Drug reactions.
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Bibliographies as Topic↗
Biomedical subjects
B U Wintroub
Publications and source records attributed to B U Wintroub.
A human lung mast cell chymotrypsin-like enzyme. Identification and partial characterization.
We have used a high performance liquid chromatography assay, which detects chymotryptic cleavage of the phe8-his9 bond of angiotensin I to yield angiotensin II, in order to examine human lung mast cells for the presence of chymotryptic activity. Mast cells, purified from human lung by enzymatic dispersion, countercurrent elutriation, and Percoll gradient centrifugation, were lysed or challenged with goat anti-human IgE. In multiple experiments angiotensin II-converting activity was detected in lysates of 10-99% pure mast cell preparations. Regression analysis of net percent release values of histamine and the angiotensin I-converting activity from dose-response experiments demonstrated a correlation between the two parameters, indicating that the chymotrypsin-like enzyme is a constituent of the mast cell secretory granule. The chymotryptic activity was completely inhibited by 10(-3) M phenylmethylsulfonylfluoride but not by 10(-3) M Captopril, and the pH optimum of activity was 7.5-9.5. Gel filtration of released material separated the activity from tryptase and demonstrated an approximate molecular weight of 30-35,000. The mast cell enzyme, like a human skin chymotrypsin-like proteinase, can be distinguished from leukocyte cathepsin G by lack of susceptibility to inhibition by bovine pancreatic trypsin inhibitor. Thus, an enzyme with limited chymotryptic specificity is present in human lung mast cells. The Michaelis constant of the enzyme for angiotensin I of 6.0 X 10(-5) M is similar to that of endothelial cell angiotensin-converting enzyme and is consistent with a reaction of physiologic importance.
Angiotensin I↗
Selective expression of 15-lipoxygenase activity by cultured human keratinocytes.
Human keratinocytes isolated from neonatal skin express 15-lipoxygenase activity at a level far greater than that of any of the other pathways for lipoxygenation of arachidonic acid. The 10,000 x g supernatant of sonicates of 10(6) keratinocytes generates 15-hydroxy-eicosatetraenoic acid from 5 micrograms/ml of arachidonic acid at a mean maximum rate of 38 ng/30 min at 37 degrees C, that is similar to the activity of the 15-lipoxygenase of human airway epithelial cells and greater than that of endothelial cells and leukocytes. The unique mediators derived from the 15-lipoxygenation of arachidonic acid, that stimulate secretion and exert hyperalgesic effects, may achieve a concentration in skin sufficient to regulate local cellular and neural functions.
Animals↗
A human platelet angiotensin I-processing system. Identification of components and inhibition of angiotensin-converting enzyme by product.
Mechanisms controlling the local generation of angiotensin II by vascular tissue are incompletely understood. Human platelets were examined for their ability to metabolize angiotensin I. Platelet-dependent angiotensin I metabolism was detected by a high performance liquid chromatography assay which allowed quantitation of angiotensin I substrate utilized and products formed. The major product of platelet-dependent angiotensin I metabolism was identified as des-Leu10-angiotensin I. The platelet des-Leu10-angiotensin I-generating activity had a pH optimum of 6.0-6.5 and was inhibited 100% by mersalyl acid (10(-4) M), 86% by leupeptin (10(-4) M), and 95% by iodoacetamide (10(-2) M). The activity had an approximate Mr = 70,000 as determined by Sephacryl S-200 gel filtration. Intact human platelets stimulated with calcium ionophore (1-10 microM) released 13.7-30.8% of the des-Leu10-angiotensin I-generating activity. Des-Leu10-angiotensin I, the major product of platelet angiotensin I metabolism, inhibited human serum and purified rabbit lung angiotensin-converting enzymes with an I50 of 3.7 X 10(-6) and 2.0 X 10(-6) M, respectively. These results suggest that the platelet may control local angiotensin II formation at vascular sites both by metabolism of the precursor peptide angiotensin I and by generation of an endogenous angiotensin-converting enzyme inhibitor, des-Leu10-angiotensin I. This platelet-dependent pathway may contribute to the control of local levels of vasoactive peptides, such as bradykinin and angiotensin II, so as to alter local tissue blood flow.
Angiotensin I↗
Cutaneous drug reactions: pathogenesis and clinical classification.
Cutaneous drug reactions may be classified with respect to pathogenesis and clinical morphology. They may be mediated by immunologic and nonimmunologic mechanisms. Immunologic reactions require host immune response and may result from IgE-dependent, immune complex-initiated, cytotoxic, or cellular immune mechanisms. Nonimmunologic reactions may result from nonimmunologic activation of effector pathways, overdosage, cumulative toxicity, side effects, ecologic disturbance, interactions between drugs, metabolic alterations, or exacerbation of preexisting dermatologic conditions. Certain defined, cutaneous, morphologic patterns are frequently associated with cutaneous drug reactions. These include urticaria, photosensitivity eruptions, erythema multiforme, disturbance of pigmentation, morbilliform reactions, fixed drug reactions, erythema nodosum, toxic epidermal necrolysis, lichenoid eruptions, and bullous reactions. In addition, certain drugs cause defined cutaneous syndromes. These include iodides and bromides, hydantoins, corticosteroids, antimalarial agents, gold, cancer chemotherapeutic agents, tetracyclines, thiazides and sulfonamides, nonsteroidal anti-inflammatory agents, and coumarin. The criteria for evaluation of possible drug reactions are presented and reviewed.
Adrenal Cortex Hormones↗
Lamellar body-enriched fractions from neonatal mice: preparative techniques and partial characterization.
Several problems have frustrated the isolation of lamellar bodies (LB) from mammalian epidermis. We obtained pellets enriched in intact LB by utilizing the staphylococcal epidermolytic toxin to provide intact, outer epidermal sheets, by controlled homogenization in a cell disrupter, and by passage of homogenates through a graded series of nuclepore filters (Science 221:962, 1983). Such preparations contained more intact LB than did fractions prepared by a variety of differential or sucrose/metrizamide discontinuous centrifugation methods. Initial characterization of the enzymatic content of this fraction revealed it to be enriched in certain hydrolytic enzymes (acid phosphatase, carboxypeptidase, cathepsin B, acid lipase, sphingomyelinase, and phospholipase A), but strikingly depleted in all sulfatases, beta-glucuronidase, and the non-lysosomal protease, plasminogen activator. Thus, LB show some properties of lysosomes, although certain characteristic lysosomal enzymes are strikingly absent. Lamellar body fractions contained 2-3 times more lipid per unit weight than did homogenates, and were enriched in phospholipids, free sterols, and glycosphingolipids, but not in other neutral lipids or ceramides. In summary, whereas some of the enzymes in LB could participate in the metabolism of LB lipid precursors to hydrophobic barrier constituents, others may attack intercellular constituents, ultimately resulting in desquamation. The lipid profile of these organelles suggests that they deliver precursors of permeability barrier lipids to intercellular domains.
Acid Phosphatase↗
Guanadrel. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in hypertension.
Guanadrel sulphate is an orally active peripheral sympathetic inhibitor (adrenergic neuron-blocking drug). In comparative studies, guanadrel was comparable in efficacy with guanethidine or methyldopa in mild to moderately severe hypertension, although generally it caused fewer central nervous system side effects than methyldopa and less orthostatic dizziness and diarrhoea than guanethidine. However, its efficacy in patients whose blood pressure remains inadequately controlled by other drugs (except diuretics alone) has yet to be adequately demonstrated. Guanadrel has a rapid onset of action and a half-life of about 10 hours, thus dose titration can be achieved more rapidly than with guanethidine, and twice daily administration is appropriate. Generally, guanadrel has been well tolerated, withdrawal of treatment due to adverse effects seldom being necessary. Thus, guanadrel appears to be a suitable alternative to methyldopa for the treatment of mild to moderately severe hypertension not controlled adequately by diuretics alone.
Antihypertensive Agents↗
Chemistry of a human monocyte-derived cell line (U937): identification of the angiotensin I-converting activity as leukocyte cathepsin G.
Angiotensin-converting enzyme, a dipeptidyl carboxypeptidase, catalyzes the conversion of angiotensin I to the vasoactive peptide angiotensin II. The finding of angiotensin-converting enzyme in dexamethasone-stimulated cultured monocytes and alveolar macrophages prompted the examination of a human monocyte-like cell line (U937) for angiotensin I-converting activity. Conversion of angiotensin I (5 X 10(-5) mol/L) to angiotensin II by U937 cell extracts (10(4) - 4 X 10(6) cells) was detected, and the pH optimum for the reaction was 7.0 to 8.0. The U937 cell angiotensin I-converting activity was purified to homogeneity by carboxymethylcellulose chromatography and trasylol affinity chromatography. The purified protein performed similarly to purified human neutrophil cathepsin G on sodium dodecyl sulfate-gradient polyacrylamide gel electrophoresis (SDS-gradient PAGE), elicited a reaction of complete identity with neutrophil cathepsin G when diffused against anti-cathepsin G antiserum, and had quantitatively similar angiotensin I-converting activity as neutrophil cathepsin G. Neutrophils and U937 cells had 143 and 52 times greater angiotensin I-converting capability than cultured monocytes or peripheral blood mononuclear cells, suggesting the relative importance of mobile cells containing cathepsin G in the local generation of angiotensin II. These data identify the angiotensin I-converting activity of the U937 cell as leukocyte cathepsin G and provide evidence that the U937 cell has neutrophil-like as well as monocyte-like characteristics.
Angiotensin-Converting Enzyme Inhibitors↗
The fibrinogenolytic activity of purified tryptase from human lung mast cells.
The capacity of purified tryptase from human lung mast cells to metabolize human fibrinogen, fibrin, and plasminogen was evaluated. Tryptase (5 micrograms/ml) inactivated the thrombin-induced clotting activity of fibrinogen (100 micrograms/ml) with essentially similar t 1/2 values of 4.6 min in the absence of heparin and 5.8 min in the presence of heparin (20 micrograms/ml) that were not appreciably different than with lysine-Sepharose-purified plasmin (5 micrograms/ml). Fibrinogen treated with tryptase together with heparin lost all detectable clotting activity by 4 hr at 37 degrees C, whereas fibrinogen treated with tryptase alone resulted in destruction of only 80% of fibrinogen clotting equivalents after 16 hr. Tryptase alone was observed to cleave only the alpha-chains of fibrinogen by electrophoresis of tryptase-treated, denatured, and reduced fibrinogen in polyacrylamide gradient gels. Tryptase together with heparin cleaved first the alpha-chain and then the beta-chain, the latter cleavage corresponding to complete loss of fibrinogen clotting activity by 4 hr. No fibrinogen fragments with anticoagulant activity were generated by tryptase. In contrast, plasmin left no residual clotting activity after 4 hr of incubation and generated fibrinogen fragments with anticoagulant activity. Plasmin sequentially cleaved the alpha, beta, and gamma subunits of fibrinogen. Tryptase alone (6 micrograms/ml) or together with heparin (20 micrograms/ml) failed to activate plasminogen (0.6 mg/ml) after a 60-min incubation at 37 degrees C. Addition of urokinase to tryptase-treated or untreated plasminogen resulted in essentially identical plasmin activities (0.32 and 0.34 U/ml, respectively), indicating that tryptase neither activates nor destroys plasminogen. Tryptase (700 ng) also failed to substantially solubilize cross-linked fibrin (2.6 micrograms) or the corresponding amount of fibrinogen bound to plastic microtiter plates with or without heparin. The failure to solubilize fibrinogen and, possibly, fibrin is consistent with the observation that the apparent m.w. by SDS polyacrylamide gel electrophoresis of unreduced fibrinogen is not appreciably altered by prior treatment with tryptase, even though cleavage of alpha-and beta-chains is revealed after reduction. Fibrinogenolysis by tryptase complements other mast cell mediators with anticoagulant properties such as heparin and suggests a significant prevention of coagulation by activated mast cells.
Blood Coagulation Tests↗
Pott's puffy tumor. A clinical marker for osteomyelitis of the skull.
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Aged↗
Granulocyte-angiotensin system. Identification of angiotensinogen as the plasma protein substrate of leukocyte cathepsin G.
Cathepsin G, a human lysosomal neutral protease, converts angiotensin I to angiotensin II and cleaves angiotensin II from a plasma protein substrate. Experiments were designed that identified and characterized cathepsin G substrate as human angiotensinogen. A total of 2, 5, and 10 micrograms of purified substrate, incubated with 2 microL of partially purified human renin (2 Goldblatt units/mg) for 60 min at 37 degrees C, generated 2, 9, and 22 pmol of angiotensin I. Cathepsin G substrate and renin substrate activities copurified during Affi-Gel Blue affinity chromatography, hydroxylapatite chromatography, phenyl-Sepharose chromatography, and S-200 gel filtration. Disc gel electrophoresis of 10 micrograms of purified protein gave a single band containing both activities. The amino-terminal sequence contained the covalent structure of angiotensin I and was Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-X-Glu-Ser-Thr-Cys-Gl u-. Reduced and unreduced angiotensinogens were subjected to sodium dodecyl sulfate gel electrophoresis, and each gel showed two bands of Mr 65 000 and 62 000. The isoelectric point of the Mr 65 000 form was pH 4.5-4.3 and the Mr 62 000 form was pH 4.9. Functional, structural, and physiochemical evidence demonstrates that the substrate of cathepsin G is angiotensinogen. Thus, human neutrophils may utilize angiotensin I or angiotensinogen as substrate for angiotensin II generation. The granulocyte-angiotensin system does not require renin or converting enzyme and may function as a mobile effector pathway which modulates tissue blood flow and/or vascular permeability.
Amino Acids↗
Disseminated cryptococcosis presenting as herpetiform lesions in a homosexual man with acquired immunodeficiency syndrome.
A 31-year-old homosexual man with acquired immunodeficiency syndrome (AIDS) had cutaneous herpetiform lesions that showed numerous encapsulated organisms on Tzanck preparation. Subsequent cultures of cerebrospinal fluid and skin biopsy specimens substantiated a diagnosis of disseminated cryptococcosis. Cutaneous cryptococcosis should be considered in the differential diagnosis for skin lesions in the population with AIDS.
Acquired Immunodeficiency Syndrome↗
Angiotensin I conversion by human and rat chymotryptic proteinases.
Human skin chymotrypsin-like proteinase, human neutrophil cathepsin G, rat mast cell chymase, and rat salivary gland tonin are cell-derived serine proteinases of similar size with specificity for amino acids of aromatic residues. Each enzyme was examined for its ability to convert angiotension I to angiotensin II and to cleave a panel of synthetic substrates. Skin chymotryptic proteinase, cathepsin G, and tonin cleaved the phe8-his9 bond of angiotensin I and converted angiotensin I to angiotensin II without further degradation. In contrast, chymase formed relatively small amounts of angiotensin II because it preferentially cleaved the tyr4-ile5 bond of angiotensin I. The rank order of angiotensin I converting activity was skin chymotryptic proteinase greater than tonin greater than cathepsin G greater than chymase. The Km and Kcat for angiotensin I conversion by the human skin enzyme were 6.6 X 10(-5) M and 50 s-1, respectively. The angiotensin I converting activity of human skin chymotryptic proteinase is equal to or greater than the peptidyl dicarboxypeptidase angiotensin-converting enzyme. Substrate specificities of each enzyme were further distinguished by use of benzoyl-L-tyrosine ethyl ester. A limited immunologic characterization of each enzyme was performed with monospecific goat antiserum to cathepsin G and chymase by Ochterlony gel diffusion. Each antiserum gave a precipitin line against its respective immunogen without evidence of cross-reactivity against the other enzymes. Human skin chymotryptic proteinase, cathepsin G, and tonin provide unique pathways for the generation of angiotensin II in tissue and may be of significance in regulation of biologic processes of the tissue microenvironment. The kinetic constants of the human skin chymotryptic proteinase for angiotensin I conversion, are consistent with the potential to carry out a reaction of physiologic importance.
Angiotensin I↗
Dermatologic training for nondermatologists.
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Dermatology↗
Identification of chemoattractant activity for lymphocytes in blister fluid of patients with bullous pemphigoid: evidence for the presence of a lymphokine.
Bullous pemphigoid is characterized by the dermal infiltration of lymphocytes, which precedes the striking influx of eosinophils as the lesion evolves into the bullous phase. This finding prompted a search for chemoattractant activity for lymphocytes in the blister fluid of untreated individuals with bullous pemphigoid. We found such activity in the bullous fluids of 6 consecutive patients but not in a patient with pemphigus vulgaris. This lymphocyte chemoattractant activity separates into 4 peaks upon Sephadex G-100 chromatography and the peak of 56,000 daltons was further evaluated. Upon quaternary aminoethyl Sephadex-anion exchange chromatography this peak elutes at 4-8 ms and with preparative isoelectric focusing it demonstrates an isoelectric point of 8.6-9.0. This activity was susceptible to degradation by trypsin and neuraminidase, but was stable upon heating to 56 degrees C for 30 min. Its chemoattractant activity is predominantly chemokinetic by checkerboard analysis. As defined by chromatography, stability, and functional characteristics, this activity is similar to a recently described human lymphocyte chemoattractant lymphokine. This finding suggests that products of activated lymphocytes are present in blister fluids of patients with bullous pemphigoid and may contribute to the early influx of lymphocytes in this disease.
Blister↗
Lymphocyte subsets and Langerhans cells/indeterminate cells in erythema multiforme.
A peroxidase-antiperoxidase study using monoclonal antibodies directed against T and B lymphocytes and Langerhans cells/indeterminate cells (LC/IC) was undertaken in order to understand more clearly the changes observed in erythema multiforme. At the various stages of development, from normal skin to target lesions, the quantity of inflammatory cells differed, but in each case the number of T8+ (cytotoxic/suppressor) cells was greater than the number of T4+ (helper/inducer) cells in the epidermis, whereas the latter exceeded the former in the dermis. Concomitant with the initial epidermis changes, there was an increase in the number of T6+ (LC/IC) cells in the upper and lower epidermis. With slight to moderate basal unit destruction, the number of LC/IC in the upper epidermis exceeded those in the lower epidermis. With severe basal unit destruction, there was a loss of LC/IC in the lower epidermis as detected by T6 reactivity. In fully formed blisters, the LC/IC in the upper half of the epidermis were decreased in parallel with the degree of epidermal necrosis. The character of the lymphocytic inflammatory infiltrate and redistribution in LC/IC are similar to those findings described in allergic contact dermatitis. The clinical, histologic, and immunopathologic changes in erythema multiforme appear to be due in part to cellular immune mechanisms with the lymphocyte as the predominant effector cell, and our data suggest a possible role for LC/IC in this disorder.
Erythema Multiforme↗
Erythema multiforme: microvascular damage and infiltration of lymphocytes and basophils.
The sequence of alterations occurring in recurrent erythema multiforme was studied with clinical observations, 1-micrometer tissue sections, and immunofluorescence techniques. Lesions evolved through 3 stages: an initial red papule, a vesicle surmounting a red papule, and a target (iris) lesion. Focal endothelial cell swelling was present in clinically normal skin. In the red papule, endothelial cytoplasmic swelling, vacuolization, and nuclear hypertrophy with luminal obliteration of superficial venules developed. These venular alterations were more marked with endothelial cell necrosis, and involved deeper venules as well in vesicular and target lesions. Lymphocytes surrounded the venules and infiltrated the lower epidermis in the red papule and the vesicular lesions. Venular damage was correlated with the degree of infiltration by lymphocytes, apparently the primary effector cell, suggesting the venule as a primary target of injury. Hypogranulated basophils were noted around venules in vesicular and target lesions. Fibrin deposits were identified within and interstitially beneath the vesicles. The presence of lymphocytes, basophils, and interstitial fibrin deposition is similar to the changes of cutaneous delayed-type hypersensitivity and suggests a role for cell-mediated immunity in the pathogenesis of erythema multiforme.
Adolescent↗
Dermatologic practice: implications for a primary care residency curriculum.
The problems encountered, diagnostic procedures performed, and treatments prescribed in dermatology were studied in a primary care practice and in a dermatology clinic. Referrals from a primary care practice to a dermatology practice were analyzed. It was determined that nine disease categories accounted for more than 75 percent of the problems encountered in both settings. Only one diagnostic procedure was performed commonly in both the primary care and dermatology practices--skin scraping for fungal infection. Approximately 90 percent of the treatments prescribed in both settings fell within 13 categories. It is proposed that these findings be the basis for designing the curriculum in dermatology for residents in primary care medicine. The curriculum also should provide practical experience in dermatology and familiarity with selected, rarely encountered dermatologic conditions that have important therapeutic implications.
Boston↗