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Biomedical subjects

P S Friedmann

Publications and source records attributed to P S Friedmann.

At least 19 recordsLinked to original sources
PubMed2006

Killed Mycobacterium vaccae suspension in children with moderate-to-severe atopic dermatitis: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: The hygiene hypothesis is often proposed to explain the high prevalence of atopy in the western world. Dysregulation of the immune system may result from inadequate exposure to micro-organisms such as mycobacteria. A small trial suggested that a killed extract of Mycobacterium vaccae ameliorates atopic dermatitis (AD). OBJECTIVES: To confirm in a large clinical trial whether killed M. vaccae ameliorates AD in 5-16-year-old children. METHODS: This was a randomized, placebo-controlled, double-blind, multi-centre study of the effect of intradermal injection of killed M. vaccae (0.1 or 1 mg) on patients, aged 5-16, with moderate-to-severe AD. Patients were followed up for 24 weeks. The primary end point was the change in severity of AD at 12 weeks, assessed using the six area, six-sign, atopic dermatitis (SASSAD) score. Secondary end points included changes in disease extent, patient's global assessment and children's dermatology life quality index. RESULTS: There were 166 patients randomized. The mean SASSAD score fell to a similar degree at week 12 in all treatment arms: from 33 to 24, (26%) in the high-dose group, from 30 to 23 (25%) in the low-dose group and from 36 to 27 (24%) in the placebo group (P>0.05). Secondary end points followed the same trend. Adverse events were generally those expected to occur in this population. Injection site reactions occurred in 32 patients at week 4. CONCLUSIONS: M. vaccae was no more effective than the placebo in ameliorating the severity of AD.

Adolescent↗
PubMed2006

Second cite.

Explore the source record for details and available documents.

Antibodies, Monoclonal↗
PubMed2006

Type 2 diabetes, psoriasis and thiazolidinediones.

Thiazolidinediones, synthetic ligands for the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) receptor, are insulin-sensitizing drugs licensed for use in selected patients with type 2 diabetes mellitus. The potential therapeutic applications of the thiazolidinediones extend to other clinical specialties such as dermatology. Rosiglitazone and pioglitazone are being evaluated for the treatment of psoriasis. Type 2 diabetes and psoriasis may coexist prompting speculation that dual benefits might accrue for patients with both conditions. A recent open pilot study suggests that oral pioglitazone may be beneficial for moderate chronic plaque psoriasis. However, changes in antidiabetic medication must be made in the knowledge of the cautions and contraindications to oral agents as well as the impact on metabolic control. Further studies are required before the use of thiazolidinediones for psoriasis can be advocated.

Aged↗
PubMed2005

What's new in the management of cutaneous T-cell lymphoma?

The aetiology and clinical management of primary cutaneous T-cell lymphoma (CTCL) and specifically of mycosis fungoides and Sezary syndrome are poorly defined. Interesting new insights into CTCL disease biology as well as a number of emerging of novel therapeutic interventions make this an increasingly interesting area for dermatologists and oncologists involved in the treatment of CTCL. This review article covers much of this new information including new drugs, such as denileukin diftitox (Ontak) a targeted cytotoxic biological agent, Bexarotene an RXR selective retinoid, anti-CD4 monoclonal antibodies (mAb), new cytotoxics agents and vaccines.

Humans↗
PubMed2004

A comparison of six and 12 PUVA treatments in the prophylaxis of polymorphic light eruption.

Polymorphic light eruption (PLE) is a common condition for which the most effective treatment is prophylactic phototherapy. This is traditionally given in courses of approximately 12-15 exposures. We compared the effect of six and 12 treatments of psoralen-UVA (PUVA) therapy, in the prophylaxis of PLE, in a side-to-side within-patient comparison pilot study. In six out of eight patients, six treatments provided as much protection as 12 treatments. Five of these six patients had reported relatively mild disease in the previous year, in comparison to the other two patients. In view of the inconvenience and increased incidence of adverse effects associated with long treatment courses, we recommend the use of short courses, particularly in patients who are relatively mildly affected.

Adult↗
PubMed2003

The role of stratum corneum and dermal microvascular perfusion in penetration and tissue levels of water-soluble drugs investigated by microdialysis.

BACKGROUND: Hydrophilic drugs are poorly absorbed when applied topically, due to low partitioning through the lipid matrix of the stratum corneum. Cutaneous blood flow rapidly clears the absorbed drug, which may result in low tissue levels. This is of importance for topically applied drugs whose site of action is within the epidermis or dermis. Dermal drug levels can be measured using cutaneous microdialysis, which is a means of continuously sampling substances from the dermal extracellular fluid. OBJECTIVES: To measure the contribution of stratum corneum barrier and microvascular perfusion in determining dermal tissue levels of hydrophilic drugs (aciclovir and penciclovir) in vivo. METHODS: Studies were performed using microdialysis of the volar surface of the forearm of healthy volunteers (n = 55) over a 5-h collection period. Stratum corneum was removed by tape stripping, and barrier disruption quantified by measurement of transepidermal water loss (TEWL); dermal microvascular perfusion was modulated by inclusion of noradrenaline in the microdialysis perfusate. RESULTS: With intact skin and normal cutaneous blood flow the concentration of penciclovir recovered was below assay threshold (0.05 ng x mL(-1). With noradrenaline-induced local vasoconstriction, the area under the curve of drug absorbed through normal skin (+/- SEM) was 13.3 +/- 2.9 ng mL(-1) h(0-5) for penciclovir and 27.6 +/- 10.6 ng mL(-1) h(0-5) for aciclovir. Removal of the stratum corneum (to glistening) by tape stripping increased penciclovir absorption by 1300-fold and aciclovir absorption by 440-fold, confirming the stratum corneum as the major barrier to hydrophilic drug absorption. Sequential barrier disruption by tape stripping gave a close correlation between penciclovir concentration absorbed per hour and barrier disruption measured by TEWL (r2 = 0.9283). There was a 15.6-fold difference in the recovery of penciclovir through barrier-deficient skin with and without cutaneous blood flow. There was no relationship between fibre depth and amount of drug dialysed, which suggests free movement of antiviral drug on reaching the aqueous environment of the dermis. CONCLUSIONS: This study defines for the first time the relationship between the degree of mechanical barrier impairment and drug absorption at the same anatomical site in humans, and the role of blood flow in drug clearance in vivo.

Acyclovir↗
PubMed2003

Mechanisms in cutaneous drug hypersensitivity reactions.

Up to 3% of all hospital admissions are due to adverse drug reactions (ADRs), and between 10% and 20% of hospital inpatients develop ADRs. Individual susceptibility to becoming 'sensitized' or allergic to a drug is thought to result from altered metabolic handling of the drug. Reactive intermediate compounds form haptens, bind to proteins and induce immune responses. Depending on whether the immune system generates antibodies or sensitized T cells, different clinical patterns of hypersensitivity may result. At present, both in vivo or in vitro tests to identify the culprit drug or to confirm the presence of hypersensitivity are not widely used because they are either not generally robust or not readily accessible. In vitro tests require the true immunogen/antigen to detect antibodies or sensitized T cells. As the metabolic basis underlying susceptibility to adverse drug reactions is elucidated, the resolution of immunological mechanisms and development of reliable tests will ensue. This will also become of great value for prediction of individuals at risk of becoming sensitized by a particular drug.

Antibody Formation↗
PubMed2002

UVR-induced oxidative stress in human skin in vivo: effects of oral vitamin C supplementation.

Previous studies of cultured skin cells and murine skin in vivo have indicated that UVR-induced damage involves the generation of reactive oxygen species and depletion of endogenous antioxidant systems. In order to explore the relevance of this to UVR-induced damage to human skin, we have undertaken a detailed examination of the time-course of changes in markers of oxidative stress in human skin following exposure to physiological amounts of UVR in vivo. In addition, we have examined the skin bioavailability of a common nutritional antioxidant, vitamin C, and have assessed the effects of supplementation on markers of oxidative stress. Our hypothesis was that acute exposure of human skin to UVR in vivo would lead to oxidation of cellular biomolecules that could be prevented by prior vitamin C treatment. A UVR-challenge of 120 mJ/cm2 of broadband UVB (peak 310 nm, range 270-400 nm) was applied to buttock skin of 8 healthy volunteers. This caused a rapid and significant rise in activity of skin catalase at 1 h and an increase in the oxidized/total glutathione ratio at 6 h post-UVR. AP-1 DNA binding also peaked at 1-6 h post-UVR, then declined rapidly to baseline levels. No significant changes were seen in skin malonaldehyde content. Oral vitamin C supplements (500 mg/day) were taken by 12 volunteers for 8 weeks resulting in significant rises in plasma and skin vitamin C content. Supplementation had no effect on the UVR-induced erythemal response. The skin malonaldehyde content was reduced by vitamin C supplementation, but surprisingly, reductions in the skin content of total glutathione and protein thiols were also seen. We speculate that this apparently paradoxical effect could be due to regulation of total reductant capacity by skin cells, such that vitamin C may have been replacing other reductants in these cells. No evidence was obtained for an effect of the supplementary vitamin C on the mild oxidative stress seen in human skin following UVR exposure.

Adult↗
PubMed2002

Traditional therapies: glucocorticoids, azathioprine, methotrexate, hydroxyurea.

The 'old favourites' used for treatment of inflammatory diseases, and hence, the original immunomodulators, include the glucocorticoids, azathioprine, methotrexate and hydroxyurea. Glucocorticoids are still one of the most effective anti-inflammatory agents because they work on several different intracellular processes and hence, block many components that contribute to inflammatory and immune responses. They bind to intracellular glucocorticoid receptors which transport them into the nucleus. Here the receptor/steroid complex may bind to many genes that interact with transcription factors including NFkappaB and AP-1, to inhibit their activation, thereby preventing activation of many genes encoding immune effector and pro-inflammatory cytokines. Also, protein kinases involved in intracellular signalling, are directly activated resulting in phosphorylation of various targets of which Annexin (AXA)-1 is critical in inhibiting biosynthesis of both purines and DNA. This results in reduced proliferation of B and T lymphocytes, reduced immune effector mechanisms and reduced recruitment of mononuclear cells including monocytes into sites of immune inflammation. Methotrexate also blocks DNA synthesis and hence cellular proliferation but also induces release of adenosine. This inhibits chemotaxis of polymorph neutrophils and release of critical cytokines such as TNF-alpha and Interleukins 6 and 8. Hydroxyurea also inhibits DNA synthesis with inhibitory effects on proliferation of lymphocytes and possibly kerationcytes. Even though many new agents with much greater selectivity are coming through into clinical use, this group of old agents still have an absolutely central position in the therapeutic armamentarium. Their value lies in the fact that they are not 'clean' drugs with narrow effects but they inhibit a wide range of mechanisms involved in immune and inflammatory processes.

Azathioprine↗
PubMed2001

Localization of a gene (MCUL1) for multiple cutaneous leiomyomata and uterine fibroids to chromosome 1q42.3-q43.

Dominant transmission of multiple uterine and cutaneous smooth-muscle tumors is seen in the disorder multiple leiomyomatosis (ML). We undertook a genomewide screen of 11 families segregating ML and found evidence for linkage to chromosome 1q42.3-q43 (maximum multipoint LOD score 5.40). Haplotype construction and analysis of recombinations permitted the minimal interval containing the locus, which we have designated "MCUL1," to be refined to an approximately 14-cM region flanked by markers D1S517 and D1S2842. Allelic-loss studies of tumors indicated that MCUL1 may act as a tumor suppressor. Identification of MCUL1 should have wide interest, since this gene may harbor low-penetrance variants predisposing to the common form of uterine fibroids and/or may undergo somatic mutation in sporadic leiomyomata.

Chromosome Mapping↗
PubMed2001

Ultraviolet-B-induced erythema is mediated by nitric oxide and prostaglandin E2 in combination.

Ultraviolet-B-induced erythema (one, two, or four times the minimal erythema dose) was reduced but not abolished by application of 1% indomethacin gel immediately after irradiation of human skin. Continuous synthesis of prostaglandins is reflected by similar levels of indomethacin-mediated inhibition of erythema at any time within 48 h after irradiation. Repeated applications of indomethacin did not increase the inhibition. Twenty-four hours after irradiation with four minimal erythema doses, mean prostaglandin E2 levels in suction blisters were 27.2 ng per ml (SEM 11) compared with 8.6 ng per ml in unirradiated skin (n = 25; p < 0.01). Prosta glandin E2 levels in dermal tissues, sampled by microdialysis (depth 0.6 +/- 0.1 mm), were 310 pg per ml (SEM 123) and 237 pg per ml (SEM 88) in irradiated and unirradiated skin, respectively (n = 7, n.s.). Nitric oxide also made a significant contribution to ultraviolet-B-induced erythema. Ultraviolet erythema was inhibited by L-NAME in a dose-related fashion with 2 mM L-NAME causing total abolition of the response. L-NAME was effective at all time points up to 48 h suggesting that NO was produced continuously. NO was undetectable in suction blister fluid but in dermal microdialysate NO was present at 44.3 ng per ml (SEM 6.2) following ultraviolet B compared with 26.0 ng per ml (SEM 8.0) in unirradiated skin (p < 0.05), approximately 1000 times the molar concentration of prostaglandin E2. These findings confirm prostaglandin E2 and NO to be mediators of ultraviolet-induced erythema. They also show that there is prolonged synthesis of both mediators within the erythemal response and that synthesis of NO is induced by lower doses of ultraviolet B compared with that of prostaglandin E2.

Blister↗