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Biomedical subjects

M A Pathak

Publications and source records attributed to M A Pathak.

At least 37 records · Page 2Linked to original sources
PubMed1984

Production of active oxygen species (1O2 and O2-.) by psoralens and ultraviolet radiation (320-400 nm).

Furocoumarins (psoralens) are potent skin photosensitizing agents that are used in combination with long-wavelength ultraviolet radiation (320-400 nm) in the treatment of psoriasis and other skin diseases. Twelve linear and angular psoralens, capable of forming monofunctional and bifunctional adducts with DNA, were examined with a view to elucidate the role of 1O2 and O2-. in evoking skin photosensitization reactions and skin carcinogenesis. The results showed that both linear psoralens (capable of forming interstrand cross-links) and isopsoralens (angular, monofunctional type) and 3-carbethoxypsoralen (a linear and monofunctional type) produced 1O2 and O2-., although at varying degrees. Psoralen and 3-carbethoxypsoralen produced 1O2 greater than isopsoralens (angelicins). However, nonphotosensitizing angelicin, 5-methylangelicin, and 4,8-dimethyl-5'-carboxypsoralen produced 1O2 greater than 8-methoxypsoralen and 5-methoxypsoralen. The three monofunctional angelicin derivatives (isopsoralens) produced more O2-. than 8-methoxypsoralen, 5-methoxypsoralen, and 3,4'-dimethyl-8-methoxypsoralen. 3-Carbethoxypsoralen, a potent generator of 1O2 and a moderate producer of O2-., was highly photolabile. Until recently, skin photosensitization reactions (erythema, edema, damage to DNA or the membrane of cutaneous cells, the inhibition of scheduled DNA synthesis and skin carcinogenesis, etc.) were believed to involve photocyclo-addition of psoralens to DNA mediated by a type-I or anoxic reaction (a sensitizer-substrate interaction through the transfer of hydrogen atoms or electrons, but no direct involvement of molecular oxygen). Oxygen-dependent sensitized photodynamic reactions of type-II, involving the production of reactive oxygen (1O2 and O2-.), were believed not to mediate psoralen photosensitization reactions. We suggest that 1O2 and O2-. may also participate in skin photosensitization and cell membrane-damaging reactions. The fact that certain monofunctional isopsoralens produce 1O2 and O2-. at rates comparable to or better than bifunctional psoralens suggests that these reactive moieties of oxygen could play a major role in explaining their recently observed carcinogenic property and cell membrane-damaging reactions (e.g., edema or inflammation, etc.).

Animals↗
PubMed1984

The role of active oxygen (1O2 and O(2)) induced by crude coal tar and its ingredients used in photochemotherapy of skin diseases.

Crude coal tar (CCT) and certain photoreactive ingredients of CCT are photosensitizing agents used in the treatment of skin diseases (psoriasis, atopic eczema, etc.). Limited information is available in elucidating the mode of action of CCT in clearing psoriasis or causing skin photosensitization reactions. The production of singlet oxygen (1O2) and superoxide radicals (O(2) or HO2), the formation of interstrand cross-links (ICL) in DNA, and the skin photosensitization reaction caused by CCT or the ingredients present in tar preparations have been examined. Both type I (oxygen-independent) and type II (sensitized reactions requiring molecular oxygen) reactions are induced by CCT. Our data show that CCT and some of the photoreactive ingredients present in CCT produce 1O2, O(2), and ICL in DNA upon exposure to UVA radiation. Based on the equivalent concentration, the efficiency of various agents to produce 1O2 was of the following order: hematoporphyrin greater than phenanthridine greater than acridine greater than methylene blue greater than CCT greater than fluoranthrene greater than anthracene greater than pyrene greater than 8-methoxypsoralen greater than anthralin greater than chloroquine greater than anthralin dimer. The O(2) formation with CCT and its ingredients was also of the same order except for anthracene which was found to be a strong producer of O(2). The therapeutic effectiveness of CCT appears to be due to: (a) its cytotoxic effects, and (b) the production of 1O2, O(2), and ICL by CCT and its photoreactive ingredients. The skin photosensitizing (smarting, edema, and erythema responses) and carcinogenic properties of CCT may also be related to the production of 1O2 and O(2) and the formation of ICL which appear to be responsible for inducing the damage to the DNA and cell membrane.

Animals↗
PubMed1984

Safety and therapeutic effectiveness of 8-methoxypsoralen, 4,5',8-trimethylpsoralen, and psoralen in vitiligo.

In this paper, we report on 366 East Indian patients with vitiligo who were treated for 2 to 3 years with either 8-methoxypsoralen (8-MOP), 4,5',8-trimethylpsoralen (TMP), or psoralen and sunlight. These patients with amelanotic macules had 10 to 70% skin involvement of 1 to 50 years duration. Male and female patients from ages 12 to 70 years were randomly assigned to 8 treatment groups; the study was conducted on a double-blind protocol. Patients in prone and supine positions were exposed to the sun for 45-60 minutes in gradually increasing doses between 11 a.m. and 2 p.m. thrice weekly and 2 hours after oral ingestion of the drug. The various drug dosage schedules investigated included 9 groups: 0.3 and 0.6 mg 8-MOP/kg; 0.8, 1.8, and 3.6 mg TMP/kg; a combination of 0.3 mg 8-MOP and 0.6 mg TMP/kg; 0.6 and 1.2 mg psoralen/kg, and a placebo. For ethical reasons, the placebo group was terminated after 9 to 12 months of therapy. All patients were photographed before enrollment and at intervals of 6, 12, 18, and 26 months during therapy. Of these patients treated for nearly 2 years, the faces of those 45% receiving the combination dose of 8-MOP plus TMP or low-dose 8-MOP (0.3 mg/kg) were fully repigmented, and nearly 60% achieved 75 to 100% repigmentation of the head and neck. The chest, abdomen, and back were repigmented nearly as well and better than the arms and legs. The patients receiving high-dose schedules of TMP and psoralen achieved better repigmentation response than those on lower dosage but still not as good as patients on 8-MOP or the combination group of 8-MOP plus TMP.(ABSTRACT TRUNCATED AT 250 WORDS)

Ficusin↗
PubMed1984

Chronic cutaneous effects of long-term psoralen and ultraviolet radiation therapy in patients with vitiligo.

Vitiligo is refractory to most therapeutic modalities. To assess the efficacy of a variety of PUVA therapies, we enrolled 596 subjects in a prospective study, and 230 were followed for up to 55 months. Various psoralen derivatives and dosage schedules were used. Each subject was examined at yearly intervals for therapeutic response and evidence of chronic PUVA toxicity. At 4 years after therapeutic inception, 29 (13%) developed lesions in remaining vitiliginous macules. Clinically, hyperkeratotic macules and hyperkeratotic, lichenoid, and telangiectatic papules were discerned. Histologic examination of these lesions revealed them to be actinic and lichenoid keratoses, verruca vulgaris, and hyperkeratosis with either hyperplasia or atrophy. No tumors were present. In perilesional skin, dermal collagen and elastic tissue degeneration, much greater in degree than reported in psoriatic skin, was observed. In this group of PUVA-treated patients, no increased risk of carcinoma was apparent during the follow-up period.

Adult↗
PubMed1984

Carcinogenic effects of monofunctional and bifunctional furocoumarins.

We initiated these studies to determine whether bifunctional (interstrand cross-linking) psoralens, such as 8-methoxypsoralen (8-MOP), are more carcinogenic than are the monofunctional, such as angelicin or isopsoralen derivatives, and 3-carbethoxysporalen (3-CP). Hairless mice (Skh:hr-1) in groups of 40 were treated three times weekly for 12 to 15 months. There were 17 groups, and the photocarcinogenic effects of 5 psoralens [8-MOP, 3-CP, 5-methylangelicin, 4,5'-dimethylangelicin (4,5'-DMA), and angelicin] were investigated. Ethanolic solutions of 0.01-0.1% psoralens were topically applied at 5.0 or 50 micrograms/cm2 from cervical to lumbar regions 45 minutes before exposure to UVA (320-400 nm) radiation (0.1, 2.5, or 7.5 joules/cm2). Control groups received either the drug application or UVA exposure only. The study revealed that isopsoralens, such as 5-methylangelicin or 4,5'-DMA, that form monofunctional adducts are more carcinogenic than bifunctional psoralens. The latency and time required for 50% prevelance of tumors was much longer with 8-MOP than with 4,5'-DMA or 5-methylangelicin. Mice treated with the latter 2 compounds had a greater number and larger tumors than mice treated with 8-MOP. The monofunctional angelicin was weakly carcinogenic, whereas 3-CP, also a monofunctional psoralen, was noncarcinogenic. Histologic examination revealed that tumors induced by 8-MOP, 5-methylangelicin, or 4,5'-DMA were all squamous cell carcinomas. Because of their skin-photosensitizing property and their ability to induce interstrand cross-links and severe damage to DNA in replication, bifunctional psoralens apparently produce more lethal damage in cells than do monofunctional isopsoralens.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Mechanisms of psoralen photosensitization reactions.

The basic aspects of cutaneous photosensitization reactions and the mode of therapeutic effectiveness of psoralens used extensively in the photochemotherapy of psoriasis and vitiligo have been reviewed. Psoralen-induced skin photosensitization and the therapeutic action of psoralens involve two distinct types of reactions that occur independently of each other and concurrently when the psoralen-treated skin (oral or topical) is exposed to 320-400 nm UV radiation. The first, type I, occurs in the absence of oxygen (anoxic) reaction and primarily involves photoreactions with DNA; the second, type II, is a sensitized reaction dependent on oxygen and involves the formation of singlet oxygen (1O2), superoxide anion (O-.2), and hydroxy radicals. The photoreactive form of psoralen is its triplet state, and the sites of reaction are 1) the cell membrane of the epidermal, dermal, and endothelial cells; 2) the cytoplasmic constituents, such as enzymes, RNA, lysosomes, etc.; 3) the cell nuclei (DNA and chromatin); and 4) psoralen-sensitized production of 1O2, O-.2, and hydroxy radicals, which we believe are responsible for cell membrane damage and vasodilation. The major damage would be initiated by a type I reaction and would be seen in the form of nuclear damage to DNA resulting from the interaction of psoralen with DNA and to a lesser extent with RNA. The skin photosensitization response (erythema, edema, membrane damage, etc.) would result from a type II reaction involving the generation of 1O2. In vitro and in vivo metabolism of 4,5',8-trimethylpsoralen and 8-methoxypsoralen is briefly outlined.

DNA↗
PubMed1984

Psoralen pharmacology: studies on metabolism and enzyme induction.

Psoralens, tricyclic furocoumarins with potent photosensitizing properties in the skin, are now widely used in the treatment of several dermatologic diseases. In this study, the metabolism of 4,5',8-trimethylpsoralen (TMP) and 8-methoxypsoralen (8-MOP) was studied in mouse liver. Orally administered TMP is transformed into several metabolites, the major one of which is 4,8-dimethyl-5'-carboxypsoralen (DMCP) in both humans and mice. Orally administered 8-MOP is metabolized into at least 5 fluorescent moieties, including 8-hydroxypsoralen, the 4'5'-dihydro-diol of 8-MOP, and furocoumaric acid. The effects of 3 psoralens, 8-MOP, TMP, and isopsoralen (angelicin) on hepatic microsomal drug-metabolizing enzymes and cytochrome P-450 were assessed in mice and rats. Administered orally to CD-1 mice daily for 6 days, 8-MOP caused twofold to threefold increases in hepatic aryl hydrocarbon hydroxylase (AHH), ethylmorphine N-demethylase, and cytochrome P-450. The absorbance maximum of the induced cytochrome was at 450 nm. Aniline hydroxylase activity was unchanged. Chronic administration of 8-MOP to Skh:hairless-1 mice caused significant enhancement of hepatic ethylmorphine N-demethylase and cytochrome P-450 but had no effect on AHH, whereas chronically administered TMP had no significant effect on any of these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Production of singlet oxygen and superoxide radicals by psoralens and their biological significance.

We have investigated a series of linear and angular furocoumarins, capable of forming either the monofunctional adducts (single strand) or bifunctional adducts (interstrand cross-links) with DNA with a view to examine the relationship of their skin photosensitizing potency, their ability to produce singlet oxygen (1O2) or superoxide radicals (O-.2 or HO.2), and their carcinogenic activity. The significance of photochemical interactions of psoralens and DNA is well known in skin photosensitization and skin carcinogenesis. Our data suggest that both monofunctional and bifunctional psoralens produce 1O2 and O-.2, and these reactive forms of oxygen may contribute to the development of skin cancer and membrane-damaging effects of these furocoumarins.

Cross-Linking Reagents↗
PubMed1983

Reusable ultraviolet monitors: design, characteristics, and efficacy.

Reusable ultraviolet dosimetry badges have been developed that provide a visual indication of daily cumulative ultraviolet (UV) exposure. These two-sided, tapelike devices measure UV radiation emitted by sunlight or an artificial UV light source exposure by means of a photochromic aziridine color change reaction that is UV-integrating but optically reversible. UV radiation falling on the exposure side of the badge generates a color change that can be seen from the opposite or readout side. End points are indicated by a visual match of the photochromic with a surrounding reference. This paper describes the construction, component characteristics, and clinical testing of two versions of a new photochromic dosimeter that selectively responds to either UVB (280-320 nm) radiation or UVA (320-400 nm) radiation of the solar spectrum. One version of this monitor, sensitive only to the mid-range UVB, has a peak sensitivity to 300 nm and has four end point markers revealing color changes corresponding to 0.4, 0.8, 2.2, and 6.5 times the minimal erythema dose of an average Caucasian. A second version, sensitive only to UVA, has a peak sensitivity at 355 nm and can monitor exposures ranging from 0.8 to 10 joules/cm2. Outdoor efficacy testing has shown that the UVB monitor is an effective predictor of UV dose-related 24-hour erythema response induced by sunlight. Following a measurement, these monitors can be rezeroed by exposing the readout side to sunlight for a few minutes. They can be reused for eight to ten times. The limitation of the sunlight-calibrated UVB monitor tag is its failure to predict erythema response produced by artificial UVB sources such as FS40 sunlamps.

Calibration↗
PubMed1983

Photobiology of melanin pigmentation: dose/response of skin to sunlight and its contents.

A randomized double-blind clinical trial involving twenty-two volunteers was conducted in two locations (Orlando, FL, and St. Paul, MN) to test the efficacy of the newly designed ultraviolet monitor badges (Sun Timers), described in another paper by us in this issue of the Journal, 1 and to establish the relationship between spectral band exposure dose and the biologic responses of erythema and pigmentation. Individuals with skin types II, III, and IV, exhibiting differences in reactivity to solar radiation, were exposed to varying doses of full-spectrum sunlight through templates mounted on the lower portion of the back. Simultaneously, on the upper portion of the back, the same volunteers were exposed through two different types of polyester filters that transmitted ultraviolet A (UVA) and visible radiation. Using templates with windows, exposures to full-spectrum sunlight, UVA, and visible radiation were carried out to 1, 2, 3, 6, and 9 sunburn units (approximately 30-270 millijoules/cm2 between 10:30 A.M. and 3:30 P.M. daylight time in mid summer), measured with the aid of a Robertson-Berger meter and an IL700 International Light radiometer. Erythema and pigmentation resulting from these exposures were graded (double-blind) immediately after exposure, at 24 hours, and after 5 days. Numerical skin response ratings at each exposure dose for different spectral bands were then averaged and plotted. It was found that the UVB monitor response was predictive of a 24-hour erythema response and 5-day pigmentation response within 30% of the biologic average for skin types II, III, and IV. UVA radiation stimulated melanogenesis. The minimal melanogenic dose (MMD) for skin type II was the same as the minimal erythemogenic dose (MED). The MMD for individuals of skin types III and IV was distinctly less than their MED. Thus, melanogenesis can be stimulated with a suberythemal dose of UVB or UVA radiation. The sun protection factor values of melanin for melanized skin have been estimated to vary from 1.0 (skin type II) to 4.3 (skin types V and VI).

Clinical Trials as Topic↗
PubMed1983

A study of the relationship between photosensitizing and therapeutic activity of 4,5',8-trimethylpsoralen, and its major metabolite 4,8-dimethyl, 5'-carboxypsoralen.

The molecular basis for the clinically observed differences in the skin photosensitizing activity and therapeutic effectiveness of the topically applied and orally administered drug trimethylpsoralen (TMP) was investigated. TMP, when tested topically, is a very potent photosensitizing and therapeutically effective furocoumarin in the treatment of psoriasis. When administered orally, however, it is significantly less photosensitizing and therapeutically a less effective drug than the commonly used furocoumarin 8-methoxypsoralen. This decreased reactivity of oral TMP is attributable to its poor solubility and rapid in vivo metabolic transformation to several inactive (nonphotosensitizing) metabolites, one of which is referred to as 4,8-dimethyl,5'-carboxypsoralen (DMeCP). The supporting evidence has been obtained by: (a) isolation of the urinary metabolite DMeCP and subsequent comparison of its properties with the synthetically prepared DMeCP and its methyl ester; (b) examining the dark and photochemical interactions of TMP, DMeCP, and DMeCP methyl ester with DNA and determining their ability to form interstrand cross-links with DNA; and (c) studying the inhibition of DNA and RNA synthesis in Ehrlich ascites tumor cells and the killing of bacteria and T2 bacteriophages. The structure-activity relationship of TMP and DMeCP also has been examined in normal human subjects and in patients with psoriasis. The order of topical therapeutic effectiveness in terms of ability to clear psoriasis plaques appeared to be: TMP greater than 8-MOP greater than DMeCP methyl ester greater than DMeCP. The data also suggest the methyl ester of DMeCP to be an interesting nonphotosensitizing furocoumarin that photoconjugates to DNA better than 8-MOP and is therapeutically effective in psoriasis.

Animals↗
PubMed1983

7-Methyl and 4,7-dimethylallopsoralen: monofunctional photoreagents toward DNA as potential photochemotherapeutic agents in hyperproliferative conditions.

7-Methyl- (1 a) and 4,7-dimethylallopsoralen (1 b), prepared about ten years ago and till now considered non-photosensitizing agents, have been re-investigated for studying their photochemical and photobiological properties. They form a molecular complex with DNA in the ground state, undergoing intercalation between two base pairs of the macromolecule. By successive irradiation with U.V.-A they covalently photobind to DNA inducing only the formation of mono-adducts. They are not able to induce erythema on guinea pig skin, but show evident antiproliferative activity on various biological substrates. Compound (1 b) shows both photochemical and photobiological properties at a degree higher than that of compound (1 a).

Animals↗
PubMed1983

The nature and molecular basis of cutaneous photosensitivity reactions to psoralens and coal tar.

The basic aspects of cutaneous photosensitization reactions and the mode of therapeutic effectiveness of psoralens and coal tar, the two groups of photosensitizing agents used extensively in the photochemotherapy of psoriasis, have been reviewed. Psoralen-induced skin photosensitization and the therapeutic action of psoralens involve two distinct types of reactions, and these two reactions occur independently of each other and concurrently when the psoralen-treated skin (oral or topical) is exposed to 320 to 400 nm of radiation. The first, type I, is an oxygen-independent reaction and primarily involves photoreaction with DNA; the second, type II, is a sensitized reaction dependent on oxygen and involves the formation of singlet oxygen (1O2). The photoreactive form of psoralen is its triplet state, and the sites of reaction are (1) the cell membrane of the epidermal, dermal, and endothelial cells; (2) the cytoplasmic constituents, such as enzymes, RNA, lysosomes, etc.; (3) the cell nuclei (DNA and chromatin); and (4) the sensitized production of 1O2, which is responsible for cell-membrane damage and vasodilation. The major damage would be initiated by a type I reaction and would be seen in the form of nuclear damage to DNA resulting from the interaction of psoralen with DNA and to a lesser extent with RNA. The skin photosensitization response (erythema, edema, membrane damage, etc.) would result from a type II reaction involving the generation of 1O2. Crude coal tar (CCT), widely used in the Goeckerman therapy for psoriasis, also produces type I and type II reactions. The therapeutic and photosensitizing actions of CCT are due to (1) the photoconjugation of the photoreactive ingredients of CCT with DNA, causing interstrand cross-links; and (2) the production of 1O2. CCT is an efficient producer of 1O2, more so than 8-methoxypsoralen, and is responsible for cell-membrane damage and cellular edema.

Cell Membrane↗
PubMed1982

Effect of epidermal growth factor on clonogenic growth of primary human tumor cells.

The effect of EGF on the soft agar colony-forming ability of fresh human tumor cells was assessed in 40 specimens obtained from various types of carcinoma including those of the breast, endometrium ovary, and other sites. Cells from four established human tumor cell lines (three breast and one endometrial) were also included in this study. The results showed that addition of EGF at a concentration of 50 ng/ml resulted in a 50% higher cloning efficiency in soft agar in 40% of the samples of fresh human tumors. When cells from tumor cell lines were plated in semi-solid medium containing EGF, the number of colonies formed was at least twice as high as controls. Cells from fresh tumor biopsies were assayed for EGF receptors to determine whether the correlation between the proliferative response in EGF-supplemented semi-solid medium as compared to control could be related to the number of EGF receptors present on the cells. Specific receptors for EGF were detected by using radioiodinated EGF in early-passage cell cultures from some of the tumors tested for clonogenicity. The number of receptors ranged from 0.3 to 3.27 X 10(5) per cell. Cells from two melanoma specimens possessed less than 0.3 X 10(3) EGF receptors per cell. We found no correlation between the number of EGF receptor on a cell surface and the mitogenic effect of EGF on the same tumor cells grown in semi-solid medium.

Biopsy↗
PubMed1982

Variegate porphyria in New England.

Variegate porphyria (VP) is an autosomal dominant disease characterized in adults by mechanical fragility and blistering of sun-exposed skin or acute visceral and neurological manifestations. The laboratory diagnosis of VP depends on a search for high levels of coproporphyrin and protoporphyrin in the feces. Variegate porphyria has been infrequently diagnosed in the United States. In this study of five New England families with VP, there were nine manifest, six latent, and six questionable cases among 40 individuals studied. This report reviews the diagnostic approach to and treatment of affected individuals and their families.

Acute Disease↗
PubMed1982

Sunscreens: topical and systemic approaches for protection of human skin against harmful effects of solar radiation.

This review deals with topical and systemic approaches for protection of human skin against the harmful effects of solar radiation. Two concerns about the deleterious effects of sun exposure involve: (1) acute effects (e.g., sunburn and drug-induced phototoxicity) and (2) potential long-term risks of repeated sun exposures leading to development of solar elastosis, keratoses, induction of both nonmelanoma and melanoma skin cancer, and alteration of immune responses and functions. Action spectra of normal and abnormal reactions of human skin to acute and chronic effects of solar radiation are presented with a view to helping the physician prescribe the appropriate sunscreens. Factors that influence acute effects of sunburn are reviewed. Various artificial methods effective in minimizing or preventing harmful effects of solar radiation, both in normal individuals and in patients with photosensitivity-related problems, are discussed. Emphasis is placed on the commercially available chemical sunscreens and their properties. Sun protection factor (SPF) values of several brand-name formulations determined with a solar simulator under indoor conditions (laboratory) and with solar radiation under natural, field conditions are presented. Factors responsible for variations of SPF values observed under indoor and outdoor conditions are reviewed. Systemic photoprotective agents and their limitations are outlined. The photobiology of melanin pigmentation (the tanning reaction) is briefly discussed, with emphasis on the dangers of using quick-tanning lotions for stimulation of the tanning reaction.

5-Methoxypsoralen↗
PubMed1982

Molecular aspects of drug photosensitivity with special emphasis on psoralen photosensitization reaction.

Photosensitization reactions involve phototoxic reactions and photoallergic reactions, which are less common. Common drugs and chemicals that photosensitize humans are listed. Phototoxic reactions include the following: 1) direct photosensitization (type I reactions), in which the reactions of the triplet-state sensitizer are directly attributable to a component other than oxygen (e.g., DNA, proteins, and cell membranes), and 2) indirect photosensitization (type II reactions), in which the triplet state of a sensitizer reacts first with molecular oxygen, producing an "active oxygen" intermediate that subsequently reacts with the biologic system. The active oxygen intermediates are singlet oxygen (1O2)k, superoxide radical anions (O(2), and hydroxy radicals. Psoralen-induced skin photosensitization appears to involve both type I and type II reactions. The formation of monofunctional bifunctional psoralen-DNA photoadducts (a type I reaction) is probably responsible for cell damage, cell death, mutation, and even skin carcinogenesis. The erythema response appears to be the result of a type II reaction.

Animals↗