Pardoprunox as adjunct therapy to levodopa in patients with Parkinson's disease experiencing motor fluctuations: results of a double-blind, randomized, placebo-controlled, trial.

AIMS: To determine the efficacy and safety of pardoprunox in levodopa-treated patients with Parkinson's disease (PD) experiencing motor fluctuations. METHODS: Patients were randomized to pardoprunox (up to 42 mg/day, n = 150) or placebo (n = 144). Pardoprunox was titrated to an optimal dose over 7 weeks, followed by a 12-week stable dose period. The primary efficacy variable was the change from baseline to study endpoint in total daily OFF time, based on patient diaries. Secondary analyses included the change in ON time without troublesome dyskinesias, UPDRS-ADL + Motor ON, UPDRS-ADL OFF and PDQ-39. Subgroup analyses explored the impact of pardoprunox on dyskinesias (UPDRS items 32 + 33), depression (Hospital Anxiety Depression Scale) and pain (Visual Analogue Scale). RESULTS: Pardoprunox significantly reduced OFF time versus placebo (-1.62 h/day versus -0.92 h/day, respectively, p = 0.0215). Compared to placebo, pardoprunox improved ON time without troublesome dyskinesias (p = 0.0386), UPDRS-ADL + Motor ON (p = 0.0003), and UPDRS-ADL OFF (p < 0.0001), while no significant difference was observed on PDQ-39. A high drop-out rate due to adverse events (AEs) (pardoprunox, 37%; placebo, 12%) suggested that the selected dose range may have been too high, and/or titration was too rapid. CONCLUSIONS: Pardoprunox decreased OFF time and increased ON time without troublesome dyskinesias in levodopa-treated PD patients. The high drop-out rate at the selected doses justifies the investigation of lower doses. The impact of pardoprunox on dyskinesias and non-motor symptoms deserves further investigation.

Safety and tolerability of pardoprunox, a new partial dopamine agonist, in a randomized, controlled study of patients with advanced Parkinson's disease.

AIMS: To investigate the safety and tolerability of pardoprunox (SLV308), a novel partial dopamine agonist, as an adjunct to levodopa in patients with advanced Parkinson's disease, using two titration schedules. METHODS: Patients were randomized to pardoprunox (n = 51) or placebo (n = 11). Pardoprunox was titrated to the highest tolerated dose (range, 0.3-42 mg/day) over 7 weeks, using a gradual dose escalation without intermediate steps (group 1) or with intermediate steps (group 2). RESULTS: The cumulative drop-out rate was greater in group 1 (without intermediate steps, 56.0%) than in group 2 (with intermediate steps, 34.6%), or with placebo (9.1%). In group 2, doses up to 18 mg/day were well tolerated with a cumulative drop-out rate of 7.7% (2/26) and a drop-out rate due to adverse events of 4.0% (1/26). The most common adverse events reported were nausea, vomiting, headache, and dizziness. There was a trend for reduced OFF time (p = 0.054) in the combined pardoprunox group compared to placebo. CONCLUSIONS: The pardoprunox safety and tolerability profile as an adjunct to levodopa was improved using a gradual titration schedule that included intermediate dose steps. Using this titration, doses up to 18 mg/day were well tolerated.

The effects of CTR-24, a biphasic oral contraceptive combination, compared to Diane-35 in women with acne.

One-hundred-and-eighty-three women were enrolled in an open, randomized, multicentre study in which the effects on acne of a low-dose biphasic oral contraceptive containing a daily dosage of 25 micrograms desogestrel and 40 micrograms ethinylestradiol (7 days) and a daily dosage of 125 micrograms desogestrel and 30 micrograms ethinylestradiol (15 days) were compared to Diane-35 containing a daily dosage of 2.0 mg cyproterone acetate and 30 micrograms ethinylestradiol (21 days) during four cycles of treatment. Clinical and photographic evaluation of acne plus laboratory assessments were done before treatment and at the end of cycle 4. A reduction with regard to the number of lesions and the degree of severity was observed in both groups. No differences were found between the two treatments in the clinical and photographic evaluation. In both treatment groups, a decrease in total testosterone and 3 alpha-17 beta-androstanediol glucuronide was observed and an increase in SHBG. The decrease in 3 alpha-17 beta-androstanediol was statistically significantly more pronounced in the Diane-35 group.

Skin vascular reactivity in healthy subjects: influence of hormonal status.

To investigate the influence of the hormonal status on skin vascular reactivity, 18 males, 18 women using oral contraceptives (oc), 17 premenopausal, and 18 postmenopausal women were studied. Finger skin temperature (FST, in degrees C) and laser Doppler flux (LDF, in perfusion units) were measured during heating (45 degrees C water bath) and cooling (15 degrees C) followed by a subsequent recovery period. Maximal heat-induced vasodilation was significantly higher in women using oc and in premenopausal women when compared with males. During cooling, FST and LDF were significantly higher in males compared with women using oc and premenopausal women, respectively. FST was also higher in postmenopausal women than in women using oc. During recovery, FST and LDF were significantly higher in males than in women using oc, and LDF was also higher in males than in premenopausal women. These findings are consistent with a less pronounced and less prolonged cold-induced vasoconstriction in males. Other hemodynamic (blood pressure or heart rate) or biological factors (age, amount of subcutaneous fat, hand volume, or body mass index) that possibly influence peripheral blood flow were found not to influence the results. The observed differences in vascular reactivity toward temperature changes between subjects with a different hormonal status suggest that sex hormones influence finger skin perfusion.

Reproducibility of the finger cooling test.

A finger cooling test is used to objectify Raynaud's phenomenon and to assess its severity. For this purpose, finger skin temperature (FST) and laser Doppler flux (LDF) are measured on the fingertips before and during cooling of the hand (16 degrees water bath for 5 min) and a subsequent recovery period (20 min). To study reproducibility, this test was performed twice within 3 months in 34 healthy subjects and in 56 Raynaud patients. Three test parameters were used in the analysis: the baseline value, the value after 12 min of recovery, and the mean level during recovery. We determined the limits of agreement (mean differences between the first and the second test +/- 2SD) and the coefficients of variation. No systematic differences between the first and the second test were found. Outside temperature did not influence FST or LDF. FST was shown to have a better reproducibility than LDF. For the baseline value in the total group the coefficient of variation was 3.3% for FST and, rather high, 21.6% for LDF. The limits of agreement for the baseline value in the total group were -4.8 to 4.2 degrees for FST and -25.2 to 22.2 arbitrary units for LDF. In conclusion, the applied cooling test has limited value in individual cases, but can be useful when comparing large groups in pathophysiologic or therapeutic studies.

Perioperative factors associated with septic arthritis after arthroplasty. Prospective multicenter study of 362 knee and 2,651 hip operations.

Perioperative factors associated with late septic arthritis after knee and hip arthroplasties were prospectively investigated. All patients received a short course of perioperative cefuroxime. After a follow-up of 1 year, septic arthritis was diagnosed in 9/362 patients (2.5 percent) after knee arthroplasty and in 17/2651 patients (0.64 percent) after hip arthroplasty. For the knee, factors associated with septic arthritis after arthroplasty were rheumatoid arthritis, wound infection, an unhealed wound, and a painful, limited knee function at discharge from the hospital. For the hip, corresponding risk factors were diabetes, failed fracture osteosynthesis, a breakdown of sterility during operation, wound infection, postoperative urinary tract infection, and an unhealed wound at discharge from the hospital or a difficult rehabilitation course. Reoperation after knee and hip arthroplasty was also clearly associated with a higher incidence of septic arthritis.

Effect of perioperative blood transfusion and cell saver on the incidence of postoperative infective complications in patients with an aneurysm of the abdominal aorta.

OBJECTIVE: To find out if there was an association between perioperative blood transfusion and the development of infective complications, and whether the use of the cell saver for autologous transfusion had any influence. DESIGN: Retrospective study. SETTING: University Hospital. SUBJECTS: 102 consecutive patients who had been operated on for aneurysms of the abdominal aorta. MAIN OUTCOME MEASURES: Morbidity and mortality. RESULTS: 32 of the 102 patients developed infective complications. Thirteen patients died (six after emergency and seven after elective operations). Nine died as a direct result of infection, one of intra-abdominal bleeding, one of necrosis of the colon, and two of cardiopulmonary complications. The incidence of infective complications was directly related to the number of units of blood transfused, being 0 when 0 or 1 was given; 11 (20%) when 2-4 units were given; 12 (55%) when 5-8 units were given; and 9 (69%) when the number was 9 or more. The cell saver had no influence on the incidence. Other factors associated with higher rates of infective complications were the insertion of a bifurcated prosthesis (p = 0.03), and emergency operation (p < 0.001). CONCLUSION: These results confirm the association between blood transfusion and the incidence of infective complications. It may be that more intensive use of the cell saver and preoperatively saved autologous blood could reduce the rate of infective complications.

Cefuroxime for prevention of postoperative coxitis. One versus three doses tested in a randomized multicenter study of 2,651 arthroplasties.

Infection prophylaxis in hip replacement with one perioperative dose of cefuroxime was evaluated in a randomized controlled multicenter study using a three-dose regimen as a control. All the operations were performed in conventionally ventilated operating theaters. Of the 2,796 hip replacements entered in the study, 145 replacements were excluded because of protocol violations. The remaining 2,651 hip replacements were analyzed: 1,327 and 1,324 in the one- and the three-dose group, respectively. There were no differences between the one-dose and the three-dose groups as regards the incidence of postoperative wound-healing problems, and urinary tract or other distant infections. The use of additional antibiotics after the perioperative prophylaxis did not differ between the treatment groups. After a mean follow-up period of 13 months, joint sepsis was diagnosed in 11 of the patients in the one-dose group (0.83 percent) and in 6 of the patients in the control group (0.45 percent). This difference was not significant. Because the estimated difference between the one-dose and the three-dose group was 0.38 percent, we could not confirm that the efficacy of one dose was equal to three doses. An extended follow-up study, with more cases of joint sepsis, may provide more conclusive data. Until then, a three-dose regimen is recommended.

Value of biochemical markers in the management of disseminated prostatic cancer.

The biochemical markers alkaline phosphatase (Alk P), prostatic acid phosphatase (PAP) and prostate-specific antigen (PSA) were measured 3-monthly in 61 patients with disseminated prostatic cancer who were treated with LHRH analogues. The decrease in Alk P and PSA during the first 6 months of treatment was significantly related to a better survival. In this follow-up study, only PSA was useful for monitoring prostatic cancer during hormonal treatment. Before it was visible on a bone scan, PSA gave an indication of tumor progression. PSA might permit omission of routine bone scanning. Consensus must be obtained about the cost-saving use of biochemical markers in the treatment of disseminated prostatic cancer. With the number of treatment options increasing, objective measures are of utmost importance. Biochemical markers can be used for prognosis and monitoring of the treatment of patients with disseminated prostatic cancer.

Myotonic dystrophy. Predictive value of normal results on clinical examination.

Myotonic dystrophy (DM) is well known for its highly variable clinical picture, including the age at which symptoms are first detected. In order to assess the proportion of asymptomatic gene carriers at different ages, we have used linked DNA markers to study individuals at 50% genetic risk of DM, in whom neurological examination, slit-lamp examination and electromyography (EMG) had failed to show diagnostic signs. A total of 139 asymptomatic offspring of DM patients were studied. Our analyses identified 11 out of these 139 as probable gene carriers. Our data show that penetrance of the DM gene increases with age. After correction for the possibility of genetic recombination between the DM gene and the DNA markers used, we calculated the residual chance of carrying the DM gene as 8.3% for clinically normal offspring aged between 20 and 39 yrs. We evaluated several factors that might influence this figure. Neither the sex of the propositus nor that of the affected parent modified the risk of carrying the DM gene. Presence of aspecific lens opacities also did not correlate with the risk of having inherited the DM gene. Since a significant proportion of DM gene carriers are not detected by neurological examination, including slit-lamp examination and EMG, these results confirm the need for DNA analysis in asymptomatic offspring of DM patients.

Antibiotic use after cefuroxime prophylaxis in hip and knee joint replacement.

The amount of additional antibiotics measured by defined daily dose (DDD) methods after 2651 hip and 362 knee replacements was assessed after prophylaxis with one or three doses (1502/1511 patients) of cefuroxime. No differences were observed between the two regimens with respect to total amount, type, indication, and duration of additional antibiotics. The incidence of joint sepsis did not differ significantly between the two trial arms, but the sample was too small for definite conclusions. There were 11.4 DDD/100 bed days of additional antibiotics used in 21% of patients after hip replacement and 15.7 DDD/100 bed days in 31% after knee replacement. For wound problems, 3.8 and 6.9 DDD/100 bed days were given in the hip- and knee-replacement groups. For distant infection, 6.5 DDD/100 bed days was administered in both groups. Duration of therapy varied only in relation to indication. Prescribed were penicillins (43% to 50%), sulfonamides (18%), cephalosporins (10% to 16%), and nitrofurantoin (8% to 13%); drug use was related to the type of infection.

Transvaginal ultrasonography and urodynamic evaluation after suspension operations: comparison among the Gittes, Stamey and Burch suspensions.

Radiological and ultrasonographic imaging enables the objective determination of bladder neck position and movement in stress urinary incontinence. Postoperative results were evaluated in 60 patients after Burch colposuspension (29) or bladder neck suspension according to the Gittes (18) or Stamey (13) method. No differences in continence rates were noted 3 months postoperatively (Gittes 83%, Stamey 85% and Burch 93% of the patients). Late results were assessed by urodynamic evaluation and transvaginal ultrasonography. The largest decrease in continence rate was observed after the Gittes procedure (44% of the patients continent, mean followup 14.7 months), in comparison with the Stamey (69% continent after 34.6 months) and Burch (86% continent after 30.5 months) procedures. Urodynamic parameters showed no significant differences for the 3 groups. Transvaginal ultrasonography did not indicate a correlation between absolute resting or stress position of the bladder neck and continence. The main factor concerning continence was the rotation angle and descent of the bladder neck during stress. Our data indicate that transvaginal ultrasonography is a safe and reliable method to evaluate the postoperative outcome for stress urinary incontinence.

Improvement of lesion detection by echographic image processing: signal-to-noise-ratio imaging.

Signal-to-noise-ratio (SNR) images were constructed by a sliding window technique. Theoretical derivations of the first order statistical properties of SNR images are given for the case of intensity coding of the original images for low number densities and for the limit case of fully developed speckle. The original images were obtained by realistic simulations of backscattering by homogeneous media, while using a range of number densities of the scatterers (isotropic scattering). The SNR imaging method is illustrated by results obtained from simulated scattering media containing a lesion that is contrasting in reflectivity level or in number density of the scatterers. A considerable improvement in lesion detection is obtained if the primary difference from the background speckle is due to a different number density of the scatterers within the lesion.

Effectiveness in inhibition of recovery of cell survival by cisplatin and carboplatin: influence of treatment sequence.

Clinical protocols have been designed to combine platinum-based drugs and radiation in the treatment of cancer. The rationale for this approach has been developed from preclinical studies demonstrating that platinum compounds can potentiate the cytotoxic effects of radiation toward cells. In the present study multicellular spheroids derived from squamous cell carcinoma cell line HN-1 have been used to study the effects of both cisplatin and carboplatin when administered prior to, concurrently, and after irradiation treatment. To study the influence of platinum compounds on sublethal damage repair, single and split doses of radiation were applied. Growth delay and proportion cured spheroids served as endpoints. Both cisplatin and carboplatin had no potentiating effect when administered 24 hr prior to irradiation. When administered 3 hr after completion of irradiation procedures, growth delay after single and split doses were enhanced to the same extent. The drug enhancement ratio for cisplatin was larger (1.5) than for carboplatin (1.2). Both single and split doses were enhanced by the same factor, which was interpreted as no effect on sublethal damage repair. When platinum compounds were present in the target cells at the time of irradiation, especially the split dose radiation response was strongly enhanced: the drug enhancement ratio was 3.9 for cisplatin and 3.2 for carboplatin. Recovery from sublethal damage was totally repressed. This study shows that platinum compounds can potentiate radiation and that for maximum effect the sequence of the two treatment modalities is of utmost importance. Moreover, these results may in part explain the heterogeneous outcomes of trials combining platinum compounds and radiation.

Sublethal damage repair in two radioresistant human tumor cell lines irradiated as multicellular spheroids.

Melanoma and lung adenocarcinoma may be amenable for radiotherapy if it were possible to increase the presently used total dose. In order to investigate this, spheroids from two cell lines of human origin, one obtained from a BRO melanoma and one from an NCI-H125 lung adenocarcinoma were exposed to graded doses (3-9 Gy) of radiation with 18-MV photons. Radiation was applied either as a single dose or as split doses with an interval of 6 h to determine the extent of sublethal damage repair. Radiation response was quantified in terms of spheroid cure and specific growth delay. Both cells lines have previously been shown to be less sensitive than a neuroblastoma and a squamous cell carcinoma cell line grown as spheroids. Data obtained from the growth delay analysis were used to calculate the extent of split-dose recovery. Repaired dose for BRO spheroids did not increase after 7 Gy, whereas in NCI-H125, the repaired dose showed a steady increase. Recovery ratios did not differ between the two cell lines, but were lower than reported for normal tissues. Both cell lines revealed a low repair capacity was expressed by the beta-value of the linear-quadratic (LQ) equation. However, repair capacity for sublethal damage as expressed by the dose repaired and the beta-value of the LQ equation was not different from values reported earlier by us for neuroblastoma and squamous cell carcinoma when grown as spheroids. This indicates that the low radiosensitivity for the cell lines used in this study is determined by the alpha-value of the LQ equation. Our results support the clinical finding that the application of increased total radiation doses in the treatment of melanoma and lung adenocarcinoma may be feasible if radiation is applied in multiple small fractions to ensure normal tissue sparing.

Peritoneal transport kinetics of glucose, urea, and creatinine during infancy and childhood.

Peritoneal handling of glucose and metabolites is reported to be higher in young children treated with CAPD than in older children. Reference curves for the standardized peritoneal equilibration test (PET) are not available for younger ages. The present study describes the results of the PET in 19 children (mean age 5.0 years, ranging from 0.3-15) during the first month of CAPD treatment. No age dependency for the handling of glucose, urea, and creatinine could be established when the group was subdivided into 1. children below the age of 3 years, and 2. children above that age. There was, however, a significant correlation between equilibration of creatinine and age, indicating more rapid equilibration at younger ages.

Transcapillary ultrafiltration and lymphatic absorption during childhood continuous ambulatory peritoneal dialysis.

Peritoneal fluid handling depends on a balance between transcapillary ultrafiltration and lymphatic absorption. Lymphatic absorption is reported to be greater in children than in adult continuous ambulatory peritoneal dialysis (CAPD) patients. The present study provides data on peritoneal fluid kinetics in a group of 17 young children (0.4-13 years of age). Net transcapillary ultrafiltration and lymphatic absorption were not dependent on age or duration of treatment. No differences were established from normal values for adult patients reported in the literature.

Separation of serum proteins by high-performance gel-permeation column systems.

Combined TSK-Gel G4000SW-G3000SW and Zorbax GF450-GF250 columns and a Superose 6 column were evaluated for the analytical gel permeation chromatographic separation of serum proteins. Serum elution profiles showed four distinct peaks, which were attributed to immunoglobulin M (IgM), alpha 2-macroglobulin, IgG and albumin. A reproducible shoulder on the IgG peak could be attributed to IgA. These purified serum proteins and other commercially obtained proteins with relative molecular masses between 1000 kDa and 10 kDa were chromatographed on the combined systems and the separate columns. The frictional coefficient-based hydrodynamic radii of these proteins showed a linear relationship with the inverse error function complement of their partition coefficients. Using this relationship, theoretical summation plots of the data obtained from the separate columns of a system correspond to plots that were calculated by treating the combined systems as one column. The best resolution was obtained with the TSK colums, but all three column systems were suitable for the separation of clinically important immunoglobulins in serum. The retention of positively charged proteins by the TSK columns becomes noticeable after relatively short usage and is a first sign of progressive loss of resolution.

Radiosensitivity of human melanoma spheroids influenced by growth rate.

The radiosensitivity of human melanoma cell line BRO was investigated using the multicellular tumor spheroid system. By adding different concentrations of bovine serum to the tissue culture medium, two different growth rates could be obtained. Spheroids (200-250 microns) were irradiated with graded single doses of X rays (2-8 Gy). The radiation response was quantified using specific growth delay, clonogenic cell survival, and spheroid cure. All three assays showed a growth rate dependent radiation response. At both growth rates the spheroid growth fraction and critical cell number were of comparable magnitude. There was a strong correlation between the radiation response of spheroid regenerating units and clonogenic cells from dispersed spheroids. Cell survival curves indicated a decreased ability to accumulate sublethal damage in fast growing multicellular tumor spheroids. From this study it appears that the intrinsic radiosensitivity of human melanoma cell line BRO cells in multicellular spheroids is modulated by intratumoral conditions.

Urinary polyamine and metabolite excretion by children with Zellweger's syndrome.

In order to investigate whether, due to a lack of peroxisomes, polyamine degradation is altered in patients with the cerebro-hepato-renal syndrome of Zellweger, we determined total, free and acetylated polyamines and some of their catabolites in urines of six patients and age-matched healthy children. The normal polyamine excretion patterns of the patients, compared to the control group, suggest that either the intracellular localisation of the polyamine degrading enzyme, polyamine oxidase, is not exclusively limited to peroxisomes or that the enzyme is located in the peroxisomal matrix.