Search PubMed⌕ Search

Biomedical subjects

K Kragballe

Publications and source records attributed to K Kragballe.

At least 127 records · Page 7Linked to original sources
PubMed1989

Pharmacokinetics of etretinate in psoriatic patients with liver fibrosis.

A study of the pharmacokinetics of etretinate in 7 psoriatic patients with liver fibrosis or liver cirrhosis is reported. Maximum plasma concentrations occurred within 1.5-4.0 hr. Absorption lag-times ranged from 0.3-2.5 hr, whereas the apparent absorption first order half-times (t1/2ka) were within the range of 0.3-1.2 hr. As judged from the AUC-values corrected for dose and body weight a six-fold interindividual variation existed with regard to the systemic availability of etretinate. Absorption and disposition rates of etretinate in subjects with hepatic fibrosis increasing to cirrhosis were not significantly altered compared with previous results in psoriatic patients with normal liver function.

Acitretin↗
PubMed1989

Treatment of psoriasis by the topical application of the novel cholecalciferol analogue calcipotriol (MC 903)

Calcipotriol (the synthetic compound MC 903) is a structural analogue of naturally occurring, biologically active calcitriol. Calcipotriol and calcitriol (1,25-dihydroxy vitamin D3) show similar receptor binding and comparable effects on cell differentiation. However, calcipotriol seems to be at least 100 times less potent in its effects on calcium metabolism. In a double-masked study involving 50 patients with psoriasis vulgaris, the efficacy and tolerability of ointments containing various calcipotriol concentrations (25, 50, or 100 micrograms/g) or the vehicle alone were compared in a study involving a right-left, within-patient randomized design. Patients were treated twice daily for 8 weeks. Marked improvement was seen in 40% of the patients treated with the 25-micrograms/g concentration of calcipotriol in 63% of patients treated with the 50-micrograms/g concentration, and in 88% treated with the 100-micrograms/g concentration. No patient treated with placebo had more than slight improvement. Five patients developed facial dermatitis during the study. The serum levels of ionized calcium were unchanged. This study demonstrates that calcipotriol ointment provides an effective and well-tolerated treatment of psoriasis vulgaris.

Administration, Topical↗
PubMed1989

Topical corticosteroids: mechanisms of action.

Corticosteroids modify the functions of epidermal and dermal cells and of leukocytes participating in proliferative and inflammatory skin diseases. After passage through the cell membrane corticosteroids react with receptor proteins in the cytoplasm to form a steroid-receptor complex. This complex moves into the nucleus, where it binds to DNA. The binding process then changes the transcription of messenger RNA (mRNA). Because mRNA acts as template for protein synthesis, corticosteroids can either stimulate or inhibit the synthesis of specific proteins. Thus corticosteroids are known to stimulate the production of a glycoprotein called lipocortin. The formed lipocortin inhibits the activity of phospholipase A2, which releases arachidonic acid, the precursor of prostanoids and leukotrienes, from phospholipids. In contrast, corticosteroids inhibit mRNA responsible for interleukin-1 formation. These actions of corticosteroids on arachidonic acid metabolism and interleukin-1 formation produce anti-inflammatory, immunosuppressive and anti-mitogenic effects. Although this theory based on protein synthesis may not explain all effects of corticosteroids, these examples illustrate that a specific action on the molecular level can explain some of the characteristic and typical pharmacological effects of topically applied corticosteroids. Additional studies of the mechanism of action of corticosteroids are warranted. Such studies will not only help to explain how corticosteroids work, but also create a background that is essential for the development of novel non-steroidal anti-inflammatory drugs.

Administration, Topical↗
PubMed1989

A low-fat diet supplemented with dietary fish oil (Max-EPA) results in improvement of psoriasis and in formation of leukotriene B5.

Several studies have indicated that certain lipoxygenation products of arachidonic acid, particularly leukotriene B4 (LTB4), may be involved in psoriatic pathophysiology. One way of inhibiting the formation of LTB4 is to replace arachidonic acid in phospholipids with eicosapentaenoic acid. Eicosapentaenoic acid is converted into LTB5, which has a lower biologic activity than LTB4. In the present study psoriatic patients were put on a low-fat diet supplemented with dietary fish oil (Max-EPA 30 ml daily), a source of eicosapentaenoic acid, for 4 months. Twenty-six out of 30 patients with psoriasis vulgaris completed the study. Moderate or excellent improvement was observed in 58% of the patients, while mild improvement or no change was observed in 19% and 23%, respectively. The capacity of peripheral blood neutrophils to synthesize LTB4 and LTB5 in vitro was determined after stimulation with A23187. Before the study, negligible amounts of LTB5 were formed. After 1 month the average of LTB5/LTB4 ratio was 0.42. No further increase of the LTB5/LTB4 ratio was found. There existed no relationship between the clinical response and the LTB5/LTB4 ratio. The results of the present study suggest that dietary fish oil supplementation may be used in the therapy in psoriasis. However, studies defining the dose and the quality of fish oils are imperative.

Adolescent↗
PubMed1989

A double-blind comparison of acitretin and etretinate in the treatment of severe psoriasis. Results of a Nordic multicentre study.

Acitretin, the free acid of etretinate, is less lipophilic and has a much shorter terminal half-life than the parent compound. The present double-blind, randomized study compared the therapeutic effectiveness and the tolerability of acitretin (n = 127) and etretinate (n = 41) in psoriasis. Patients were treated with 40 mg daily for the first 4 weeks and with an individually adjusted dose for the subsequent 8 weeks. The average daily doses of acitretin (0.54 mg/kg/day) and etretinate (0.65 mg/kg/day) were similar. The PASI (Psoriasis Area and Severity Index) scores improved in parallel in the 2 treatment groups. At the completion of the study, the PASI score improvement was 75.8% for acitretin and 70.8% for etretinate. Both acitretin and etretinate resulted in mucocutaneous side effects. Assessments of tolerability by investigators and patients showed a statistically significant difference in favour of etretinate. These results demonstrate that acitretin and etretinate have similar therapeutic effectiveness in psoriasis. Although the tolerance to acitretin was lower than to etretinate, acitretin offers the important advantage of a much shorter period of potential teratogenicity and is, therefore, to be preferred in women of childbearing potential.

Acitretin↗
PubMed1989

Antibodies to the Borrelia burgdorferi flagellum in patients with scleroderma, granuloma annulare and porphyria cutanea tarda.

It is generally accepted that cutaneous Lyme borreliosis comprises erythema chronicum migrans, lymphadenosis benigna cutis, and acrodermatitis chronica atrophicans. In recent years the tick-borne spirochete Borrelia burgdorferi has been associated with a number of other cutaneous disorders. We therefore investigated sera from 175 patients with localized scleroderma (morphea) (n = 64), systemic sclerosis (n = 74), granuloma annulare (n = 16) and porphyria cutanea tarda (n = 21) with the new, highly sensitive and specific Borrelia burgdorferi flagellum ELISA assay. As controls (n = 297) served normal healthy volunteers and patients with other skin diseases. It was found that the distribution of individual antibody values and the median antibody levels were identical in controls and in patients with scleroderma, granuloma annulare and porphyria cutanea tarda. These data do not support the hypothesis of an etiological association between Borrelia burgdorferi infection and scleroderma, granuloma annulare or porphyria cutanea tarda.

Adolescent↗
PubMed1989

Dietary supplementation with a combination of n-3 and n-6 fatty acids (super gamma-oil marine) improves psoriasis.

Psoriasis may improve during dietary supplementation with fish oil containing n-3 fatty acids including eicosapentaenoic acid. In the present study 17 psoriatic patients were treated with Super Gamma-Oil Marine containing a combination of n-3 and n-6 fatty acids (linoleic acid and gammalinolenic acid). After 4 months, excellent improvement was observed in 2 patients, moderate improvement in 8, mild improvement in 4, and no improvement in 3 patients. These results may indicate that a combination of n-3 and n-6 fatty acids is useful for the treatment of psoriasis. However, controlled studies including more patients are warranted.

Adult↗
PubMed1989

Multiple bites from the larvae of the tick Ixodes ricinus. A case report.

The case is presented of a 32-year-old man with multiple reddish-blue papules on both thighs and sporadic on the lower part of the trunk and lower legs, clinically compatible with multiple 'insect' bites. The lesions were found to be multiple bites from larvae of the tick Ixodes ricinus. The larvae are about 1 mm long, live very close to the ground, and mainly parasitize small rodents. They are, therefore, generally not well known. Although seldom encountered, we suggest that bites from the larvae of the tick Ixodes ricinus should be kept in mind in patients with multiple 'insect' bites, especially in periods with high tick activity. The differential diagnosis is important because the larvae may cause infection with the spirochete Borrelia burgdorgferi.

Adult↗
PubMed1988

Mass spectrometry of underivatized 15-hydroxyeicosatetraenoic acid and 15-hydroxyeicosapentaenoic acid.

A direct mass spectrometric method for 15-hydroxy metabolites of arachidonic acid and of eicosapentaenoic acid is described. 15-Hydroxyeicosanoids have the capacity to inhibit the formation of leukotrienes, potent mediators of inflammation formed by the 5-lipoxygenase pathway of arachidonic acid metabolism and may therefore have anti-inflammatory properties. 15-Hydroxyeicosatetraenoic acid (15-HETE) and 15-hydroxyeicosapentaenoic acid (15-HEPE) were synthesized using soybean lipoxygenase and arachidonic acid and eicosapentaenoic acid as substrates. These hydroxy fatty acids were then purified by reversed-phase high-performance liquid chromatography. This modified procedure provides rapid synthesis of multimilligram quantities of 15-hydroxyeicosanoids for in vitro and in vivo studies. Electron impact mass spectra of 15-HETE and 15-HEPE could be obtained directly without derivatizations.

Chromatography, High Pressure Liquid↗
PubMed1988

In vitro inhibition of leukotriene B4 formation by exogeneous 5-lipoxygenase inhibitors is associated with enhanced generation of 15-hydroxy-eicosatetraenoic acid (15-HETE) by human neutrophils.

Leukotrienes, products of the 5-lipoxygenase pathway of arachidonic acid metabolism, have been suggested to play a pathogenic role in psoriasis, because of their ability to induce skin inflammation and to stimulate epidermal proliferation. The 15-lipoxygenase product 15-hydroxy-eicosatetraenoic acid (15-HETE) has no proinflammatory capacity. In contrast, it can inhibit the activity of the 5-lipoxygenase. The purpose of the present study was to study the effect of 5-lipoxygenase inhibitors on the formation of 15-HETE by human neutrophils in vitro. Purified neutrophils were incubated with A 23187 (5 microM) and arachidonic acid (25 microM) with and without different inhibitors of 5-lipoxygenase activity (RS 43179, benoxaprofen, NDGA, and CP 66248). Methods for identifying eicosanoids included RP-HPLC and radioimmunoassay. Formation of leukotriene B4 was inhibited in a dose-dependent way, which was strongly correlated with a concomitant increase in the formation of 15-HETE (r = 0.97, p less than 0.01). The cyclooxygenase inhibitor indomethacin did not change 15-HETE formation. The stimulation of 15-HETE formation was not associated with cell damage as assessed by LDH release. Furthermore, identical incubations of T lymphocytes, characterized by a low 5-lipoxygenase activity, did not result in increased 15-HETE formation. These results show that inhibition of 5-lipoxygenase activity can lead to increased formation of 15-HETE. Because 15-HETE inhibits formation of 5-LO products, it may amplify the effect of 5-lipoxygenase inhibitors.

Arachidonate Lipoxygenases↗
PubMed1988

Improvement of psoriasis vulgaris after intralesional injections of 15-hydroxyeicosatetraenoic acid (15-HETE).

Psoriatic skin lesions are characterized by elevated levels of 5- and 12-lipoxygenase products (leukotrienes B4, C4, and D4, and 12-hydroxyeicosatetraenoic acid [12-HETE]), which can stimulate epidermal proliferation and induce skin inflammation. 15-Hydroxyeicosatetraenoic acid (15-HETE) has the potential to inhibit the activity of 5- and 12-lipoxygenases. The purpose of the present study was to determine the therapeutic effect of intralesional injections of 15-HETE. 15-HETE was formed by oxidation of arachidonic acid by soybean lipoxygenase, purified by reversed-phase high-performance liquid chromatography, and identified by mass spectrometric analysis. Thirteen patients took part in the investigation. Plaques with a diameter of approximately 1 cm were injected with 0.1 ml of 10 mumol/L 15-HETE, 0.1 ml of 1 mumol/L 15-HETE, or 0.1 ml of saline weekly. After 3 weeks the effect was evaluated clinically and histologically by an observer uniformed of the treatment given. We found that plaques injected with 10 mumol/L 15-HETE had cleared completely in four patients and improved considerably in seven. In one patient minimal improvement only was seen and in one patient no change was observed. Injection of 1 mumol/L 15-HETE was without effect in 11 patients and improvement was observed in two patients. Of the plaques injected with saline, minimal improvement was observed in one patient; otherwise the plaques had not changed. Injection of 0.1 ml of 10 mumol/L 15-HEPE (identical to 15-HETE except for five double bonds instead of four) induced only minimal improvement in one of four patients. The results imply that 15-HETE by a dose-dependent and stereospecific mechanism can improve psoriasis.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-Response Relationship, Drug↗
PubMed1988

Pharmacokinetics of etretin and etretinate during long-term treatment of psoriasis patients.

The aromatic retinoic acid derivative etretin has recently been introduced in the treatment of severe psoriasis and other dyskeratoses. Hitherto, the use of the carboxylic acid ester analogue, etretinate, has been hampered by an extremely long elimination half-life of up to 120 days for this drug. Seven patients of either sex from whom we recently reported single-dose pharmacokinetics have been studied after 1 and 3 months multiple dose administration of the drugs. Four were given etretin and three etretinate. Etretin, both as drug and as metabolite, was absorbed faster than etretinate as judged from t-lag, tm and t 1/2 ka. Etretin as drug was eliminated faster than the metabolite etretin, t 1/2 beta 2.39 +/- 1.16 days compared to 6.51 +/- 2.06 days. In patients receiving etretinate the terminal disposition or elimination half-lives for cisetretin (t 1/2 lambda 3 15.9 +/- 9.9 days) were longer than for the metabolite etretin and exhibit a pronounced interindividual variation from 4.25 to 22.8 days. Similarly, cis-etretin accumulated very marked in comparison to the metabolite etretin of the drug etretinate. Assuming 40% systemic availability for both drugs, the central compartment of distribution constituted about 12-32% in case of etretin and about 0.8-3.6% in case of etretinate of the calculated apparent total volume of distribution at steady state, which showed mean values of 3.5 and 39.6 1.kg.-1, respectively, presumably reflecting the higher lipophilic nature of the latter compound.

Acitretin↗
PubMed1988

Lipoxygenase products in experimental septic arthritis in dogs.

Induction of an experimental septic arthritis was performed in the juvenile dog knee by an intra-articular injection with Staphylococcus aureus. From plasma, lipoxygenase (LO) products of arachidonic acid were separated by reversed-phase high-performance liquid chromatography (RP-HPLC) after extraction of lipids. The plasma samples did not contain UV-detectable amounts of LO products other than the LTB4 metabolite 20-COOH-LTB4, and 12-HETE. Small amounts of chemokinetically active material were found coeluting with the eluate fraction of 20-COOH-LTB4, LTB4 and 12-HETE after RP-HPLC. After 48 hours of septic arthritis, resulting in a massive acute joint inflammation, no significant changes in LO products were observed.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1988

Changes in lipoxygenase products from synovial fluid in carrageenan induced arthritis in dogs.

A non-suppurative chronic arthritis was induced in the juvenile dog knee by intra-articular instillations with Carrageenan. Lipoxygenase products of arachidonic acid were separated from synovial fluid by reversed-phase high-performance liquid chromatography (RP-HPLC). After ten weeks we observed an accumulation of leukotriene B4 (LTB4) in synovial fluid in five out of six experimental knees (0.94 to 5.5 ng/ml), as judged by integrated optical density. Biological activity of LTB4 was confirmed by chemokinesis. LTB4 was not detected in control knees. The 15-lipoxygenase products, 15-hydroxyeicosatetraenoic acid (15-HETE) and 13-hydroxy-9,11-octadecadienoic acid (13-HODD), being inhibitors of 5-lipoxygenase, were found in relatively high levels in the control knees compared to the arthritic knees. The results denote LTB4 as a pro-inflammatory local mediator during carrageenan-induced arthritis; possibly, the decreased levels of 15-HETE and 13-HODD in the arthritic knees may have a regulatory function, thus facilitating LTB4 generation.

Animals↗
PubMed1988

15-Hydroxyeicosatetraenoic acid (15-HETE) specifically inhibits LTB4-induced chemotaxis of human neutrophils.

15-Hydroxyeicosatetraenoic acid (15-HETE), a 15-lipoxygenase (15-LO) product of arachidonic acid has the potential to inhibit leukotriene formation. In the present study the effect of 15-HETE on leukotriene B4 (LTB4)-induced polymorphonuclear leukocytes (PMN) and monocyte chemotaxis was investigated. LTB4-induced chemotaxis of PMNs was inhibited in a dose-dependent manner by 15-HETE. Maximum inhibition (68%) occurred at a 15-HETE concentration of 10(-4) M. The 15-LO product of eicosapentaenoic acid (15-HEPE) was approximately 10 times less potent in inhibiting LTB4-induced PMN chemotaxis. LTB4-induced chemotaxis of monocytes was unaffected by both 15-HETE and 15-HEPE. Using N-formyl-methionyl-leucyl-phenylalanine (FMLP) and complement split product C5a as chemoattractants, 15-HETE did not decrease PMN chemotaxis. Furthermore, 15-HETE itself did not affect random migration of leukocytes. The present results demonstrate that 15-HETE inhibits LTB4-induced chemotaxis of PMNs in vitro in a specific and selective way. Because 15-HETE not only inhibits formation, but also the effect of LTB4, it may be important in regulating LTB4-induced inflammation.

Adult↗
PubMed1987

Heterogeneous distribution of lipoxygenase products in psoriatic skin lesions.

Several biologically active lipoxygenase products or arachidonic acid (AA) have been demonstrated in psoriatic skin lesions. The purpose of the present study was to determine the amounts of the different lipoxygenase products simultaneously in psoriatic skin. Slices of psoriatic skin were obtained at different levels with a keratome. Extracted lipids were identified by high performance liquid chromatography, UV-absorption spectrum, radioimmunoassay, and chemokinesis. Leukotriene B4 (LTB4), and 12- and 15-hydroxy-eicosatetraenoic acid (HETE) were detected in most psoriatic lesions. However, there was a remarkable variation from lesion to lesion. The biopsy specimens contained: 276.2 +/- 126.0 pg/g wet tissue of LTB4, 3,130.0 +/- 2,898.0 ng/g wet tissue of 12-HETE, and 3,633.0 +/- 1,692.0 ng/g wet tissue of 15-HETE. No correlation was found between the levels of the different lipoxygenase products. The content of each of the identified lipoxygenase products was higher in the superficial part of the biopsy specimen consisting of approximately two-thirds of the epidermis plus papillary dermis than in the lower part consisting of approximately one-third of the epidermis plus some reticular dermis. Also, there was a great variation from one anatomical region to another within the same patient. Because these lipoxygenase products possess different biological activities, the variation in their occurrence may be important for understanding their potential role in psoriasis. To determine which lipoxygenase products may be of pathogenic importance, analysis of early psoriatic lesions is warranted.

Humans↗