[Diagnostic quiz: pruritus and papules].
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Acantholysis↗
Biomedical subjects
Andrea Krautheim
Publications and source records attributed to Andrea Krautheim.
Beta-cell toxicity of ATP-sensitive K+ channel-blocking insulin secretagogues.
A prolonged exposure of isolated pancreatic islets to insulin secretagogues, the imidazolines phentolamine, alinidine and idazoxan (100microM each), the sulfonylurea tolbutamide (500microM), or the alkaloid quinine (100microM) resulted in morphological damage of 4-18% of beta-cells compared to less than 2% in controls. Thus, the question arose whether K(ATP) channel-blocking insulin secretagogues are beta-cell toxic as has already been suggested for sulfonylureas. The concentration- and time-dependency of the secretagogue-associated toxicity was documented by viability assays in insulin-secreting HIT T15 cells. Treatment for 24h with idazoxan reduced MTT conversion by 50% at 100microM and by 98% at 1000microM. Phentolamine and quinine reduced viability comparably at 1000microM, but were less toxic at 100microM. On the other hand, the imidazoline alinidine and the sulfonylurea tolbutamide were only moderately toxic (less than 40% viability loss at 1000microM). The imidazoline efaroxan appeared even to be non-toxic. Apoptotic DNA fragmentation and DEVD-caspase activation was observed at 100microM of idazoxan and phentolamine, whereas at 1000microM signs of necrosis predominated. Alinidine, tolbutamide and quinine treatment did not increase markers of apoptotic cell death. Blocking Ca(2+) influx by D600 did not diminish secretagogue-associated toxicity. Electron microscopy confirmed the validity of these observations for beta-cells in intact mouse islets. In summary, beta-cell toxicity of the tested insulin secretagogues varied widely and did not depend on a prolonged Ca(2+) influx via L-type Ca(2+) channels. Thus, secretagogue-mediated closure of K(ATP) channels is apparently not per se beta-cell toxic.
Animals↗
Topical treatment in acne: current status and future aspects.
During the last 20 years, the number of topical and systemic drugs for the treatment of acne vulgaris has been enriched. Topical drugs on the one hand have been newly discovered or further developments of already available agents such as in the group of retinoids or galenic formulation have improved efficacy or local tolerance. Topical retinoids are a mainstay in acne treatment since 1962. All-trans retinoic acid was the first and is still in use. Its irritative potential has led to the new galenics, i.e. incorporation in microsponges and in propolyomers, which increased the tolerability significantly. The isomer of tretinoin, isotretinoin, has the same clinical efficacy, but also a lower irritancy. A real breakthrough was adapalene, a retinoid-like agent, with a different retinoid receptor-binding profile, but in addition to the same clinical efficacy on inflammatory and non-inflammatory acne lesions compared to tretinoin, a better tolerability and, therefore, compliance. Unfortunately, over the past years topical retinoids have been less used in inflammatory acne than they should be, taking the the mechanisms of action into account. Topical antimicrobials, in particular topical antibiotics, should be used less often than in the past and only for short periods to avoid the development of resistances. It seems better to combine those agents with topical retinoids, with BPO or with azelaic acid to enhance the efficacy and slow down the development of resistance. BPO is still the gold standard for papular-pustular acne of mild-to-moderate type in concentrations of 2-5%. Azelaic acid is an alternative with efficacy on the comedo and is antibacterial without development of resistances. Finally, the physical removal by electrocautery or CO(2) laser of multiple densely packed closed comedones, macrocomedones and microcysts is necessary to enhance the efficacy of topical comedolytic agents and to speed up the therapeutic results. Photodynamic therapy has not yet been proven efficacious in controlled studies. Blue and red light can probably be used in association with local agents but enhancement of the irritative potential of topical and systemic agents has to be considered.
Acne Vulgaris↗
Transdermal penetration of topical drugs used in the treatment of acne.
Acne vulgaris is a very common skin disease. Most patients present with mild to moderate acne comedonica or papulopustulosa grade I-II. The first-line treatment for these cases is generally via the topical route, whereas systemic medication is indicated when higher severity grades with small nodes or scarring occur. There are several topical agents available that affect at least one of the main pathogenetic factors responsible for the development of acne: hyperseborrhoea, hyperkeratosis, microbial colonisation and inflammatory and immunological reactions. Topical retinoids have a comedolytic and anticomedogenic activity, and some of them have anti-inflammatory potency. Azelaic acid and benzoyl peroxide have a moderate to strong antibacterial effect without inducing bacterial resistance, which is becoming a significant problem with the increasing use of topical antibacterials. Topical antiandrogens may soon be available for the treatment of the pathogenetic factor hyperseborrhoea. The transdermal penetration and the resulting systemic bioavailability of the various topical agents has not been widely considered. Apart from the retinoids, which can be associated with the risk of embryotoxicity/teratogenicity, and clindamycin, which might cause pseudomembranous colitis, information on the systemic pharmacokinetics of other topical agents is not readily available. There is still no consensus on the safe use of topical retinoids in pregnancy, and the occurrence of pseudomembranous colitis after the topical use of clindamycin does not appear to be of clinical relevance. In general, topical anti-acne agents are well tolerated and, as would be expected from their limited transdermal uptake, other significant safety concerns have not so far arisen.
Acne Vulgaris↗
Nonradioactive technique to measure protein phosphatase 2A-like activity and its inhibition by drugs in cell extracts.
A nonradioactive assay has been developed that can be used to measure serine/threonine protein phosphatase (PP) activity, especially PP2A, in crude extracts from different cell lines. For this technique commercially available casein is used as an already phosphorylated substrate. The prerequisite for reliable measurements is the removal of free phosphate from cell extracts and substrate preparations with desalting columns. The use of different nonspecific or specific inhibitors as well as inhibition characteristics observed after extract dilution suggests that in the absence of magnesium, PP2A-like activity in the extracts is measured by this technique. Inclusion of magnesium allowed the detection of a protein phosphatase activity that is activated by magnesium, which is presumably PP2C. The use of structurally different as well as structurally related inhibitors of PP2A gave results comparable to those of reports from the literature that were obtained with radioactive assays. Thus, our data supported our hypothesis that this nonradioactive assay can be used for the identification of newly synthesized PP inhibitors as well as for performing structure-activity analysis within groups of such new agents.
Animals↗
Acne: topical treatment.
Acne vulgaris is a common skin disease, affecting about 70-80% of adolescents and young adults. It is a multifactorial disease of the pilosebaceous unit.(1) The influence of androgens at the onset of adolescence leads to an enlargement of the sebaceous gland and a rise in sebum production. Additional increased proliferation and altered differentiation of the follicular epithelium eventually blocks the pilosebaceous duct, leading to development of the microcomedo as the primary acne lesion. Concomitantly and subsequently, colonization with Propionibacterium acnes increases, followed by induction of inflammatory reactions from bacteria, ductal corneocytes, and sebaceous proinflammatory agents (Fig 1).(2-5)
Acne Vulgaris↗
Update in retinoid therapy of acne.
The pathogenesis of acne, the most common skin disease, is complex and multifactorial. Clinical experience has demonstrated that parallel targeting of various pathogenetic factors, achieved either by mono- or combination therapy with appropriate drugs, represents the most effective approach to treating acne. Topical retinoids have been shown to expulse mature comedones, reduce microcomedone formation, and exert immunomodulatory effects. They have broad anti-acne activity without the risk of inducing bacterial resistance, which justifies their use as first-line treatment in most types of noninflammatory and inflammatory acne and makes them uniquely suitable as long-term medication to maintain remission after cessation of initial combination therapy. Systemic isotretinoin as a monotherapeutic agent strongly affects all four major pathogenetic factors and has been, in the hand of experienced dermatologists, a potent and safe agent for the treatment of severe and recalcitrant acne forms for more that 20 years. However, patient counseling, careful monitoring, and evaluation and management of adverse events are necessary. The use of isotretinoin has experienced a drawback now that its indication has been lowered from a first-line to a second-line medication.
Acne Vulgaris↗