Life Extension Magazine®

Issue: Sep 2009

Colon Cancer

Prevalence and risk factors of chronic venous insufficiency.

Venous disease in the legs occurs very commonly in the general population in Western countries. Around one third of women have trunk varices. A lower prevalence has been observed in men but some recent surveys have suggested that the occurrence in men may be comparable to that in women. The prevalence increases with age but the incidence of new cases appears to be constant throughout adult life. Open venous ulcers occur in about 0.3% of the adult population and a history of open or healed ulceration occurs in around 1%. The etiology of chronic venous disease in the legs is unknown. A genetic predisposition may be present but evidence for this and for a mode of inheritance is lacking. There is some suggestion that prolonged standing may be a risk factor but studies are open to considerable bias. In women, obesity and previous pregnancy has been associated with the presence of varicose veins but the evidence is inconsistent. There have been few well-conducted studies examining diet and bowel habit as a risk factor. The risk of ulceration is related to the severity of varicosities and venous insufficiency, and is increased following deep vein thrombosis. Much further research is required to investigate the cause of this common condition in the general population.

Angiology. 2001 Aug;52 Suppl 1:S5-15

Efficacy of a 6-month treatment with Daflon 500 mg in patients with venous leg ulcers associated with chronic venous insufficiency.

AIM: Epidemiological data show that standard compression therapy for leg ulceration in chronic venous insufficiency (CVI) often fails to effectively improve patients’ condition. This study assesses the contribution of Daflon 500 mg added to conventional therapy in the healing of hypostatic ulcers of CVI patients. METHODS: Patients of about 65 years were included, with ulcers > or = 2 and > or = 10 cm diameter on 1 or 2 limbs, Doppler ankle/arm pressure index > 0.9, and no recent history of skin graft. Controls (n=68) remained on compression alone while the tested group (n=82) also received Daflon 500 mg 2 tablets/day during 6 months. Treatment could be stopped as soon as the reference ulcer appeared fully healed. Primary endpoints were the rate of healed ulcers and the time to complete healing assessed by planimetry/photography and clinical examination. Variations of the ulcer surface, appearance of the skin, and clinical symptoms of CVI were the secondary criteria. RESULTS: Only 7% of Daflon 500 mg patients necessitated the full 6 month therapy. Whatever the lesion size, from W8 significantly more healed ulcers were observed under Daflon 500 mg (p=0.004), and the ulcer surface was more reduced (p=0.012). For large ulcers, the rate of healing was approximately 2-fold higher with Daflon 500 mg, and the percentage of ulcers healed before W24 was significantly higher (p=0.008). Heavy leg sensation was significantly improved by Daflon 500 mg from W4 (p < 0.05). No treatment-related side effects were reported and the acceptability was considered excellent by 85% of Daflon 500 mg patients. CONCLUSION: Six months of Daflon 500 mg in addition to compression significantly improve some clinical symptoms and accelerate the healing process in patients with ulcerous complications of CVI, with a good acceptability.

Int Angiol. 2003 Mar;22(1):24-31

Surgical correction of varicose vein disease under micronized diosmin protection (results of the Russian multicenter controlled trial DEFANS).

The paper presents the results of DEFANS trial (Detralex - assessment of efficacy and safety for combined phlebectomy). The study enrolled 245 patients with varicose vein disease, who underwent unilateral combined phlebectomy. The main group (n=200) received micronized diosmin (Detralex, 1,000 mg/day) for 2 weeks before and 30 days after the procedure; control group (n=45) did not receive Detralex in pre- and postoperative period. Pain severity by 10-point visual analog scale (VAS), an area of subcutaneous hemorrhage in the zone of femoral great saphenous vein resection (by original 12-point scale) and subjective feelings of limb heaviness and fatigability were evaluated 7, 14, and 30 days after the procedure. Subjective symptoms and the area of subcutaneous hemorrhage were significantly lower in the main group, then in control: 7 days after the procedure VAS score was 2.9 and 3.5, respectively; hemorrhage area - 3.4 and 4.6 points, respectively. The same trend was observed for limb heaviness and fatigability, evidencing the better exercise and orthostatic tolerance among patients of the main group in early postoperative period. Quality of life assessment by CIVIQ failed to reveal statistically significant difference between main and control groups in 4-weeks postoperative follow-up. Micronized diosmin in pre- and postoperative period after plebectomy helps to attenuate pain syndrome, to decrease postoperative haematomas and accelerate their resorption, to increase exercise tolerance in early postoperative period.

Angiol Sosud Khir. 2007;13(2):47-55

Evaluation of clinical efficacy of a venotonic drug: lessons of a therapeutic trial with hemisynthesis diosmin in “heavy legs syndrome.”

Venous-type symptoms, i.e. painful sensation of heavy, swollen or restless legs, influenced by orthostatism and warm environment, significantly alters quality of life of a large proportion of women. Although the condition is frequently associated with chronic venous insufficiency, no demonstrable hemodynamic abnormality of the superficial as well as deep venous systems of the lower limbs can be found in many patients. The pathogenesis of this syndrome remains unknown, and there is no objective measurement of any biological nor hemodynamic parameters that can be used for its assessment. Diosmine and other flavane derivatives have been shown beneficial in this condition using various discomfort indexes. The aim of this work was to compare the therapeutic efficacy of two formulations of the same compound diosmine. In the analysis, particular attention was paid to the signification and usefulness of discomfort scales. This study was a double-blind, placebo-controlled therapeutic trial, comparing the efficacy of a new formulation, hemisynthesis diosmine 600 mg, one tablet per day taken in the morning, versus the usual tablet formulation of 300 mg taken twice a day (morning and evening). Treatment blindness was assured by the double placebo method. Two parallel groups were treated 28 days with one or the other treatment. Randomization was performed with stratification by center. The main evaluation criteria were a composite scale of venous type symptoms (i.e. the sum of individual score 0-4 of each symptom), and a visual analog auto-evaluation scale quoted each week by the patient. The global opinion of the physician on treatment adequacy to the clinical situation, and the degree of patient satisfaction (four grade scales) were used as subsidiary criteria. In order to increase the homogeneity of the study sample, inclusion was restricted to non-menopaused women aged 18 years and over, having given written informed consent, complaining of distressing sensation of heavy legs, without history of venous thrombosis, varicose veins, superficial or deep venous reflux at the duplex-scan examination. Patients with other causes of pain in the lower limbs, taking analgesic medications or requiring elastic stocking were not included. 255 patients participated in the trial. Eighteen withdrew, equally distributed in both groups (6 lost, 5 interfering diseases, and two dropouts for side effects, namely headache and gastric pain). Twenty additional patients complained of detrimental events not requiring treatment withdrawal, equally distributed between both groups, and mainly involving digestive functions. The results confirmed a similar efficacy of the two drug regimens, and a small but significantly better improvement of the patients’ auto-evaluation of their discomfort on the analogic scale (p = 0.021) for hemisynthesis diosmine 600 mg, mainly during the first two weeks; for all four criteria, the gamma risk showed that the once-a-day 600 mg preparation at least as effective as 300 mg twice daily (p < 0.001). On a methodological point of view, the comparison of evaluation criteria showed that the composite scale, although giving the feeling of a comprehensive and quantitative appraisal of the discomfort in the legs, was almost equivalent to a standard four grade rating of heaviness, which appeared as the central symptom of this condition. Auto-evaluation through an analogic scale proved to be more informative, more sensitive, less influenced by the physician’s feelings and allow easier assessment of the time-course of the drug’s effects. Global evaluations by the patient and the physician did not give additional information but could be used as quality criteria, assessing the coherence of the results obtained with the scales. This study demonstrated a similar efficacy of the two drug regimens, with a more rapid effectiveness of the 600 mg preparation taken once a day.

J Mal Vasc. 1998 Apr;23(2):106-12

Activity of purified diosmin in the treatment of hemorrhoids.

Several theories on the etio-pathogenesis and physio-pathology of hemorrhoids have been up to now proposed. From the fisio-pathological viewpoint, particular importance is retained by the vascular factor, which in its turn is influenced by mechanical and sphinceric factors, that impair the venous back-flow. In the evidence of an hemorrhoidal crisis, characterized by local oedema, pain and bleeding, the use of bioflavonoid drugs is deemed to be the first choice. We investigated the use of purified diosmin, given at a dose of two 450 mg tablets bid for the first 7 days, then at 1 tablet bid for up to 2 months, in a group of 66 patients suffering from primitive hemorrhoids of grade 1-4. Our results confirmed diosmin efficacy in decreasing both pain and bleeding: reduction rates of 79% and 67%, respectively, were reached in the first treatment week. In the second week, figures were 98% and 86%, respectively. Diosmin tolerability was excellent: this characteristic makes the drug very easy to handle by the general practitioner and also useful to the proctologist in the preparation of patient to further treatments.

Clin Ter. 2000 Sep-Oct;151(5):341-4

Diosmin therapy alters the in vitro metabolism of noradrenaline by the varicose human saphenous vein.

We have previously shown that diosmin 30-100 mumol/l reduces the metabolism of noradrenaline (NA) in fragments of varicose saphenous veins obtained at surgery. Since diosmin is widely used in patients with chronic venous insufficiency we decided to test if the drug, administered in therapeutic doses to patients, would affect NA metabolism in the veins of the individuals so treated. Sex- and age-matched patients in which surgery was indicated were allocated in the order of admission to control (n = 5) or treated groups (n = 6; 600 mg twice a day, orally, during 10 days). Fragments of saphenous vein were incubated with [3H]NA 0.2 mumol/l during 60 min; the interval between operation and incubation was less than 30 min. Column chromatography and liquid scintillation counting were used to measure [3H]NA and its metabolites. In the treated group, accumulation of [3H]NA was significantly reduced and the formation of metabolites approximately halved. The present results show that oral administration of diosmin has evident effects on the in vitro metabolism of noradrenaline by the varicose tissue.

Pharmacol Res. 1991 Oct;24(3):253-6

Diosmin pretreatment affects bioavailability of metronidazole.

OBJECTIVE. To screen for inhibitory effects of diosmin on cytochrome P(450)-mediated metabolism of metronidazole in healthy volunteers. DESIGN. Before/after non-blinded investigation conducted in healthy male volunteers. METHODS. After an overnight fast, metronidazole (two 400 mg tablets) was administered to 12 volunteers, either alone or after a 9-day pretreatment period with a once-daily dose of diosmin 500 mg tablets under direct observation. Serum concentrations of metronidazole up to 48 h postdose and urinary concentrations of metronidazole and its two major metabolites up to 24 h postdose were measured using reversed-phase high-performance liquid chromatography. RESULTS. Metronicazole plasma AUC((0- infinity )) and C(max) were significantly higher after diosmin pretreatment by (mean) 27% and 24%, respectively. However, time to reach peak concentration (t(max)) was not affected significantly. Urinary excretion of acid and hydroxy metabolites in urine was decreased significantly, while excretion of unchanged metronidazole was increased. CONCLUSION. Diosmin pretreatment significantly altered the metabolism of metronidazole, as demonstrated by changes in plasma pharmacokinetics as well as by urinary recovery of both parent drug and its major metabolites. This may be caused by the inhibition of cytochrome P(450) enzymes.

Eur J Clin Pharmacol. 2003 Apr;58(12):803-7

Micronised purified flavonoid fraction: a review of its use in chronic venous insufficiency, venous ulcers and hemorrhoids.

Micronised purified flavonoid fraction (MPFF) [Daflon 500 mg], an oral phlebotropic drug consisting of 90% micronised diosmin and 10% flavonoids expressed as hesperidin, improves venous tone and lymphatic drainage, and reduces capillary hyperpermeability by protecting the microcirculation from inflammatory processes. The absorption of diosmin is improved by its micronisation to particles with a diameter <2 microm. Compared with placebo, MPFF 500 mg twice daily significantly decreased ankle or calf circumference, and improved many symptoms of chronic venous insufficiency (CVI) and plethysmographic parameters in two randomised, double-blind, 2-month studies. Improvement in symptoms was parallelled by an improvement in health-related quality of life in a nonblind, 6-month trial. Significantly more venous leg ulcers </=10 cm in diameter completely healed with MPFF 500 mg twice daily plus standard management (compression and local treatment) for 2-6 months than with standard management alone or with placebo in a nonblind and a double-blind trial. The addition of MPFF to standard management was cost effective in a retrospective pharmacoeconomic analysis of the 6-month trial. Compared with placebo, the duration and/or intensity of individual symptoms of grade 1 or 2 acute internal haemorrhoids improved significantly with 3 tablets of MPFF 500 mg twice daily for 4 days then 2 tablets of MPFF 500 mg twice daily for 3 days. Two tablets of MPFF 500 mg daily for 60 or 83 days reduced the frequency, duration and/or severity of acute haemorrhoidal symptoms and improved the overall signs and symptoms of chronic (recurrent) haemorrhoids compared with placebo. Compared with a control group, MPFF significantly reduced the risk of secondary bleeding after elective haemorrhoidectomy. In clinical trials, MPFF had a tolerability profile similar to that of placebo; the most frequently reported adverse events were gastrointestinal and autonomic in nature. In conclusion, MPFF is a well established and well tolerated treatment option in patients with CVI, venous ulcers, or acute or chronic internal haemorrhoids. MPFF is indicated as a first-line treatment of oedema and the symptoms of CVI in patients in any stage of the disease. In more advanced disease stages, MPFF may be used in conjunction with sclerotherapy, surgery and/or compression therapy, or as an alternative treatment when surgery is not indicated or is unfeasible. The healing of venous ulcers </=10 cm in diameter is accelerated by the addition of MPFF to standard venous ulcer management. MPFF may reduce the frequency, duration and/or intensity of symptoms of grade 1 or 2 acute internal haemorrhoids, and also the severity of the signs and symptoms of chronic haemorrhoids.

Drugs. 2003;63(1):71-100

A double-blind, placebo-controlled trial of a new veno-active flavonoid fraction (S 5682) in the treatment of symptomatic capillary fragility.

The efficacy and safety of a new veno-active flavonoid fraction (S 5682) consisting of micronized diosmin (90%) and hesperidin (10%) have been studied in 100 patients with symptomatic capillary fragility in a double-blind, randomized, placebo-controlled trial. Treatment lasted 6 weeks and consisted of 2 daily tablets of either S 5682 or placebo. Patients were examined at weeks 0, 2, 4, and 6. Compared to placebo, capillary resistance, assessed by the negative suction cup method, was significantly higher in the S 5682 group at week 4 (219 +/- 10 mmHg versus 159 +/- 8 mmHg; p < 0.001) and week 6 (261 +/- 12 mmHg versus 163 +/- 9 mmHg; p < 0.001). This resulted in a significant improvement of symptoms of capillary fragility (spontaneous ecchymosis, epistaxis, purpura, petechiae, gingivorrhagia, metrorrhagia and conjunctival haemorrhage) in S 5682 treated patients (p < 0.001). S 5682 was well tolerated. The rate of side-effects spontaneously volunteered by the patients was similar in both groups. We, therefore, conclude that S 5682 increases to a large extent the capillary resistance in patients with abnormal capillary fragility without significant side-effects.

Int Angiol. 1993 Mar;12(1):69-72.

From symptoms to leg edema: efficacy of Daflon 500 mg.

This article reviews the mechanisms by which micronized purified flavonoid fraction (MPFF; Daflon 500 mg) acts on symptoms as well as on edema in patients with chronic venous disease, in the light of new advances in the understanding of the pathophysiology of this chronic condition. Deterioration of venous wall tone followed by valve dysfunction leading eventually to varicose veins are the key pathophysiologic features that produce venous hypertension. Both mechanical and biological factors are responsible for the deterioration of the venous wall in large veins. These are decreased shear stress and hypoxia of the media and of the endothelium, which act as triggering factors for biochemical reactions leading to inflammation. There is a body of evidence that inflammation in chronic venous insufficiency (CVI) plays a role right from the early stages of venous dysfunction and venous valve restructuring. The whole process of venous wall stretching and dilation is painful and may present as leg heaviness, a sensation of swelling, and paresthesia. Daflon 500 mg relieves symptoms, edema, and red blood cell aggregation, which cause paresthesia and restless legs. At the level of the microcirculation, dysfunction of microvessels is observed, characterized by an increase in capillary permeability followed by skin changes. The earliest manifestation of microcirculatory disorder is edema. At this level, Daflon 500 mg acts favorably on microcirculatory complications by normalizing the synthesis of prostaglandins and free radicals. It decreases bradykinin-induced microvascular leakage and inhibits leukocyte activation, trapping, and migration. Its efficacy in decreasing CVI edema and ankle swelling has been proven in rigorous studies that are reviewed in this paper. Daflon 500 mg, a well-established oral flavonoid that consists of 90% micronized diosmin and 10% flavonoids expressed as hesperidin, may be prescribed from the very beginning of the disease for the relief of pain and edema, and in any CVI patient presenting with symptoms as well. Daflon 500 mg is thus the first-line treatment for edema and symptoms of CVI at any stage of the disease. At advanced disease stages, Daflon 500 mg may be used in conjunction with sclerotherapy, surgery, and/or compression therapy or as an alternative treatment when other treatments are not indicated or not feasible.

Angiology. 2003 Jul-Aug;54 Suppl 1:S33-44

The impact of psoriasis on health care costs and patient work loss.

BACKGROUND: There are few comprehensive estimates of the cost of psoriasis in the United States. OBJECTIVE: We sought to quantify the incremental direct medical and indirect work loss costs associated with psoriasis. METHODS: A de-identified claims database from 31 self-insured employers during the period 1998 to 2005 was used. Patients with at least two psoriasis diagnosis claims (N = 12,280) were compared with 3 control subjects (matched on year of birth and sex) without psoriasis. Multivariate two-part regression analysis was used to isolate the incremental cost of psoriasis by controlling for comorbidities and other confounding factors. RESULTS: After multivariate adjustment, the incremental direct and indirect costs of psoriasis were approximately $900 and $600 (P < .001) per patient per year, respectively. LIMITATIONS: The database used in this study does not contain information on patient out-of-pocket costs or loss of productivity costs at work. CONCLUSION: The incremental cost of psoriasis is approximately $1500 per patient per year, with work loss costs accounting for 40% of the cost burden.

J Am Acad Dermatol. 2008 Nov;59(5):772-80

Cardiovascular disease and risk factors among psoriasis patients in two US healthcare databases, 2001-2002.

BACKGROUND: Cardiovascular diseases or risk factors (CVDR) seem to be more common in psoriasis patients than in the general population. OBJECTIVE: We assessed the relationship of psoriasis with CVDR by analysis of healthcare claims data using a cross-sectional, prevalence-based study design. PATIENTS AND MeTHODS: The IMS Health and MarketScan claims databases were used to identify adults with psoriasis diagnostic codes. Non-psoriasis controls were matched 3:1 based on age, gender, census region and previous medical insurance coverage. Odds ratios evaluated the relative prevalence of CVDR, and Mantel-Haenszel confidence intervals were estimated. RESULTS: CVDR prevalence was generally higher in psoriasis patients than controls in both datasets. Odds ratios for atherosclerosis, congestive heart failure, type 2 diabetes, and peripheral vascular disease were >or=1.20 for psoriasis patients. Elevated disease severity was associated with a higher rate of CVDR, but varied somewhat by dataset and condition. Conclusions: Elevated CVDR rates were found in psoriasis patients compared with controls. This pattern merits further examination.

Dermatology. 2008;217(1):27-37

Psoriasis and the risk of diabetes and hypertension: a prospective study of US female nurses.

OBJECTIVE: To evaluate the independent association between psoriasis and risk of diabetes and hypertension. DESIGN: A prospective study of female nurses who were followed up from 1991 to 2005. SETTING: Nurses’ Health Study II, a cohort of 116,671 US women aged 27 to 44 years in 1991. PARTICIPANTS: The study included 78,061 women who responded to a question about a lifetime history of physician-diagnosed psoriasis in 2005. Women who reported a diagnosis of diabetes or hypertension at baseline were excluded. Main Outcome Measure: New diagnosis of diabetes or hypertension, obtained from biennial questionnaires. RESULTS: Of the 78,061 women, 1,813 (2.3%) reported a diagnosis of psoriasis. During the 14 years of follow-up, a total of 1560 incident cases (2%) of diabetes and 15,724 incident cases (20%) of hypertension were documented. The multivariate-adjusted relative risk of diabetes in women with psoriasis compared with women without psoriasis was 1.63 (95% confidence interval, 1.25-2.12). Women with psoriasis were also at an increased risk for the development of hypertension (multivariate relative risk, 1.17; 95% confidence interval, 1.06-1.30). Age, body mass index, and smoking status did not significantly modify the association between psoriasis and risk of diabetes or hypertension (P values for interaction, > or =.07). CONCLUSIONS: In this prospective analysis, psoriasis was independently associated with an increased risk of diabetes and hypertension. Future studies are needed to find out whether psoriasis treatment will reduce the risk of diabetes and hypertension.

Arch Dermatol. 2009 Apr;145(4):379-82

Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.

Psoriasis is a common immune-mediated disorder that affects the skin, nails and joints. To identify psoriasis susceptibility loci, we genotyped 438,670 SNPs in 1,409 psoriasis cases and 1,436 controls of European ancestry. We followed up 21 promising SNPs in 5,048 psoriasis cases and 5,041 controls. Our results provide strong support for the association of at least seven genetic loci and psoriasis (each with combined P < 5 x 10(-8)). Loci with confirmed association include HLA-C, three genes involved in IL-23 signaling (IL23A, IL23R, IL12B), two genes that act downstream of TNF-alpha and regulate NF-kappaB signaling (TNIP1, TNFAIP3) and two genes involved in the modulation of Th2 immune responses (IL4, IL13). Although the proteins encoded in these loci are known to interact biologically, we found no evidence for epistasis between associated SNPs. Our results expand the catalog of genetic loci implicated in psoriasis susceptibility and suggest priority targets for study in other auto-immune disorders.

Nat Genet. 2009 Feb;41(2):199-204

Safety and efficacy of a milk-derived extract in the treatment of plaque psoriasis: an open-label study.

BACKGROUND: XP-828L is a nutraceutical compound obtained by the extraction of a growth factors-enriched protein fraction from bovine milk. XP-828L may improve psoriasis. OBJECTIVES: An open-label study was performed to determine the efficacy, tolerability and safety of XP-828L in the treatment of plaque psoriasis. METHODS: Eleven adult patients with chronic, stable plaque psoriasis on 2% or more of body surface area (BSA) received 5 g of oral XP-828L twice daily for 56 days. RESULTS: All 11 patients completed the 56 days of treatment. At day 28, 6 of the 11 patients showed a reduction in PASI score. At 56 days, seven subjects had a decrease in PASI score ranging from 9.5% to 81.3%. Eight (8) out of 11 patients agreed to participate in an additional 8-week extension treatment phase. Improvement of psoriasis was maintained during the extension period. No clinically significant adverse events or laboratory abnormalities occurred. CONCLUSION: XP-828L may improve psoriasis in patients with mild-to-moderate psoriasis.

J Cutan Med Surg. 2005 Dec;9(6):271-5

XP-828L in the treatment of mild to moderate psoriasis: randomized, double-blind, placebo-controlled study.

BACKGROUND: XP-828L, a protein extract obtained from sweet whey, has demonstrated potential benefit for the treatment of mild to moderate psoriasis in an open-label study. OBJECTIVE: To study in a randomized, double-blind, placebo-controlled study the safety and efficacy of XP-828L in the treatment of mild to moderate psoriasis. DESIGN: XP-828L 5 g/d (group A, n = 42) or placebo (group B, n = 42) was given orally for 56 days followed by XP-828L 5 g/d in group A and by XP-828L 10 g/d in group B for an additional 56 days. RESULTS: Patients receiving XP-828L 5 g/d for 56 days had an improved Physician’s Global Assessment (PGA) score compared with patients under placebo (p < .05). Considering the data of group A only, the PGA score improved from day 1 to day 56 (p < .01); the Psoriasis Area and Severity Index score improved as well, but to a lesser extent (p < .05). CONCLUSION: Oral administration of 5 g/d XP-828L compared with a placebo significantly improved the PGA score of patients with mild to moderate psoriasis.

J Cutan Med Surg. 2006 Sep-Oct;10(5):241-8

Association of patient-reported psoriasis severity with income and employment.

OBJECTIVE: We sought to examine whether psoriasis severity was associated with patient income and employment. METHODS: Respondents (> 30 years old) to National Psoriasis Foundation surveys (2003-2005) were classified by reported body surface area as having mild (< 3%), moderate (3%-10%), or severe (> 10%) psoriasis. The relationship between severity and household income (< $30,000 vs > or = $30,000) and employment was assessed by logistic regression, adjusting for age, age at onset, sex, race, and drug treatment. RESULTS: Probability of low income (< $30,000) was significantly greater among patients with severe disease than those with mild disease (P = .0002). Patients with severe disease had lower probability of working full time compared with patients with mild psoriasis but it was not statistically significant. Significantly more patients with severe psoriasis (17%) versus mild (6%) reported that psoriasis was the reason for not working (P = .01). LIMITATIONS: Household income was self-reported and may be influenced by household composition, which is unknown. Psoriasis severity was patient reported and not physician assessed. CONCLUSIONS: This study demonstrated that income and employment were negatively impacted among patients with severe psoriasis compared with mild psoriasis.

J Am Acad Dermatol. 2007 Dec;57(6):963-71

Treatments for psoriasis and the risk of malignancy.

BACKGROUND: There are multiple therapeutic options for the treatment of moderate to severe psoriasis. The process of choosing among potential treatment options requires both the physician and the patient to weigh the benefits of individual modalities against their potential risks. Traditional systemic therapies for psoriasis, including methotrexate (MTX) and cyclosporine (CsA), have a well-documented array of toxicities, particularly end-organ toxicities. Over the past several years, the use of biologic therapies for the treatment of moderate to severe psoriasis has been a major clinical and research focus. With the advent of these novel immunosuppressive therapies, one of the central safety issues surrounding these agents is their potential to increase the risk of malignancy. OBJECTIVE: Our objective was to review the risk of malignancy associated with therapies for moderate to severe psoriasis, including phototherapy, traditional systemic therapies, and biologic therapies. We reviewed the existing body of literature in order to define the known incidence of malignancy associated with psoralen and ultraviolet A (PUVA), narrowband and broadband ultraviolet B (UVB), MTX, CsA, mycophenolate mofetil (MMF), and biologic therapies, including alefacept, efalizumab, infliximab, etanercept, adalimumab, and ustekinumab. RESULTS: PUVA, when given long term, is associated with increased risks of cutaneous squamous cell carcinoma and malignant melanoma. Reviews of studies on UVB, both narrowband and broadband, do not indicate any increased risk of nonmelanoma skin cancer or melanoma. The traditional systemic psoriasis therapies-MTX, CsA, and MMF-may be associated with an increased risk of lymphoproliferative disorders during treatment, demonstrated in clinical trials in patients with rheumatoid arthritis and documented in case reports concerning psoriasis patients. The risk of malignancy with biologic therapy is still unclear. However, the majority of studies examining this carcinogenic risk suggest that tumor necrosis factor-alpha inhibitors may cause a slightly increased risk of cancer, including nonmelanoma skin cancer and hematologic malignancies. LIMITATIONS: The majority of studies cited in this review lack the power and randomization of large clinical trials, as well as the long-term follow-up periods which would further substantiate the hypothetical link between these antipsoriatic treatment regimens and the potential for malignancy. Because of the substantial lack of clinical data, the majority of studies evaluated focus on the treatment of patients with rheumatoid arthritis, which is a systemic inflammatory disorder comparable to psoriasis. Additionally, the increased risk of malignancy associated with psoriasis itself is a confounding factor. CONCLUSION: Many of the therapies for moderate to severe psoriasis, including PUVA, traditional systemic therapies, and some biologic therapies, may increase the risk of malignancy. Appropriate patient counseling and selection, as well as clinical follow-up, are necessary to maximize safety with these agents. Further long-term study is necessary to more precisely quantify the risks associated with biologic therapies.

J Am Acad Dermatol. 2009 Jun;60(6):1001-17

Topical 8-methoxypsoralen enhances the therapeutic results of targeted narrowband ultraviolet B phototherapy for plaque-type psoriasis.

Targeted broadband ultraviolet B (UVB) phototherapy as well as 308-nm excimer laser have been reported to significantly improve or clear localized psoriatic plaques within 5 to 10 treatments when medium fluences [i.e. 4-6 multiples of minimal erythema doses (MED)] were used. Our study was conducted to determine the effects of different concentrations of topical 8-methoxypsoralen (8-MOP) cream when used in combination with targeted UV phototherapy with regard to number of treatments and cumulative UV doses to clear localized psoriasis. Ten evaluable patients with stable plaque-type psoriasis completed the study. Three different concentrations of 8-MOP creams (0.001%, 0.01% and 0.1%) were applied prior to irradiation with 4 MEDs of targeted narrowband UVB (NB-UVB), whereas 0.001% 8-MOP cream was used in conjunction with 5 J/cm(2) UVA. All irradiations took place once weekly for 12 weeks. Psoriasis severity index (PSI) score was used to evaluate the efficacy of the treatment. With area-under-the-curve analysis, 0.1% 8-MOP/NB-UVB was superior to other modalities in reducing the PSI scores. The number of treatments and cumulative NB-UVB doses necessary to achieve PSI-95, a 95% reduction in the scores, was also lower in the 0.1% 8-MOP/NB-UVB group, although the differences were not statistically significant. We conclude that topical 8-MOP cream enhances the therapeutic effects of targeted NB-UVB phototherapy without significantly increasing the short-term adverse effects.

J Eur Acad Dermatol Venereol. 2008 Jan;22(1):50-5

308 nm monochromatic excimer light in dermatology: personal experience and review of the literature.

For over five years, we have been using a new ultraviolet B ray source, a Xenon-Chloride lamp emitting non-coherent, monochromatic 308-nm light that represents the natural evolution of the excimer laser. A source of monochromatic excimer light (MEL) produces 50 mW/cm(2) power density at a distance of 15 cm from the source and has a maximum irradiating area of 504 cm(2), this feature representing the greatest therapeutic advantage offered by 308 nm sources. On the other hand, the benefits offered by the MEL compared to traditional phototherapies are essentially correlated to the fact that there is no need to administer oral psoralens (PUVA therapy) and that sessions need to be repeated only every 7-15 days, an important condition for the improvement of the patient’s quality of life (since at least 2-3 weekly sessions are required with the traditional UVB therapy). Using MEL, UV B light can be applied on the entire body, with partial subintrant skin irradiations, or on one or just a few individual patches, taking care to accurately protect the healthy surrounding skin and allowing for a phototherapy exclusively targeted onto the lesion to be treated. Clinical indications and the reasons for choosing MEL for the treatment of photosensitive skin disorders are virtually identical to those stated for PUVA therapy or narrowband UV B light. Due to the absence of photosensitizing substances and drug-induced toxicity, patients who work in the open air, pregnant women and patients suffering from liver or kidney failure can also be treated. Furthermore, the short time required for sessions, the duration of cycles and the selective exposure of the skin areas to be treated undoubtedly represent significant benefits for patients in terms of safety and efficacy. In addition to psoriasis, the use of MEL can also be extended to other pathologies such as vitiligo, alopecia areata, atopic dermatitis and patch-stage IA mycosis fungoides with encouraging results.

G Ital Dermatol Venereol. 2008 Oct;143(5):329-37

Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology.

In the United States, colorectal cancer (CRC) is the third most common cancer diagnosed among men and women and the second leading cause of death from cancer. CRC largely can be prevented by the detection and removal of adenomatous polyps, and survival is significantly better when CRC is diagnosed while still localized. In 2006 to 2007, the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology came together to develop consensus guidelines for the detection of adenomatous polyps and CRC in asymptomatic average-risk adults. In this update of each organization’s guidelines, screening tests are grouped into those that primarily detect cancer early and those that can detect cancer early and also can detect adenomatous polyps, thus providing a greater potential for prevention through polypectomy. When possible, clinicians should make patients aware of the full range of screening options, but at a minimum they should be prepared to offer patients a choice between a screening test that primarily is effective at early cancer detection and a screening test that is effective at both early cancer detection and cancer prevention through the detection and removal of polyps. It is the strong opinion of these 3 organizations that colon cancer prevention should be the primary goal of screening.

Gastroenterology. 2008 May;134(5):1570-95

Systemic treatment of colorectal cancer.

Colorectal cancer is the fourth most common noncutaneous malignancy in the United States and the second most frequent cause of cancer-related death. Over the past 12 years, significant progress has been made in the systemic treatment of this malignant condition. Six new chemotherapeutic agents have been introduced, increasing median overall survival for patients with metastatic colorectal cancer from less than 9 months with no treatment to approximately 24 months. For patients with stage III (lymph node positive) colon cancer, an overall survival benefit for fluorouracil-based chemotherapy has been firmly established, and recent data have shown further efficacy for the inclusion of oxaliplatin in such adjuvant treatment programs. For patients with stage II colon cancer, the use of adjuvant chemotherapy remains controversial, but may be appropriate in a subset of individuals at higher risk for disease recurrence. Ongoing randomized clinical trials are evaluating how best to combine currently available therapies, while smaller studies are evaluating new agents, with the goal of continued progress in prolonging life among patients with metastatic colorectal cancer and increasing cure rates among those with resectable disease.

Gastroenterology. 2008 May;134(5):1296-310

Curcumin for chemoprevention of colon cancer.

The most practical approach to reduce the morbidity and mortality of cancer is to delay the process of carcinogenesis through the use of chemopreventive agents. This necessitates that safer compounds, especially those derived from natural sources must be critically examined for chemoprevention. A spice common to India and the surrounding regions, is turmeric, derived from the rhizome of Curcuma longa. Pre-clinical studies in a variety of cancer cell lines including breast, cervical, colon, gastric, hepatic, leukemia, oral epithelial, ovarian, pancreatic, and prostate have consistently shown that curcumin possesses anti-cancer activity in vitro and in pre-clinical animal models. The robust activity of curcumin in colorectal cancer has led to five phase I clinical trials being completed showing the safety and tolerability of curcumin in colorectal cancer patients. To date clinical trials have not identified a maximum tolerated dose of curcumin in humans with clinical trials using doses up to 8,000 mg per day. The success of these trials has led to the development of phase II trials that are currently enrolling patients. Overwhelming in vitro evidence and completed clinical trials suggests that curcumin may prove to be useful for the chemoprevention of colon cancer in humans. This review will focus on describing the pre-clinical and clinical evidence of curcumin as a chemopreventive compound in colorectal cancer.

Cancer Lett. 2007 Oct 8;255(2):170-81

Fruit and vegetable intake and prevalence of colorectal adenoma in a cancer screening trial.

BACKGROUND: Research on the association between fruit and vegetable intake and risk of colorectal adenoma is inconclusive. OBJECTIVE: We studied whether intake of fruit, vegetables, or their subgroups is associated with a lower risk of prevalent colorectal adenoma. DESIGN: In men and women (aged 55-74 y) who were screened for colorectal cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) (1993-2001), we compared 3,057 cases with at least one prevalent histologically verified adenoma of the distal large bowel with 29,413 control subjects. Using a food-frequency questionnaire, we quantified intake of fruit and vegetables in the 12 mo before screening as energy-adjusted pyramid servings/d (ps/d). Adjusted odds ratios (ORs) and 95% CIs were estimated by logistic regression. RESULTS: Risk of distal adenoma was significantly lower among subjects in high (approximately 5.7 ps/d) versus low (approximately 1.2 ps/d) quintiles of total fruit intake (OR: 0.75; 95% CI: 0.66, 0.86, P for trend <0.001), which was not completely explained by dietary folate or fiber intake. Inverse associations between adenoma and total fruit intake were observed regardless of adenoma histopathology and multiplicity. However, the protective effect was seen only for colon and not rectal adenoma. Total vegetable intake was not significantly associated with reduced risk of adenoma. ORs for colorectal adenoma among persons with high versus low intakes of deep-yellow vegetables, dark-green vegetables, and onions and garlic were significantly related to lower risk of adenoma, although the P for trend for dark-green vegetables was not significant. CONCLUSION: Diets rich in fruit and deep-yellow vegetables, dark-green vegetables, and onions and garlic are modestly associated with reduced risk of colorectal adenoma, a precursor of colorectal cancer.

Am J Clin Nutr. 2007 Dec;86(6):1754-64

New mechanisms and the therapeutic potential of curcumin for colorectal cancer.

Curcumin is a polyphenol derived from Curcuma longa. Over the last few years, a number of studies have provided evidence of its main pharmacological properties including chemosensitizing, radiosensitizing, wound healing activities, antimicrobial, antiviral, antifungical, immunomodulatory, antioxidant and anti-inflammatory. More recent data provide interesting insights into the effect of this compound on cancer chemoprevention and chemotherapy. In fact, preclinical studies have shown its ability to inhibit carcinogenesis in various types of cancer including colorectal cancer (CRC). Curcumin has the capacity of interact with multiple molecular targets affecting the multistep process of carcinogenesis. Also, curcumin is able to arrest the cell cycle, to inhibit the inflammatory response and the oxidative stress and to induce apoptosis in cancer cells. Likewise, it has been shown to possess marked antiangiogenic properties. Furthermore, curcumin potentiates the growth inhibitory effect of cyclo-oxygenase (COX)-2 inhibitors and traditional chemotherapy agents implicating another promising therapy regimen in the future treatment of CRC. However, its clinical advance has been hindered by its short biological half-life and low bioavailability after oral administration. This review is intended to provide the reader an update of the bioavailability and pharmacokinetics of curcumin and describes the recently identified molecular pathways responsible of its anticancer potential in CRC.

Mol Nutr Food Res. 2008 Sep;52(9):1040-61

Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer.

Curcumin, derived from the rhizome of Curcuma longa L. and having both antioxidant and anti-inflammatory properties, inhibits chemically induced carcinogenesis in the skin, forestomach, and colon when it is administered during initiation and/or postinitiation stages. This study was designed to investigate the chemopreventive action of curcumin when it is administered (late in the premalignant stage) during the promotion/progression stage of colon carcinogenesis in male F344 rats. We also studied the modulating effect of this agent on apoptosis in the tumors. At 5 weeks of age, groups of male F344 rats were fed a control diet containing no curcumin and an experimental AIN-76A diet with 0.2% synthetically derived curcumin (purity, 99.9%). At 7 and 8 weeks of age, rats intended for carcinogen treatment were given s.c. injections of azoxymethane (AOM) at a dose rate of 15 mg/kg body weight per week. Animals destined for the promotion/progression study received the AIN-76A control diet for 14 weeks after the second AOM treatment and were then switched to diets containing 0.2 and 0.6% curcumin. Premalignant lesions in the colon would have developed by week 14 following AOM treatment. They continued to receive their respective diets until 52 weeks after carcinogen treatment and were then sacrificed. The results confirmed our earlier study in that administration of 0.2% curcumin during both the initiation and postinitiation periods significantly inhibited colon tumorigenesis. In addition, administration of 0.2% and of 0.6% of the synthetic curcumin in the diet during the promotion/progression stage significantly suppressed the incidence and multiplicity of noninvasive adenocarcinomas and also strongly inhibited the multiplicity of invasive adenocarcinomas of the colon. The inhibition of adenocarcinomas of the colon was, in fact, dose dependent. Administration of curcumin to the rats during the initiation and postinitiation stages and throughout the promotion/progression stage increased apoptosis in the colon tumors as compared to colon tumors in the groups receiving AOM and the control diet. Thus, chemopreventive activity of curcumin is observed when it is administered prior to, during, and after carcinogen treatment as well as when it is given only during the promotion/progression phase (starting late in premalignant stage) of colon carcinogenesis.

Cancer Res. 1999 Feb 1;59(3):597-601

Curcumin induces apoptosis in HCT-116 human colon cancer cells in a p21-independent manner.

Several micronutrients present in fruits and vegetables exhibit anticancer activity as a result of their actions on molecular targets involved in carcinogenesis and tumor progression. Curcumin, a phenolic phytochemical derived from the rhizome of Curcuma longa, exhibits both cancer-preventative activity and growth inhibitory effects on neoplastic cells. Several studies report that curcumin inhibits cancer cell proliferation and induces apoptosis in cancer cells through p21-mediated cell cycle arrest. Cancer cells that are deficient in p21 are also reported to be more prone to undergo apoptosis in response to a variety of cytotoxic agents. In this study, we determined whether curcumin-induced cytotoxicity in cultures of HCT-116 human colon cancer cells was dependent on p21 status. Curcumin killed wild-type HCT-116 cells in a dose- and time-dependent manner, as measured in an MTT cell viability assay. Moreover, an equivalent cytotoxic effect by curcumin was observed in both p21(+/+) and p21(-/-)HCT-116 cells, indicating that curcumin-induced cytotoxicity was p21-independent. Primary cultures of human dermal fibroblasts were less sensitive than HCT-116 colon cancer cells to lower doses of curcumin, suggesting a degree of selectivity for neoplastic cells. Western blot analysis showed that cell death in curcumin-treated cultures of p21(+/+) and p21(-/-) HCT-116 cells was associated with a reduction in pro-caspase-3 and PARP-1 cleavage, which are indicative of apoptosis. We conclude that curcumin-induced apoptosis in HCT-116 colon cancer cells does not depend on p21 status.

Exp Mol Pathol. 2008 Jun;84(3):230-3

Celecoxib and curcumin additively inhibit the growth of colorectal cancer in a rat model.

BACKGROUND: Multiple studies have indicated that specific COX-2 inhibitors may prevent CRC. However, the long-term use of COX-2 inhibitors is not toxicity-free and may be limited due to its cardiovascular side effects. The present study was carried out to examine the chemopreventive effects of celecoxib and curcumin alone and in combination using the 1,2-dimethylhydrazine (DMH) rat model. METHODS: Male rats were injected with DMH and randomly divided into four groups that consumed one of the following diets: (a) AIN-076 control diet; (b) AIN-076/curcumin (0.6%); (c) AIN-076/celecoxib (0.16%), or (d) AIN-076/celecoxib (0.16%) and curcumin (0.6%). Aberrant crypt foci (ACF) were identified by intensive staining with methylene blue in comparison to the surrounding normal crypts. RESULTS: The average number of ACF per rat colon was 64.2 +/- 3 in the control group, 39 +/- 5 and 47 +/- 10 for the curcumin- and celecoxib-treated group, respectively, and 24.5 +/- 6 in the group that had received both agents. CONCLUSIONS: In vivo, curcumin augments the growth inhibitory effect of celecoxib. This may be clinically important as this dose of celecoxib can be achieved in human serum following standard anti-inflammatory dosing of 100 mg.

Digestion. 2006;74(3-4):140-4

Novel resveratrol analogs induce apoptosis and cause cell cycle arrest in HT29 human colon cancer cells: inhibition of ribonucleotide reductase activity.

Resveratrol (3,4’,5-trihydroxy-trans-stilbene; RV), an ingredient of wine, exhibits a broad spectrum of antiproliferative effects against human cancer cells. In order to enhance these effects, we modified the molecule by introducing additional methoxyl and hydroxyl groups. The resulting novel RV analogs, M5 (3,4’,5-trimethoxy-trans-stilbene), M5A (3,3’,4,5’-tetramethoxy-trans-stilbene) and M8 (3,3’,4,4’,5,5’-hexahydroxy-trans-stilbene) were investigated in HT29 human colon cancer cells. Cytotoxicity was evaluated by clonogenic assays and the induction of apoptosis was determined using a specific Hoechst/propidium iodide double staining method. Cell cycle distribution was evaluated by FACS. The influence of M8 on the concentration of deoxyribonucleoside triphosphates (dNTPs), the products of ribonucleotide reductase (RR), was determined by high-performance liquid chromatography. M5 and M5A caused a dose-dependent induction of apoptosis and led to remarkable changes of the cell cycle distribution. After treatment with M5, growth arrest occurred mainly in the G2-M phase, whereas incubation with M5A resulted in arrest in the G0-G1 phase of the cell cycle. Incubation of HT29 cells with M8 produced a significant imbalance of intracellular dNTP pools, being synonymous with the inhibition of RR activity. The dATP pools were abolished, whereas the dCTP and dTTP pools increased. Due to these promising results, the investigated RV analogs deserve further preclinical and in vivo testing.

Oncol Rep. 2008 Jun;19(6):1621-6

Transcriptome and proteome profiling of colon mucosa from quercetin fed F344 rats point to tumor preventive mechanisms, increased mitochondrial fatty acid degradation and decreased glycolysis.

Quercetin has been shown to act as an anticarcinogen in experimental colorectal cancer (CRC). The aim of the present study was to characterize transcriptome and proteome changes occurring in the distal colon mucosa of rats supplemented with 10 g quercetin/kg diet for 11 wk. Transcriptome data analyzed with Gene Set Enrichment Analysis showed that quercetin significantly downregulated the potentially oncogenic mitogen-activated protein kinase (Mapk) pathway. In addition, quercetin enhanced expression of tumor suppressor genes, including Pten, Tp53, and Msh2, and of cell cycle inhibitors, including Mutyh. Furthermore, dietary quercetin enhanced genes involved in phase I and II metabolism, including Fmo5, Ephx1, Ephx2, and Gpx2. Quercetin increased PPARalpha target genes, and concomitantly enhanced expression of genes involved in mitochondrial fatty acid (FA) degradation. Proteomics performed in the same samples revealed 33 affected proteins, of which four glycolysis enzymes and three heat shock proteins were decreased. A proteome-transcriptome comparison showed a low correlation, but both pointed out toward altered energy metabolism. In conclusion, transcriptomics combined with proteomics showed that dietary quercetin evoked changes contrary to those found in colorectal carcinogenesis. These tumor-protective mechanisms were associated with a shift in energy production pathways, pointing at decreased cytoplasmic glycolysis and toward increased mitochondrial FA degradation.

Proteomics. 2008 Jan;8(1):45-61

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