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Biomedical subjects

M Picardo

Publications and source records attributed to M Picardo.

At least 109 records · Page 6Linked to original sources
PubMed1989

Azelaic acid--biochemistry and metabolism.

Medium chain length dicarboxylic acids (DA) from C8 to C13 are competitive inhibitors of tyrosinase in vitro. The introduction of electron acceptor groups or electron donor groups into the 2 and/or the 8 position of the molecule enhances or reduces respectively the inhibitory effects of DA. In addition to tyrosinase, DA can reversibly inhibit thioredoxin reductase, NADPH cytochrome P450 reductase, NADH dehydrogenase, succinic dehydrogenase and H2CoQ-Cytochrome C oxidoreductase. Among DA, azelaic acid (AA, C9 dicarboxylic acid) is extensively used because: 1) it is much cheaper than other DA; 2) it has no apparent toxic or teratogenic or mutagenic effect; 3) when administered perorally to humans, at the same concentrations as the other DA, it reaches much higher serum and urinary concentrations. Serum concentrations and urinary excretion obtained with intravenous or intra-arterial infusions of AA are significantly higher than those achievable by oral administration. Together with AA, variable amounts of its catabolites, mainly pimelic acid, are found in serum and urine, indicating an involvement of mitochondrial beta-oxidative enzymes. Short-lived serum levels of AA follow a single 1 h intravenous infusion, but prolonging the period of infusion with successive doses of similar concentration produces sustained higher levels during the period of administration. These levels are consistent with the concentrations of AA capable of producing a cytotoxic effect on tumoral cells in vitro. AA is capable of crossing the blood-brain barrier: its concentration in the cerebrospinal fluid is normally in the range of 2-5% of the values in the serum.

Animals↗
PubMed1989

Effect of dicarboxylic (C6 and C9) acids on a human squamous carcinoma cell line in culture.

In tissue culture, azelaic acid (C9) has been shown to have an anti-proliferative and cytotoxic effect on human and murine malignant melanocytes, with inhibition of mitochondrial oxido-reductase enzymes and DNA synthesis, and damage to mitochondria. Recent reports of effects on differentiation of normal keratocytes have led to the present study of its effects on a squamous carcinoma cell line. Cells were exposed to single doses of disodium salts of azelaic (C9(2)Na) and adipic (C6(2)Na) acids at concentrations of 10(-2)M and 5 x 10(-2)M for 48 hrs. Only C9(2)Na at 5 x 10(-2) M for 4 hrs., and longer, significantly affected proliferation, and the cells exhibited massive swelling of mitochondria with loss of cristae. The results further confirm the probable value of azelaic acid as a general anti-tumoral agent rather than a specifically melanocytotoxic one. They could justify clinical studies on the effect of topical azelaic acid therapy on squamous cell carcinoma in vivo.

Adipates↗
PubMed1989

[Azelaic acid in the treatment of acne].

This review is an update of the literature accumulated over the past 6 years following the original observation that topically applied azelaic acid, a non-toxic C9 dicarboxylic acid, has a beneficial therapeutic effect on acne vulgaris. These studies have shown that azelaic acid has a modulating influence on the process of keratinization, and that it acts as a keratolytic and anti-comedogenic agent. There is evidence that it inhibits mitochondrial and microsomal oxido-reductases, including 5-alpha-reductase, and that it may interfere with the process of sebogenesis. It has a spectrum of antimicrobial activity, both in vitro and in vivo, against aerobic microorganisms and is effective against the anaerobic Propionibacterium acnes. Extensive multi-centre clinical trials have established that topical azelaic acid (a 20% cream) is an effective treatment for all types of acne. It compares well with other agents, such as topical tretinoin or benzoyl-peroxide, or oral tetracycline. It is non-irritant, and does not give rise to allergic or photo-toxic reactions. Its use is not associated with teratogenicity, possible endocrine unbalance, or the disadvantages of antibiotic treatment. It can be applied for long periods, in recurrences, and as maintenance "spot" therapy against individual lesions.

Acne Vulgaris↗
PubMed1989

[Seborrhea-like dermatitis in the acquired immunodeficiency syndrome. Clinical, histological, and microbiological aspects and biochemical findings].

Seventy-six patients diagnosed as having seborrheic dermatitis (SD) were divided into two groups: group A (n = 22) otherwise healthy subjects (HIV negative) and group B (n = 54) HIV positive (ARC and AIDS cases). Thirty normal healthy subjects without SD were considered as control (group C). The three groups were subjected to the following analyses: A) skin surface lipids (SSL) and fatty acid pattern of cholesterol esters, wax esters, triglycerides and free fatty acids fractions in the affected areas; B) plasma levels of Vitamin E and fatty acids of phospholipids; C) erythrocyte glutathione peroxidase (3 cases for each group); D) frequency of Pityrosporum species in the affected areas; E) skin biopsy in the affected areas (2 cases for each group). Histological findings paralleled those reported in the Literature. SSL composition, fatty acid pattern and frequency of Pityrosporum species did not show significant variation among the 3 groups. On the contrary the blood levels of Vitamin E, polyunsaturated fatty acids of phospholipids and glutathione peroxidase were found significantly lower in A and B groups than in the controls.

AIDS-Related Complex↗
PubMed1989

[Mechanism of azelaic acid action in acne].

The physiopathologic mechanism of acne seems to be dependent on four main factors: a) sebum production and excretion; b) type of keratinization of the follicular channel; c) microbial colonization of the pilosebaceous unit and d) inflammatory reaction of the perifollicular area. Azelaic acid is effective in the treatment of acne because it possesses an activity against all of these factors. Azelaic acid is a competitive inhibitor of mitochondrial oxidoreductases and of 5 alpha-reductase, inhibiting the conversion of testosterone to 5-dehydrotestosterone. It also possesses bacteriostatic activity to both aerobic and anaerobic bacteria including Propionibacterium acnes. Azelaic acid is an anti-keratinizing agent, displaying antiproliferative cytostatic effects on keratinocytes and modulating the early and terminal phases of epidermal differentiation.

Acne Vulgaris↗
PubMed1989

Hyperpigmentary disorders--mechanisms of action. Effect of azelaic acid on melanoma and other tumoral cells in culture.

Azelaic acid has been shown to have a dose- and time-dependent inhibitory effect on both proliferation and cell viability of murine and human melanoma cells at a concentration of 10(-3) M and higher. It also has an inhibitory effect on DNA synthesis and plasminogen activator activity, and causes swelling and vacuolation of mitochondria. These effects have also been observed with other tumoral cells in culture-lymphoma and leukaemia derived cell lines, and human squamous cell carcinoma. Normal cells in culture are not generally affected by exposure to azelaic acid. Tissue culture experiments have confirmed the clinical activity and efficacy of azelaic acid, and biochemical conclusions as to its mode of action.

Animals↗
PubMed1988

Nickel sensitivity: effects of prolonged oral intake of the element.

25 nickel-sensitive females were given 10 mg NiSO4 in water in a single dose. 18 experienced generalized or localized flare-ups. 15 days later, 17 of the 25 patients were given gradually increasing daily doses of NiSO4 in water for 3 months. 14 ended the trial without flare-up, 3 had to stop because of intense worsening of cutaneous manifestations. A relationship does exist between the daily oral intake of nickel and its clinical manifestations, but it is not uniform and depends on the changing quantities and, above all, on the manner of intake. It would seem that a 10 mg NiSO4 oral challenge represents a sudden and large intake of the element to which the majority of sensitized subjects are not able to adapt. On the other hand, a gradual intake permits a majority of subjects to adapt to the element. We hypothesize that this behaviour is more likely due to intestinal adaptivity than to immunological tolerance.

Administration, Oral↗
PubMed1987

Comparative cytotoxicity of phenols in vitro.

Two melanotic human melanoma cell lines, IRE 1 and IRE 2, and the lymphoma- and leukaemia-derived cell lines Raji and K 562, were exposed to different concentrations (from 5 X 10(-3) M to 10(-5) M) of phenols, both substrates (s) and non-substrates (ns) of tyrosinase, in the presence or absence of the oxygen-radical-scavenger enzymes superoxide dismutase, catalase and peroxidase. Monophenols were tyrosine (s), 4-hydroxyanisole (s) and butylated hydroxyanisole (ns); diphenols were L-3,4-dihydroxyphenylalanine (s), dopamine (3,4-dihydroxyphenethylamine) (s), terbutylcatechol (s), hydroquinone (s) and resorcinol (ns); triphenols were 6-hydroxydopa (3,4,6-trihydroxyphenylalanine) (s) and methyl gallate (s). Triphenols and o- and p-diphenols underwent complete oxidation in culture medium within 24 h of incubation and were significantly more toxic than monophenols and the m-diphenol resorcinol, which, under the same cultural conditions, were much more stable. No significant differences in percentage survival were found among the different cell lines for each drug tested. The major component of toxicity up to 24 h of di- and tri-phenols is due to toxic oxygen species acting outside the cells and not to cellular uptake of these phenols as such. In fact the addition of oxygen-radical-scavenger enzymes significantly (P less than 0.01) decreased the adverse effect of these drugs on all cell lines. The lower toxicity of monophenols and resorcinol as compared with that of di- and tri-phenols is due, in our opinion, to the fact that they are less oxidized under the conditions existing in the culture medium, and therefore do not produce sufficient levels of oxygen radicals. For these compounds, a primary intracellular action has to be taken into account to explain their cytotoxicity.

Anisoles↗
PubMed1987

Mechanism of antitumoral activity of catechols in culture.

Cell lines Raji and K 562, lacking tyrosinase, and two melanotic human melanoma cell lines (IRE 1 and IRE 2), were exposed to concentrations from 5 X 10(-3) M to 10(-5) M of different phenols which are substrates of tyrosinase, i.e. l-dopa, dopamine, hydroquinone, terbutylcatechol, and of phenols which are not substrates of the tyrosinase, i.e. resorcinol, butylated hydroxyanisole and hydroquinone dimethyl ether. Cultures were carried out in the presence or in the absence of oxygen radical scavenger enzymes superoxide dismutase, catalase and peroxidase. The stability of each substance in culture medium was assayed by high performance liquid chromatography (HPLC). Results showed that: catechols which are substrates of tyrosinase decompose fully after 24 hr in medium; they are equally toxic for melanoma and non-melanoma cell lines; their toxicity increases when they are preincubated in medium for 24 hr and 48 hr before addition of cells; their toxicity is significantly reduced by addition of scavenger enzymes; on the contrary, phenols not substrates of tyrosinase are stable in medium and their toxicity is not reduced by scavenger enzymes. It is concluded that tyrosinase does not play a major role in catechol toxicity in vitro, which is probably due to some products of catechol decomposition, especially oxygen radicals, acting outside the cells.

Anisoles↗
PubMed1987

Contact dermatitis to fragrances.

2 groups of patients (1200 and 1500 respectively) were patch tested with different concentrations of perfume mix and fragrance raw materials. The study was to evaluate the incidence of contact dermatitis to fragrances in Roma, Italy, and the influence of limited variations in fragrance and perfume mix concentrations on patch test responses. The results showed that a decrease in the perfume mix concentration from 16% to 8% correlated with a decrease in the % of positive patients (from 5.2% to 3.6%). Variations in the concentration of fragrance raw materials did not influence the % of positive reactions in the 2 groups. The perfume mixture at 16% or 8% gave some positive results, without a corresponding reaction to any of the constituents, that were not related to an excited skin syndrome.

Adult↗
PubMed1987

Scanning electron microscopy of human and murine melanoma cells exposed to medium chain-length (C6-C12) dicarboxylic acids in tissue culture.

Human and murine (Harding-Passey and Cloudman) melanoma cells were exposed to various concentrations (1 x 10(-3) M-1 x 10(-1) M) of adipic (C6), azelaic (C9), and dodecanedioic (C12) acids for 1-6 hours in tissue culture, and the effects on shape and surface topography were examined by scanning electron microscopy. Effects, i.e., rounding up, concentration of microvilli, blebbing, and prominence of retraction fibrils were time and dose dependent, and for the same concentrations and exposure times, C12 had a greater effect than C9, and both a significantly greater effect than C6. These differential reactions to the three diacids parallel previously reported effects on cell kinetics and viability. The changes could be due to a prime effect on the cell membrane, or they might reflect phases of the cell cycle directed by action of the diacids on the nucleus; this latter seems unlikely. An effect on the cytoskeleton is possibly involved.

Animals↗
PubMed1986

Lipoxygenase activity of Pityrosporum in vitro and in vivo.

Lipid peroxidation has been investigated both in cultures of Pityrosporum supplemented with different lipid classes and in skin surface lipids from patients affected with pityriasis versicolor. Thin-layer chromatography (TLC) and 2 spectrophotometric methods were used: the indirect thiobarbituric acid test and the direct N,N-diethyl-1,4-phenylene-diammonium sulfate (DEPD) test. The coupling of the DEPD test with the TLC technique performed by different eluent systems allowed the detection of the specific lipoperoxides deriving from the oxidation of the different lipid classes. In the cultures, Pityrosporum was capable of peroxidating not only unsaturated free fatty acids, but also unsaturated triglycerides, cholesterol, and squalene. A similar lipid peroxidation was observed in patients with pityriasis versicolor in skin lipids from areas positive for fungal hyphae and spores and fluorescent under the UV lamp (366 nm). The lipoperoxide values were significantly higher (p less than 0.05) than in skin lipids from normal controls. Hyphae and spore-negative areas of patients with pityriasis versicolor, whether apparently normal or achromic, showed no evidence of a significant lipid peroxidation and neither did skin areas of patients with pityriasis alba. Though further investigations are necessary, it seems reasonable to suggest, in analogy with other biologic systems, that the presence in skin lipids of a significant amount of highly reactive and cytotoxic lipoperoxides may play a role in the pathogenesis of skin alterations in pityriasis versicolor, including damage to melanocytes and resulting achromia.

Cholesterol↗
PubMed1986

Immune complexes in patients with contact dermatitis.

By C1q binding assay, circulating immune complexes (cic) were detected in 19 out of 30 patients with contact dermatitis to nickel or chromium. Their presence was correlated with the duration of the disease, while any patients positive for cic showed any signs of type III immunopathological lesions. Atomic absorption analysis of the polyethlylene glycol precipitates (PEG ppt) from the sera of 16 patients--8 positive and 8 negative for cic--revealed an amount of nickel or chromium significantly higher in the PEG ppt from the sera of patients positive for cic.

Antigen-Antibody Complex↗
PubMed1986

Observations on cell kinetics and viability of a human melanoma cell line exposed to dicarboxylic acids in tissue culture.

Cultures of human melanoma cell line B0008 were exposed to the disodium salts of azelaic acid (C9 2Na), adipic acid (C6 2Na) and dodecanediaic acid (C12 2Na) at 10(-2) M and 5 x 10(-2) M for 24 hrs. None of the diacid salts had a significant effect on growth rate or viability of the cells, at 10(-2) M for 24 hrs nor had C6 2Na any effect at 5 x 10(-2) M. At 5 x 10(-2) M for 24 hrs, both C9 2Na, and C12 2Na had a significant effect in reducing both growth and viability. These effects were accompanied by morphological evidence of cell death, and swelling of mitochondria and accumulation of lipid droplets within cytoplasm of still viable cells.

Adipates↗
PubMed1985

Activity of azelaic acid on cultures of lymphoma- and leukemia-derived cell lines, normal resting and stimulated lymphocytes and 3T3 fibroblasts.

Azelaic acid (C9- -dicarboxylic acid) is a competitive inhibitor of tyrosinase and some oxidoreductase in vitro, and in vivo has a beneficial effect on lentigo maligna and malignant melanoma. A definite cytotoxic effect in cultures of malignant melanocytes was also reported. In order to establish if the cytotoxic effect of the diacid is exerted equally in the absence of tyrosinase, lymphoma- and leukemia-derived cell lines were cultured for 72 hr with 10(-3) M, 10(-2) M and 5 X 10(-2) M C9 disodium salt. Normal resting lymphocytes, lymphocytes activated by phytohemoagglutinin, and mouse Balb/c 3T3 fibroblasts were also tested to study a possible effect of azelaic acid on DNA synthesis and cell duplication. At 10(-3) M C9 had no effect on the viability of all the cells tested; at 10(-2) M and 5 X 10(-2) M, C9 2Na had a 50-80% cytotoxic effect on lymphoma- and leukemia-derived cell lines, while at the same concentrations it was not toxic to normal lymphocytes, either resting or stimulated, or to 3T3 fibroblasts. The experiments on cellular incorporation of (1-9 14C) azelaic acid showed that the radiocarbon uptake was two to three times higher for lymphoma- and leukemia-derived cell lines than for lymphocytes, either resting or stimulated, or 3T3 fibroblasts. Biochemical analysis revealed that the diacid underwent beta-oxidation in all the cell cultures. Fractionated centrifugations of 3T3 fibroblasts cultured in the presence of radiolabelled azelaic acid (2 X 10(-4) M) plus cold C9 2Na (10(-2) M), showed that the radioactivity was mainly concentrated in the cytoplasm. The results, being similar to those obtained by adding azelaic acid to cultures of melanoma cells, suggest that the cytotoxic effect of azelaic acid may be due to interference with mitochondrial oxido-reductase enzymes, rather than with tyrosinase. The difference in reaction between lymphoma- and leukemia-derived cell lines and normal or stimulated lymphocytes, and 3T3 fibroblasts, could be explained on the basis of a different degree of permeability of the cell membrane, and/or to a possible different sensitivity of reaction of mitochondrial functions. A similar argument could be used to explain the absence of an effect of dicarboxylic acids upon normal as compared with hyperactive or malignant melanocytes in vivo.

Animals↗