A phase 1 trial of riluzole in spinal muscular atrophy. A placebo-controlled trial of gabapentin in spinal muscular atrophy. Open-label randomized trial of oral trimethoprim-sulfamethoxazole, doxycycline, and chloramphenicol compared with trimethoprim-sulfamethoxazole and doxycycline for maintenance therapy of melioidosis. Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia. Ofloxacin versus trimethoprim/sulfamethoxazole in the treatment of uncomplicated urinary tract infection. SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy. Impact of glucose self-monitoring on non-insulin-treated patients with type II diabetes mellitus. Randomized controlled trial comparing blood and urine testing. The efficacy of self-monitoring of blood glucose in the management of patients with type 2 diabetes treated with a gliclazide modified release-based regimen. A multicentre, randomized, parallel-group, 6-month evaluation (DINAMIC 1 study). Randomized controlled trial of the efficacy of adjuvant immunochemotherapy and adjuvant chemotherapy for colorectal cancer, using different combinations of the intracutaneous streptococcal preparation OK-432 and the oral pyrimidines 1-hexylcarbamoyl-5-fluorouracil and uracil/tegafur.
Severe spinal muscular atrophy (SMA) (Werdnig-Hoffmann disease, acute SMA, and SMA I) is a disease of the motor neuron characterized by onset before 6 months of age, failure ever to achieve sitting without support, and a life expectancy of 2 years or less. There is no known treatment for SMA, and, until recently, no therapeutic trials have been attempted. There is reason to believe that glutamate, an excitatory neurotransmitter, enhances programmed cell death of anterior horn cells. Riluzole, a glutamate inhibitor, has been shown to slow the rate of decline in patients with amyotrophic lateral sclerosis, another form of motor neuron disease.
                To determine whether a glutamate inhibitor might be tolerated by infants with SMA and, furthermore, whether this medication could have a positive effect on life expectancy.
                Subjects with homozygous deletions of the survival motor neuron gene were recruited from pediatric neuromuscular clinics and randomized in a 2:1 ratio, 2 riluzole to 1 placebo. Neurologic examination was performed at the first visit by one of the investigators. Complete blood count, hepatic and renal screens, and urinalysis were performed at baseline, 2 weeks, 1 month, 2 months, 3 months, 6 months, and 9 months after drug or placebo was started. An electrocardiogram was done at baseline, 3 months, 6 months, and 12 months. Treatment was stopped after 9 months, and blood work was repeated at 12 months. Treatment was reinstituted at 1 year if requested by the parents. The enrollment goal was 30 patients; however, support from the pharmaceutical company was withdrawn when Rhone-Poulenc Rorer was taken over by Aventis. The investigational review boards of the participating centers approved the protocol and consent forms.
                Seven patients received riluzole and 3 received placebo medication. All 3 patients in the placebo group died (mean age, 9 months). Three of 7 who received active drug are still living at ages 513 years, 4 years, and 30 months. None of the 10 subjects experienced adverse effects or changes in laboratory test results. None showed any change in motor abilities.
                Riluzole appears to be safe in young children. This was a limited study with insufficient power to show a difference between the 2 groups. Because there is a suggestion of possible benefit in treated subjects, we recommend further study of riluzole in pediatric patients with SMA. To evaluate the efficacy of gabapentin in increasing muscle strength of patients with spinal muscular atrophy (SMA).
                Preclinical data in experimental models of motor neuron disease suggest a neuroprotective effect of gabapentin.
                Gabapentin (1200 mg), or placebo, was administered three times daily in a randomized, double-blind trial for 12 months. The primary outcome measure was the average percent change from baseline, based on the measurement of strength in four muscles (elbow flexion and hand grip bilaterally) for each patient. Drug efficacy was examined by comparing the percent change in strength for patients on drug vs. placebo. Secondary efficacy variables included: forced vital capacity (FVC), SMA functional rating scale (SMAFRS), and mini-Sickness Impact Profile (SIP).
                Eighty-four patients, with type II or III SMA, were enrolled at eight sites across the United States. There were no differences in baseline features. There was no difference between the placebo and drug groups in any outcome measure.
                This study demonstrates the feasibility of this trial design and provides data for the design of future clinical trials in SMA. Melioidosis (infection caused by Burkholderia pseudomallei) requires a prolonged course of oral antibiotics following initial intravenous therapy to reduce the risk of relapse after cessation of treatment. The current recommendation is a four-drug regimen (trimethoprim [TMP], sulfamethoxazole [SMX], doxycycline, and chloramphenicol) and a total treatment time of 12 to 20 weeks. Drug side effects are common; the aim of this study was to compare the efficacy and tolerance of the four-drug regimen with a three-drug regimen (TMP-SMX and doxycycline). An open-label, randomized trial was conducted in northeast Thailand. A total of 180 adult Thai patients were enrolled, of which 91 were allocated to the four-drug regimen and 89 to the three-drug regimen. The trial was terminated early due to poor drug tolerance, particularly of the four-drug regimen. The culture-confirmed relapse rates at 1 year were 6.6% and 5.6% for the four- and three-drug regimens, respectively (P = 0.79). The three-drug regimen was better tolerated than the four-drug regimen; 36% of patients receiving four drugs and 19% of patients receiving three drugs required a switch in therapy due to side effects (P = 0.01). The duration of oral therapy was significantly associated with relapse; after adjustment for confounders, patients receiving less than 12 weeks of oral therapy had a 5.7-fold increase of relapse or death. A combination of TMP-SMX and doxycycline is as effective as and better tolerated than the conventional four-drug regimen for the oral treatment phase of melioidosis. Evidence that the metabolism of phospholipids and polyunsaturated fatty acids (PUFA) is abnormal in schizophrenia provided the rationale for intervention studies using PUFA supplementation. An initial open label study indicating efficacy for n-3 PUFA in schizophrenia led to two small double-blind pilot studies. The first study was designed to distinguish between the possible effects of two different n-3 PUFA: eicosapentaenoic acid (EPA) and docohexaenoic acid (DHA). Forty-five schizophrenic patients on stable antipsychotic medication who were still symptomatic were treated with either EPA, DHA or placebo for 3 months. Improvement on EPA measured by the Positive and Negative Syndrome Scale (PANSS) was statistically superior to both DHA and placebo using changes in percentage scores on the total PANSS. EPA was significantly superior to DHA for positive symptoms using ANOVA for repeated measures. In the second placebo-controlled study, EPA was used as a sole treatment, though the use of antipsychotic drugs was still permitted if this was clinically imperative. By the end of the study, all 12 patients on placebo, but only eight out of 14 patients on EPA, were taking antipsychotic drugs. Despite this, patients taking EPA had significantly lower scores on the PANSS rating scale by the end of the study. It is concluded that EPA may represent a new treatment approach to schizophrenia, and this requires investigation by large-scale placebo-controlled trials. A multicenter randomized study was conducted to compare the efficacy and safety of ofloxacin with that of trimethoprim/sulfamethoxazole (TMP/SMX) in the treatment of uncomplicated urinary tract infection in adults. Patients were randomized to receive either oral ofloxacin 200 mg daily for three days (102 patients), or oral TMP/SMX 160 mg/800 mg twice daily for seven days (100 patients). The pathogen was eradicated in 73 (97.3%) of the 75 evaluable patients receiving ofloxacin and in 66 (97.1%) of the 68 evaluable patients receiving TMP/SMX. The most frequently isolated pathogens were Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis. More urinary pathogens were susceptible to ofloxacin than to TMP/SMX, although this difference was not statistically significant. The clinical cure rate for patients receiving ofloxacin was 93.3%, with 4% improved and 2.7% failed. For patients receiving TMP/SMX, the clinical cure rate was 86.4%, with 12.1% improved and 1.5% failed. Side effects were reported by 29.7% of the patients receiving ofloxacin and by 40.4% of the patients receiving TMP/SMX. Drug-related adverse experiences, as determined by the investigators, occurred in 5% of the ofloxacin patients and in 15.2% of the TMP/SMX patients, a statistically significant difference. No patients receiving ofloxacin, compared with three patients receiving TMP/SMX, discontinued therapy because of an adverse reaction. These results indicate that short-course ofloxacin is as effective as TMP/SMX in the treatment of uncomplicated urinary tract infection. Ofloxacin therapy is also better tolerated than TMP/SMX. Valproic acid (VPA) has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA) in vitro and in vivo.
                Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL, a non-ambulatory group of "sitters" (cohort 1) and an ambulatory group of "walkers" (cohort 2). Here, we present results for cohort 1: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2-8 years of age. Sixty-one subjects were randomized 1:1 to placebo or treatment for the first six months; all received active treatment the subsequent six months. The primary outcome was change in the modified Hammersmith Functional Motor Scale (MHFMS) score following six months of treatment. Secondary outcomes included safety and adverse event data, and change in MHFMS score for twelve versus six months of active treatment, body composition, quantitative SMN mRNA levels, maximum ulnar CMAP amplitudes, myometry and PFT measures.
                At 6 months, there was no difference in change from the baseline MHFMS score between treatment and placebo groups (difference = 0.643, 95% CI = -1.22-2.51). Adverse events occurred in >80% of subjects and were more common in the treatment group. Excessive weight gain was the most frequent drug-related adverse event, and increased fat mass was negatively related to change in MHFMS values (p = 0.0409). Post-hoc analysis found that children ages two to three years that received 12 months treatment, when adjusted for baseline weight, had significantly improved MHFMS scores (p = 0.03) compared to those who received placebo the first six months. A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores (p = 0.007).
                This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA. Weight gain, age and treatment duration were significant confounding variables that should be considered in the design of future trials.
                Clinicaltrials.gov NCT00227266. The goal of this study was to compare the relative efficacy and cost of self-monitoring of blood glucose (SMBG) with routine urine testing in the management of patients with type II (non-insulin-dependent) diabetes mellitus not treated with insulin. Fifty-four patients with type II diabetes mellitus, not treated with insulin, who had inadequate glucose control on diet alone or diet and oral hypoglycemic agents were studied. Patients performed SMBG or urine glucose testing as part of a standardized treatment program that also included diet and exercise counseling. During the 6-mo study, both the urine-testing and SMBG groups showed similar improvement in glycemic control; within each group, there were significant improvements in fasting plasma glucose (reduction of 1.4 +/- 3.2 mM, P less than 0.03) and glycosylated hemoglobin (reduction of 2.0 +/- 3.4%, P less than 0.01) levels. Seventeen (31%) of 54 patients actually normalized their glycosylated hemoglobin values, 9 in the urine-testing group and 8 in the SMBG group. Comparisons between the urine-testing and SMBG groups showed no significant differences in mean fasting plasma glucose (P greater than 0.86), glycosylated hemoglobin (P greater than 0.95), or weight (P greater than 0.19). In patients with type II diabetes mellitus not treated with insulin, SMBG is no more effective, but is 8-12 times more expensive, than urine testing in facilitating improved glycemic control. Our results do not support widespread use of SMBG in diabetic patients not treated with insulin. To determine if therapeutic management programmes for type 2 diabetes that include self-monitoring of blood glucose (SMBG) result in greater reductions in glycated haemoglobin (HbA1c) compared with programmes without SMBG in non-insulin requiring patients.
                Multicentre, randomized, parallel-group trial. A total of 610 patients were randomized to SMBG or non-SMBG groups. Patients in both groups received the same oral antidiabetic therapy using a gliclazide modified release (MR)-based regimen for 27 weeks. The primary efficacy end-point was the difference between groups in HbA1c at the end of observation.
                A total of 610 patients were randomized: 311 to the SMBG group and 299 to the non-SMBG group. HbA1c decreased from 8.12 to 6.95% in the SMBG group and from 8.12 to 7.20% in the non-SMBG group; between-group difference was 0.25% (95% CI: 0.06, 1.03; p = 0.0097). Symptoms suggestive of mild to moderate hypoglycaemia was the most commonly reported adverse event, reported by 27 (8.7%) and 21 (7.0%) patients in the SMBG and non-SMBG groups, respectively; the incidence of symptomatic hypoglycaemia was lower in the SMBG group.
                In patients with type 2 diabetes, the application of SMBG as an adjunct to oral antidiabetic agent therapy results in further reductions in HbA1c. We investigated the efficacy and safety of adjuvant immunochemotherapy and adjuvant chemotherapy for colorectal cancer, using different combinations of the intracutaneous streptococcal preparation OK-432 and the oral pyrimidines 1-hexylcarbamoyl-5-fluorouracil (carmofur, HCFU) and uracil/tegafur (UFT).
                Patients with stage II, III, or IV (Dukes' B, C) colorectal cancer were enrolled and randomly assigned to one of three groups: an immunochemotherapy group (mitomycin C [MMC] + 5-fluorouracil [5-FU] + HCFU + OK-432), a chemotherapy group (MMC + 5-FU + HCFU), and a control group (surgery alone) for those with colon cancer (study 1); and an immunochemotherapy group (MMC + 5-FU + UFT + OK-432), a chemotherapy group (MMC + 5-FU + UFT), and a control group (surgery alone) for those with rectal cancer (study 2).
                A total of 760 patients with colon cancer and 669 patients with rectal cancer were entered into this randomized clinical trial (RCT). The incidence of side-effects was in the order of: immunochemotherapy group > chemotherapy group > control group in both the cohort of patients with colon cancer and the cohort with rectal cancer. In particular, the frequency of leucopenia and skin disorders was significantly higher than control groups. There were no severe adverse events such as death related to the adjuvant therapy. In both the colon cancer and rectal cancer cohorts, no significant difference in the 5-year survival rate and disease-free survival rate was noted among the three groups.
                The results of an RCT demonstrated that the combination of MMC + 5-FU + HCFU + OK-432 for colon cancer and that of MMC + 5-FU + UFT + OK-432 for rectal cancer could not prolong the survival of patients with surgically resected colorectal cancer, but that both combinations were well tolerated as adjuvant therapy. We investigated the efficacy and safety of adjuvant immunochemotherapy and adjuvant chemotherapy for colorectal cancer, using different combinations of the intracutaneous streptococcal preparation OK-432 and the oral pyrimidines 1-hexylcarbamoyl-5-fluorouracil (carmofur, HCFU) and uracil/tegafur (UFT).
There is no proven efficacious drug treatment for SMA types II and III.