Review & meta-analysis: isopropanolic black cohosh extract iCR for menopausal symptoms - an update on the evidence.

A systematic literature search revealed 35 clinical studies and one meta-analysis comprising 43,759 women, of which 13,096 were treated with isopropanolic Cimicifuga racemosa extract (iCR). Compared to placebo, iCR was significantly superior for treating neurovegetative and psychological menopausal symptoms, with a standardized mean difference of -0.694 in favor of iCR (p < 0.0001). Effect sizes were larger when higher dosages of iCR as monotherapy or in combination with St. John's wort (Hypericum perforatum [HP]) were given (-1.020 and -0.999, respectively), suggesting a dose-dependency. For psychological symptoms, the iCR+HP combination was superior to iCR monotherapy. Efficacy of iCR was comparable to low-dose transdermal estradiol or tibolone. Yet, due to its better tolerability, iCR had a significantly better benefit-risk profile than tibolone. Treatment with iCR/iCR+HP was well tolerated with few minor adverse events, with a frequency comparable to placebo. The clinical data did not reveal any evidence of hepatotoxicity. Hormone levels remained unchanged and estrogen-sensitive tissues (e.g. breast, endometrium) were unaffected by iCR treatment. As benefits clearly outweigh risks, iCR/iCR+HP should be recommended as an evidence-based treatment option for natural climacteric symptoms. With its good safety profile in general and at estrogen-sensitive organs, iCR as a non-hormonal herbal therapy can also be used in patients with hormone-dependent diseases who suffer from iatrogenic climacteric symptoms.

Comparing Nalmefene and Naltrexone in Alcohol Dependence: Are there any Differences? Results from an Indirect Meta-Analysis.

BACKGROUND: The mu-opioid antagonist naltrexone is one of the few approved pharmacotherapies for the treatment of alcohol dependence. Recently, the mu-opioid antagonist and partial kappa agonist nalmefene was approved by the European Medicines Agency for the reduction of alcohol consumption in adult patients with alcohol dependence. To date, no head-to-head studies have compared the efficacy and safety of naltrexone and nalmefene in reducing alcohol consumption. METHODS: An indirect meta-analysis of randomized controlled studies on these 2 medications was conducted. A random effects model was used to measure effects and compare the 2 medications. 4 placebo-controlled studies with nalmefene and 13 with naltrexone were included. RESULTS: A statistically significant advantage of nalmefene towards naltrexone in the 2 patient-relevant outcome efficacy criteria, quantity and frequency of drinking, was found. Both drugs had a benign safety profile. CONCLUSIONS: This indirect meta-analysis indicates an advantage of nalmefene over naltrexone. Nalmefene is an effective and well-tolerated medication for the reduction of alcohol consumption. Additional data are necessary to demonstrate possible advantages of nalmefene over naltrexone in the treatment of alcohol dependence.

Ultra-thin resin embedding method for scanning electron microscopy of individual cells on high and low aspect ratio 3D nanostructures.

The preparation of biological cells for either scanning or transmission electron microscopy requires a complex process of fixation, dehydration and drying. Critical point drying is commonly used for samples investigated with a scanning electron beam, whereas resin-infiltration is typically used for transmission electron microscopy. Critical point drying may cause cracks at the cellular surface and a sponge-like morphology of nondistinguishable intracellular compartments. Resin-infiltrated biological samples result in a solid block of resin, which can be further processed by mechanical sectioning, however that does not allow a top view examination of small cell-cell and cell-surface contacts. Here, we propose a method for removing resin excess on biological samples before effective polymerization. In this way the cells result to be embedded in an ultra-thin layer of epoxy resin. This novel method highlights in contrast to standard methods the imaging of individual cells not only on nanostructured planar surfaces but also on topologically challenging substrates with high aspect ratio three-dimensional features by scanning electron microscopy.

Tolerability of a new fast updosed immunologically enhanced subcutaneous immunotherapy formulation with an optimized allergen to adjuvant ratio under routine practice conditions: a noninterventional observational study.

BACKGROUND AND OBJECTIVES: A fast updosed immunologically enhanced subcutaneous immunotherapy (SCIT) formulation with an optimized allergen to aluminium hydroxide ratio was first introduced in September 2009 in Germany. A large randomized controlled trial showed that the formulation had considerable immunologic effects and good tolerability. In this open-label, uncontrolled, noninterventional study, tolerability was investigated during routine application. PATIENTS AND METHODS: Patients with allergic rhinoconjunctivitis and/or asthma were treated with pollen and mite allergens using a 5-injection updosing schedule (AVANZ: 300, 600, 3000, 6000 and 15 000 SQ+ units) with weekly intervals, followed by a maintenance schedule with injections of 15,000 SQ+ units.Adverse events (AEs) were recorded by physicians, and symptoms and use of symptomatic medication were analyzed before the start of therapy and after an average 8-month treatment period. RESULTS: SCIT was documented by 362 allergists in 1036 patients between September 2009 and February 2011. AEs mainly consisted of local reactions during updosing (in 24.5% of patients). Systemic reactions were observed during updosing (8.4%) and maintenance therapy (1.7%), the most frequent of which was dyspnea. Overall, tolerability and the effect of treatment were rated as good or very good by 94.9% and 86.6% of patients and by 96.2% and 89.6% of physicians, respectively. CONCLUSIONS: In this open-label, noninterventional study, fast updosed immunologically enhanced SCIT (AVANZ) was well tolerated in a large group of patients.

Identifying patients with axial spondyloarthritis in primary care: how useful are items indicative of inflammatory back pain?

BACKGROUND: The value of clinical items defining inflammatory back pain to identify patients with axial spondyloarthritis (SpA) in primary care is unclear. OBJECTIVE: To identify predictive clinical parameters for a diagnosis of axial SpA in patients with chronic back pain presenting in primary care. METHODS: Consecutive patients aged < 45 years (n=950) with back pain for > 2 months who presented to orthopaedic surgeons (n=143) were randomised based on four key questions for referral to rheumatologists (n=36) for diagnosis. RESULTS: The rheumatologists saw 322 representative patients (mean age 36 years, 50% female, median duration of back pain 30 months). 113 patients (35%) were diagnosed as axial SpA (62% HLA B27+), 47 (15%) as ankylosing spondylitis (AS) and 66 (21%) as axial non-radiographic SpA (nrSpA). Age at onset ≤ 35 years, improvement by exercise, improvement with non-steroidal anti-inflammatory drugs, waking up in the second half of the night and alternating buttock pain were identified as most relevant for diagnosing axial SpA by multiple regression analysis. Differences between AS and nrSpA were detected. No single item was predictive, but ≥ 3 items proved useful for good sensitivity and specificity by receiver operating characteristic modelling. CONCLUSION: This study shows that a preselection in primary care of patients with back pain based on a combination of clinical items is useful to facilitate the diagnosis of axial SpA.

Factors associated with response in depressed elderly outpatients treated with escitalopram in a naturalistic setting in Germany.

BACKGROUND: An open, multi-centre study was designed to address the effectiveness and tolerability profile of treatment with escitalopram under naturalistic conditions, in elderly outpatients (above 65 years of age) with depression. PATIENTS AND METHODS: A total of 2 050 patients completed 8 weeks of treatment with escitalopram. Rating scales included a short version of the Montgomery-Asberg Depression Rating Scale (svMADRS), the Clinical Global Impression - Severity scale (CGI-S), and the Clinical Global Impression -Improvement scale (CGI-I) for the assessment of various clinical parameters. RESULTS: Most patients improved in their general state of health and showed a decrease in the severity of their depression. The majority (82.7%) of patients received initially 10 mg/day escitalopram. The mean svMADRS total score decreased from 31.9+/-7.9 at baseline to 14.2+/-8.5 at week 8. On completion, 63.9% of the patients were responders (> or =50% decrease of svMADRS total score from baseline) and 48.6% were remitters (svMADRS total score < or =12 at week 8). Statistically significantly more patients aged between 66 and 75 years responded to treatment and achieved remission than those aged >75 years. Logistic regression, using stepwise backward elimination, was used to model response to treatment. Statistically significant positive factors were having a current episode < or =1 month and duration of illness < or =1 year. Significant negative factors were being male, being older than 75 years, and having need of further psychotropic medication. Compared to patients diagnosed with unspecified dementia with other symptoms being predominantly depressive (F03, according to ICD-10), the response to escitalopram was significantly better for patients with depressive episodes (F32) or recurrent depressive episodes (F33), but significantly worse for patients with affective disorder (F31 or F34). The differences versus affective disorders were significant, while those for depressive episodes and recurrent depressive episodes vs. affective disorders were not significant. CONCLUSION: This observational study corroborates the effectiveness and tolerability of escitalopram treatment for elderly patients in a naturalistic treatment setting.

Identification of a region in the human IRS2 promoter essential for stress induced transcription depending on SP1, NFI binding and ERK activation in HepG2 cells.

Recent studies have discovered changes in the insulin-/IGF1 signaling affecting glucose metabolism and the molecular pathogenesis of human hepatocellular cancer. Insulin/IGF1 receptor mediates its intracellular effects by recruitment of one out of the four different insulin receptor substrates (IRS). To investigate mechanisms of IRS2 expression, we analyzed transcriptional regulation of IRS2 in human HepG2 cells. We identified a region 688 bp upstream of the translation start codon responsible for approximately 90% of basal human IRS2 promoter activity in HepG2 cells, and confirmed binding of specificity protein 1 (also called Sp1 transcription factor, SP1) and nuclear factor 1 (NFI) in this region. Mutation of both SP1 and NFI binding sites or inhibition of extracellular signal regulated kinase (ERK) suppressed IRS2 promoter activity almost completely, revealing a major role of MAP kinases (MAPK) for IRS2 transcription. Activating this cascade with oxidative stress increased IRS2 promoter activity and endogenous IRS2 expression substantially. IRS2 promoter activity rose even more after additional inhibition of p38MAPK indicating an inhibitory effect of p38MAPK on ERK mediated IRS2 transcription. Activation of the MAPK pathway using interleukin 1, beta (IL1B) increased IRS2 promoter activity similar to oxidative stress. In contrast IL1B decreases and inhibition of the MAPK pathway increases IRS1 promoter activity revealing opposed effects of IL1B and ERK on the expression of different IRS proteins. In conclusion we discovered a specific region (-688 to -611 bp) in the IRS2 promoter essential for basal promoter activity and oxidative stress induced transcription depending on ERK activation and SP1 and NFI binding in human hepatocytes.

[Prospective study using a modified Montgomery-Asberg Depression Scale]. / Einsatz einer modifizierten MADRS bei depressiven Patienten in einer prospektiven Kohortenstudie.

BACKGROUND: The Montgomery-Asberg Depression Scale (MADRS) is one of the most widely used scales in depression research today. Although relatively pragmatic in its present form, it still takes too long to complete when little time is available, e.g. in observational studies in outpatient settings. A shortened version of the MADRS (sv-MADRS) was therefore developed for use in such situations. The object of this study was to demonstrate indirectly that the sv-MADRS corresponds adequately with the standard MADRS. PATIENTS AND METHODS: In the context of an observational study, 11,790 depressive patients were treated with escitalopram. A total of 11,580 with documented sv-MADRS and severe disorder according to the Clinicians's Global Impression Scale (CGI) could be included in the analysis of baseline findings prior to treatment with escitalopram. A total of 10,910 completed the 8-week observational period. RESULTS: At baseline the sv-MADRS shows high internal consistency, which corresponds well with the German version of the MADRS. Overall the cross-sectional variables and those of change and evaluation show high correlations between CGI and sv-MADRS. CONCLUSION: Results of validity analyses of correlation with the CGI severity measure and with the factor structure of the original MADRS version are encouraging. Further evaluations are required to test comparability with the original version.

Quality of life is improved in breast cancer patients by Standardised Mistletoe Extract PS76A2 during chemotherapy and follow-up: a randomised, placebo-controlled, double-blind, multicentre clinical trial.

The objective of this randomised, multicentre, double-blind clinical trial was to investigate the impact of PS76A2, an aqueous mistletoe extract standardised to mistletoe lectins, on quality of life (QoL) in breast cancer patients. A total of 352 patients were randomly allocated to 2 groups receiving PS76A2 (15 ng mistletoe lectin/0.5 ml) or matching placebo twice weekly for 4 to 6 cycles of CMF (cyclophosphamide, methotrexate, fluorouracil) chemotherapy followed by 2 months follow-up. The primary efficacy end-point was the change from baseline of 3 FACT-G subscales (physical, emotional and functional well-being) during the fourth CMF cycle. Secondary measures included GLQ-8 (8 linear analogue self-assessment scales), Spitzer's uniscale and haematological variables. The main variables of safety analysis were adverse events, including injection site reactions and clinical laboratory tests. The results showed that physical, emotional and functional well-being improved upon PS76A2, but deteriorated following placebo. The treatment differences were statistically significant for the 3 subscales as well as for the summary score FACT-G, which was analysed as O'Brien's rank sum of its 3 subscales: The total score increased by 4.40 +/- 11.28, indicating a higher QoL after PS76A2, but decreased by 5.11 +/- 11.77 with placebo (p<0.0001). The GLQ-8 sum of 8 LASA scales was analysed as a summary score of GLQ-5 (sum of item nos. 1, 5, 6, 7, 8) and GLQ-3 (sum of item nos. 2, 3, 4). GLQ-5 characterises typical aspects of QoL, while GLQ-3 consists of 3 side-effects of CMF (feeling sick, numbness or pins and needles, loss of hair). GLQ-5 decreased by 42.9 +/- 125.0 upon PS76A2, indicating an improvement in QoL, but increased by 60.3 +/- 94.0 upon placebo (p<0.0001). GLQ-3 deteriorated in both groups (PS76A2: 13.9 +/- 52.4; placebo: 34.5 +/- 57.0), but the differences in favour of PS76A2 were, nevertheless, statistically significant (p=0.0007). The total score GLQ-8 improved by 28.9 +/- 154.6 after PS76A2 and deteriorated by 94.8 +/- 141.1 after placebo (p<0.0001). Spitzer's uniscale improved by 12.2 +/- 30.7 upon PS76A2 and deteriorated by 10.8 +/- 26.1 with placebo (p<0.0001). After follow-up without chemotherapy, a significant treatment difference in favour of PS76A2 was determined by means of FACT-G, GLQ-8 and Spitzer's uniscale. PS76A2 was well tolerated in this trial, with the exception of slight local reactions in 17.6% of the PS76A2 group. In conclusion, PS76A2 (15 ng mistletoe lectin/0.5 ml twice weekly) was shown to be safe and effective in improving QoL in breast cancer patients during chemotherapy and follow-up.

Efficacy and tolerance of an oral enzyme combination in painful osteoarthritis of the hip. A double-blind, randomised study comparing oral enzymes with non-steroidal anti-inflammatory drugs.

OBJECTIVE: The objective of this study was to establish the non-inferiority of an oral enzyme therapy (Phlogenzym-(PE)) as compared to the non-steroidal anti-inflammatory drug (NSAID) diclofenac (DC) in patients with osteoarthritis (OA) of the hip. METHODS: Ninety patients presenting with painful episodes of OA of the hip were treated for 6 weeks in one study centre in a phase III, randomised, double blind, parallel group trial. Altogether, 45 patients were treated in the PE group and 45 patients were treated in the DC group. Primary efficacy criteria were: WOMAC dimensions pain, joint stiffness and function, and Lequesne index as multiple endpoint according to O'Brien. The efficacy criteria were analysed applying the test of non-inferiority with regard to mean changes and frequencies, t-test, U test, ANCOVA and descriptive methods. RESULTS: Within the 6 weeks observation period, the adjusted changes from baseline to endpoint of the target parameters worked out as follows (adjusted differences, mean +/- SEM): WOMAC subscale pain (PE -10.3 +/- 1.2, DC -9.5 +/- 1.2), WOMAC subscale joint stiffness (PE -3.9 +/- 0.5, DC -3.6 +/- 0.5), WOMAC subscale physical function (PE -31.7 +/- 3.5, DC -29.7 +/- 3.5), Lequesne's index (PE -2.89 +/- 0.47, DC -2.27 +/- 0.47). Non-inferiority of PE as compared to DC with regard to the O'Brien's global sum of the standardised adjusted changes from baseline to endpoint in pain, stiffness, physical function, and Lequesne's index was established with p = 0.0025. PE was simultaneously non-inferior as compared to DC with regard to the 4 single endpoints: WOMAC subscale pain (p = 0.0033), WOMAC subscale joint stiffness (p = 0.0061), WOMAC subscale physical function (p = 0.0039), Lequesne's index (p = 0.0008) (closed test procedure). The equivalence tests remained insignificant due to comparatively lower effects of DC. For 71.1% of the PE patients and for 61.4% of the DC patients rates of good or very good global investigator assessments of efficacy were calculated (test of non-inferiority: p = 0.0011). In the majority of patients, tolerability was judged in both drug groups as very good or good. CONCLUSION: This trial showed significant non-inferiority from 6 weeks treatment with PE in patients with OA of the hip with regard to the WOMAC dimensions pain, stiffness and physical function, to Lequesne's index, to the investigator and patients assessments of efficacy, and to the responder rates based on pain, physical function, and patient assessment of efficacy. With regard to drug tolerability some tendencies in favour of PE were detected. However, in this study there was no real difference between PE and DC 100 mg/day, implying an equal benefit-risk relation between the substances. PE may well be recommended for the treatment of patients with osteoarthritis of the hip with signs of inflammation as indicated by a high pain level.

Initiation of hypertension treatment with a fixed-dose combination or its monocomponents -- does it really matter?

Despite efforts to diagnose and treat hypertension effectively, the goal of lowering blood pressure (BP) levels is rarely achieved, as treatment is often initiated with a single antihypertensive agent. The aim of this study was to assess the safety and efficacy of a first-line fixed-dose combination treatment compared with treatment with its monocomponents over a period of 4 weeks. Patients (n = 149) with essential hypertension were randomised to receive 2.5 mg of either ramipril or felodipine ER or the fixed-dose combination of ramipril 2.5 mg/felodipine ER 2.5 mg over a 4-week treatment period. BP and heart rate were measured by conventional methodology and 24-hour ambulatory blood pressure measurements. Treatment with the fixed-dose combination was significantly more effective in reducing systolic and diastolic BP (-15.8/-9.2 mmHg) compared with its monocomponents, ramipril (-7.6/-3.8 mmHg) and felodipine ER (-8.0/-5.0 mmHg). No significant difference could be observed in the occurrence of a greater fall in systolic and diastolic BP 6 h after the first dose of the three study medications. The adverse effects reported were mild, and less number of patients in the fixed-dose combination complained of adverse events. It can be concluded that initiating antihypertensive treatment with a low fixed-dose combination of ramipril/felodipine ER is more effective and safe when compared with treatment with its monocomponents.

Usefulness of specific immunotherapy in patients with atopic dermatitis and allergic sensitization to house dust mites: a multi-centre, randomized, dose-response study.

BACKGROUND: The effect of specific immunotherapy (SIT) on eczema in atopic dermatitis is not known. Therefore, a multi-centre, randomized dose-response trial, double-blind with respect to the efficacy of a biologically standardized depot house dust mite preparation was performed. METHODS: Eighty-nine adults with a chronic course of atopic dermatitis, SCORAD >or=40 and allergic sensitization to house dust mites [CAP-FEIA >or=3] were included, of whom 51 completed the study. Subcutaneous SIT with a house dust mite preparation (Dermatophagoides pteronyssinus/D. farinae) applying maintenance doses of 20, 2,000 and 20,000 SQ-U in weekly intervals for 1 year. The main outcome measures addressed the change of the SCORAD as average of the values after 9 and 12 months of SIT in comparison with the value at baseline. RESULTS: The SCORAD declined in the three dose groups in a dose-dependent manner (P = 0.0368, Jonckheere-Terpstra test) and was significantly lower in the two high-dose groups (2,000, 20,000 SQ-U) compared with the low-dose group of 20 SQ-U (P = 0.0379, U-test) after 1 year of SIT. The use of topical corticosteroids was significantly reduced with higher doses (P = 0.0007, Mantel-Haenszel chi-square test). CONCLUSIONS: Allergen-SIT for 1 year with a house dust mite preparation is able to improve the eczema in patients with atopic dermatitis who are sensitized to house dust mite allergens and reduces the need for topical corticosteroids. SIT may be valuable in the treatment of this chronic skin disease.

Efficacy and safety of 6.25 mg t.i.d. feverfew CO2-extract (MIG-99) in migraine prevention--a randomized, double-blind, multicentre, placebo-controlled study.

The efficacy and tolerability of a CO(2)-extract of feverfew (MIG-99, 6.25 mg t.i.d.) for migraine prevention were investigated in a randomized, double-blind, placebo-controlled, multicentre, parallel-group study. Patients (N = 170 intention-to-treat; MIG-99, N = 89; placebo, N = 81) suffering from migraine according to International Headache Society criteria were treated for 16 weeks after a 4-week baseline period. The primary endpoint was the average number of migraine attacks per 28 days during the treatment months 2 and 3 compared with baseline. Safety parameters included adverse events, laboratory parameters, vital signs and physical examination. The migraine frequency decreased from 4.76 by 1.9 attacks per month in the MIG-99 group and by 1.3 attacks in the placebo group (P = 0.0456). Logistic regression of responder rates showed an odds ratio of 3.4 in favour of MIG-99 (P = 0.0049). Adverse events possibly related to study medication were 9/107 (8.4%) with MIG-99 and 11/108 (10.2%) with placebo (P = 0.654). MIG-99 is effective and shows a favourable benefit-risk ratio.

The effects of short-term immunotherapy using molecular standardized grass and rye allergens compared with symptomatic drug treatment on rhinoconjunctivitis symptoms, skin sensitivity, and specific nasal reactivity.

BACKGROUND: The efficacy and safety of short-term immunotherapy with molecular standardized allergens (STI) has been demonstrated by double-blind placebo-controlled clinical trials. The aim of this study was to compare STI with symptomatic drug treatment. METHODS: Forty-eight patients with rhinoconjunctivitis to grass and/or rye pollen were treated either with STI (ALK(7), n = 24) plus anti-allergic drugs or anti-allergic drugs, alone (n = 24) in a prospective, randomized study. Symptoms and use of drugs were reported in patient diaries and titrated nasal provocation and skin prick tests were performed at baseline, before, and after season. RESULTS: Median overall symptom (P = 0.022, U test) and medication scores (P = 0.003) were significantly lower in the STI group, as was the result for a simultaneous analysis of conjunctival, nasal, and bronchial symptom scores and medication (P = 0.005). Sensitivity in the nasal provocation test decreased in the STI group but not in the drug-treated group. These differences became significant directly after STI (P = 0.027) as well as after the grass pollen season (P < 0.001). Skin sensitivity did not change in the STI group but increased in the drug-treated group after season, with a significant difference between the two groups for the erythema (P < 0.001). CONCLUSIONS: STI reduces grass pollen-induced rhinoconjunctivitis symptoms and drug use, and specific nasal reactivity and skin sensitivity, more efficiently than a standard symptomatic treatment.

Clinical effects of specific immunotherapy: a two-year double-blind, placebo-controlled study with a one year follow-up.

BACKGROUND: A new depot allergoid of house dust mite (Dermatophagoides pteronyssinus - D.pt) has been created in line with the principles and methodology established in the successful development of pollen allergoids. A two-year double-blind placebo-controlled clinical trial, with one further follow-up year of active treatment, has been conducted to assess clinical efficacy and tolerance. METHODS: 40 patients (20 verum and 20 placebo) with IgE-mediated mite allergy and a history of moderate to severe perennial symptoms of rhinoconjunctivitis with or without asthma participated in a 2-year randomized, double-blind, placebo-controlled trial. Actively treated patients were included in a follow-up year. Active treatment was performed with an aluminium hydroxide adsorbed house dust mite allergoid. Parameters for baseline data and clinical efficacy: nasal challenge, quantitative skin prick testing, Visual Analog Scale (VAS), patients' diaries, physician's assessment of patients? health condition, symptoms and use of anti-allergic medication as well as adverse reactions and changes in specific IgG4 and IgE antibodies. RESULTS: The trial detected superiority (p < 0.05) of mite depot allergoid versus placebo with regard to VAS and symptom intensity sum score in patients who needed anti-allergic medication in the baseline period. Significant differences (p < 0.05) between verum and placebo groups were also seen for patients' reactivities to nasal challenges and prick tests with allergen. The blinded assessment by the physician documented a significant difference (p < 0.05) between the groups in favour of active treatment. After reaching the maximum dose as well as after 12 and 24 months, specific IgG4 antibody concentrations were significantly elevated in the verum group (p < 0.05) by comparison with placebo. Local reactions were less frequent in the verum group and no systemic adverse reactions occurred. A third year of active treatment resulted in further improvement and documented the advantage of booster therapy to stabilize the clinical success. CONCLUSION: Specific immunotherapy with a mite depot allergoid induced significant clinical improvements versus placebo. Safety was assessed as excellent, and no systemic adverse reactions occurred.

A prospective, randomized, double-blind, placebo-controlled multi-centre study on the efficacy and safety of sublingual immunotherapy (SLIT) in children with seasonal allergic rhinoconjunctivitis to grass pollen.

BACKGROUND: Especially in childhood, sublingual immunotherapy (SLIT) could offer advantages over subcutaneous therapy. However, limited data on its efficacy is available. METHODS: In four German centres 97 children (age 3-14 years) with allergic rhinoconjunctivitis to grass pollen were enrolled in a prospective, double-blind trial comparing SLIT (Pangramin SLIT; ALK-SCHERAX, 0.5 microg major allergens, three times per week, 32 months) with placebo. Primary endpoint was a multiple symptom-medication score for changes in seasonal diary entries between the first and third year of the study (SLIT n=39; placebo n=38). RESULTS: The multiple symptom-medication score was significantly reduced by SLIT to 77.3% of the placebo group (P=0.0498). The subsequent analysis of the single endpoints did not reveal significant differences for symptom scores in favour of SLIT (85.1% of placebo group; P=0.22). However, the medication score improved significantly (67.1% of placebo group; P=0.0025). Furthermore, secondary endpoints assessing in vivo immune responses did not differ significantly between the groups. However, retrospective analysis showed some inhomogeneity for clinical and in vitro parameters at the beginning of the study. Allergic side effects with possible relation to the study drug were reported in both groups (SLIT 49%, placebo 27%, P=0.026). CONCLUSION: Our study indicates that SLIT had a positive effect on the reduction of a multiple symptom-medication score, mainly by significantly reducing rescue medication use, but had no significant effect on symptoms alone in children with rhinoconjunctivitis to grass pollen compared with a placebo.

Specific immunotherapy in honeybee venom allergy: a comparative study using aqueous and aluminium hydroxide adsorbed preparations.

BACKGROUND: For the immunotherapy of Hymenoptera venom allergy various preparations and treatment protocols are in use. However, controlled studies making direct comparisons of the efficacy and safety of different regimens are rare. OBJECTIVE: To assess prospectively different venom immunotherapy (VIT) protocols using an aqueous or an aluminium hydroxide adsorbed allergen preparation for the treatment of honeybee venom (HBV) allergy. METHODS: Sixty-five HBV allergic patients (42 males, 23 females; aged 17-75 years) with a history of systemic anaphylactic reactions (SARs) to honeybee stings were treated according to three different regimens. During the incremental phase, patients in group A (n = 21) or B (n = 21) received an aqueous preparation according to a rush protocol. Patients in group C (n = 23) were treated with conventional ("slow") VIT using an aluminium hydroxide adsorbed depot preparation. The maintenance dose was 100 microg venom in all groups. Maintenance treatment in group A was performed with the aqueous preparation administered every 4 weeks, whereas in groups B and C the depot preparation was administered every 8 weeks (group B) or every 4 weeks (group C). A sting challenge test with a living honeybee was performed in 49 patients, 6-12 months after reaching the maintenance dose. Another seven patients were stung accidentally by a honeybee ("field sting"). RESULTS: Treatment with the aqueous preparation evoked large local reactions more frequently than the depot preparation in the dose increase phase [53/693 (7.6%) vs 8/206 (3.9%); P = 0.059] and also in the course of maintenance therapy [85/172 (49.4%) vs 58/478 (12.1%); P < 0.001]. During the dose increase phase, systemic side-effects seemed to occur more frequently in patients on rush VIT with the aqueous preparation compared to patients initially treated with the conventional schedule using the depot preparation [13/42 (31.0%) vs 3/23 (13.0%); not significant). When re-stung by the culprit insect, SARs were observed in 3/20 patients (15.0%) in group A, 2/18 (11.1%) in group B and 3/18 (16.7%) in group C (not significant). CONCLUSIONS: The aluminium hydroxide adsorbed HBV preparation caused fewer large local reactions than the aqueous preparation. The therapeutic efficacy of the three treatment protocols did not differ.

Safety aspects of a coumarin-troxerutin combination regarding liver function in a double-blind placebo-controlled study.

OBJECTIVE: Coumarin is reported to elevate liver function tests (LFT) values. In a prospective, placebo-controlled, clinical trial, efficacy and safety of a coumarin-containing combination (SB-LOT) were evaluated in the treatment of chronic venous insufficiency. Here, we report on the drug safety of coumarin with special respect to liver reaction. METHODS: 114 patients were treated with SB-LOT (30 mg coumarin and 180 mg troxerutin t.i.d.) and 117 with placebo during a period of 16 weeks. LFT values (ALT, AST, AP and gamma-GT) were monitored at baseline, 4, 6, 8, 12 and 16 weeks of therapy. Adverse drug reactions were assessed regarding causality. Additionally, lymphocyte proliferation test was used to identify allergic reactions. Logistic regression analysis was performed to identify possible risk factors. RESULTS: No serious adverse drug reactions occurred. Elevations of LFT were assessed as biochemical abnormality. Specific clinical symptoms such as jaundice did not occur. Only 1 patient reported fatigue and exhaustion. Logistic regression estimated a basic risk for elevation of LFT of 4.9% under SB-LOT and 2.1% under placebo. Hepatitis in the history and diseases of the liver were identified as risk factors. CONCLUSION: This evaluation contributes to safety data of SB-LOT in man. LFT elevation is transient and the low risk of the SB-LOT therapy to increase LFT value can be limited when risk factors are considered.