et les agents modulant lamplitude cette post-hyperpolarisation possèdent un intérêt thérapeutique potentiel (schizophrénie, maladie de Parkinson, maladie dAlzheimer, épilepsie,). Dans un premier temps, cette étude pharmacochimique de la N-méthyl-laudanosine (NML) a permis de mettre en évidence un composé tertiaire possédant une affinité significative vis-à-vis des canaux SK. Cette observation a initié la recherche de bloqueurs non quaternaires des canaux SK. Dans cette seconde partie, deux groupes de composés ont été préparés et testés. Dune part, des bis-isoquinoliniums ont montré des affinités 50 x plus élevées que celle de la NML. Dautre part, la préparation et la résolution de bis-1,2,3,4-tétrahydroisoquinoléines a permis dobtenir un stéréoisomère 4 x plus affin que la NML. Ce composé tertiaire a été caractérisé sur le plan chimique et physico-chimique (cristallographie RX, lipophilie et pKas) et étudié dans un modèle comportemental chez le rat. Sur base des premiers résultats comportementaux, un effet central a effectivement été observé.

Accelerated growth in wireless communications in recent years has led to the emergence of portable devices that employ several wireless communication standards to provide multiple functionality such as cellular communication, wireless data communication and connectivity, entertainment and navigation, within the same device. Industry drive is towards reduction of the number of radio frequency (RF) front-end receivers required to cater to the various standards/bands within a single device to reduce cost, size and power consumption. The current trend is to use broadband/multi-standard or reconfigurable RF front-ends to cater to two or three standards at a time for cost-effective RF front-end solutions. The direct conversion receiver architecture has become attractive as it offers a full on-chip front-end solution without the need for expensive external components. Passive current-mode mixers are used in these receivers to eliminate mixer flicker noise. The in-band current signals are typically in the micro-amp range after mixer downconversion. Transimpedance amplifiers are used to convert the downconverted current signals to voltage, and they provide amplification in the process. Because of the co-existence of multiple-radios within each device, large blocker currents downconvert close to the channel bandwidth after the mixer. Conventionally, single-pole transimpedance amplifier (TIA) filters are used to provide out-of-band (OOB) signal filtering. This requires high resolution analog-to-digital converters (ADCs) later in the receiver chain for signal processing. Providing higher order filtering before the ADC relaxes its specifications and this reduces the ADC and ADC calibration cost and complexity. Typically, an extra filtering stage is provided in the form of a cascaded filtering block after the single-pole TIA. In this work, higher order filtering is embedded within the TIA in the form of active feedback. In addition to relaxing the ADC specifications, this proposed TIA provides improved large signal linearity such as P1dB compression point. Furthermore, since the extra-circuitry is not in the signal path, in-band flicker noise and linearity are not degraded. The proposed TIA filter has been designed in IBM 90nm technology with a supply voltage of 1.2V. It can tolerate close-in blocker magnitudes of 4.5mA at 60MHz and higher before in-band 1dB compression is reached.

published_or_final_version / Medicine / Master / Doctor of Medicine

Context: Although the long-term goal of antihypertensive therapy is to reduce adverse clinical outcomes, the only way to evaluate the efficacy of treatment in an individual is the magnitude of blood pressure (BP) reduction. ACE inhibitors and angiotensin receptor blockers (ARBs) are two drug classes that, by different mechanisms, inhibit the renin-angiotensin- aldosterone system that regulates BP. As these drugs are widely prescribed for hypertension, it is essential to determine and compare their effects on BP, heart rate and tolerability. Objectives: 1) To determine the dose-related effect of ACE inhibitors and ARBs on BP, heart rate and withdrawals due to adverse effects (WDAE), compared with placebo in the treatment of primary hypertension (SBP ≥ 140 mm Hg and/or ≥ DPB 90 mm Hg); and 2) To compare the relative effect on BP, heart rate and WDAE of a) each ACE inhibitor with other ACE inhibitors, b) each ARB with other ARBs, and c) all ACE inhibitors with all ARBs. Methods: Two systematic reviews of published, double-blind, randomized, controlled trials (RCTs) evaluating the BP lowering efficacy of fixed dose monotherapy with an ACE inhibitor or ARB compared with placebo for a duration of 3 to 12 weeks in patients with primary hypertension were conducted. Electronic databases were searched for RCTs and similar trial inclusion criteria and methods of analysis were used in both reviews. Results: Ninety two RCTs evaluated the dose-related BP lowering efficacy of 14 ACE inhibitors in 12 954 participants with a baseline BP of 157.1/101.2 mm Hg. Forty six RCTs evaluated the dose-related BP lowering efficacy of 9 ARBs in 13 451 participants with a baseline BP of 155.6/101.0 mm Hg. The best estimate of the near maximal trough BP reduction for ACE inhibitors and ARBs was -8/-5 mm Hg and -8/-5 mm Hg, respectively. ACE inhibitors and ARBs do not affect heart rate. The evidence for short-term WDAE (tolerability) was incomplete and weak and did not demonstrate a difference between the two classes of drugs. Conclusion: ACE inhibitors and ARBs are not different individually or as drug classes in BP lowering efficacy.

In Multi-Standard receivers, multiple radios co-exist in close proximity. A desired signal can be accompanied by significantly stronger out-of band interferers or blockers, which can severely degrade a receiver's sensitivity through gain compression of the blocks in the receiver chain. This work presents a new Transimpedance Amplifier (TIA) low-pass filter architecture which seeks to solve the out-of-band blocker problem of the existing architectures. A higher order filtering is embedded within the TIA in the form of an active feedback to provide more attenuation to out-of-band blockers. The active feedback circuitry feeds back an equivalent amount of current to the input node to cancel out incoming out-of-band blockers while maintaining an acceptable voltage swing at the output of the TIA. The proposed TIA filter has a channel bandwidth of 20MHz, and can processes interferers of +/- 10mA fully differential without saturating the opamps. The maximum single ended voltage swing at all the nodes is +/- 200mV. All the circuits were designed in IBM 180nm CMOS process with a supply voltage of 1.8V.

Context: Although the long-term goal of antihypertensive therapy is to reduce adverse clinical outcomes, the only way to evaluate the efficacy of treatment in an individual is the magnitude of blood pressure (BP) reduction. ACE inhibitors and angiotensin receptor blockers (ARBs) are two drug classes that, by different mechanisms, inhibit the renin-angiotensin- aldosterone system that regulates BP. As these drugs are widely prescribed for hypertension, it is essential to determine and compare their effects on BP, heart rate and tolerability. Objectives: 1) To determine the dose-related effect of ACE inhibitors and ARBs on BP, heart rate and withdrawals due to adverse effects (WDAE), compared with placebo in the treatment of primary hypertension (SBP ≥ 140 mm Hg and/or ≥ DPB 90 mm Hg); and 2) To compare the relative effect on BP, heart rate and WDAE of a) each ACE inhibitor with other ACE inhibitors, b) each ARB with other ARBs, and c) all ACE inhibitors with all ARBs. Methods: Two systematic reviews of published, double-blind, randomized, controlled trials (RCTs) evaluating the BP lowering efficacy of fixed dose monotherapy with an ACE inhibitor or ARB compared with placebo for a duration of 3 to 12 weeks in patients with primary hypertension were conducted. Electronic databases were searched for RCTs and similar trial inclusion criteria and methods of analysis were used in both reviews. Results: Ninety two RCTs evaluated the dose-related BP lowering efficacy of 14 ACE inhibitors in 12 954 participants with a baseline BP of 157.1/101.2 mm Hg. Forty six RCTs evaluated the dose-related BP lowering efficacy of 9 ARBs in 13 451 participants with a baseline BP of 155.6/101.0 mm Hg. The best estimate of the near maximal trough BP reduction for ACE inhibitors and ARBs was -8/-5 mm Hg and -8/-5 mm Hg, respectively. ACE inhibitors and ARBs do not affect heart rate. The evidence for short-term WDAE (tolerability) was incomplete and weak and did not demonstrate a difference between the two classes of drugs. Conclusion: ACE inhibitors and ARBs are not different individually or as drug classes in BP lowering efficacy.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 4 uppsatser.

Thesis (doctoral)--Lund University, 1994. / Added t.p. with thesis statement inserted.