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- Apelqvist, G, et al.
(författare)
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Dynamic and kinetic effects of chronic citalopram treatment in experimental hepatic encephalopathy
- 2000
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Ingår i: Clinical neuropharmacology. - : Ovid Technologies (Wolters Kluwer Health). - 0362-5664 .- 1537-162X. ; 23:6, s. 304-317
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Tidskriftsartikel (refereegranskat)abstract
- Chronic hepatic encephalopathy (HE) is a neuropsychiatric syndrome that arises in liver-impaired subjects. Patients with HE display various neuropsychiatric symptoms including affective disturbances and may therefore likely receive treatment with novel thymoleptics like citalopram (CIT). The simultaneous pharmacokinetic and pharmacodynamic outcome of the commonly used serotonin-selective thymoleptic drugs in liver-impaired subjects with pending chronic HE is far from understood today. We therefore investigated the effects of chronic, body-weight-adjusted (10 mg ╖ kg-1 ╖ day-1), treatment with CIT in rats with and without portacaval shunts (PCS). Open-field activity was monitored. The 5-HT, 5-HIAA, noradrenaline (NA), and dopamine (DA) output were assessed in the frontal neocortex. The racemic levels of CIT and its metabolites DCIT and DDCIT, including the S- and R-enantiomers, were determined in serum, brain parenchyma, and extracellular fluid. The rats with PCS showed higher (2-3-fold) levels of CIT than rats undergoing a sham treatment with CIT in all compartments investigated. The PCS rats also showed elevated levels of DCIT and DDCIT. No major differences in the S/R ratios between PCS rats and control rats could be detected. The CIT treatment resulted in neocortical output differences between PCS rats and control rats mainly within the 5-HT and DA systems but not within the NA system. For the 5-HT system, this change was further evidenced by outspoken elevation in 5-HT output after KCl-depolarizing challenges. Moreover, the CIT treatment to PCS rats was shown to "normalize" the metabolic turnover of 5-HT, measured as a profound lowering of a basal elevation in the 5-HIAA levels. The CIT treatment resulted in an increased or "normalized" behavioral activity in the PCS group. Therefore, a dose-equal chronic treatment with CIT in PCS rats produced pharmacokinetic and pharmacodynamic changes not observed in control rats. The results further support the contention of an altered 5-HT neurotransmission prevailing in the chronic HE condition. However, the tentatively beneficial behavioral response also seen following chronic CIT treatment to PCS rats in this study has to be viewed in relation to both the pharmacokinetic and pharmacodynamic changes observed.
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| 5. |
- Lundin, Anders, et al.
(författare)
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Efficacy and Safety of the Dopaminergic Stabilizer Pridopidine (ACR16) in Patients With Huntington's Disease
- 2010
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Ingår i: Clinical neuropharmacology. - 0362-5664 .- 1537-162X. ; 33:5, s. 260-264
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To evaluate the efficacy and safety of the dopaminergic stabilizer pridopidine (ACR16) in patients with Huntington's disease (HD). Methods: In a randomized, double-blind, placebo-controlled, 4-week trial, patients with HD received pridopidine (50 mg/d, n = 28) or placebo (n = 30). The primary outcome measure was the change from baseline in weighted cognitive score, assessed by cognitive tests (Symbol Digit Modalities, verbal fluency, and Stroop tests). Secondary outcome measures included changes in the Unified Huntington's Disease Rating Scale, Hospital Anxiety and Depression Scale, Leeds Sleep Evaluation Questionnaire, Reitan Trail-Making Test A, and Clinical Global Impression of Change. Safety assessments were also performed. Results: There was no significant difference between pridopidine and placebo in the change from baseline of the weighted cognitive score. However, secondary measures such as affective symptoms showed trends toward improvement, and there was significant improvement in voluntary motor symptoms compared with placebo (P<0.05). Pridopidine was well tolerated, with a safety profile similar to placebo. Conclusions: Pridopidine shows promise as a treatment for some of the symptoms of HD. In this small-scale study, the most notable effect was improvement in voluntary motor symptoms. Larger, longer-term trials are warranted.
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| 8. |
- Nyholm, Dag, et al.
(författare)
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Circadian rhythmicity in levodopa pharmacokinetics in patients with Parkinson disease
- 2010
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Ingår i: Clinical neuropharmacology. - 0362-5664 .- 1537-162X. ; 33:4, s. 181-185
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES:: The purpose of this study was to compare daytime and nighttime plasma pharmacokinetics (PK) of levodopa in patients with Parkinson disease. METHODS:: Four-hour plasma profiles of levodopa were captured in 8 patients with Parkinson disease after the second daily levodopa dose and after the identical dose at bedtime. Patients were fasting 2 hours before and 2 hours after dose intakes, except standardized amounts of tap water. Body position was upright during daytime testing and supine during nighttime testing. Four patients were additionally tested at daytime in supine position. RESULTS:: The absorption rate was significantly delayed at nighttime dosing. The time at which the maximum peaks occurred was delayed from 25 (15-240) to 105 (20-240) minutes, respectively. Maximum concentrations were significantly lower at night, but the plasma exposure (area under the curve, 0-4 hours) was unaffected. Supine daytime plasma PK was in between day and night results. CONCLUSIONS:: There is a slower absorption rate of levodopa during nighttime, probably related to delayed gastric emptying. However, the extent of absorption and bioavailability were unaffected. As the effect of posture on plasma PK was less than the effect of nighttime, this study suggests that the circadian rhythm has a pronounced effect on gastric emptying and absorption rate. Nevertheless, body position may also be an important factor, and it can be recommended that levodopa tablets be taken in upright position that probably should be sustained for at least 30 minutes.
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| 9. |
- Nyholm, Dag, et al.
(författare)
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Complexity of Motor Response to Different Doses of Duodenal Levodopa Infusion in Parkinson Disease
- 2012
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Ingår i: Clinical neuropharmacology. - 0362-5664 .- 1537-162X. ; 35:1, s. 6-14
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Forskningsöversikt (refereegranskat)abstract
- OBJECTIVE: The aim was to elaborately describe individual pharmacokinetic-pharmacodynamic profiles in patients with difficult-to-treat dyskinesias treated with levodopa/carbidopa intestinal gel infusion. METHODS: A nonrandomized, partly blinded, investigator-initiated trial was conducted in 5 patients with idiopathic Parkinson disease who were difficult to keep in "on" state without dyskinesia. Levodopa/carbidopa intestinal gel (Duodopa) doses of 80% to 120% of individually and clinically optimized dosage were infused during five 4-hour periods. Pharmacokinetic profiling, blinded assessment of video recordings, and objective movement analysis were applied every 20 to 30 minutes. RESULTS: Individual correlations between plasma levodopa concentrations and corresponding motor scores 20 to 30 minutes after the sampling time were significant in all patients (P < 0.05 and P < 0.001). Motor scores were generally stable during the 4-hour periods. The objective test revealed that motor performance was faster the more dyskinetic the patients were. Mean individual Treatment Response Scale scores were positive in 24 of the 25 steady-state periods. Dystonia was always combined with choreic dyskinesias. CONCLUSIONS: Motor response from different doses of levodopa/carbidopa intestinal gel is in a broad sense predictable even in dyskinetic patients although major interindividual differences in dose requirement, plasma levels, and motor response are found. That motor performance was faster the more dyskinetic the patients were implies that motor performance may be better with moderate dyskinesia than with mild dyskinesia. This may explain why patients with persistent dyskinesias choose to keep their doses above the dyskinesia threshold. There is no ideal therapeutic window in such patients, but levodopa infusion offers stable motor response.
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| 10. |
- Nyholm, Dag, et al.
(författare)
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Enteral Levodopa/Carbidopa infusion in advanced Parkinson disease : Long-term exposure
- 2008
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Ingår i: Clinical neuropharmacology. - 0362-5664 .- 1537-162X. ; 31:2, s. 63-73
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: In patients with advanced Parkinson disease, levodopa/carbidopa formulated as a gel suspension (Duodopa) permits continuous delivery into the small intestine using a portable pump, resulting in less variability in levodopa concentrations and fewer motor fluctuations and dyskinesias than with oral levodopa administration. This is a retrospective analysis of the long-term clinical experience with this agent. Methods: All but 1 of the patients who had received enteral levodopa infusion treatment between January 1, 1991, and June 30, 2002, consented to a review of their hospital charts. Results: Of the 65 patients with initial testing of the treatment, 86% opted for continued treatment via percutaneous endoscopic gastrostomy or gastrojejunostomy. Total exposure to levodopa infusion was 216 patient-years (mean, 3.7 years). Maximum treatment duration was 10.7 years. Fifty-two patients were treated for 1 year or longer. The adverse effect profile of levodopa/carbidopa infusion was similar to that observed with oral administration of levodopa. Seven deaths occurred, all considered unrelated to the treatment. Intestinal tube problems, including dislocation of the intestinal tube to the stomach, were the most common technical problem, occurring in 69% of the patients during the first year. The optimal daily dose of levodopa decreased by an average of 5% during follow-up. Conclusions: The safety of enteral infusion of levodopa/ carbidopa formulated as a gel suspension was found acceptable. For most patients, the technical challenges posed by the enteral infusion system were offset by the improvement in motor fluctuations and dyskinesias offered by this technique.
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