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.

Clinical advantages of COMT inhibition with entacapone - a review.

Two catechol- O-methyltransferase (COMT) inhibitors, entacapone and tolcapone, were developed during the 1990's to be used as adjuncts to levodopa (LD) - dopa decarboxylase (DDC) inhibitors in the treatment of Parkinson's disease (PD). Entacapone is currently in wide clinical use, while tolcapone can be used in restricted indications only, due to its hepatotoxicity. COMT inhibitors prolong the elimination of LD, while DDC inhibitors mainly increase its absorption; both mechanisms leading to increased bioavailability of LD. The pharmacokinetic properties of LD, carbidopa and entacapone are quite similar, and entacapone is administered concomitantly with LD plus carbidopa. Entacapone prolongs the clinical effect of each LD dose by 30 to 40 minutes; this effect is seen already after the first entacapone dose. When LD is administered in several frequent daily doses, addition of entacapone reduces the daily fluctuations of plasma LD by 30 to 40%. Based on studies with home diaries, entacapone increases the daily ON-time by an average of one to two hours, and reduces the daily OFF-time correspondingly in patients with PD with motor fluctuations. The daily LD dose has been reduced by 10 to 30%. These positive effects are sustained in long term use over several years. There is still scant information of the benefit of entacapone in patients without motor fluctuations. Entacapone can cause both dopaminergic and non-dopaminergic adverse events. Increased dyskinesias are most frequently recorded in patients with motor fluctuations. The dopaminergic adverse events can usually be diminished by reducing the LD dose. Non-dopaminergic adverse events are abdominal pain and diarrhea. Diarrhoea has led to discontinuation in 3 to 4% of the patients in clinical trials. Entacapone has not been connected to liver toxicity and there are no indications to follow laboratory safety during treatment. The benefit-risk ratio of entacapone is considered favorable.A triple LD/carbidopa/entacapone combination tablet has recently been developed. Three LD strengths (50, 100 and 150 mg) are available, each contains 200 mg of entacapone. The majority of the patients can be managed with these three LD strengths. Entacapone has today an established position in treatment of PD patients with motor fluctuations, either as a separate tablet or as the triple LD combination.

The tolerability and efficacy of entacapone over 3 years in patients with Parkinson's disease.

The long-term safety and efficacy of the catechol-O-methyltransferase (COMT) inhibitor entacapone was investigated in a 3-year open-label extension of the 6-month double-blind placebo-controlled Nordic (NOMECOMT) study. After a wash-out following this study, 132 patients with Parkinson's disease (PD) experiencing motor fluctuations treated with levodopa/dopa decarboxylase (DDC) inhibitor received additional therapy with entacapone 200 mg, administered with each dose of levodopa. The most common adverse events (AEs) were insomnia (30%), dizziness (20%), nausea (20%), aggravated parkinsonism (17%) and hallucinations (14%). Only 19 (14%) patients discontinued because of AEs. Most dopaminergic AEs occurred shortly after initiation of entacapone, and these could be managed by levodopa down-adjustment. The mean duration of benefit of a single dose of levodopa increased significantly from 2.1 to 2.8 h (P < 0.01) at 3 months and remained prolonged for the whole study. At the end of the study, the mean daily dose of levodopa was significantly decreased from baseline (from 737 to 696 mg; P < 0.05). The patients' global assessment indicated that 69% of patients improved when given entacapone and this proportion was maintained until the end of the study (64%). There was a significant worsening of disability upon withdrawal of entacapone. In conclusion, entacapone given in combination with levodopa, has a good long-term safety profile and a sustained beneficial effect in patients with PD with motor fluctuations.

Efficacy and safety of entacapone in Parkinson's disease patients with suboptimal levodopa response: a 6-month randomized placebo-controlled double-blind study in Germany and Austria (Celomen study).

OBJECTIVES: To determine the efficacy and safety of the catechol-O-methyltransferase (COMT) inhibitor entacapone, used as an adjunct to levodopa, in Parkinson's disease (PD) patients. PATIENTS AND METHODS: In this parallel group, randomized, double-blind study, 301 PD patients, the majority with motor fluctuations, received entacapone (200 mg) or placebo with each daily dose of standard or controlled-release (CR) levodopa. The 24-week treatment period was followed by 2 weeks of entacapone withdrawal. Efficacy was determined by home diaries ('on' and 'off' times), Unified Parkinson's Disease Rating Scale (UPDRS) and changes in levodopa dosage, and safety by adverse-event inquiry, vital signs, electro cardiography (ECG) and laboratory tests. RESULTS: In the total population, the UPDRS activities of daily living and motor scores were significantly improved (P < 0.05) by entacapone vs placebo. In fluctuating patients, 'on' time increased (1.7 h) and 'off' time decreased (1.5 h) significantly more with entacapone than with placebo (0.5 and 0.6 h, respectively; P < 0.05), and the daily levodopa dose was reduced by 54 mg with entacapone and increased by 27 mg with placebo (P < 0.05). Entacapone benefit was lost on withdrawal. Entacapone efficacy was comparable between patients using CR and standard levodopa preparations. Increased dyskinesias (entacapone 34%, placebo 26%) and nausea (10 and 5%, respectively), mostly occurring shortly after treatment initiation, were generally managed by reducing the levodopa dose. Diarrhoea (entacapone 8%, placebo 4%) was seldom severe. There were no differences in vital signs, ECG or laboratory results. CONCLUSION: Entacapone is an effective and safe levodopa extender and enhancer, improving the symptomatic efficacy of levodopa in PD and adding to the patients' benefit.

The effect of COMT inhibition with entacapone on cardiorespiratory responses to exercise in patients with Parkinson's disease.

The inhibition of catechol-O-methyltransferase (COMT) may impair catecholamine clearance resulting in unwanted cardiac and hemodynamic events. We therefore studied the effects of entacapone, an inhibitor of peripheral COMT, on cardiorespiratory and plasma noradrenaline (NA) responses to exercise and on respiratory muscle strength in l-dopa treated patients with Parkinson's disease (PD). A randomized, double-blind, cross-over study with two 1week treatment periods was performed in 15 PD patients. The test battery included analysis of hemodynamics, gas exchange parameters and plasma NA during a maximal exercise test, assessment of maximal static airway pressures and pre- and post-exercise motor scores of the Unified Parkinson's Disease Rating Scale (UPDRS). The first test was done after withholding l-dopa overnight ('run-in' test, off-phase). The second and third tests were done in on-phase after 1week treatment with either entacapone 200mg or placebo given with each dose of l-dopa. No differences in maximal work load, plasma NA, or in cardiorespiratory responses to either maximal or work rate standardized submaximal exercise were observed between entacapone and placebo, except for O(2) pulse, which was slightly lower (p < 0.05) after entacapone at submaximal exercise level. Maximal airway pressures were similar between the study treatments and run-in. Exercise had no effect on motor UPDRS after either study treatment or during the run-in test. No serious adverse events were observed. The results of this study suggest that entacapone does not change the work capacity, work efficiency or respiratory muscle strength in l-dopa treated PD patients with mild to moderate disease severity, and that its use with l-dopa seems to be safe in conditions of maximal physical effort. However, data from the long-term use of COMT inhibitors are needed to confirm these findings.

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.

Supersonic gas chromatography/mass spectrometry.

A new gas chromatography/mass spectrometry (GC/MS) system was designed and evaluated which we have named 'Supersonic GC/MS'. It is based on a modification of a commercially available GC/MS system to include a supersonic molecular beam (SMB) MS interface. In this system the standard electron ionization (EI) ion source was replaced with a fly-through EI ion source mounted in the path of the SMB. A hyperthermal surface ionization (HSI) ion source combined with a 90 degrees ion mirror (for the EI-produced ions) was also added, and placed inside the quadrupole mass analyzer in place of its original EI ion source. The 'Supersonic GC/MS' system requires 18 cm added bench space plus the addition of an air-cooled 60 L/s diffusion pump and a 537 L/min rotary pump. The system is user friendly since all the gas flow rates, heated zones, sampling and data analysis are performed the same way as the original system and are computer-controlled via the original software. Similar EI sensitivity was obtained as with the original system for hexachlorobenzene and octafluoronaphthalene, while improved EI detection limits were demonstrated for methyl stearate and eicosane due to the significant enhancement of their molecular ion abundances. A GC/MS detection limit of 500 ag for pyrene was demonstrated using HSI. Good supersonic expansion cooling was achieved with large alkanes, despite the use of a rotary pump at the nozzle chamber instead of a diffusion pump. High temperature GC/MS analysis was demonstrated for large polycyclic aromatic hydrocarbons (PAHs) including ovalene and decacyclene (ten rings). Library searches with EI mass spectra are demonstrated, and it is explained why the enhancement of the molecular ion actually improves the library search in most cases. The analysis of large phthalate esters is also described, and the improvement obtained is shown to originate from their enhanced molecular and high mass fragment ions.

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.

Entacapone and selegiline with L-dopa in patients with Parkinson's disease: an interaction study.

Both the catechol-O-methyltransferase (COMT) inhibitor entacapone and the monoamine oxidase B (MAO-B) inhibitor selegiline are L-dopa extenders. Both are used, often simultaneously, as adjuncts to L-dopa/dopa decarboxylase (DDC) inhibitor treatment of Parkinson's disease (PD). Their possible interactions have not been previously studied in a double-blind manner.We studied clinical response, tolerability, haemodynamics and cardiac rhythm in 16 PD patients with end-of-dose-type motor fluctuations. The patients' individual L-dopa/DDC inhibitor treatment was stabilized before the experimental treatments. This was followed by three consecutive, randomized, double-blind 2-week treatment periods with entacapone (200mg with each L-dopa dose), selegiline (10mg o.d.) or both entacapone and selegiline with the L-dopa/DDC inhibitor medication. Clinical efficacy (L-dopa test with repeated motor and dyskinesia scoring) and safety (orthostatic test, 24-h ambulatory ECG, haematological and clinical chemistry variables and adverse events) evaluations were performed before each treatment (control) and at the end of each treatment period.All three treatments, entacapone, selegiline, and entacapone+selegiline as adjunct to L-dopa/DDC inhibitor improved (p<0.05) clinical disability compared to L-dopa only but they did not differ significantly from each other. Dyskinesias increased with all the treatments, statistically significantly (p<0.01) with entacapone+selegiline. No significant differences in haemodynamics were observed between control and any of the experimental treatments, or between the experimental treatments in the orthostatic test. One patient already had symptomatic orthostatism before experimental treatments (control). In two other patients orthostatism emerged after the introduction of selegiline, and in one after every experimental treatment. Twenty-four-hour ECG did not show any differences in supraventricular or ventricular extrasystoles or heart rate between treatments. No statistically significant differences were observed in adverse events or in haematology and clinical chemistry variables. One patient treated with entacapone+selegiline discontinued the study due to dizziness and insomnia. Our results suggest that co-administration of entacapone with L-dopa/DDC inhibitor, with or without selegiline, improves clinical disability, is safe, but may also enhance dopamine-related adverse events to some extent in PD patients with end-of-dose type motor fluctuations.

The catechol-O-methyltransferase (COMT) inhibitor entacapone enhances the pharmacokinetic and clinical response to Sinemet CR in Parkinson's disease.

OBJECTIVES: Entacapone is a specific, potent, peripherally acting catechol-O-methyltransferase (COMT) inhibitor. It has been shown to improve the bioavailability of plasma levodopa and extend its clinical effect when used as an adjunct to standard levodopa preparations, but there is little experience of the effect of entacapone on controlled release levodopa preparations. METHODS: A double blind, placebo controlled, single dose, randomised, cross over trial was performed in 14 patients with Parkinson's disease with motor fluctuations to investigate the clinical effect of a single dose of entacapone (200 mg) when administered with either standard levodopa-carbidopa (Sinemet) or controlled release levodopa-carbidopa preparations (Sinemet CR). RESULTS: When entacapone was administered with standard Sinemet the duration of the clinical response to standard Sinemet was longer in comparison with the response after placebo (p=0.02). Moreover, in the same patients, entacapone significantly increased the duration of the clinical response to Sinemet CR (p=0.05) without prolonging the latency of response or enhancing dyskinesias. CONCLUSIONS: These data confirm the clinical efficacy of entacapone-standard Sinemet combination. They also indicate that adding entacapone to controlled release levodopa preparations might provide a useful treatment option in patients with Parkinson's disease with motor fluctuations. A double blind clinical trial with a chronically administered entacapone-Sinemet CR combination is, however, required to verify this viewpoint.

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.

Pharmacokinetics of oral entacapone after frequent multiple dosing and effects on levodopa disposition.

OBJECTIVE: Entacapone is a peripherally acting catechol O-methyltransferase (COMT) inhibitor used as an adjunct to each daily levodopa/dopa decarboxylase (DDC) inhibitor dose in the treatment of Parkinson's disease. Parkinsonian patients with advanced disease and motor fluctuations take several doses of levodopa daily, due to the short action of levodopa in this patient population. The present study was conducted in order to evaluate the pharmacokinetics of entacapone after multiple dosing and the pattern of COMT inhibition in erythrocytes during the first day of dosing as well as during steady state. Furthermore, the disposition of plasma levodopa and carbidopa was studied after a single dose of levodopa/carbidopa during the same conditions. METHODS: Twelve healthy male volunteers received 200 mg entacapone eight times daily during study day 1 and day 6 at 2-h intervals from 0800 hours to 2200 hours. During days 3, 4 and 5, 200 mg of entacapone was taken ten times daily, from 0800 hours to 0200 hours on the following day. One levodopa/carbidopa tablet (100/25 mg) was taken on study day 1 and day 6 at 1000 hours. Plasma entacapone concentrations and erythrocyte COMT activities were measured frequently on study days 1-2 and 6-7, and twice daily on study days 3-5. Pharmacokinetic parameters calculated from plasma drug concentrations on days 1-2 and 6-7 were compared with each other. RESULTS: There were no differences in maximal plasma concentration (Cmax), time to maximal drug concentration in plasma (tmax), elimination half-life (t1/2) and area under the plasma concentration-time curve (AUC) of entacapone between day 1 and day 6. The mean t1/2 values of entacapone were 1.3 h and 1.8 h during the first and sixth days, respectively; the difference was not significant. No signs of accumulation of entacapone were noted after the first day. Entacapone reduced erythrocyte COMT activity after the first dose, and this effect was quite stable during frequent dosing. There were no indications of accumulation of COMT inhibition during frequent dosing of entacapone. There were no between-day differences in Cmax, t1/2 (2.4 h on days 1-2 and 2.3 h on days 6-7) or AUC of levodopa, whereas tmax occurred at 0.8 h on day 1 and at 1.2 h on day 6 (P = 0.03). There were no between-day differences in the pharmacokinetic parameters (Cmax, tmax and AUC) of carbidopa. CONCLUSION: Even when dosed frequently, there are neither indications of accumulation of entacapone nor of its COMT inhibiting activity.

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.

Entacapone enhances levodopa-induced reversal of motor disability in MPTP-treated common marmosets.

Oral administration of levodopa (L-dopa) (2.5-25.0 mg/kg) plus carbidopa (12.5 mg/kg p.o.) to MPTP-treated common marmosets produced a dose-related increase in locomotor activity and a corresponding decrease in motor disability. Pretreatment with the peripheral COMT inhibitor entacapone (12.5 mg/kg p.o.) enhanced the intensity and duration of the increase in locomotor activity and the reversal of motor disability produced by a threshold dose of L-dopa (2.5 mg/kg p.o.) plus carbidopa. By contrast, entacapone pretreatment did not potentiate the increased locomotor activity or reversal of motor disability produced by a near-maximal dose of L-dopa (12.5 mg/kg p.o.) plus carbidopa. The effects of entacapone (5.0-25.0 mg/kg p.o.) were dose related, with doses of > 12.5 mg/kg tending to produce less potentiation of L-dopa's effects compared to lower doses. Pretreatment with entacapone (12.5 mg/kg p.o.) without carbidopa caused a short-lasting enhancement of L-dopa's (12.5 mg/kg p.o.) action, whereas pretreatment with carbidopa (12.5 mg/kg p.o.) alone had a more dramatic effect. However, pretreatment with both carbidopa and entacapone produced the greatest overall motor response. In conclusion, entacapone enhances the motor response produced by a low-threshold dose of L-dopa plus carbidopa. However, optimization of both the dose of L-dopa and entacapone appears necessary to obtain the maximal therapeutic response.

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.