No description available.

No description available.

No description available.

published_or_final_version / Pharmacology and Pharmacy / Master / Master of Medical Sciences

No description available.

No description available.

Chronic neuropathic pain, epilepsy, depression and anxiety disorders have been treated successfully with pregabalin. Normal subjects, epileptics and patients with neuropathic pain to whom pregabalin was prescribed showed an improvement in objective and subjective sleep parameters. To determine if pregabalin’s sleep enhancing effect is an independent process, it is necessary to test pregabalin in primary insomniacs who do not have conditions that could be treated by pregabalin. My study was designed as a double blind, randomised, crossover, placebo controlled trial, with 50 milligrams of pregabalin or placebo was administered for eight consecutive nights. I performed polysomnographic recordings on eight female chronic primary insomniacs on five nights. Sleep recordings were performed prior to the intervention, and on the first night and eighth night of each treatment. Subjects filled out subjective scales at baseline and night eight of every treatment. While polysomnography and subjective scales showed that my subjects were insomniac, sleep variables during the pregabalin or placebo period were unchanged when compared to baseline. A daily dose of 50 mg pregabalin did not have any significant effects on either sleep architecture or subjective sleep variables in female chronic primary insomniacs.

Calcium channel blockers (CCB) was studied extensively in cardiology for their tissue protective effect following myocardial infarction; we hypothesized that administration of a CCB would interfere with the processes that result in exercise-induced muscle damage (EIMD) and delayed onset muscle soreness. To investigate the effects of a CCB on a development and recovery from EIMD, we used a double blind, placebo controlled protocol to administer CARDIZEM CD, 240 mg/day, for 6 days to 30 college age males and females. To induce EIMD, subjects performed 4 sets of 10 repetitions of squat, leg press, leg extension, and leg curl. We observed no treatment related difference in CPK or DOMS levels. Overall, peak quadriceps force (PQF) were not different between the Placebo and Diltiazem groups, but PQF was significantly greater in the Diltiazem groups immediately after the weight lifting bout. Average quadriceps force (AQF) values decreased in both groups following the exercise bout; however, no difference existed between the groups (p>.05). The Diltiazem group PQF and AQF values returned to the pre-exercise levels 24 hours earlier than did the Placebo group. Neutrophils decreased by 21% in the Diltiazem group compare with a 1.4% increase in the Placebo group, due to large variability in the neutrophil count at the baseline, this difference was not significant. Lymphocytes were not affected by CCB treatment. Administration of diltiazem did not interfere with the development of EIMD as measured by CPK release and the DOMS scores. Diltiazem appeared to affect quadriceps force generation immediately following the weight lifting bout and to speed the recovery of muscle force to pre-exercise level in our sample of college age adults. Heart rate was significantly lower in the Diltiazem group after the administration. There was no difference in either systolic or diastolic blood pressure after the administration between the Diltiazem and Placebo groups. The incidence of side effects was very low and similar in both groups. The administration of this dose and preparation of diltiazem does not change heart rate or blood pressure in a clinically significant fashion, and was well tolerated in our sample of college age adults. / Graduation date: 1997

The calcium signal has emerged as an imponant component of intracellular regulation. Pineal function was thought to be slowed by the prominent calcification seen with increasing age, but recently it has been shown that calcium plays a crucial role in the adrenergic regulation of the gland. Beta-adrenoceptor stimulation increases melatonin (aMT) synthesis by increasing the activity of cyclic 3 '-5' adenosine mono phosphate (cAMP). Cyclic-AMP regulates the production of the pineal hormone, melatonin, from serotonin via the rate-limiting enzyme N-acetyltransferase (NAT). Increased intracellular cAMP is essential to the adrenergic induction of NAT. Noradrenaline(NA)also elevates pinealocyte cyclic guanosine monophosphate (cGMP). Adrenergic regulation of these cyclic nucleotides involves both α₁ - and β-adrenoceptors. Beta-adrenoceptor stimulation is an absolute requirement. Alphal-adrenoceptor activation, which is ineffective alone, serves to amplify the β-stimulated cAMP and cGMP responses via a positive effect on a Ca²⁺⁻/ phospholipiddependent protein kinase (Protein kinase-C) and a net influx of Ca²⁺ into the pinealocyte. Previous studies suggest the use of organic calcium channel blockers (CCBs) as probes of calcium-mediated processes. Applying this concept, the study set out to investigate the influence of a representative of each of the structurally diverse groups of calcium channel blockers viz. verapamil, diltiazem and nifedipine, and to examine their effect on β-adrenoceptor stimulation. It used the β-agonist isoprenaline (ISO) and the mixed [α₁/β]agonist noradrenaline (NA), for its combined [α₁/β]adrenoceptor stimulation, on agonist-induced increases in the production of radio-labelled aMT and N-acetylserotonin(aHT) -measured as the sum of N-acetylated product- from [¹⁴C] serotonin. This was done using organ cultures of rat pineal glands. It was speciously assumed that this drug paradigm would allow the determination of Ca²⁺ influx and/or the blocking thereof in the reported potentiation by using ISO as a non Ca²⁺ -entry stimulating agonist, compared with NA and its Ca²⁺ -entry stimulating properties. Surprisingly, all 3 CCB's potentiated the effect of NA. Only diltiazem was found not to potentiate the effect of ISO. In an attempt to uncover the reason for these results, the study moved toward a mechanistic approach,focusing in an antecedent manner on the various steps in the indole metabolic pathway to identify the point at which the change occurred, and hence possibly elucidate the mechanism responsible for the paradoxical increase. Experiments which assayed the levels of NAT, under the same drug conditions, showed the paradoxical increase to be already evident at this stage. Secondary experiments confirmed that NA stimulation of the pineal is dependent on Ca²⁺, both in organ culture and with NAT: the Ca²⁺ chelator EGTA abolished adrenergically-induced stimulation, while Ca²⁺ added after EGTA, restored the enzyme activity. The ionophore A23187 (which is able to transport Ca²⁺ directly into the pinealocyte via a mechanism which differs from the α₁ - mechanism) when used in conjunction with ISO or NA, was able to potentiate the responses of these two agonists relative to control values (agonist-alone), but by itself had no effect. With the enzyme NAT critically dependent upon cAMP for its induction, it was decided to determine the levels of cAMP and then those of its regulator, cAMP-phosphodiesterase (cAMP-PDE). This reasoning was prompted by reports of anti-calmodulin activity shown by the CCBs, in addition to their channel blocking effects. By binding to calmodulin (CaM), the CCBs are reportedly able to inhibit the CaM-dependent activation of cAMP-PDE. Following NA stimulation, verapamil caused a significant decrease in cAMP-PDE levels and an increase in cAMP. The other CCBs showed a similar trend. Glands stimulated with ISO in the presence of verapamil and nifedipine showed no significant differences in cAMP or cAMP-PDE levels. Diltiazem, however, was found to decrease the effect of ISO on cAMP while causing a concomitant increase in cAMP-PDE. This i) supported a possible hypothesis that the observed enhancement is a result of cAMP levels remaining elevated due to an inhibition of cAMP-PDE by the CCEs and ii) pointed to the possible presence of a CaM-sensitive PDE within the rat pineal gland. To test this hypothesis, two drugs which are more specific in their actions on CaM effects were chosen to see if the earlier results could be mimicked and thereby confirmed. Glands stimulated with NA in the presence of the specific CaM inhibitor R 24571 showed increased NAT activity and [¹⁴C]-aMT production. cAMP-PDE levels were clearly down, thus corroborating the possibility of cAMP-PDE inhibition. Glands incubated in the presence of M&B 22948, a CaM-sensitive PDE inhibitor, showed similar increases in NAT activity and [¹⁴C]-aMT. These findings therefore support the initial results and although indirect, confirm the hypothesis that the paradoxical increase following predominantly NA stimulation could be a result of cAMP levels remaining elevated, due to inhibition by the CCEs of the CaM-dependent activation of its regulator cAMP-PDE. In summary, data presented herein concur with proposals that: i) the CCEs are not specific enough to be used as tools to research Ca²⁺ -mediated events, as they appear to have sites of action other than the voltage operated channel (VOC); eg. binding to calmodulin, ii) there are functional differences between the CCEs as shown by diltiazem in this series of experiments, iii) there is a CaM-sensitive-PDE present in the pineal.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences