Thesis (M.Sc. (Pharmacy)) - Rhodes University, 2006.

Boston University. University Professors Program Senior theses. / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / 2031-01-02

Made available in DSpace on 2014-06-11T19:25:25Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-06-23Bitstream added on 2014-06-13T20:53:14Z : No. of bitstreams: 1 kiguti_lra_me_botib.pdf: 1147680 bytes, checksum: 2af4ebdd84a8cedf1deef8d15145e30a (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A ejaculação precoce é a disfunção sexual masculina com maiores taxas de incidência e prevalência. De etiologia complexa, as principais abordagens farmacológicas desta condição têm sido a utilização de anestésicos locais, inibidores seletivos da recaptura de serotonina e mais recentemente, inibidores da fosfodiesterase tipo 5. O reflexo ejaculatório é um processo altamente organizado com a interação de áreas centrais encefálicas e espinhais, centros autonômicos simpáticos e parasimpáticos além de reflexos somáticos. O sistema nervoso autônomo simpático, através da ativação de adrenoceptores 1 ( 1-ARs), particularmente o subtipo 1A, desempenha papel fundamental na fase de emissão do reflexo ejaculatório através da modulação da contratilidade de órgãos como o ducto deferente, vesícula seminal e próstata. Além disso, a participação do influxo de cálcio extracelular via canais de cálcio dependentes de voltagem tipo L (canais de cálcio tipo L) na atividade contrátil destes órgãos é bem caracterizada. Devido à importância dos 1-ARs e canais tipo L no reflexo ejaculatório, este trabalho avaliou a eficácia do antagonista de 1-ARs Tamsulosin e das diidropiridinas bloqueadoras de canais de cálcio Nifedipina e (S)-(+)-Niguldipina no retardo da ejaculação em ratos. Os resultados obtidos demonstram que a atividade contrátil do ducto deferente e vesícula seminal ao estímulo adrenérgico via ativação de 1-ARs in vitro é fortemente inibida pelo antagonista de 1-ARs Tamsulosin e pelas bloqueadoras de canais de cálcio Nifedipina e (S)-(+)-Niguldipina. Entretanto, embora a contração destes órgãos e, portanto, a fase de emissão do reflexo ejaculatório tenha sido afetada, a latência ejaculatória dos animais não foi alterada. Estes resultados indicam que o bloqueio de canais de cálcio tipo L ou o antagonismo de 1-ARs no ducto deferente... / Premature ejaculation is one of the most common male sexual dysfunctions. With complex aetiology, the main pharmacological approaches involve local anesthetics, selective serotonin reuptake inhibitors and, more recently, phosphodiesterase 5 inhibitors. The sympathetic nervous system plays a crucial role in the ejaculation, controlling vasa deferentia, seminal vesicles and prostate contraction through 1- adrenoceptor ( 1-AR) activation. In addition, the contractions of these organs are dependent on influx of extracellular calcium through L-type voltage-dependent calcium channels (L-type calcium channels). Due to the involvement of 1-ARs and L-type calcium channels in the ejaculatory reflex, this dissertation evaluated the efficacy of the 1-AR antagonist Tamsulosin and of dihydropyridine calcium channel blockers Nifedipine and (S)-(+)-Niguldipine in the delay of ejaculation in rats. The results showed that the vas deferens and seminal vesicle contraction in response to 1-AR activation is potently inhibited by Tamsulosin, Nifedipine and (S)-(+)- Niguldipine. However, although vas deferens and seminal vesicles contractions have been inhibited, the ejaculatory latency in vivo was not affected. These results show that although L-type calcium channel blockade and 1-ARs antagonism in the vas deferens and seminal vesicle are effective in the inhibition of events related to the seminal emission phase of ejaculation, they are not able to delay the ejaculation. The present results indicate that modulation of contractions of organs involved in seminal emission is not a suitable strategy to retard of ejaculation

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. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

Sensory transmission was studied in trigeminal root ganglia (TRG) of guinea pigs, using intracellular recording techniques. One approach was to examine in detail the effects of applications of different K⁺-channel blockers on the membrane voltage responses and outward currents of TRG neurons, in order to better understand the fundamental processes that affect their excitabilities and repetitive spike discharge. The second approach was to examine several endogenous substances for their effects on the excitabilities of TRG neurons. In addition, a strategy was developed for electrophysiological recording from neurons in human sympathetic ganglia. Successful investigations of these neurons revealed properties similar to certain reported characteristics of sympathetic neurons in experimental animals, including high (~29 MΩ input resistances, pharmacological sensitivity of spikes to the specific Na⁺-channel blocker tetrodotoxin (TTX, 1 µM) and to selective K⁺-channel blockers -- 4-aminopyridine (4-AP, 1 mM) and tetraethylammonium (TEA, 10 mM). The investigations demonstrated the potential value of these in vitro preparations for studies of the human condition. The investigations in TRG neurons demonstrated that bath applications of TEA (0.1-10 mM) and 4-AP (0.05-5 mM) or Cs⁺ applied internally from the recording electrode, produced an increase in input resistance and a decrease threshold for spike generation in all neurons. Also, applications of 4-AP increased subthreshold oscillations of the membrane potential and enhanced the repetitive spike firing evoked by intracellular injections of current pulses, or elicited spontaneous firing. In contrast, TEA or Cs⁺ applications blocked the oscillations and the spike afterhyperpolarizations (AHPs) without exaggerating repetitive discharge. These investigations suggestedthat several pharmacologically distinct K -currents contribute to the control of excitability in TRG neurons. Comparison of combined actions of 4-AP and TEA with those of Cs⁺, suggested that other ions in addition to K⁺ may contribute to postspike events. Single electrode voltage-clamp analyses revealed transient outward currents that were evoked at the termination of hyperpolarizing voltage commands from holding potentials near -40 mV. The activation was rapid (<5ms) and inactivation (T≃19 ms) complete at potentials within the activation range (-40 to -75 mV). During combined application of TTX (1 µM) and TEA (10 mM), fast activating, sustained currents (>1 s) were evoked by depolarizing commands from holding potentials near -70 mV. These currents were blocked completely by the additional applications of 4-AP (5 mM). Applications of TEA (0.1 mM to 10 mM) produced dose-dependent reductions of the transient outward currents. Applications of Cs⁺ also blocked the currents. However, administrations of 4-AP (0.05 to 5 mM) only slightly reduced these currents and high doses of muscarinic agonists had no effect. The high sensitivity to TEA, and not to 4-AP, suggest a fundamental distinction from similar currents observed previously in other neurons of vertebrates and invertebrates, and hence this transient outward current in TRG neurons, is termed I(T)- The kinetics of I(T) suggest its involvement in the spike AHPs. Therefore, blockade of I(T) by TEA may interfere indirectly with the re-activation of voltage-dependent Na⁺-channels, leading to decreases in repetitive discharge ability. The TEA-insensitive sustained outward current presumably has an inhibiting influence on repetitive discharge. Conditions that interfere with this current, such as blockade of K⁺-channels by 4-AP without a significant blockade of I(T), strongly favour the generation of repetitive discharge in TRG neurons. The investigations using electrical stimulation of axons revealed that changes in the resting potential could inhibit the invasion of spikes into the perikarya, or facilitate the generation of ectopic spike discharges. Applications of 4-AP (1 mM) facilitated the perikaryal invasion of spikes evoked by axonal stimulation, and also resulted in the appearance of fast (~10 ms) depolarizations that reached spike threshold in the absence of applied stimuli. These investigations provided direct evidence that the perikarya of sensory neurons are capable of spike generation, and suggest that this behavior may occur in normal or pathophysiological conditions. The most notable effects of autacoids were those of substance P and histamine, whereas bradykinin did not affect neuronal membrane properties. Applications of substance P in micromolar doses evoked large (up to 45 mV), reversible depolarizations in the majority of neurons, whereas histamine applications produced similar depolarizations only in a small portion of the TRG neurons. Increases in the repetitive discharge abilities of neurons were evident during substance P-induced depolarizations. Studies on the ionic mechanism of substance P action revealed that the peptide-applications resulted in activation of inward currents as well as blockade of outward currents. In addition, it was shown that Na⁺ and Mg²⁺ were involved in the mechanism of action. These findings represent the first demonstration of the profound actions of substance P on the perikaryal membranes of sensory neurons in mammals. The excitatory actions of this endogenous peptide also give rise to the possibility of physiological actions of substance P at multiple sites in the trigeminal system. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

Objective: To determine whether echocardiography affects the decisions to use beta blockers or to recommend bacterial endocarditis prophylaxis in patients suspected of having mitral valve prolapse (MVP). Design: Retrospective review of echocardiograms and clinical records. Setting: Military tertiary care hospital. Patients: 127 patients with clinically suspected MVP (105) or incidentally discovered MVP (22). Main results: Beta blockers were used more often in patients with suspected MVP and positive echocardiograms (45%) than in patients with normal echocardiograms (13%, p<0.001). Bacterial endocarditis prophylaxis was recommended more often in patients with suspected MVP and positive echocardiograms (65%) than in patients with normal echocardiograms (11%, p<0.001). Presence or absence of a murmur did not influence the decision to recommend bacterial endocarditis prophylaxis. Patients in whom MVP was incidentally discovered were unlikely to receive either beta blockers or the recommendation for bacterial endocarditis prophylaxis. Conclusions: The results of echocardiography affect the decisions to use beta blockers or to recommend bacterial endocarditis prophylaxis in patients with suspected MVP.

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Th ocular bilateral hypotensive effect after unilateral topical administration of medetomidine and 4 analogs was demonstrated in a dose-response study (0.5%-2%) in NZW rabbits (bilateral IOP-lowering efficacy: medetomidine>detomidine and MPV-1440>MPV-1441 and MPV-305BIII).

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