A high polymerized grass pollen extract is efficacious and safe in a randomized double-blind, placebo-controlled study using a novel up-dosing cluster-protocol.

BACKGROUND: Cluster immunotherapy represents an interesting alternative to conventional up-dosing schedules because it allows achieving the maintenance dose within a shorter time interval. In this study, the efficacy and safety of cluster immunotherapy with a high polymerized allergen extract of a grass/rye pollen mixture have been evaluated in a randomized, double-blind, placebo-controlled, multicenter study. METHODS: In total, 121 patients with allergic rhinoconjunctivitis due to grass pollen were randomized 1 : 1 to verum or placebo group. A short cluster up-dosing schedule of only 1 week was applied to achieve the maintenance dose which was administered monthly during the study period of 1 year. Total combined symptom and medication score (TCS) was defined as primary outcome parameter. Secondary outcome parameters were individual symptom and medication scores, 'well days,' global improvement as well as immunological effects and nasal allergen challenge. The safety profile was evaluated based on the European academy of allergy and clinical immunology grading system. RESULTS: Significant reduction in the verum compared to the placebo group (intention-to-treat, population, verum: n = 55; placebo: n = 47) was found regarding TCS (P = 0.005), rhinoconjunctivitis total symptom score (RTSS, P = 0.006), and total rescue medication score (TRMS, P = 0.002). Additionally, secondary outcomes such as 'well days,' nasal challenge results, and increase of specific IgG4 were in favor of the active treatment. All systemic adverse reactions (0.8% of all injections in the verum group) were of mild intensity. No severe reactions related to the study medication were observed. CONCLUSION: Cluster immunotherapy with high polymerized grass pollen extracts resulted in significant clinical efficacy and has been shown to be a safe treatment for grass pollen-allergic patients.

Galantamine treatment in outpatients with mild Alzheimer's disease.

OBJECTIVE: To assess long-term effectiveness of galantamine in community-dwelling persons with mild Alzheimer's disease. METHODS: Prospective open-label trial including patients with mild AD (NINCDS-ADRDA criteria) treated with galantamine for up to 36 months. Outcome parameters included ADAS-cog/11, Bayer-ADL scale (self- and caregivers' ratings), 10-item NPI and CGI-change, safety and tolerability measures. Data are presented based on ITT analyses (LOCF). RESULTS: Seventy-five patients (55% women; mean ADAS-cog 22.3; mean age 70.2 years) were treated with galantamine for approximately 36 months. About 60% (n=45) received a total daily dose of 24 mg galantamine at final visit. After 3, 6, and 12 months of treatment, mean improvements in ADAS-cog ranged between 2.2 and 3.0 points (all P<0.05). After 24-month treatment, ADAS-cog returned to baseline value and at 3-year follow-up, patient deteriorated on average by 2.9 points. There was significant improvement on the NPI scale between baseline and 3- to 12-month follow-up (all P<0.05) and at 3-year endpoint, a slight deterioration was noted. Activities of daily living (B-ADL) decreased significantly after 24 months in self-ratings and after 12 months in caregivers' ratings. Fifty-four patients reported at least one AE, most of them occurring during the first 2 years of treatment. Among the most frequently (>10%) reported AEs irrespective of causal relationship to study medication were nausea (17.3%), dizziness (12%), and vomiting (10.7%). CONCLUSION: Galantamine was generally safe and well tolerated during the 3-year observation period. Cognition, behavior, and activities of daily living improved during 12 months treatment. At 3-year follow-up, worsening in all outcomes was measured; however, cognition remained improved compared with an untreated population.

Seizure and cognitive outcomes in children and adolescents with epilepsy treated with topiramate.

This 12-week open label study explored cognitive and seizure outcomes of 53 children treated with topiramate (TPM). The digit symbol test and verbal learning memory test were administered at baseline and study endpoint. Topiramate was started either in monotherapy or add-on therapy. Overall, 57% of children experienced a ≥50% seizure reduction, 36% became seizure free and cognitive testing revealed no significant changes during TPM therapy. Due to the heterogeneity of the study population, post hoc analyses were added to compare patients in initial or conversion to TPM monotherapy as well as patients who continued add-on therapy. Verbal learning memory test parameters showed neither significant differences within any subgroup comparing baseline with endpoint nor significant differences between described subgroups except for one finding. The digit symbol test revealed no differences between each subgroup between baseline and endpoint. Comparing pre-post differences, TPM monotherapy was associated with better cognitive outcomes than treatment in add-on therapy. These results have to be interpreted with caution given the short study duration and the heterogeneity of the study population. Despite these limitations, our overall results suggest that treatment with topiramate is associated with improved seizure control without significant changes in cognitive functions at the low doses tested.

Exploring efficacy and tolerability outcomes in patients with difficult-to-treat epilepsy receiving adjunctive topiramate at different titration rates--an exploratory study.

OBJECTIVE: To compare rapid vs regular titration of topiramate concerning efficacy and safety. MATERIALS AND METHODS: Open-label, prospective, single-center study exploring efficacy and tolerability of two adjunctive dosing regimens of topiramate (TPM) in adult patients with difficult-to-treat epilepsy. Based on investigator judgment, 21 of 50 consecutive patients received a rapid titration (starting dose 50 mg/day, stepwise increase with 50 mg/day after 3 days each until reaching the target dose), while the other 29 patients received titration according to the German prescribing information (starting dose 25 mg/day, stepwise increase with 25-50 mg/day every 7 days). Patients were observed until the target dose was reached and 3 months thereafter. RESULTS: Mean final dosages were 136 mg/day (regular titration) and 213 mg/day (rapid titration). Efficacy and tolerability measures did not differ significantly. Forty-six percent of all patients experienced a seizure reduction of > or = 50%; 14% became seizure free. No serious adverse events occurred. The most common adverse effects were tiredness (20%), memory and language difficulties (18% each), slowness in thinking and speech (10%), psychomotor disturbance (8%) and paresthesia (8%). CONCLUSIONS: This study suggests that rapid and conventional titration generate similar tolerability, safety and effectiveness in selected patients.

Effectiveness of low dose of topiramate following rapid titration in multiply handicapped children and difficult-to-treat epilepsy.

This prospective, observational, single arm, monocentric study explored efficacy and tolerability outcomes of rapid oral initiation of topimarate in children with difficult to treat epilepsy. The study population consisted of 19 multiply handicapped children (mean age 4.4 years, range 0.6-15.3 years). The observation period was 12 weeks and included 7 visits. The mean initial dose of topiramate was 1.1 mg/kg body weight/d (range: 0.66-2.67 mg/kg/d) following rapid titration. The mean final dose was 3.3 mg/kg/d (range 0.5-6.7 mg/kg/d). An at least 50% reduction of seizure frequency compared to baseline was observed in 9 of 19 patients (47.4%). Six patients (31.6%) had a slight reduction of seizure frequency (<50%) and 4 patients (21.1%) experienced an increase of seizure frequency. A total number of 29 adverse events were documented in 17 of 19 patients. Most frequently captured were fatigue (26.3% of patients), decreased appetite (15.8%) and psychiatric disturbances (15.8%). No serious adverse events were reported. These data might suggest that in certain clinical circumstances rapid dose escalation with topiramate followed by a low maintenance dose might be a good therapeutic option for pediatric patients with difficult to treat epilepsy.

Topiramate in add-on therapy: results from an open-label, observational study.

An open-label, observational prospective study assessed the effectiveness of topiramate (TPM) as add-on therapy. A total of 450 patients aged 12 and above with a diagnosis of epilepsy and at least one epileptic seizure during the 12-week retrospective baseline were to be documented. After baseline evaluation, topiramate was added. Ninety-five percent of patients had at least one baseline AED, most commonly Carbamazepine (53%) or Valproate (34%). In 5% TPM was started in monotherapy. Topiramate dose titration and target dose was determined by clinical response and side effect profile. Patients were intended to be followed for a total of 1 year which included 6 visits during which seizure frequency, adverse events, weight as well as clinical global impression were recorded. During the 12 weeks retrospective baseline, a median of 2.8 seizures per month were recorded which reduced significantly to 0.7 per month during the complete treatment phase (p < 0.0001). Seventy-two percent of patients had a > or =50% seizure reduction. Ten percent of patients were seizure free during the study. The most commonly reported adverse events were difficulties with memory (4.2%), somnolence (3.6%), and dizziness (2.7%). Overall, topiramate was well tolerated, and only 5% of patients discontinued treatment due to an adverse event. Retention in the study was higher than previously reported during randomized, dose controlled studies and is likely due to individualized doses as well as slower titration used.

Galantamine: a cholinergic patch in the treatment of alcoholism: a randomized, placebo-controlled trial.

OBJECTIVES: The involvement of the central cholinergic system in alcohol abuse behavior is well known. It is possible that the reinforcing effects of ethanol are partially mediated by nicotinic receptors, which modulate neurotransmitter release. It was demonstrated that the application of a cholinesterase inhibitor reduces alcohol consumption in alcohol-preferring rats. This suggests that galantamine (GAL), a cholinesterase inhibitor, could be effective when seeking to prolong abstinence in recently detoxified alcoholics. This study represents the first reported clinical trial of a cholinergic drug in alcohol-relapse prevention. PATIENTS AND METHODS: We investigated the efficacy and safety of GAL by conducting a 24-week randomized, placebo-controlled, multicentric clinical trial on 149 recently detoxified alcoholics. Survival analyses (Kaplan-Meier) were performed to reveal evidence of prolonged abstinence periods in patients who received GAL. RESULTS: Our findings did not support our hypothesis. GAL did not extend the time to first severe relapse. However, additional post hoc analyses suggest that relapsed patients treated with GAL consume less ethanol per drinking day than patients treated with placebo. CONCLUSIONS: GAL seems to be ineffective when used in relapse prevention of detoxified alcoholics. It is possible that alcohol needs to be "on board" for GAL to be beneficial. This could explain why our post hoc analysis showed that GAL possibly reduces the alcohol consumption of relapsers. If confirmed, GAL could play a role in the reduction of harmful alcohol use and at-risk consumption.

Fluorouracil plus leucovorin as effective adjuvant chemotherapy in curatively resected stage III colon cancer: results of the trial adjCCA-01.

PURPOSE: Adjuvant postoperative treatment with fluorouracil (5-FU) and levamisole in curatively resected stage III colon cancer significantly reduces the risk of cancer recurrence and improves survival. Biochemical modulation of 5-FU with leucovorin has resulted in increased remission rates in metastatic colorectal cancer, thus reflecting an increased tumor-cell kill. The impact of 5-FU plus leucovorin on survival and tumor recurrence was analyzed in comparison with the effects of 5-FU plus levamisole in the prospective multicentric trial adjCCA-01. PATIENTS AND METHODS: Patients with a curatively resected International Union Against Cancer stage III colon cancer were stratified according to T, N, and G category and randomly assigned to receive one of the two adjuvant treatment schemes: 5-FU 400 mg/m(2) body-surface area intravenously in the first chemotherapy course, then 450 mg/m(2) x 5 days; 12 cycles, plus leucovorin 100 mg/m(2) (arm A), or 5-FU plus levamisole (Moertel scheme; arm B). RESULTS: Six hundred eighty (96.9%) of 702 patients enrolled onto this study were eligible. After a median follow-up time of 46.5 months, the 5-FU plus leucovorin combination significantly improved disease-free survival (P =.037) and significantly decreased overall mortality (P =.0089) in comparison with 5-FU plus levamisole. In a multivariate proportional hazards model, adjuvant chemotherapy emerged as a significant prognostic factor for survival (P =.0059) and disease-free survival (P =.03). Adjuvant treatment with 5-FU plus levamisole as well as with 5-FU plus leucovorin was generally well tolerated; only a minority of patients experienced grade 3 and 4 toxicities. CONCLUSION: After a curative resection of a stage III colon cancer, adjuvant treatment with 5-FU plus leucovorin is generally well tolerated and significantly more effective than 5-FU plus levamisole in reducing tumor relapse and improving survival.

Urinary excretion of immunoreactive luteinizing hormone-releasing hormone-like material in children correlation with pubertal development.

Immunoreactive LRH (iLRH)-like material has been measured in extracts of urine from normal children and adolescents, adult men and women, and postmenopausal women. The urinary excretion of iLRH-like material was significantly greater in pubertal than in prepubertal subjects and in boys than girls at both stages of sexual maturation [prepubertal males, 3.26 +/- 0.49 ng/24 h (SE; n = 24); pubertal males, 5.94 +/- 1.36 (n = 12); prepubertal females, 1.14 +/- 0.21 (n = 19); pubertal females, 2.85 +/- 0.56 (n = 13)]. In adult males (n = 5) the urinary excretion of iLRH-like material was 7.8 +/- 1.3 ng/24 h, and in adult women in the follicular phase of the menstrual cycle (n = 8) it was 2.9 +/- 0.3. In five postmenopausal women the urinary iLRH-like content was 7.32 +/- 0.92 ng/24 h (P less than 0.01 relative to normal pubertal and adult women). In children the 24-h urinary excretion of iLRH-like material was positively correlated with chronological and bone ages, Tanner stage of genital (male) and breast (female) development, and the urinary excretion of LH and FSH in males. It did not correlate with the urinary excretion of either LH or FSH in females. Carboxymethylcellulose chromatography of extracts of urine from pubertal boys and girls, adult men and women, and postmenopausal women suggested that the iLRH-like material may be the 2-10 fragment of LRH rather than the intact decapeptide.

Effects of forskolin on spontaneous behavior, rectal temperature and brain cAMP levels of rats: interaction with rolipram.

The effects of systemically administered forskolin, a direct activator of the catalytic subunit of adenylate cyclase, on locomotor activity, rectal temperature and the incidence of grooming and head twitches were studied in rats. Forskolin, 0.1-25 mg/kg, decreased locomotor activity and lowered rectal temperature. The incidence of grooming and head twitches increased dose-dependently after forskolin, 6.25 25 mg/kg. The combination of a threshold dose of forskolin with a threshold dose of the cAMP-selective phosphodiesterase (PDE) inhibitor rolipram resulted in a marked, statistically significant enhancement of the behavioral, hypothermic and brain cAMP elevating effect. The present findings support the assumption that enhanced brain cAMP availability is associated with a characteristic behavioral syndrome in rats as was previously shown with dibutyryl cAMP or neurotropic cAMP-selective PDE inhibitors like rolipram. Ro 20-1724 or ICI 63 147.

Effect of chronic subcutaneous minipump infusion of lisuride upon locomotor activity of rats.

Male Wistar rats were infused continuously for 14 days with lisuride 0.25 mg/kg/day or with vehicle via subcutaneously implanted osmotic minipumps. Locomotor activity was measured at 5 hours, 1, 7 and 14 days after implantation. Thereafter the minipumps were removed and 1, 7 and 21 days later the locomotor activity was recorded after a subcutaneous challenge dose of lisuride 0.1 mg/kg. In the course of continuous infusion the lisuride-treated rats showed a persistent stimulation of locomotor activity which remained almost constant throughout the whole period of exposure. At all intervals after removal of the minipumps lisuride challenge produced a less pronounced locomotor stimulation in lisuride-infused rats compared to vehicle-infused animals. This observation contrasts with the findings after chronic subcutaneous bolus treatment of rats with 0.25 mg/kg lisuride once daily for 29 days which resulted (1) in a progressive enhancement of the locomotor stimulatory effect and (2) in a longlasting hyperresponsiveness towards a subcutaneous challenge dose of lisuride 0.025 mg/kg. These results are discussed with respect to the advantage of the constant availability of lisuride at central dopamine receptors for the management of patients with advanced Parkinson's disease showing fluctuations in motor performance probably related to the kinetics of conventional oral therapy.

Holocaust survivors' perspectives on the euthanasia debate.

The paper reports on a qualitative analysis of 15 personal interviews with holocaust survivors in Israel concerning their perceptions of similarities and differences between socially-assisted dying and the holocaust policies. The design of the study was exploratory/descriptive and asked the following questions: "Some discussions have expressed similarities between Nazi Germany and euthanasia. Do you believe the comparison is justified? In what ways are euthanasia and the holocaust similar? In what ways are they different?" Participants concluded that profound differences existed between Nazi Germany and socially assisted dying. These differences were established from four different perspectives in 10 different themes, and demonstrated by 24 different examples of the themes. Informants further cautioned philosophers about comparisons between the holocaust and other human behaviors. The survivors perceived that such a comparison has negative consequences for their own well-being, the dignity of their family members, the next generation and the Israeli society.

Hereditary gingival fibromatosis and growth retardation.

OBJECTIVE: To describe two patients with hereditary gingival fibromatosis (HGF) and growth hormone deficiency and to review the literature on HGF and related endocrine abnormalities. METHODS: We present case reports of two patients (first cousins)-an 8-year-old girl and a 13-year-old boy-with an existing diagnosis of HGF, who were assessed because of presumed growth failure. Both patients underwent growth hormone stimulation testing and more in-depth endocrine evaluation, including measurement of morning cortisol, adrenocorticotropic hormone (ACTH), and prolactin levels as well as thyroid function tests. An ACTH stimulation test was also performed. Radiologic evaluation included assessment of bone age and magnetic resonance imaging of the brain. RESULTS: In addition to HGF, both patients had short stature, subnormal growth velocity, and delayed bone age but no abnormalities on magnetic resonance imaging of the brain. Serum prolactin levels and results of thyroid function tests were normal. Subnormal growth hormone response was noted during hypoglycemia and pharmacologic stimuli with clonidine and levodopa. The female patient, who also had recurrent hypoglycemic episodes, had a suboptimal cortisol and ACTH response during hypoglycemia. On the ACTH stimulation test, she showed an inadequate cortisol response at 30 minutes but a normal response at 60 minutes. The male patient had normal morning cortisol and ACTH levels plus a normal response to ACTH stimulation. Both patients are responding well to treatment with growth hormone. The girl is also receiving cortisol replacement and has had no further episodes of hypoglycemia. CONCLUSION: Although HGF has been described as an isolated finding, it can occur as part of a syndrome, including infrequent endocrine abnormalities such as growth hormone insufficiency. The cause of the growth hormone deficiency remains unclear in these two patients. We believe that patients with HGF should be monitored carefully for a prolonged period for growth as well as other endocrine abnormalities.

[Comparison of the effectiveness of physical training with parenteral drug therapy in Fontaine stage IIb peripheral arterial occlusive disease]. / Vergleich der Effizienz des physikalischen Trainings gegenüber parenteraler medikamentöser Therapie bei peripherer arterieller Verschlusskrankheit im Stadium IIb nach Fontaine.

In an open, randomized study in patients with peripheral arterial occlusive disease in state IIb according to Fontaine the clinical efficacy and tolerability of Actovegin upon intravenous and intraarterial application was examined compared to vascular training. 30 patients were included in each of the three therapy groups. Over a period of four weeks each patient received daily therapy--except for weekends. Patients of group I received a daily intravenous infusion of 250 ml Actovegin 20% p.i. the patients in group II received this medication by the intraarterial route. The third patient group received standardized vascular training. From a total of 90 patients 73 completed the study according to the study protocol. In all three groups the therapy resulted in the improvement of pain-free and pain-limited walking distances. Upon comparison of relative changes in the intraarterial and intravenous group significant differences turned out: whereas patients in the intravenous group achieved a mean increase in pain-free walking distance of 37.8%, a mean increase in walking distance of 44.9% in the intraarterial group was observed. With respect to maximum walking distances the relative improvements amounted to a mean of 44.0% in the intravenous group, and 64.3% in the intraarterial group. After training over four weeks in the vascular-training group the patients achieved a mean increase in pain-free walking distance of 69.6% and 53.5% in pain-limited walking distance. This meant a significantly greater improvement in pain-free walking distance compared to the intravenous group; the difference compared to the intraarterial group was not significant; however the mean values indicated that the vascular-training group showed greater improvements in pain-free walking distance, and more moderate improvements in maximum walking distance than the intraarterial group. However, these results were significantly modified, if a differentiation was made in the vascular-training group between patients with high and low compliance. In the patients' rating all three therapies were described as throughout beneficial, however, less positive for the intravenous therapy, which is in accordance to the results of changes in walking-distance. The results of the present study are discussed having in mind physical therapy being limited through contraindications and insufficient patient compliance.

[Treatment of behavioral disorders in dementia with risperidone in psychogeriatric out-patients]. / Therapie demenzassoziierter Verhaltens- störungen mit Risperidon bei ambulanten gerontopsychiatrischen Patienten.

BACKGROUND: The atypical neuroleptic drug risperidone has been approved for the treatment of behavioural and psychological symptoms of dementia for more than three years in Germany. To assess the efficacy and tolerability of risperidone in general practice two open-label prospective studies were performed. PATIENTS AND METHOD: In 7142 patients with dementia the treatment course with risperidone was examined over 6 resp. 8 weeks. Efficacy was evaluated by assessing the target symptoms agitation, aggression, sleep-wake-cycle disturbances, social withdrawal, suspiciousness, and delusion. Furthermore, the global impression was rated by the physician and the caregiver at the end of the study. The tolerability of risperidone was documented by monitoring blood pressure, heart rate, bodyweight, and adverse events. RESULTS: 6170 patients complied with the inclusion criteria for analysis. Risperidone achieved statistically significant improvements of behavioural symptoms at an average dose of 1,5 mg/d (90% of patients received < or = 2 mg/d). 92% of the patients showed a favourable treatment response as defined by a > or = 30% improvement of the total score of the target symptoms. This improvement was already apparent 2 and 3 weeks after the start of treatment, respectively. A subgroup analysis demonstrated statistically significant improvements of target symptoms with risperidone also in patients who had been pre-treated with other neuroleptics. The global impression of physician and caregiver was positive in over 90% of patients. Adverse events were seen in 309 of 6170 patients (5,7%). CONCLUSION: Risperidone was highly effective and well tolerated in the treatment of behavioural disturbances in dementia under routine conditions of general practice.