Ultrasound for management of pediatric nasal fractures.

BACKGROUND: Nasal bone fractures are common in children but can be challenging to diagnose accurately in the first days due to swelling and tenderness. While X-rays and computed tomography have limitations, ultrasound may be a radiation-free and cost-effective alternative for diagnosing and treating nasal fractures. METHODS: A prospective cohort study at a tertiary referral hospital between 2021-2023. Children who had sustained nasal trauma were included. A radiologist and a non-radiologist blindly reviewed ultrasound scans, and the results were compared to the physical examination performed by a senior otolaryngologist. If closed reduction was necessary, ultrasound was employed during the procedure. The primary outcome was the assessment of nasal fractures in children using ultrasound; Secondary outcomes included success rates for closed reduction and test reliability. RESULTS: Of the 50 children (mean age: 11 years, interquartile range: 6-15 years, 36 [72%] males), 22 (44%) were clinically diagnosed with a nasal fracture. Interobserver reliability for nasal fracture by ultrasound was 92%, with a Cohen's kappa coefficient of k=0.91. The sensitivity and specificity of ultrasound in detecting nasal fractures were 90% and 89%, respectively, with positive and negative predictive values of 86% and 93%, respectively. Closed reduction was performed on 18 children, with (n=11) or without (n=7) ultrasound, with the former showing better alignment results (82% vs. 71%). CONCLUSIONS: Ultrasound has a high negative predictive value in identifying nasal fractures in children with swollen noses during presentation. This enables to avoid further unnecessary referrals and interventions. Ultrasound-guided closed reduction of nasal fractures demonstrates improved outcomes; however, further large-scale randomized studies are required to validate our findings.

Effects of neurodevelopmental risk factors on brainstem maturation in premature infants.

BACKGROUND: Interpeak latencies (IPL), as measured by the auditory brainstem-evoked responses (ABR) test, represent the conduction time, and therefore the maturation of the brainstem auditory pathway. We aimed to study the effect of various risk factors for the neurodevelopmental delay on the conduction time in the auditory pathway among normal hearing premature infants, at term postmenstrual age (PMA). METHODS: Retrospective analysis of 239 premature infants (gestational age 32.5 ± 2.1 weeks, birth weight 1827 ± 483 g). Interpeak latencies, demographic data, and risk factors were recorded. RESULTS: Sex, PMA at ABR test, being small for gestational age (SGA), intraventricular hemorrhage (IVH) or periventricular leukomalacia (PVL), and days of invasive ventilation were found to significantly affect the IPL's in the auditory pathway in a univariate analysis. Multivariable regression analysis revealed that male sex and less advanced PMA at the examination were independent factors associated with prolonged IPL's, while bronchopulmonary dysplasia, IVH or PVL and being SGA shortened the IPL's. Non-invasive mechanical ventilation, did not affect the caudal part of the auditory pathway, despite its high noise level. CONCLUSIONS: Among various risk factors for the neurodevelopmental delay, male sex was associated with delayed, while IVH or PVL, BPD and SGA could be associated with accelerated auditory brainstem maturation. IMPACT: Auditory brainstem-evoked response (ABR) test, among normal hearing infants, can serve as a clinical tool to assess brainstem auditory maturation. Different neurodevelopmental risk factors could have different effects on the maturity of the auditory pathway. Male sex is significantly associated with prolonged interpeak latencies (IPL) among preterm and term infants, while intraventricular hemorrhage or periventricular leukomalacia, bronchopulmonary dysplasia, and being small for gestation age may be associated with shortened IPL The corrected age at ABR testing is of significance, among preterm and term infants.

Simultaneous inhibition of catechol-O-methyltransferase and monoamine oxidase A: effects on hemodynamics and catecholamine metabolism in healthy volunteers.

OBJECTIVE: 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. BACKGROUND: Entacapone, a COMT inhibitor, is studied as an adjunct to levodopa treatment in patients with Parkinson's disease. Moclobemide, an MAO-A inhibitor, is already in clinical use as an antidepressant. It is likely that entacapone and moclobemide will be used concomitantly in the future in patients who have both Parkinson's disease and depression. It was therefore considered to be important to investigate the tolerability of combined COMT and MAO-A inhibition with entacapone and moclobemide. DESIGN AND METHODS: This was a randomized, single-dose, double-blind crossover study of 12 healthy male volunteers. The treatments were either placebo, 200 mg entacapone, 150 mg moclobemide, or the combination of entacapone and moclobemide in single doses. Heart rate, blood pressure, impedance cardiography, and plasma concentrations of catecholamines and their metabolites were measured both at rest and during submaximal standardized bicycle exercise. RESULTS: Entacapone and moclobemide (either alone or in combination) did not change heart rate, blood pressure, or any hemodynamic parameter at rest or during exercise compared with placebo. Neither were the concentrations of norepinephrine and epinephrine in plasma influenced. Both drugs had the expected effects on catecholamine metabolite concentrations in plasma. The decrease in the concentration of 3-methoxy-4-hydroxyphenylglycol (MHPG) induced by moclobemide was not potentiated by entacapone. CONCLUSION: The combined use of therapeutic single doses of entacapone and moclobemide in healthy volunteers did not affect the hemodynamics or concentrations of unconjugated norepinephrine and epinephrine in plasma. Other mechanisms are capable of regulating the concentrations of norepinephrine and epinephrine in circulating blood (and apparently also at receptors in the heart and vascular tissue) when both COMT and MAO-A activity are inhibited to a significant extent. This was also the case during marked sympathetic stimulation. The changes in the catecholamine metabolite concentrations provide evidence of effective COMT and MAO inhibition. Concentrations of MHPG in plasma are determined mainly by MAO-A activity because COMT inhibition did not have an additional effect on the moclobemide-induced decrease in plasma MHPG.

The effect of entacapone on the disposition and hemodynamic effects of intravenous isoproterenol and epinephrine.

BACKGROUND: Entacapone is a potent, selective catechol-O-methyltransferase (COMT) inhibitor. Entacapone could potentiate the hemodynamic effects of exogenously administered catecholamines, which are substrates of the COMT enzyme. DESIGN AND METHODS: Originally, the study was to follow a placebo-controlled, randomized crossover design. Because of two cases of ventricular arrhythmia, a decision was made to terminate the study before its completion. Six subjects went through the isoproterenol and epinephrine infusions while taking placebo and five other subjects while taking entacapone. The actual design was thus one with two parallel groups with random allocation and double-blind drug administration. The subjects were given either a single dose of 400 mg entacapone or placebo 30 minutes before the start of isoproterenol or epinephrine infusions. Four dosages of epinephrine (1.5, 3, 6, or 12 micrograms/min) and isoproterenol (0.5, 1, 1.5, or 2 micrograms/min) were infused (5 minutes for each level). Heart rate and blood pressure were measured and ECG was monitored. The concentrations of isoproterenol and epinephrine in plasma were determined by HPLC. RESULTS: The maximal increase in heart rate during isoproterenol infusion after entacapone administration (40 +/- 11 beats/min, mean +/- SD) was statistically greater (p = 0.0496) than after placebo administration (27 +/- 7 beats/min). The increase in heart rate during epinephrine infusion was 25 +/- 13 beats/min after entacapone administration and 14 +/- 9 beats/min after placebo administration (p = 0.127). There were no statistically significant differences between entacapone and placebo in blood pressure or in plasma concentrations of isoproterenol and epinephrine. CONCLUSION: We conclude that entacapone may potentiate the chronotropic and arrhythmogenic effects of exogenously administered isoproterenol and epinephrine.

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 less than 0.001), (2) a decrease of 27% in the plasma concentration of its methylation product 3-methoxy-4-hydroxyphenylethyleneglycol (p less than 0.05), and (3) a 25% reduction in the urinary excretion of the methylated metabolites 3-methoxy-4-hydroxymandelic acid and homovanillic acid (p less than 0.05). Nitecapone was well tolerated and seemed to be hemodynamically safe in humans.

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

OBJECTIVE: To assess the pharmacodynamics of levodopa among patients with Parkinson's disease showing end-of-dose fluctuations at different doses of entacapone. METHODS: Nineteen patients participated in a randomized, double-blind phase II study with a crossover design. Doses of 50, 100, 200, or 400 mg entacapone or placebo were given with the patient's individual levodopa-dopa decarboxylase inhibitor dose. Blood samples were withdrawn for pharmacokinetic analysis, and the clinical response was measured using the motor part of the Unified Parkinson's Disease Rating Scale. A population pharmacodynamic model was developed with the NONMEM program. RESULTS: A sigmoidal Emax model with an effect compartment was used to relate plasma concentrations of levodopa with clinical response. In the population analysis two covariate relationships were found. The first was E0 = 55.2, [1 + 0.012. (Dur-13)], where E0 is the initial motor Unified Parkinson's Disease Rating Scale score, and Dur is the duration of disease in years. The second was C50(carbidopa) = 951 ng/ml; C50(benserazide) = 1238 ng/ml, where C50 is the steady-state plasma concentration of levodopa eliciting half of maximum attainable effect, and carbidopa and benserazide are the dopa decarboxylase inhibitors given in the study. No effect of entacapone on clinical response beyond its influence on levodopa pharmacokinetics was found. Interindividual and interoccasion variabilities were estimated. CONCLUSIONS: A population pharmacodynamic model for levodopa was built that took into account interindividual and intraindividual variability. The main finding was that entacapone does not alter the concentration-effect curve of levodopa, suggesting that entacapone acts at the level of peripheral pharmacokinetics of levodopa and that plasma levels of 3-O-methyldopa have a negligible role in the pharmacodynamics of levodopa.

Effect of entacapone, a COMT inhibitor, on clinical disability and levodopa metabolism in parkinsonian patients.

We studied the effect of entacapone, a selective catechol-O-methyltransferase inhibitor, on the bioavailability and clinical effect of levodopa in Parkinson's disease (PD). On day 1 (control day), nine patients received their own levodopa (plus benserazide) medication only; for the next 7 days they received 200 mg of entacapone with each dose of levodopa (tid or qid). We evaluated disability in the morning (8 AM) before drug administration and then at 1-hour intervals until 6 PM on days 1, 2, and 8, using a modified motor part of the Unified Parkinson's Disease Rating Scale. Repeated blood samples were taken before and during the 4 hours after the morning drugs for pharmacokinetic evaluation of entacapone and of levodopa and its metabolites. Added to the levodopa treatment, entacapone decreased clinical disability by about 16% (p < 0.05) from day 1 to day 8. The area under the curve (AUC) of levodopa increased by 38% (p < 0.01) after administration of a single dose of entacapone and by 40% (p < 0.05) after 7 days of multiple dosing with entacapone. Entacapone did not change the Tmax and Cmax values of levodopa. After 7 days of treatment with entacapone, the AUC of 3-O-methyldopa had decreased by 44% (p < 0.01) and of homovanillic acid by 26% (p < 0.05) as compared with treatment with levodopa alone. Four patients became slightly more dyskinetic during entacapone treatment than before it. The combination of entacapone and levodopa was well tolerated, judged by the lack of significant changes in hemodynamic and safety variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of peripheral catechol-O-methyltransferase inhibition on the pharmacokinetics and pharmacodynamics of levodopa in parkinsonian patients.

Catechol-O-methyltransferase (COMT) metabolizes a portion of administered levodopa and thus makes it unavailable for conversion to dopamine in the brain. In an open-label trail, we examined the effects of entacapone, a peripheral inhibitor of COMT, administered acutely or for 8 weeks, on the pharmacokinetics and pharmacodynamics of levodopa in 15 parkinsonian subjects with a fluctuating response to levodopa. Acutely and chronically administered entacapone similarly decreased the plasma elimination of orally and intravenously administered levodopa. Absorption of levodopa was minimally affected. During chronic entacapone treatment, daily levodopa dosages were reduced by 27% yet mean plasma levodopa concentrations were increased by 23%. Plasma 3-O-methyldopa concentrations were decreased by 60%. Entacapone increased the duration of action of single doses of levodopa by a mean of 56%. The percent of the day "on" after 8 weeks of entacapone treatment was 77%; it dropped to 44% upon withdrawal of entacapone. We conclude that inhibition of COMT by entacapone increases the plasma half-life of levodopa and augments the antiparkinsonian effects of single and repeated doses of levodopa.

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.

Influence of beta blockade and intrinsic sympathomimetic activity on hemodynamics, inotropy and respiration at rest and during exercise.

The degree of intrinsic sympathomimetic activity (ISA) is reported to influence the effects of beta blockade at rest, but the effects during exercise are not well documented. Heart rate, blood pressure and left ventricular (LV) function (as assessed by systolic time intervals) were measured at rest and during upright bicycle exercise as well as with flow-volume spirometry at rest in 13 healthy volunteers. The measurements were performed before and 4 and 24 hours after a single oral dose of pindolol (10 mg), nadolol (80 mg) and acebutolol (400 mg) in a double-blind, randomized, crossover manner. All drugs reduced heart rate, but nadolol had the most pronounced and longest bradycardic effect at rest. Diastolic blood pressure was only slightly influenced by the drugs, whereas systolic pressure was significantly lower compared with control values, especially during exercise (p less than 0.001). Neither preejection period (PEP) nor LV ejection time (LVETc) was changed at rest after pindolol, but PEP increased and LVETc decreased significantly after nadolol (p less than 0.05 for PEP and p less than 0.01 for LVETc) and acebutolol (p less than 0.05 for both). During exercise, PEP and LVET were significantly longer after all 3 drugs compared with control values. Only nadolol, which lacks ISA, significantly decreased expiratory flow values (p less than 0.05). Thus, unlike the other beta blockers, pindolol (with strong ISA) did not depress LV function at rest, while during exercise all 3 beta blockers had equal adverse effects. The degree of ISA appears to be important in determining the hemodynamic effects of beta-blocking drugs.

Effect of hydroxyethyl starch and dextran on plasma volume and blood hemostasis and coagulation.

Six healthy male subjects were given in a crossover fashion medium molecular weight (HES 125) and low molecular weight (HES 40) hydroxyethyl starch, dextran, and balanced salt solution by intravenous infusion. The plasma volumes were determined using labeled albumin and plasma protein measurements. Three properties of factor VIII protein complex and indices of blood coagulation and hemostasis were measured before and after the infusions. Both the salt solution and HES 40 increased plasma volume, but their effect wore off within 3 hours. Dextran and HES 125 increased plasma volume significantly (P less than 0.001) more than the salt solution did, and the expansion was maintained for 24 hours. Plasma volume increases (dextran and HES 125) were associated with high nonglucose carbohydrate levels in plasma and low levels in urine. No or slight increases in plasma volumes (HES 40), on the other hand, were associated with low and high carbohydrate levels in plasma and urine, respectively. Serum alpha-amylase activity increased significantly after both HES preparations as compared to salt solution. Dextran and HES 125 decreased all the three values of factor VIII, these decreases being maximal 3 to 6 hours after administration and highest (about 25 per cent) for F VIII R:Ag and F VIII R:cof. It is concluded that HES 125 and dextran are equally effective plasma expanders.

Comparison of slow-release indomethacin and diflunisal in patients with arthrosis.

A double-blind, crossover study was carried out in 44 patients with osteoarthrosis of the hip or knee to compare the efficacy and tolerability of treatment with a new slow-release formulation of indomethacin (50 mg) with that of diflunisal (250 mg). After a 1-week wash-out period, patients were allocated at random to receive 2 tablets daily of one or other preparation for 6 weeks before being crossed over to the alternative drug for a further 6 weeks. Aspirin was allowed as a rescue analgesic throughout the study. Subjective assessments of pain and objective assessments of joint mobility were made before the start of treatment and at the end of each period, and details were recorded of rescue analgesic usage and any side-effects. Analysis of the results from 42 patients showed that whilst both treatments helped to alleviate pain, patients' overall evaluation of efficacy at the end of the study indicated that indomethacin was slightly more effective than diflunisal and there was a significant preference for indomethacin. Both drugs were well tolerated and none of the side-effects, reported in about 15% of patients on each drug, resulted in any withdrawals.

Comparison of a slow-release indomethacin tablet and naproxen in osteoarthrosis.

A double-blind, crossover study was performed in 21 out-patients with osteoarthrosis of the hip or knee to compare the efficacy and tolerability of a new slow-release formulation (multiple units dose preparation) of indomethacin (50 mg) with those of naproxen (250 mg). After a wash-out period of 1 week, the patients were randomized to receive 2 tablets daily of one or other preparation for 3 weeks. This was followed by another wash-out period of 1 week, whereafter the patients were crossed over to the alternative drug for another 3 weeks. Subjective assessments of pain and objective assessment of joint mobility and the use of acetylsalicylic acid as rescue analgesic were used to evaluate the efficacy of the treatment. Analysis of results from 19 patients showed that both drugs effectively alleviated pain, and there was no difference between indomethacin and naproxen in this respect. There were 2 withdrawals, 1 on naproxen due to inefficacy and 1 on indomethacin due to gastro-intestinal side-effects. Otherwise, the drugs were well tolerated and side-effects occurred to the same extent on both drugs. This study confirms the good efficacy and tolerability of the new slow-release indomethacin preparation.

Nitrogen utilization during postoperative, low nitrogen, high caloric parenteral nutrition.

Twenty elderly patients having undergone colonic resection were randomized into two regimens of postoperative parenteral nutrition. Fructoglucose satisfied the basal caloric needs of the patients. Amino acids were given as a mixture that provided 0.11 (0.09-0.14; mean and range) g/kg/day of nitrogen only. In half of the patients the energy intake was doubled with fat emulsion. The mean nitrogen-energy ratios in grams of nitrogen/kcal/day were 1:201 and 1:336 in the two groups, respectively. Both regimens were given for three days, starting from the first postoperative day. On the first day, the mean nitrogen balance was negative in both groups. On the third day, the mean balance was slightly positive in the amino acid, fructoglucose plus fat emulsion group, but negative in amino acid plus fructoglucose group. Amino acid concentrations in plasma and urine were markedly elevated in both groups, but relative concentrations in plasma remained rather normal. Apparently, a positive postoperative nitrogen balance can be obtained with restricted amino acid supply, if energy is provided in abundance.

SnifProbe: new method and device for vapor and gas sampling.

SnifProbe is based on the use of 15 mm short pieces of standard 0.53 mm I.D. capillary or porous layer open tubular columns for sampling airborne, headspace, aroma or air pollution samples. A miniaturized frit-bottomed packed vial named MicroSPE was also prepared which served for the sampling of solvent vapors and gases as well as liquid water. The short (15 mm) trapping column is inserted into the SnifProbe easy-insertion-port and the SnifProbe is located or aimed at the sample environment. A miniature pump is operated for pumping 10-60 ml/min of the air sample through the short piece of column to collect the sample. After a few seconds up to a few minutes of pumping, the short column is removed from the SnifProbe with tweezers (or gloved hands) and placed inside a glass vial of a direct sample introduction device (ChromatoProbe) having a 0.5 mm hole at its bottom. The ChromatoProbe sample holder with its glass vial and sample in the short column are introduced into the GC injector as usual. The sample is then quickly and efficiently desorbed from the short sample column and is transferred into the analytical column for conventional GC and/or GC-MS analysis. We have explored the various characteristics of SnifProbe and demonstrated its applicability and effectiveness in many applications. These applications include: the analysis of benzene, toluene and o-xylene in air, SO2 in air, perfume aroma on hand, beer headspace, wine aroma, coffee aroma, cigarette smoke, trace chemical warfare agent simulants, explosives vapors, ethanol in human breath and odorants in domestic cooking gas. SnifProbe can be operated in the field or at a chemical process. The sample columns can be plugged and stored in a small union storage device, placed in a small plastic bag, marked and brought to the laboratory for analysis with the full power of GC and/or GC-MS. Accordingly, we feel that the major and most significant feature of SnifProbe is that it brings the field and process to the laboratory. Thus, SnifProbe can extend the "arm" of the GC and GC-MS laboratory and enable high-quality field and process analysis.

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 Parkinson's 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.

The effects of different repeated doses of entacapone on the pharmacokinetics of L-Dopa and on the clinical response to L-Dopa in Parkinson's disease.

We performed a double-blind, placebo-controlled, randomized, crossover, multiple-dose study on entacapone in 25 patients with Parkinson's disease with levodopa (L-Dopa) treatment-related fluctuations. A run-in period was followed by four 2-week treatment periods during which the patients took 4 to 6 daily doses of L-Dopa concomitantly with 100, 200, or 400 mg of entacapone or with placebo. The effects were assessed at the end of each period; the inhibition of soluble catechol-O-methyltransferase (S-COMT) activity in red blood cells and the plasma concentrations of entacapone, L-Dopa, and 3-O-methyldopa (3-OMD) were measured and clinical effects assessed on an 18-hour home diary. Twenty-one patients completed the study. Entacapone decreased the COMT activity from predose level: 100 mg by 25%, 200 mg by 33%, and 400 mg by 32% (p < 0.001 vs. placebo for each dose). Correspondingly, the 3-OMD concentrations decreased by 39%, 54%, and 66% with 100-, 200-, and 400-mg doses, respectively. The elimination half-life of L-Dopa was prolonged by 23% (p < 0.05), 26% (p < 0.001), and 48% (p < 0.001), and the area under the curve of L-Dopa increased by 17% (p < 0.05), 27% (p < 0.001), and 37% (p < 0.001) with the increasing doses. Despite a significant decrease in the daily dose of L-Dopa, entacapone decreased the proportion of daily "off" time: 100 mg by 11%, 200 mg by 18%, and 400 mg by 20% compared with placebo. However, this decrease was not statistically significant for any of the doses in this small patient population. The dyskinetic "on" time did not increase with different doses of entacapone. All doses were well tolerated, and no severe adverse events were reported. The study showed that repeated dosing of entacapone inhibits the COMT activity in a dose-dependent manner and thereby reduces the loss of L-Dopa to 3-OMD. Therefore, the area under the curve of L-Dopa is increased and the patient's clinical condition improved.

Effect of entacapone, a COMT inhibitor, on the pharmacokinetics and metabolism of levodopa after administration of controlled-release levodopa-carbidopa in volunteers.

We studied the effect of entacapone, a catechol-O-methyltransferase (COMT) inhibitor, on the pharmacokinetics and metabolism of levodopa after administration of a controlled-release (CR) levodopa-carbidopa preparation (Sinemet CR) in an open, randomized trial in 12 healthy male volunteers. The inhibition of soluble COMT (S-COMT) in red blood cells (RBCs) was also measured. Single graded doses of entacapone (100-800 mg) were administered concomitant with a single oral dose of CR levodopa, or CR levodopa was given without entacapone (control treatment), at least 1 week apart. Plasma concentrations of levodopa, 3-O-methyldopa (3-OMD), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), carbidopa, and entacapone were determined for pharmacokinetic calculations. Entacapone decreased dose-dependently the activity of S-COMT in RBCs with a maximal inhibition of 66% after the highest dose (800 mg). Entacapone increased the area under the plasma concentration-time curve (AUC) of levodopa; the increase was highest (33%) after the 400-mg dose. Entacapone did not influence time to maximal concentration (Tmax) of levodopa. Entacapone was absorbed faster than levodopa from the CR preparation. The AUCs of 3-OMD and HVA decreased and that of DOPAC increased dose-dependently after entacapone, maximally by 69, 38, and 74%, respectively. Higher doses of entacapone (400 mg and 800 mg) decreased the AUC, but not Tmax of carbidopa. Over the dose range studied, entacapone was well tolerated. Entacapone is an effective COMT inhibitor. It improves the pharmacokinetic profile of levodopa when used in combination with a CR levodopa preparation, as it does with a standard levodopa preparation. The results justify further clinical studies with entacapone in combination with CR preparations of levodopa.

The effect of catechol-O-methyl transferase inhibition by entacapone on the pharmacokinetics and metabolism of levodopa in healthy volunteers.

We studied the effect of inhibiting the enzyme catechol-O-methyltransferase (COMT) by a novel COMT inhibitor, entacapone, on the pharmacokinetics and metabolism of levodopa in 12 healthy male volunteers. Single increasing oral doses of entacapone (50-400 mg) were administered concomitantly with a single oral dose of levodopa/carbidopa (100/25 mg). The subjects were treated with carbidopa (100 mg t.i.d.) for 1 day prior to the administration of study drugs. Plasma concentrations of levodopa; its metabolites 3-O-methyldopa (3-OMD), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA); as well as carbidopa and entacapone were determined for pharmacokinetic calculations. Entacapone dose-dependently increased the area under the plasma concentration-time curve (AUC) of levodopa; the increase was 65% after the 400 mg dose of entacapone. Neither Cmax nor Tmax of levodopa was statistically significantly influenced by entacapone. Entacapone dose-dependently decreased the AUC of 3-OMD, maximally by 58%. The AUC of DOPAC was statistically significantly increased but no change in the AUC of HVA was observed after entacapone. No drug-related adverse events or hemodynamic effects were observed. The in vivo biochemical effects of entacapone indicate that it is an orally active COMT inhibitor and that it may improve the therapeutic efficacy of levodopa in Parkinson's disease.