Efficacy and augmentation during 6 months of double-blind pramipexole for restless legs syndrome.

BACKGROUND: Pramipexole is an effective treatment for restless legs syndrome (RLS), but no controlled studies have lasted >12 weeks. METHODS: RLS patients (N=331) with pretreatment serum ferritin >30 ng/mL were randomly assigned to take double-blind optimized pramipexole (0.125-0.75 mg/d) or placebo for 26 weeks. The primary efficacy endpoint was change in International RLS Study Group Rating Scale (IRLS) score. Other endpoints assessed global change, symptoms, and QoL. Patients maintained symptom diaries. Cases meeting predefined criteria for suspected augmentation were reviewed by a blinded expert panel, which used a predefined algorithm. RESULTS: Among 321 patients providing post-baseline data, of whom 234 completed 26 weeks, pramipexole was more effective than placebo by multiple endpoints, including an adjusted mean IRLS score change of -13.7 vs. -11.1 (p=0.0077) and an IRLS responder rate (≥50% score reduction) of 58.6% vs. 42.8% (p=0.0044). Efficacy showed considerable country-to-country variability. Six-month incidence of confirmed augmentation was 9.2% for pramipexole and 6.0% for placebo. The rate increased with treatment duration for pramipexole but not placebo. Treatment-related adverse events (AEs) were more likely for pramipexole than for placebo, but discontinuation due to AEs was less likely. CONCLUSIONS: During a 6-month period, pramipexole was effective, safe, and generally well tolerated. Because risk of augmentation may have increased over 6 months, it should be studied in longer trials. Beginning or mild augmentation is difficult to distinguish from natural RLS fluctuation, at least in a non-iron-deficient population.

Increased absorption of digoxin from the human jejunum due to inhibition of intestinal transporter-mediated efflux.

BACKGROUND AND OBJECTIVES: The contribution of transport in the small intestine by the apically located efflux pump P-glycoprotein to variable drug absorption in humans is still poorly understood. We therefore investigated whether inhibition of intestinal P-glycoprotein-mediated efflux by quinidine leads to increased absorption of the P-glycoprotein substrate digoxin. METHODS: Using a multilumen perfusion catheter, we investigated the impact of P-glycoprotein inhibition on absorption of two compounds: the P-glycoprotein substrate digoxin and the marker for passive transcellular absorption antipyrine. Two 20cm adjacent jejunal segments were isolated with the multilumen perfusion catheter in seven healthy subjects. Unlabelled and deuterated digoxin and antipyrine, respectively, were simultaneously infused into either of the intestinal segments. One of the segments was additionally perfused with the P-glycoprotein inhibitor quinidine. Intestinal perfusates were collected for 3 hours, and drug concentrations were determined in the intestinal perfusates, plasma and urine. RESULTS: Quinidine did not affect the disposition of antipyrine. In contrast, coadministration of quinidine into one jejunal segment caused a considerable increase in the amount of digoxin absorbed from this segment compared with the absorption from the other quinidine-free segment (22.3 +/- 8.9% vs 55.8 +/- 21.2% of the dose; p < 0.05). Accordingly, the area under the plasma concentration-time curve and the maximum plasma concentration of digoxin were considerably higher when luminal quinidine was coadministered (p < 0.05 and p < 0.001, respectively). Differences in digoxin absorption from the two intestinal segments were also reflected by pronounced differences in urinary digoxin elimination (5.5 +/- 3.3% vs 19.2 +/- 8.1% of the dose; p < 0.01). CONCLUSIONS: P-glycoprotein inhibition in enterocytes increases systemic exposure of orally administered drugs that are P-glycoprotein substrates. These data highlight the importance of the small intestine as an active barrier against xenobiotics.

Osteoarthritis of the knee--clinical assessments and inflammatory markers.

OBJECTIVE: The present cross sectional study was performed to test the hypothesis that in osteoarthritis (OA) of the knee severity of this disease is related to local levels of inflammatory metabolites and their corresponding enzymes. METHODS: From 41 patients with OA of the knee (age range 45-79 years) undergoing arthroscopy blood, synovial fluid (SF) and synovial membrane (SM) were collected. Clinical conditions were primarily assessed by the WOMAC-index and radiographic grading (K&L-grade). Concentrations of PGE(2), TxB(2)and NO(2/3)and that of IL-6, IL-1 alpha, IL-1 beta, TNF alpha, COX-2 and iNOS were determined in SF and SM, respectively. RESULTS: With advancing age K&L-grade and COX-2 in SM increased significantly (P=0.005 and P=0.01, respectively). TNF alpha and IL-1 alpha were not detectable in SM samples. Apart from a correlation between PGE(2)and WOMAC-index (r=0.36, P=0.035) no significant relationships could be found between the various inflammatory parameters and any of the assessed clinical signs. CONCLUSIONS: Apparently no direct relationships exist between the measured markers of inflammation (e.g. PGE(2), NO(2/3)) or the involved enzymes (e.g. COX-2, iNOS) and the severity of OA of the knee. The degenerative condition of this disease might be due to the more local, mainly mechanical injury with little systemic upset. However, further longitudinal studies are needed to clarify whether the assessed biochemical markers could serve as predictors for the progression of OA.

P-glycoprotein function in the elderly.

OBJECTIVE: The MDR1-encoded P-glycoprotein (Pgp) represents the best-studied membraneous efflux pump defending the body against xenobiotics. Various polymorphisms (single nucleotide polymorphisms; SNPs) in the MDR1 gene have been identified, and a silent mutation in exon 26 (C3435T) has been correlated with duodenal expression of Pgp, which might affect the disposition of certain drugs. The C3435T SNP has been shown to be linked to another SNP (G2677T/A) in exon 21 which leads to an amino acid exchange. So far, the influence of age on Pgp function has been neglected. As the function of Pgp might be altered in advanced age, we investigated in groups of fit and frail elderly subjects whether the efflux of the Pgp-probe rhodamine 123 from CD56(+) natural killer cells was age dependent and whether it was affected by the two SNPs. METHODS: Leukocytes were isolated from blood of 18 healthy elderly subjects (mean age 69 years) and 20 geriatric frail patients (mean age 78 years) and data compared with 21 previously studied young healthy Caucasian individuals (mean age 33 years). Subjects were homozygous for either CC- or TT-genotype (SNP C3435T) and additionally differentiated according to genotype GG or TT of the SNP G2677T. Using flow cytometry, rhodamine fluorescence was monitored in CD56(+) cells. RESULTS: In contrast to the young controls, in both elderly populations no significant difference between the CC and TT genotypes (exon 26) could be observed in rhodamine fluorescence. Furthermore, only for the TT genotype (exon 26) did frail elderly demonstrate some reduced Pgp function ( P=0.03) if compared with the young healthy subjects. If the three groups were compared independent of the genotype, no age effects were observed. For all assessed genotypes, there was no significant difference between fit and frail elderly subjects. CONCLUSION: Aging and frailty have apparently only a minor impact on this validated cellular Pgp model and it could be assumed that function of Pgp is quite well preserved in patients of advanced age.

Influence of age and cytochrome P450 2C9 genotype on the steady-state disposition of diclofenac and celecoxib.

OBJECTIVE: To analyse the influence of age and cytochrome P450 (CYP) 2C9 genotype on the steady-state disposition of the standard NSAID diclofenac and the new COX-2 selective inhibitor celecoxib, both of which are metabolised by the polymorphically expressed CYP2C9. DESIGN: Double-blind randomised crossover study under steady-state conditions. SUBJECTS: 12 young (age 32 +/- 5 years, bodyweight 71 +/- 12kg; mean +/- SD) and 12 elderly (68 +/- 2 years, 82 +/- 15kg) healthy, drug-free, nonsmoking Caucasians of both sexes. METHODS: All subjects received oral celecoxib (200mg twice daily) and diclofenac (75mg twice daily) for 15 days separated by a drug-free interval of at least 3 weeks. Following the last morning dose, multiple blood samples were taken for 25 hours. Concentrations of celecoxib and diclofenac were measured by specific and sensitive high performance liquid chromatography. Identification of CYP2C9 genotype was performed by genomic DNA sequencing. Pharmacokinetic parameters for total and unbound drugs were individually analysed by noncompartmental techniques. RESULTS: For diclofenac, area under the concentration-time curve over the dosage interval (AUC(tau)) was larger in young subjects (3.2 +/- 1.0 mg * h/L) than in older individuals (2.4 +/- 0.4 mg * h/L; p < 0.05). As the terminal half-life (t((1/2)Z)) was very similar in both groups (3.9 +/- 4.4 vs 3.5 +/- 3.3 hours), either less complete absorption in the elderly or their higher bodyweight could account for the difference. For celecoxib, AUC(tau) (5.8 +/- 1.7 vs 5.6 +/- 2.3 mg * h/L) and t((1/2)z) (11.8 +/- 8.7 vs 11.2 +/- 2.9 hours) were almost identical in young and older subjects. Plasma protein binding of both NSAIDs was unaffected by age, and apparent oral clearances for unbound drugs were not different between the two groups of healthy subjects. When considering the genotype of all individuals (CYP2C9*1/*1, n = 10; CYP2C9*1/*2, n = 6; CYP2C9*2/*2, n = 2; CYP2C9*1/*3, n = 4; CYP2C9*3/*3, n = 1), no association with any pharmacokinetic parameter of either drug was apparent. Moreover, there was no significant correlation between the AUC values of celecoxib and diclofenac. CONCLUSIONS: Age and CYP2C9 genotype do not significantly affect the steady-state disposition of celecoxib and diclofenac. This would indicate that both drugs need no dosage reduction in the elderly (at least up to 75 years) and that, besides CYP2C9, additional CYP species contribute to the elimination of both agents.