Ariel Gordin

Rapid reversal of circadian blood pressure rhythm in shift workers.

The blood pressure and heart rates of seven normotensive shift workers were monitored automatically for 24 h with a non-invasive ambulatory method on 3 different days. The first monitoring session took place at the end of an ordinary work period of morning shifts, the second on the first day of a period of night shifts, and the third on the last day of a period of night shifts. The circadian blood pressure rhythm, which showed a normal pattern during the daytime work shift, was totally reversed from the first day of the night shift. The blood pressure rhythm closely followed the sleep-wakefulness cycle. The changes in circadian heart rate rhythm were not as pronounced as those in blood pressure but showed a similar trend.

General properties and clinical possibilities of new selective inhibitors of catechol O-methyltransferase

1. The structure of catechol O-methyltransferase (COMT) has been recently characterized and a series of new and selective COMT inhibitors developed. 2. Entacapone, nitecapone and tolcapone are nitrocatechol-type potent COMT inhibitors in vitro (Ki in nanomolar range). They are also very selective for COMT and active in vivo even after oral administration. CGP 28014 is a pyridine derivative that is active only in vivo. 3. In animal studies, these compounds inhibit effectively the O-methylation of L-dopa, thus improving its bioavailability and brain penetration and potentiating its behavioural effects. 4. Entacapone and nitecapone have mainly a peripheral effect whereas tolcapone and CGP 28014 also inhibit O-methylation in the brain. 5. In man, entacapone, nitecapone and tolcapone all inhibit dose dependently the COMT activity in erythrocytes. These COMT inhibitors also decrease the amount of COMT dependent metabolites of adrenaline and noradrenaline in plasma. 6. In human volunteers, entacapone, tolcapone and CGP 28014 improve the bioavailability of L-dopa and inhibit the formation of 3-O-methyldopa. 7. In the first clinical studies in patients with Parkinsons disease, both entacapone and tolcapone potentiate and prolong the therapeutic effect of L-dopa.

Simultaneous inhibition of catechol‐O‐methyltransferase and monoamine oxidase A: Effects on hemodynamics and catecholamine metabolism in healthy volunteers

To evaluate the effects of simultaneous pharmacologic inhibition of catechol‐O‐methyltransferase (COMT) and monoamine oxidase type A (MAO‐A) on hemodynamics and catecholamine metabolism in healthy volunteers at rest and during exercise.

The effect of catechol-O-methyltransferase inhibition with entacapone on cardiovascular autonomic responses in L-Dopa-treated patients with Parkinson's disease

We have compared the effects of entacapone, a peripherally acting catechol-O-methyltransferase (COMT) inhibitor, and placebo on cardiovascular autonomic responses in L-Dopa/dopa decarboxylase inhibitor–treated patients with Parkinsons disease (PD). In a double-blind, randomized, crossover study with two consecutive 1-week treatment periods, a battery of cardiovascular reflex tests (orthostatic, Valsalva, deep breathing, and isometric hand grip tests) was performed in a group of 15 patients with idiopathic PD. The first set of tests was performed after withholding L-Dopa overnight (control, “off” stage). The second and third sets of tests were performed in “on” stage after 1-week treatment with either entacapone 200 mg or placebo administered with each dose of L-Dopa/dopa decarboxylase (DDC) inhibitor. Valsalva, deep breathing, and orthostatic tests demonstrated no statistically significant differences in the ratio of the longest and shortest electrocardiographic R-to-R wave (R-R) intervals between entacapone and placebo or between study treatments and control. Blood pressure responses to both orthostatic challenge and prolonged isometric work (hand grip test) were similar between treatments. Systolic orthostatic hypotension was observed in only one patient during the control test, but it occurred more frequently after L-Dopa/DDC inhibitor, regardless of concomitant administration of either entacapone (n = 3) or placebo (n = 4). Peripheral COMT inhibition with entacapone does not significantly alter cardiovascular autonomic responses in L-Dopa-treated patients with PD.

Population pharmacodynamic modeling of levodopa in patients with Parkinson's disease receiving entacapone

To assess the pharmacodynamics of levodopa among patients with Parkinsons disease showing end‐of‐dose fluctuations at different doses of entacapone.

Entacapone increases levodopa exposure and reduces plasma levodopa variability when used with sinemet CR

Entacapone is a catechol-O-methyltransferase (COMT) inhibitor used as an adjunct to levodopa/dopa decarboxylase inhibitors in the treatment of Parkinsons disease. Entacapone increases the bioavailability and reduces the daily variation of plasma levodopa when administered with standard levodopa preparations. These parameters were studied when entacapone was administered with a controlled-release levodopa preparation after repeated administrations throughout the day in 16 healthy male volunteers. On 2 test days, 200 mg entacapone or placebo was administered 4 times during the day at 4-hour intervals concomitantly with a single dose of controlled-release levodopa/carbidopa 100 mg/25 mg (Sinemet CR). Plasma levodopa, 3-O-methyldopa (3-OMD), and carbidopa concentrations were measured before intake of the medication and then every 30 minutes for 16 hours (until midnight), and less frequently up to 24 hours after the first levodopa dose. The minimum, maximum, and average concentration of levodopa; the daily variation of levodopa concentration; and the area under the time concentration curve (AUC) were calculated. The mean (±SD) plasma levodopa AUC was 39% (P = 0.0001) higher with entacapone (11,802 ± 1454 ng/hour/mL) compared with placebo (8465 ± 927 ng/hour/mL). The daily variation of plasma levodopa was reduced by about 25% with entacapone (P < 0.01). Entacapone significantly reduced plasma 3-OMD concentration by about 50% (P = 0.0001), indicating marked COMT inhibiting activity. There were no differences in plasma carbidopa concentrations. Entacapone significantly increased the bioavailability of levodopa and reduced its daily variation when administered concomitantly with a controlled-release levodopa preparation.

Exercise hemodynamics and catecholamine metabolism after catechol‐O‐methyltransferase inhibition with nitecapone

The effect of catechol‐O‐methyltransferase inhibition with nitecapone (OR‐462) on the hemodynamic responses to exercise and catecholamine metabolism was studied in 10 healthy male volunteers (aged 19 to 26 years). Nitecapone, a new specific and selective catechol‐O‐methyltransferase inhibitor, was given at increasing single oral doses up to 100 mg. Nitecapone did not influence resting or exercise heart rate, blood pressure, systolic time intervals, or plasma catecholamine levels. It altered the metabolic profile of catecholamines as shown by (1) an increase of 140% in the plasma concentration of the monoamine oxidase–dependent metabolite 3,4‐dihydroxyphenylethyleneglycol (p < 0.001), (2) a decrease of 27% in the plasma concentration of its methylation product 3‐methoxy‐4‐hydroxyphenylethyleneglycol (p < 0.05), and (3) a 25% reduction in the urinary excretion of the methylated metabolites 3‐methoxy‐4‐hydroxymandelic acid and homovanillic acid (p < 0.05). Nitecapone was well tolerated and seemed to be hemodynamically safe in humans.

Vasodilatory effects of carvedilol and pindolol.

Summary: The effects of three different nonselective &bgr;‐blockers on central and peripheral hemodynamics as well as on pulmonary function were compared in 13 healthy subjects (19–37 years). The subjects were given carvedilol 50 mg, pindolol 10 mg, propranolol 80 mg, and placebo orally twice daily for 1 week in a double‐blind, crossover, randomized manner. Heart rate, blood pressure, arterial calf blood flow (venous occlusion strain gauge plethysmography), and pulmonary function (flowvolume spirometry) were measured at the first and at the last trial day. Heart rate and blood pressure were lower on carvedilol and propranolol than on pindolol and placebo; the maximal bradycardiac effect was 13 and 17 beats/min and hypotensive effect 9/10 mm Hg and 10/7 mm Hg on carvedilol and propranolol, respectively. Both carvedilol and pindolol increased arterial flow by about 40% (p < 0.05 and p < 0.01, respectively) and reduced peripheral resistance by about 34% (p < 0.05 and p < 0.01, respectively), the effect persisting after 1 week of treatment. None of the medications had any noteworthy effects on pulmonary function. Two subjects complained of tremor on pindolol. We conclude that carvedilol and pindolol possess distinct vasodilatory properties. Carvedilol had a stronger hypotensive effect than pindolol and was well tolerated.

Lipoprotein lipase activity in adipose tissue and skeletal muscle of human diabetics during insulin deprivation and restoration

Twelve insulin-dependent diabetic patients were deprived of insulin for 12 h, and thereafter given an 8-h i.v. infusion of insulin. Lipoprotein lipase (LPL) activity was determined from heparin eluates of adipose tissue and skeletal muscle before and after insulin infusion. In spite of development of marked hyperglycemia and hyperketonaemia during the insulin deprivation the LPL activity of the two tissues remained mostly within normal range. During the subsequent insulin administration the LPL activity of adipose tissue increased by 36% (p less than 0.05) whereas the skeletal muscle LPL remained unchanged. The result is compatible with the view that human adipose tissue LPL is more sensitive to insulin than the corresponding enzyme of muscle.

Cardiovascular and behavioral changes after ICV infusion of TRH in the conscious goat

Thyrotropin releasing hormone was infused during 5 min into the lateral brain ventricle (ICV) of conscious goats in doses ranging from 125 to 4000 ng. Changes in blood pressure, heart rate and behavior were studied. TRH in doses of 500--4000 ng raised the mean blood pressure and both the magnitude and the duration of the response was related to the dose. The onset of the rise occurred in average 8 min after the start of the infusion. The heart rate fell somewhat with all doses. No consistent changes were observed in the respiration rate. TRH caused several behavioral changes beginning about 6 min after the start of infusion. The goats often decreased their locomotor activity. They were frequently bleating except after the lowest dose. These results support the view that TRH affects several vital functions in the central nervous system.