Dose-dependent kinetics of the enantiomers of MK-571, an LTD4-receptor antagonist

Summary The disposition of the enantiomers of MK-571 (MK-0679 and L-668,018) following single i. v. doses of MK-571 (L-660,711) was studied in a three way cross-over study in 12 healthy male volunteers. Each volunteer received 75 mg, 300 mg and 600 mg i. v. doses of MK-571 at weekly intervals.The disposition of both enantiomers appeared dose-dependent, since the AUC increased disproportionately faster than the dose. The dose dependency was much more pronounced for L-668,018: its AUC increased 6-fold from the 75 to the 300 mg dose, 16-fold from 75 to 600 mg and 2.7 fold from 300 to 600 mg. For MK-0679, the corresponding increases in AUC were 4.8-, ll-, and 2.3 fold. Regardless of dose, the elimination of L-668,018 was more rapid than that of MK-0679.The disposition of MK-0679 needs to be investigated independently to detect any potential influence of L-668,018 on its disposition.     

The use of microimplants in orthodontic anchorage.

PURPOSE: Various types of temporary implants have been introduced to serve as orthodontic anchorage. The hypothesis of this study is that microimplants of 1.2 mm diameter can be used as orthodontic anchors, and that their success is related to their length. The aim of this study is to determine the incidence of anchor retention after orthodontic force application for moving teeth, and to determine the relationship of microimplant length to retention rate. METHODS: Fifty-nine microimplants (diameter: 1.2 mm) were placed in 29 patients as orthodontic anchorages. After 2 weeks of microimplant placement, a force of 100 to 200 g was loaded with an elastometric chain or NiTi coil spring. Risk factors were characterized as to why a microimplant may fail, and Fisher's exact test was used for statistical analysis. RESULTS: Nine microimplants were removed and the overall success rate was 84.7%. Exploring the causes for failure, we found significant differences between the length of microimplants and success rate; 6 mm was 72.2% and 8 mm was 90.2%. CONCLUSIONS: The results suggest that microimplants are suited as an alternative orthodontic anchorage. We recommend that 8-mm microimplants are preferable to 6-mm.     

Effects of timolol and acetazolamide on intraocular pressure elevation following argon laser iridotomy.

To study the effect of hypotensive agents on intraocular pressure elevation following argon laser iridotomy, 0.5% timolol maleate topically and acetazolamide 125 mg orally were given in 39 eyes, one hour prior to laser iridotomy, with 29 eyes serving as the control. The mean pressure two hours after laser iridotomy was 18.9 +/- 7.2 mmHg in the control group and 12.8 +/- 3.9 mmHg in the pretreated group. Ocular pressure was elevated from the baseline pressure of the prelaser status in two eyes (5%) only in the timolol-acetazolamide treated group and in 16 eyes (55%) in the control group. The pressure elevation two hours after laser iridotomy was significantly less in the timolol-acetazolamide pretreated group.     

Effect of food on pharmacokinetics of cefuroxime axetil in Chinese subjects.

The effect of food on the pharmacokinetics of cefuroxime axetil was studied. Twelve healthy male subjects were included in this study. They were given single oral 500 mg doses of cefuroxime axetil alone or with food based on a balanced two-way crossover design. Plasma cefuroxime concentrations were assayed by the high performance liquid chromatographic method. When the drug was given alone, the area under the curve (AUC) was 15.77 +/- 4.12 mg*h/L, Cmax was 4.20 +/- 1.05 mg/L, Tmax was 2.36 +/- 0.84 h, T1/2 was 1.56 +/- 0.26 h, and Clp/F was 34.13 +/- 10.39 L/h; 45.12 +/- 9.59% of the dose was recovered in the urine within 24 hours, and the renal clearance was 12.58 +/- 4.41 L/h. When the drug was given with food, the corresponding AUC was 23.46 +/- 4.57 mg*h/L, Cmax was 7.10 +/- 1.41 mg/L, Tmax was 2.04 +/- 1.32 h, T1/2 was 1.40 +/- 0.23 h, and Clp/F was 21.93 +/- 5.18 L/h; the 24-hour urinary recovery was 69.33 +/- 6.13% and the renal clearance was 12.58 +/- 2.99 L/h. The above pharmacokinetic parameters obtained from the two regimens were compared by two-way ANOVA corrected for the change-over effect. No significant difference was found for Tmax, T1/2 or renal clearance (p > 0.05). Higher AUC, Cmax, urinary recovery and lower Clp/F values were observed for the regimen with food (p < 0.05). The plasma drug concentrations resulting from the regimen with food were higher throughout the 12-hour sampling period when compared to the regimen without food.(ABSTRACT TRUNCATED AT 250 WORDS)     

Saturation and inversion transfer studies of creatine kinase kinetics in rabbit skeletal muscle in vivo

The steady-state kinetics of the creatine kinase reaction in rabbit skeletal muscle in vivo was investigated using inversion and saturation magnetization transfer techniques. Both techniques determined the forward rate of this reaction (creatine phosphate ATP) as approximately 0.3 s-1. This corresponds to a flux of 10 mumol creatine phosphate/s/g muscle. The saturation transfer technique underestimated the reverse reaction by approximately 56%. This result is likely due to the participation of ATP in other interactions in skeletal muscle not involving creatine phosphate.     

Prediction of functional outcomes in stroke inpatients receiving rehabilitation.

BACKGROUND AND PURPOSE: Early identification of predictive factors relevant to functional outcomes for stroke patients is important to the establishment of an effective continuing care program. The objective of this study was to identify the predictive factors related to functional outcome at discharge after stroke rehabilitation therapy. METHODS: 105 first-time stroke patients admitted to the inpatient rehabilitation department of a university-based medical center were recruited for this prospective study. The functional outcomes of the patients were assessed at admission and at discharge using the Functional Independence Measure (FIM). Severity of stroke was determined using the Canadian Neurological Scale (CNS). Age, gender, side of hemiplegia (SIDE), type of stroke (TYPE), onset to admission interval (OAI), and length of rehabilitation stay (LORS) were also included as predictor variables. RESULTS: The mean (+/- SD) FIM score at discharge (76.6 +/- 26.4) correlated strongly (r = 0.78, p < 0.001) with the admission FIM score (56.3 +/- 24.1), moderately (r = 0.46, p < 0.001) with the admission CNS score (6.1 +/- 2.2), negatively (r = -0.38, p < 0.001) with age (63.2 +/- 12.3 years), negatively (r = -0.26, p = 0.009) with OAI (24.2 +/- 16.0 days), and negatively (r = -0.29, p = 0.002) with LORS (34.7 +/- 16.8 days). Stepwise regression analyses indicated that admission FIM score, age, and admission CNS score were the strongest predictors of functional outcome and accounted for 66% of the total variation in discharge FIM total score. The admission FIM score was the best predictor and accounted for 61% of the variation. CONCLUSIONS: The findings of this study imply that the admission FIM scores for inpatients receiving stroke rehabilitation can be used to predict functional outcomes at discharge from hospital.     

Three-dimensional ultrasound diagnosis of Larsen syndrome with further characterization of neurological sequelae.

Larsen syndrome consists of skeletal dysplasia with multiple joint dislocations and a characteristic facies. The basis of this abnormality is a generalized mesenchymal disorder involving connective tissues. We describe our findings in a woman who was referred at 28 weeks' gestation due to multiple fetal anomalies suspected initially at an 18-week ultrasound examination. On three-dimensional (3D) ultrasound we found the fetus had bilateral genu recurvatum. Further 3D examination at 36 weeks confirmed the lower limb anomaly and revealed facial anomalies that led to the diagnosis of Larsen syndrome. An elective Cesarean section was performed at 38 weeks' gestation to minimize neurological sequelae. Magnetic resonance imaging was performed postnatally and showed pachygyria, colpocephaly and agenesis of the corpus callosum. In this case, 3D ultrasound facilitated the prenatal diagnosis of Larsen syndrome. A careful prenatal investigation for other associated anomalies such as those of the cardiovascular or neurological systems is warranted with this diagnosis. These associated lesions are likely to have a greater impact on prognosis than the classic symptoms of Larsen syndrome and a collaborative approach is necessary to optimize delivery and postnatal management of an affected fetus.     

A comparative study of etanercept plus methotrexate and methotrexate alone in Taiwanese patients with active rheumatoid arthritis: a 12-week, double-blind, randomized, placebo-controlled study.

BACKGROUND AND PURPOSE: Etanercept (Enbrel), a recombinant tumor necrosis factor receptor fusion protein, has been shown to be effective in the treatment of patients with rheumatoid arthritis (RA). The purpose of this study was to compare the efficacy and safety of etanercept in combination with methotrexate (MTX) and MTX alone in Taiwanese patients with active RA. METHODS: In this double-blind study, 58 patients with active RA who were maintained on MTX therapy at a stable dose of 12.5 to 20 mg per week for 4 weeks were randomized to receive either etanercept 25 mg (n = 29) or placebo (n = 29) by subcutaneous injection twice weekly over a period of 12 weeks. The primary endpoint was the reduction of tender and swollen joint counts by 20% (ACR 20), 50% (ACR 50), and 70% (ACR 70) as determined by the American College of Rheumatology criteria at the 12th week. RESULTS: The addition of etanercept to MTX resulted in a greater reduction in the number of tender (7.00 vs 2.45, p = 0.012) and swollen joints (8.55 vs 3.86, p = 0.017), and in serum levels of C-reactive protein (1.26 mg/dL vs 0.45 mg/dL, p = 0.014) compared to MTX alone after 12 weeks of therapy. In addition, the global assessment of disease activity by both physicians and patients, duration of morning stiffness, pain visual analog scale score, and Health Assessment Questionnaire were all improved by etanercept plus MTX therapy. Results for the overall improvement in disease activity assessed by ACR 20 (90% vs 34%), ACR 50 (66% vs 10%) and ACR 70 (24% vs 0%) all favored the etanercept plus MTX group. However, the adverse events were comparable between the 2 treatment groups. CONCLUSION: Etanercept in combination with MTX was well tolerated and provided significantly more clinical benefit than MTX alone in Taiwanese patients with active RA.     

Ovarian stimulation by clomiphene citrate and hMG in combination with cetrorelix acetate for ICSI cycles

BACKGROUND: The introduction of GnRH antagonists such as cetrorelix acetate has made possible the simplification of ovarian stimulation. However, the most effective protocol for their administration has not yet been clearly defined. METHODS: Forty women with male-factor infertility undergoing 40 ICSI cycles were included in the study. Clomiphene citrate at 100 mg a day was given from cycle day 3 through day 7. hMG at 150 IU was given on cycle days 4, 6 and 8, and was adjusted from day 9 according to the follicular and hormone responses. Cetrorelix acetate at 2.5 mg was administered when the leading follicle reached 14 mm. The remaining 0.5 mg was divided into two 0.25 mg injections for possible later use. Serum FSH, LH, estradiol and progesterone levels were measured daily from the day of cetrorelix acetate injection until hCG was given. RESULTS: Serum LH level was suppressed effectively for 4 days. Four patients (10%) needed one or two additional injections of 0.25 mg cetrorelix acetate. No premature LH surge was detected in any of the women treated. Sixteen women became pregnant (40%), of which 14 pregnancies (35%) were ongoing at the time of writing. CONCLUSIONS: This study demonstrates that this new protocol is feasible for couples with male-factor infertility undergoing ICSI.