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.

Isopropanolic black cohosh extract and recurrence-free survival after breast cancer.

OBJECTIVE: To investigate the influence of an isopropanolic Cimicifuga racemosa extract (iCR) on recurrence-free survival after breast cancer, including estrogen-dependent tumors. METHODS: This pharmacoepidemiologic observational retrospective cohort study examined breast cancer patients treated at general, gynecological and internal facilities linked to a medical database in Germany. The main endpoint was disease-free survival following a diagnosis of breast cancer. The impact of treatment with iCR following diagnosis was analyzed by Cox-proportional hazards models, controlling for age and other confounders. RESULTS: Of 18,861 patients, a total of 1,102 had received an iCR therapy. The mean overall observation time was 3.6 years. Results showed that iCR was not associated with an increase in the risk of recurrence but associated with prolonged disease-free survival. After 2 years following initial diagnosis, 14% of the control group had developed a recurrence, while the iCR group reached this proportion after 6.5 years. The primary Cox regression model controlling for age, tamoxifen use and other confounders demonstrated a protractive effect of iCR on the rate of recurrence (hazard ratio 0.83, 95% confidence interval 0.69 0.99). This effect remained consistent throughout all variations of the statistical model, including subgroup analyses. TNM status was unknown but did not bias the iCR treatment decision as investigated separately. Hence, it was assumed to be equally distributed between treatment groups. Correlation analyses showed good internal and external validity of the database. CONCLUSION: An increase in the risk of breast cancer recurrence for women having had iCR treatment, compared to women not treated with iCR is unlikely.

A randomized, double-blind, placebo-controlled, clinical dose-response trial of an extract of Baptisia, Echinacea and Thuja for the treatment of patients with common cold.

The aim of this study was to verify the efficacy and safety of an herbal medication containing an extract of a mixture of Baptisiae tinctoriae radix, Echinaceae pallidae/purpureae radix and Thujae, occidentalis herba (SB-TOX) in the treatment of upper respiratory tract infections (URIs), and to test whether SB-TOX's clinical efficacy is dose dependent. A total of 91 adults (mean age 42.1 +/- 13.0 years) were randomised to receive 19.2 mg of SB-TOX (n=31), 9.6 mg SB-TOX (n=29) or placebo (n=31) three times daily for 3-12 days. Since a "running nose" is the main symptom of a common cold, the total number of facial tissues used throughout the clinical duration of their cold was the primary efficacy parameter. In the intention-to-treat analysis, this total number of tissues decreased with increasing extract dose. The slope across groups according to the Jonckheere test was significant (p = 0.0259). In the high-dose group, the standardised effect size delta/SD was 0.46 compared with placebo. Time to relevant improvement in cold symptoms (measured as the time until less than 30 tissues per day were used) was 1.1 days (95% CI 0.52; 1.67), 0.76 days (95% CI 0.28; 1.24) and 0.52 days (95% CI 0.22; 0.82) in the placebo, low-dose and high-dose groups, respectively (p(LogRank) = 0.0175). No adverse events were reported. This study demonstrates the efficacy and safety of SB-TOX in the treatment of URIs, and that its efficacy is dose dependent.

Effect of oral administration of freshly pressed juice of Echinacea purpurea on the number of various subpopulations of B- and T-lymphocytes in healthy volunteers: results of a double-blind, placebo-controlled cross-over study.

BACKGROUND: In a recent double-blind placebo-controlled crossover-study the "immune stimulatory" effects (activation of macrophages leading to enhanced phagocytosis and production of several cytokines) of Echinacea purpurea preparations (EPP) which were observed in vitro experiments and following parenteral administration could not be confirmed following oral application of the drug in healthy volunteers. The aim of the present study was to investigate whether or not oral EPP has any effect on important lymphocyte-subpopulations. SUBJECTS AND METHODS: Forty healthy male volunteers (age range 20-40 years) participated in the study. They received either a commercially available pressed juice of E. purpurea herbs or placebo juice using a double-blind placebo-controlled cross-over design with two treatment periods of 14 days. The total number of lymphocytes and 12 subgroups of lymphocytes were determined by using Flow-cytometry. RESULTS: After 1 week of treatment with verum the mean value of the total number of lymphocytes decreased slightly (-6%, p = 0.033) compared to the initial value. Treatment for 1 and 2 weeks with EPP had only minor effects on two of the 12 subtypes of lymphocytes. No significant changes were observed in the verum period for the following types of cells: T- and B-lymphocytes, CD4 + - and CD8 + -T-lymphocytes including the subgroups of "naive" and "memory" CD4 + - and CD8 + -T-lymphocytes as well as the natural killer cells. Using a modified version of the Wilcoxon-Mann-Whitney-U-test, which is claimed to be optimal for the evaluation of the results of studies with a cross-over design, a significant difference was found for the number of CD8 + -T-lymphocytes and natural killer cells corresponding to either a decrease during treatment with verum or an increase in the number of these cells in the placebo period. CONCLUSION: Oral administration of EPP for 1 and 2 weeks has only minor effects on two out of 12 lymphocyte subpopulations determined in the study. The small differences observed in the number of CD8 + -T lymphocytes and natural killer cells are only of questionable physiological relevance.

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.

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.

Single copy of variant CYP2A6 alleles does not confer susceptibility to liver dysfunction in patients treated with coumarin.

OBJECTIVE: Coumarin, used in the treatment of chronic venous diseases, is mainly metabolized to non-toxic 7-hydroxy-coumarin by CYP2A6. At least, 3 variant alleles, CYP2A6*2, CYP2A6*3 and CYP2A6*4A, have been shown to encode catalytically defective proteins. Sporadic elevation of liver enzymes has been reported on the chronic administration ofcoumarin. We sought to determine if susceptibility to coumarin-associated liver dysfunction is genetically determined by polymorphism in CYP2A6 and impairment of the 7-hydroxylation ofcoumarin. Additionally, we were interested in the effect of polymorphism on smoking because of the predominant role of CYP2A6 in the metabolism of nicotine. METHODS: The investigation was performed prospectively within a randomized double-blind clinical trial of the coumarin-containing drug SB-LOT (90 mg coumarin + 540 mg troxerutin/d) vs. placebo in 231 German patients with chronic venous insufficiency. Monitoring of the hepatic status involved regular measurements of liver function during the 16-week treatment. Genotyping of CYP2A6 was carried out by means of PCR and confirmed by DNA sequencing analysis. RESULTS: The allelic frequencies of the variant CYP2A6*2 and CYP2A6*3 alleles were 0.023 and 0.014, respectively. There was no significant difference in the incidence of liver dysfunction between heterozygotes with CYP2A6*2, CYP2A6*3 and wild-type homozygotes. CYP2A6 polymorphism had no significant effect on smoking behavior. CONCLUSION: No evidence was obtained that the studied polymorphism in CYP2A6 is a determinant of the coumarin-associated liver dysfunction.

The efficacy and safety of a coumarin-/troxerutin-combination (SB-LOT) in patients with chronic venous insufficiency: a double blind placebo-controlled randomised study.

BACKGROUND: The objective was to evaluate the oedema-protective effect of a vasoactive drug (coumarin/troxerutin [SB-LOT]) plus compression stockings in patients suffering from chronic venous insufficiency after decongestion of the legs as recommended by the new guidelines. PATIENTS AND METHODS: 231 patients were randomly assigned medical compression stockings plus SB-LOT (90 mg coumarin and 540 mg troxerutin per day) or medical compression stockings plus placebo for the first 4 weeks and SB-LOT or placebo for the second 12 weeks of the study. The primary efficacy endpoint was the lower leg volume measured by well-established water plethysmometry. RESULTS: 226 patients were evaluated. After ceasing compression stockings, an edema protective effect was detected in the SB-LOT-group but not in the controls. Recurrence of leg volume increase was by 6.5 +/- 12.1 ml and by 36.7 +/- 12.1 ml in the SB-LOT and placebo group, respectively (p = 0.0402). The local complaint score and general aspects of quality of life were also superior for the SB-LOT-group (p = 0.0041). Significant differences were also observed with regard to clinical global impression and therapeutic effect. No serious adverse drug reaction or clinically relevant impairment of laboratory parameters occur. CONCLUSION: This study confirms the oedema-protective effect of SB-LOT in chronic venous insufficiency and provides a treatment option for patients who discontinue compression after a short time.

The efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis--a double-blind, multicentre, randomized placebo-controlled dose-response study.

Tanacetum parthenium (feverfew), is a well-known herb for the prophylactic treatment of migraine. The primary objective was to show a dose-response of a new stable extract (MIG-99) reproducibly manufactured with supercritical CO2 from feverfew (T. parthenium). Furthermore, the study should provide data on the safety and tolerability of MIG-99. In a randomized, double-blind, multicentre, controlled trial with an adaptive design, the clinical efficacy and safety of three dosages of MIG-99 (2.08 mg; 6.25 mg; 18.75 mg t.i.d.) were compared with placebo. The patients (n = 147) suffered from migraine with and without aura according to International Headache Society (IHS) criteria and were treated with one of the study medications for 12 weeks after a 4-week baseline period. The primary efficacy parameter was the number of migraine attacks during the last 28 days of the treatment period compared with baseline. Secondary endpoints were total and average duration and intensity of migraine attacks, mean duration of the single attack, number of days with accompanying migraine symptoms, number of days with inability to work due to migraine as well as type and amount of additionally taken medications for the treatment of migraine attacks. The design of the study included a pre-planned adaptive interim analysis for patients with at least four migraine attacks within the baseline period. With respect to the primary and secondary efficacy parameter, a statistically significant difference was not found between the overall and the confirmatory intention-to-treat (ITT) sample in the exploratorily analysed four treatment groups. The frequency of migraine attacks for the predefined confirmatory subgroup of patients (n = 49) with at least four migraine attacks during the baseline period decreased in a dose-dependent manner (P = 0.001). The highest absolute change of migraine attacks was observed under treatment with 6.25 mg t.i.d. (mean +/- SD = -1.8 +/- 1.5 per 28 days) compared with placebo (-0.3 +/- 1.9; P = 0.02). Overall, 52 of 147 (35%) patients reported at least one adverse event (AE). The incidence of AEs in the active treatment groups was similar to that in the placebo group, and no dose-related effect was observed in any safety parameter. MIG-99 failed to show a significant migraine prophylactic effect in general. Accordingly, in the ITT analysis a dose-response relationship could not be observed. MIG-99 was shown to be effective only in a small predefined subgroup of patients with at least four attacks during the 28-day baseline period where the most favourable benefit-risk ratio was observed with a dosage of three capsules of 6.25 mg MIG-99 extract per day. Because of the low number of patients, these findings need to be verified in a larger sample. The incidence of AEs was similar for all treatment groups.

Physiological investigation of a unique extract of black cohosh (Cimicifugae racemosae rhizoma): a 6-month clinical study demonstrates no systemic estrogenic effect.

OBJECTIVE: This study sought to confirm the efficacy and safety of the currently recognized dose of Cimicifugae racemosae rhizoma (40 mg/day) and to evaluate a higher dose and its associated physiological effects. METHODS: We conducted a controlled, randomized, double-blinded parallel group study of perimenopausal and postmenopausal women treated with two different doses (39 mg and 127.3 mg) of a unique C. racemosa preparation over a 24-week period. Efficacy and tolerability were determined by the Kupperman Menopause Index, Self-Rating Depression Scale (SDS), a global assessment of tolerability, adverse events, routine hematology, and biochemical tests. To determine if the unique C. racemosa preparation exerts its effect through an estrogen-identical mode of action, we investigated vaginal cytology and gynecologically relevant hormones. RESULTS: Both perimenopausal and postmenopausal patients tolerated the treatment well, and menopausal symptoms decreased regardless of dose (responder rate 70% and 72%, respectively). The lack of change in vaginal cytology measures indicates a nonestrogenic effect of the tested extract in this critical organ. Likewise, the lack of significant changes in the levels of gynecologically relevant hormones does not indicate an overall estrogenic effect. CONCLUSIONS: The higher dose did not exert a significantly greater effect on any end point. Thus, the currently recognized standard dose of the isopropanolic aqueous C. racemosa extract should be preferred over the higher dose. Despite the absence of a placebo group, this study suggests that C. racemosa extract is associated with improvement in menopause symptoms without evidence of estrogenlike effects.

[Immunomodulation by herbal agents. A double-blind study in a medical university hospital involving a hepatitis B vaccine adjuvant model]. / Immunmodulation durch pflanzliche Wirkstoffe. Doppelblindstudie an einer medizinischen Universitätsklinik am Adjuvansmodell zur Hepatitis-B-Impfung.

AIMS: Using the hepatitis B vaccination as a model, to investigate the extent to which the herbal immunomodulator, Esberitox N, supports seroconversion. METHOD: 346 medical students participated in the placebo-controlled, randomized double-blind study. They took 3 x 2 tablets of the test substances daily, beginning 3 days prior to the injection and ending two weeks after it. The target outcomes were seroconversion and the level of the anti-HBs titer. RESULTS: The data of 157 volunteers treated with the test substance, and 161 treated with placebo were analysed. After the first injection, the seroconversion rate was 22% in both test substance and placebo groups, and showed no advantage for the volunteers receiving the test substance. After the second injection, 89% of all members of each group revealed seroconversion. After the first injection, anti-HBs titers were appreciably higher in the test substance group (n = 34) than in the placebo group (n = 36; PWilcoxon = 0.003). The respective median values were 37.0 IU/L (95% CI: 18-68) and 15.5 IU/L (95% CI: 8-30). CONCLUSION: The immunomodulator tested has negligible influence on seroconversion, but does enhance the immune response of subjects experiencing seroconversion.

Differential therapy of mild to moderate depressive episodes (ICD-10 F 32.0; F 32.1) with St. John's wort.

The purpose of this report was to evaluate specific depressive symptoms that are most suitable for a therapy with the Ze 117 St. John's wort extract. We examined the antidepressant efficacy and drug safety of Ze 117 and fluoxetine in a multicentric prospective randomized double-blind parallel group comparison according to generally accepted guidelines such as the Declaration of Helsinki and GCP. We treated outpatients (n = 240; Ze 117: 126; fluoxetine: 114) with mild to moderate depressive episodes (ICD-10: F 32.0, F 32.1; HAMD range: 16-24) with either two tablets St John's wort (Ze 117; 500 mg extract/day) or fluoxetine (20 mg/day) for 6 weeks. Antidepressant efficacy was evaluated with the validated HAMD psychometric method. A validated analysis of HAMD subscores was made to verify the efficacy for certain depressive symptoms. The main results were: * The HAMD responder rate was 60% in the Ze 117 group compared to 40% in the fluoxetine group (p = 0.005). * Particularly, there was a marked decrease of depressive agitation (pre-post comparison: 46%) and anxiety symptoms (44%) during the therapy with St. John's wort. Depressive obstruction (44%) and sleep disorders (43%) were reduced during the treatment, too. There were no statistically significant differences between the treatment groups. * Adverse events occurred in 28 patients (25%) in the fluoxetine group and in 18 (14%) of the St. John's wort group (p < 0.07). St. John's wort extract is a clinically effective equivalent to fluoxetine regarding overall depressive symptoms and main symptoms of depressive episodes. An especially interesting overall observation is that Ze 117 is particularly effective in depressive patients suffering from anxiety symptoms. St. John's wort revealed better safety and tolerability data than fluoxetine.

Prophylaxis of radiogenic sialadenitis and mucositis by coumarin/troxerutine in patients with head and neck cancer--a prospective,randomized, placebo-controlled, double-blind study.

OBJECTIVE: To study the efficacy of coumarin/troxerutine for the protection of salivary glands and mucosa during irradiation. DESIGN: Prospective, randomized, placebo-controlled, double-blind trial. SETTING: University hospital, Germany. PATIENTS: 48 patients who had radiotherapy to the head and neck. MAIN OUTCOME MEASURES: Salivary gland scintigraphy and acute side-effects of radiotherapy (Radiation Therapy Oncology Group (RTOG) score). RESULTS: 23 patients (11 experimental, 12 placebo) completed the study. The global efficacy measure combining scintigraphy and RTOG score favoured the experimental arm (P=0.07). The RTOG score showed significantly fewer acute side-effects of radiation in the experimental arm (P<0.05). CONCLUSION: The results suggest that coumarin/troxerutine have a favourable effect in the treatment of radiogenic sialadenitis and mucositis.

Efficacy and mode of action of an immunomodulator herbal preparation containing Echinacea, wild indigo, and white cedar.

Using the example of an allopathic herbal combined preparation containing Echinacea root, wild indigo root, and white cedar leaf tips (Echinaceae radix + Baptisiae tinctoriae radix + Thujae occidentalis herba = Esberitox N), the efficacy and mode of action of a phytoimmunomodulator, or immune system enhancer, is described. Efficacy of the immunomodulator has been demonstrated in studies of acute viral respiratory tract infections and infections requiring antibiotic therapy. In a recent study compliant to GCP, the therapeutic superiority of the herbal immunomodulator over placebo was confirmed as statistically significant and clinically relevant. The present overview describes a model of the antigen-independent mode of action of phytoimmunomodulation ("immunobalancing").

[Prospective double-blind study of prophylaxis of radioxerostomia with Coumarin/Troxerutine in patients with head and neck cancer]. / Prospektive, doppelblinde Therapiestudie zur Prophylaxe der Radioxerostomie durch Cumarin/Troxerutin bei Patienten mit Kopf-Hals-Karzinomen.

AIM: Prospective, randomized placebo-controlled double-blind study to prove the efficacy of Coumarin/Troxerutine (Venalot Depot) for protection of salivary glands during a head and neck irradiation. PATIENTS AND METHOD: Forty-eight radiotherapy patients (60 Gy) with head and neck cancer were included in this trial. During radiotherapy the salivary glands were located in the core irradiation field. Primary efficacy parameters were sialometry, quantitative salivary gland scintigraphy and clinical evaluation of early effects of radiotherapy (RTOG-score, Table 1). All data were collected at 6 assessments: 1 week pre-radiation (U1), at start (U2), half time (U3) and end (U4) of irradiation, 8 days (U5) and 28 days (U6) after the end of irradiation (Figure 1). RESULTS: Twenty-three patients (11 verum, 12 placebo) completed the study with all assessments. Sialometrically, all patients were severely (half of radiotherapy) or completely (end of radiotherapy) xerostomatic (Figure 2). In a global efficacy measure according to O'Brien combining scintigraphy and RTOG there was a tendency for a higher efficacy of verum compared to placebo (p = 0.068). After start of irradiation therapy, the RTOG-score showed continuously and significantly lower early radiation effects under verum than under placebo (U3 vs U6: p < 0.05, area under curve: p = 0.032; Table 2, Figure 3). The scintigraphically determined excretion fraction was slightly less impaired in the verum group compared to the placebo treatment (p = 0.12. Figure 4). There was no difference in drug safety between placebo and verum for adverse events, changes in the activity of liver enzymes and for global impression of tolerability. CONCLUSIONS: The results give support for an advantageous effect of Venalot Depot in the treatment of radiogenic sialadenitis and mucositis. In even a small number of evaluable patients, early clinical effects of irradiation (RTOG-score) were less pronounced in the active treatment group than in the placebo group, but the sample size was too low to prove statistically also the benefit of coumarin/troxerutine with the scintigraphic method. Sialometry seems not suitable for the assessment of early radiation effects.

Long-term maintenance therapy with cyclosporine and posttreatment survey in severe psoriasis: results of a multicenter study. German Multicenter Study.

BACKGROUND: Although cyclosporine has been found to be effective therapy for severe psoriasis, only limited data exist about efficacy and safety during long-term treatment with a low-dose regimen. Furthermore, little is known about the course of psoriasis after drug withdrawal. OBJECTIVE: Our purpose was to assess the results of long-term therapy with cyclosporine for severe psoriasis with particular regard to efficacy and safety, as well as the disease course after stopping treatment. METHODS: A multicenter study of 217 patients treated with 1.25, 2.5, or 5.0 mg/kg per day of cyclosporine was performed. Duration of treatment ranged from 6 to 30 months followed by a posttreatment period of 3 months. Efficacy was assessed by the Psoriasis Area and Severity Index and safety was monitored by clinical and laboratory investigations. RESULTS: Patients with severe psoriasis showing a reduction in the Psoriasis Area and Severity Index of 75% with their individual dose of cyclosporine maintained clinical improvement during continuous maintenance therapy. Newly occurring side effects were less frequent during the maintenance phase than in the induction phase. After withdrawal of cyclosporine, worsening of psoriasis requiring antipsoriatic therapy was seen in about half of the patients. CONCLUSION: Cyclosporine is effective for long-term therapy for severe psoriasis and does not lead to severe deterioration of the disease after drug withdrawal.

Highly purified omega-3-polyunsaturated fatty acids for topical treatment of psoriasis. Results of a double-blind, placebo-controlled multicentre study.

We report the results of a multicentre, double-blind, placebo-controlled study of topical therapy with omega-3-polyunsaturated fatty acids (omega-3-PUFA) in 52 patients suffering from moderate plaque-type psoriasis. In each patient, two similar stable psoriatic plaques served as indicator lesions for the study. One indicator lesion was randomly assigned to treatment with topical preparations of highly purified omega-3-PUFA in one of two concentrations (1 or 10%), and the other was treated with placebo. Efficacy assessment was based on changes in local psoriasis severity index, area involved, erythema, desquamation, induration and pruritus. After 8 weeks of treatment, all indicator lesions had improved significantly, compared with baseline. However, no statistically or clinically relevant differences between the omega-3-PUFA-treated and the placebo-treated lesions were found. Therapy was well tolerated and, apart from one patient who developed perilesional eczema, no clinically relevant adverse events occurred. In conclusion, topical omega-3-PUFA were not effective in a randomized, placebo-controlled, double-blind setting. Results of non-blind trials should be (re-)considered with caution.

Metabolism of arachidonic acid by human epidermal cells depends upon maturational stage.

Synthesis of 12- and/or 15-HETE by human epidermal cells was investigated after separating basal cells from suprabasal epidermal cell layers. We found that the main metabolite of 3H-arachidonic acid (3H-AA), formed by freshly prepared upper epidermal layers (stratum granulosum and spinosum), upon RP-HPLC co-eluted with authentic 3H-12-HETE. A 3H-15-HETE co-eluting peak selectively occurred in chromatograms obtained from supernatants of fractions containing basal cells. Supernatants of freshly prepared suspensions rich in basal keratinocytes appeared to contain 3H-15-HETE as their main 3H-AA metabolite, by far exceeding the recovered amounts of 3H-12-HETE. Moreover, keratinocytes cultured for 1 week or longer were found to produce predominantly a 3H-AA metabolite co-eluting with 3H-15-HETE. In supernatants of cultured cells, little if any 3H-12-HETE was detectable. Cultured human skin fibroblasts were not found to produce relevant amounts of HETE. Genuine tissue rich in basal cells, i.e., cells of hair follicles, were found to form twice as much 3H-15-HETE as 3H-12-HETE (3H-15-HETE/3H-12-HETE-ratio = 1.9 +/- 0.8; n = 7). Apparently, different epidermal layers are able to produce a characteristic pattern of 3H-AA metabolites. 3H-15-HETE generation seems to be a marker for proliferating keratinocytes, whereas 3H-12-HETE formation appears to be typical for differentiating suprabasal epidermal cells. Our results may explain the heretofore varying patterns of AA-metabolites by keratinocytes reported in the literature.