Biomedical subjects

J L McCullough

Publications and source records attributed to J L McCullough.

At least 19 recordsLinked to original sources

PubMed2004

The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo.

1 Tegaserod (Zelnorm) is a potent 5-hydroxytryptamine4 (5-HT4) receptor agonist with clinical efficacy in disorders associated with reduced gastrointestinal motility and transit. The present study investigated the interaction of tegaserod with 5-HT2 receptors, and compared its potency in this respect to its 5-HT4 receptor agonist activity. 2 Tegaserod had significant binding affinity for human recombinant 5-HT2A, 5-HT2B and 5-HT2C receptors (pKi=7.5, 8.4 and 7.0, respectively). The 5-HT2B receptor-binding affinity of tegaserod was identical to that at human recombinant 5-HT4(c) receptors (mean pKi=8.4) in human embryonic kidney-293 (HEK-293) cells stably transfected with the human 5-HT4(c) receptor. 3 Tegaserod (0.1-3 microm) inhibited 5-HT-mediated contraction of the rat isolated stomach fundus potently (pA2=8.3), consistent with 5-HT(2B) receptor antagonist activity. Tegaserod produced, with similar potency, an elevation of adenosine 3',5' cyclic monophosphate in HEK-293 cells stably transfected with the human 5-HT4(c) receptor (mean pEC50=8.6), as well as 5-HT4) receptor-mediated relaxation of the rat isolated oesophagus (mean pEC50=8.2) and contraction of the guinea-pig isolated colon (mean pEC50=8.3). 4 Following subcutaneous administration, tegaserod (0.3 or 1 mg kg(-1)) inhibited contractions of the stomach fundus in anaesthetized rats in response to intravenous dosing of alpha-methyl 5-HT (0.03 mg kg(-1)) and BW 723C86 (0.3 mg kg(-1)), selective 5-HT2B receptor agonists. At similar doses, tegaserod (1 and 3 mg kg(-1) subcutaneously) evoked a 5-HT4 receptor-mediated increase in colonic transit in conscious guinea-pigs. 5 The data from this study indicate that tegaserod antagonizes 5-HT2B receptors at concentrations similar to those that activate 5-HT4 receptors. It remains to be determined whether this 5-HT2B receptor antagonist activity of tegaserod contributes to its clinical profile.

Animals↗

PubMed2001

Photodynamic therapy of actinic keratoses with topical aminolevulinic acid hydrochloride and fluorescent blue light.

BACKGROUND: Aminolevulinic acid hydrochloride (ALA, Levulan) applied topically to actinic keratoses (AKs) leads to accumulation of the photosensitizer protoporphyrin IX, which, when activated by exposure to light, eradicates AKs. OBJECTIVE: We examined the safety and efficacy of photodynamic therapy using topical 20% ALA in a solution formulation and varying blue light doses to treat multiple AKs on the face and scalp. METHOD: This is a multicenter, investigator-blinded, randomized, vehicle-controlled study. RESULTS: Thirty-six patients with clinically typical AKs were treated with 20% ALA; 14 to 18 hours later, they were irradiated with a nonlaser fluorescent blue light source. With the optimal light dose of 10 J/cm(2), 88% of the AKs completely cleared 8 weeks after a single photodynamic treatment, compared with 6% after treatment with vehicle and light. CONCLUSION: Topical ALA PDT using a nonlaser, blue light source is an effective treatment for multiple AKs.

Administration, Topical↗

PubMed2000

Reducing wrinkles and other signs of aging.

As the aging population increases so does the demand for more effective modalities to combat the ravages of skin aging. It is important for dermatology nurses to understand and be able to explain to patients the preventive measures for skin aging and what can be realistically expected from currently available treatments.

Cosmetics↗

PubMed1997

Ablation of human nail by pulsed lasers.

BACKGROUND AND OBJECTIVE: The hard and resistant structure of the nail plate forms a natural barrier that limits the penetration of topical drugs. To overcome this barrier, the use of pulsed laser systems has been suggested. The purpose of this study was to evaluate the effect of four laser systems on nail plate ablation rates, ablation efficiencies, and subsequent craters morphology. STUDY DESIGN/MATERIAL AND METHODS: Solid state Er:YAG (2.94 microns, 250 microseconds), a Ho:YSGG (2.08 microns, 250 microseconds), a XeC1 Excimer (308 nm, 15 ns), and a novel solid-state ultrashort pulse laser (1.05 microns, 350 fs) were used. Ablation rates, surface morphology, and extent of collateral damage were evaluated using light and electron microscopy. RESULTS: Best ablation efficiencies were demonstrated with the ultrashort pulsed laser (1 micron/mJ), whereas maximum material removal per pulse was obtained with the Er:YAG laser (80 microns/ pulse). Scanning electron microscopy showed cracking damage with both Ho:YSGG and Er:YAG. XeC1 and the ultrashort pulse system left tissue surfaces free of cracks or thermal damage. CONCLUSION: With its minimal acoustical and mechanical impact, high efficiency, and negligible collateral damage, the ultrashort pulse laser at 3 J/cm2 was found to be the optimal laser system for nail ablation.

Humans↗

PubMed1997

Photodynamic therapy using topically applied dihematoporphyrin ether in the treatment of cervical intraepithelial neoplasia.

OBJECTIVE: To perform a phase I study of topically applied dihematoporphyrin ether (DHE) in the photodynamic treatment (PDT) of cervical intraepithelial neoplasia (CIN) using fixed DHE doses and application schedules, and a variable dose of 630 nm red light delivered by an argon-pumped dye laser. METHODS: Between February 1993 and April 1994, 24 nonpregnant women with a histologic diagnosis of CIN were enrolled. All patients had lesions involving at least 25% of the cervix that were colposcopically visible. Using a cervical cap, 2 ml of a 1% solution of DHE (Photofrin) in a 4% Azone and isopropyl alcohol vehicle were applied to the cervix 24 hr prior to PDT. An argon-pumped dye laser providing light at 630 nm was then used to perform PDT. Light was coupled into a 400-microm silica fiber optic terminating in a microlens which focused the laser radiation onto a circular field of uniform light intensity perpendicular to the tissue. The entire ectocervix was treated in a single field including a margin of 3-5 mm of normal cervix. Using a constant power density (150 mW/cm2) to avoid thermal injury, the PDT energy was increased every 4 patients in a phase I fashion (40, 60, 80, 100, 120, and 140 J/cm2). RESULTS: Thirteen patients with CIN I, 7 patients with CIN II, and 4 patients with CIN III were treated. The maximal energy density was well tolerated. Toxicity was minimal with no patients experiencing local necrosis, sloughing, or scarring; however, a mild vaginal discharge was noted in several patients. Systemic effects were absent. After 12 months of follow-up at 3-month intervals, 22 patients are evaluable of whom 15 (68%) are disease free. One patient was lost to follow-up and in another the cervical cap was dislodged. Four of the 7 failures or recurrences occurred at energy densities of 80 J/cm2 or less, while 8 of 11 (73%) patients were treated successfully with PDT at an energy density of 100 to 140 J/cm2. CONCLUSIONS: PDT with DHE and an argon-pumped dye laser at 630-nm wavelength delivering an energy density of 140 J/cm2 is safe and effective in treating CIN. Phase II studies using PDT at the prescribed application schedule and dose are indicated.

Administration, Topical↗

PubMed1997

Photodynamic therapy of actinic keratosis with topical 5-aminolevulinic acid. A pilot dose-ranging study.

OBJECTIVE: To examine the safety and efficacy of photodynamic therapy using topical 5-aminolevulinic acid (ALA) and red light to treat actinic keratoses (AKs). DESIGN: Actinic keratoses were treated with topical ALA (concentrations of 0%, 10%, 20%, or 30%) under occlusion for 3 hours. Before photodynamic therapy, sites were examined for fluorescence. Sites were irradiated with an argon pumped dye laser (630 nm) at fluences of 10 to 150 J/cm2. SETTING: Academic medical center. PATIENTS: Forty patients with 6 clinically typical, previously untreated AKs per patient. MAIN OUTCOME MEASURE: Complete resolution and decrease in lesion area of the AK relative to baseline evaluated at weeks 1, 4, 8, and 16. RESULTS: Three hours after ALA administration, lesions showed moderate red fluorescence. Cutaneous phototoxic effects, localized erythema and edema, peaked at 72 hours. Patients experienced mild burning and stinging during light exposure. Eight weeks after a single treatment using 30% ALA, there was total clearing of 91% of lesions on the face and scalp and 45% of lesions, on the trunk and extremities. No significant differences were observed in clinical responses with treatment using 10%, 20%, or 30% ALA. All concentrations of ALA were more effective than treating AKs with vehicle and light. CONCLUSIONS: Topical photodynamic therapy with ALA is an effective treatment of typical AKs. Complete clearing of nonhypertrophic AKs can be achieved with 10%, 20%, or 30% ALA that is easily tolerated by the patient. Lesions on the face and scalp are more effectively treated than lesions on the trunk and extremities. Hypertrophic AKs did not respond effectively.

Administration, Cutaneous↗

PubMed1996

Selective photosensitizer distribution in vulvar condyloma acuminatum after topical application of 5-aminolevulinic acid.

OBJECTIVE: Our purpose was to determine the feasibility of selective photosensitization of vulvar condylomas by use of tropical application of 5-aminolevulinic acid. STUDY DESIGN: In vivo fluorescence was assessed and biopsy specimens of condylomas were taken for fluorescence microscopy in 24 patients at different times after application of 2.5% 5-aminolevulinic acid ointment or 20% 5-aminolevulinic acid cream. RESULTS: Both in vivo fluorescence imaging and fluorescence microscopy showed selective fluorescence of condylomas of the labia minora and vestibule only within short time intervals, because fluorescence of poorly keratinized normal epithelium was induced by both 5-aminolevulinic acid formulations. In non-hair-bearing skin, lesional fluorescence remained highly selective. Fluorescence microscopy showed that 90 minutes after drug application peak selectivity in epithelial lesional fluorescence was significantly higher with 2.5% 5-aminolevulinic acid ointment (4.5 +/- 0.9) than it was with 20% cream (2.1 +/- 0.2). CONCLUSION: Selective fluorescence of vulvar condyloma acuminatum can be induced by nonselective topical 5-aminolevulinic acid application. Studies evaluating selective photodynamic destruction of condylomas are justified.

Administration, Topical↗

PubMed1995

Elevated numbers of proliferating mononuclear cells in the peripheral blood of psoriatic patients correlate with disease severity.

Although psoriasis is characterized by the accumulation of activated proliferating lymphoid cells in the psoriatic skin lesion, it is not known whether these cells are activated and proliferating before entry into the psoriatic plaque. The current study evaluates the number and phenotype of proliferating lymphoid cells in the blood of psoriatic patients. Proliferation of peripheral blood mononuclear cells was evaluated on cytospun preparations of these cells using autoradiographic techniques after pulsing the mononuclear cells with 3H-methyl thymidine for 2 h. The phenotypes of the labeled peripheral blood mononuclear cells were determined combining autoradiography and immunohistochemistry with monoclonal antibodies directed at CD3, CD4, CD8, CD11c, CD22, and human leukocyte antigen-DR. The data demonstrated elevated numbers of proliferating lymphoid cells in the blood of psoriatic patients compared with normal nonpsoriatic volunteers (p < 0.01). Furthermore, the number of circulating proliferating mononuclear cells increased significantly with increasing psoriasis skin disease severity (correlation coefficient 0.95; p < 0.0001). When the phenotype of the proliferating cells in the blood was examined, the numbers of T cells (CD3+, CD4+, CD8+ cells), B cells (CD22+ cells), monocytes (CD11c+ cells), and human leukocyte antigen-DR+ cells were significantly elevated compared with nonpsoriatic skin (p < 0.01) and increased with increasing disease activity (correlation coefficient range 0.48-0.74; p < 0.05). The data suggest a generalized systemic activation of T, B, and monocytic cells that results in labeling of up to 0.16% of the circulating mononuclear cells with 3H-methyl thymidine (i.e., proliferating and presumably activated) when assayed in vitro.

Cell Division↗

PubMed1995

Methotrexate therapy of psoriasis: differential sensitivity of proliferating lymphoid and epithelial cells to the cytotoxic and growth-inhibitory effects of methotrexate.

Although methotrexate (MTX) is one of the most clinically effective therapies employed to treat psoriasis, the mechanism by which low-dose MTX acts to modulate the hyperplasia of psoriasis, leading to the restoration of clinically normal skin, is only partially understood. MTX has been considered a cytotoxic agent that mediates its effect primarily on proliferating or cycling epidermal cells. Recently, proliferating lymphoid cells have been identified in psoriatic lesions, raising the possibility that proliferating lymphoid cells could be another target cell that is killed by MTX. In this study, we examined the growth-inhibitory and cytotoxic effects of MTX on proliferating lymphoid cells [THP-1 (macrophage), and MOLT-4 (T cell)], epithelial cells (HeLa, and HaCat), and normal human keratinocytes (NHK) in vitro. The proliferating cells were exposed to MTX for 24 h, and placed in fresh media to mimic the transient MTX blood levels that result from once-weekly therapy. THP-1 and MOLT-4 were found to be 10-100 times more sensitive to the cytotoxic effects of MTX than were HeLa and HaCat, and more than 1000 times more sensitive than primary human keratinocytes. At MTX concentrations that would be expected to occur in vivo during once-weekly therapy, a large percentage (> 95%) of proliferating lymphoid targets would be killed, and only a small percentage (< 10%) of proliferating epidermal cells would be affected. This in vitro data suggests that in psoriasis proliferating lymphoid cells are more likely than epithelial cells to be a major cellular target of MTX in vivo.

Cell Division↗

PubMed1995

Effectiveness of topical therapy for psoriasis: results of a national survey.

Topical therapy is the major treatment approach for patients with psoriasis. However, the effectiveness of available drugs (response rates and long-term maintenance) is not well known. This study investigated the current perceptions of American dermatologists on the effectiveness of topical medications for patients with mild or limited psoriasis. In a survey of 225 American dermatologists, class I to II topical steroids were regarded as most effective: 29 percent of dermatologists expected most of their patients to experience clearing of lesions when treated with these agents. Much lower response rates were found with medium and low-potency steroids, anthralin, or tars. The percentage of patients whose skin remained clear of lesions decreased to 50 percent while receiving maintenance corticosteroid therapy by three months and to 29 percent after one year. Topical corticosteroids were considered less effective than the available photo/systemic therapies by 79 percent of physicians. More effective topical modalities need to be developed to treat patients with mild/limited psoriasis.

Administration, Topical↗

PubMed1991

Free-tissue transfers for limb salvage utilizing in situ saphenous vein bypass conduit as the inflow.

Using vein grafts to bypass sclerotic and occluded arterial segments is a well-established technique in vascular surgery. For infrapopliteal bypass, autogenous veins have better patency rates than synthetic grafts. Although not resolved, in situ bypasses seem to be better than reversed bypasses, especially for "far away" segments. Although the etiology is not understood, it is a well-known clinical finding that sclerosis affects arteries more than the veins and, as a whole, is more advanced in lower extremities compared with the trunk and upper extremities. Our experience with eight patients in whom critical soft-tissue defects were covered with free-tissue transfers in severely compromised lower extremities utilizing the in situ saphenous vein bypass as the inflow is presented. Simultaneous bypass and free-tissue transfers were performed in seven and delayed free-tissue transfer was done in one. Follow-up ranged from 6 months to 3 years. To date, two patients underwent amputations. Five patients are able to maintain bipedal ambulation. One patient is wheelchair-bound with intact lower extremities. In well-selected patients, this procedure may offer an alternative treatment to amputation. However, because of the complexity of these combined procedures, we strongly urge careful patient selection.

Adult↗

PubMed1991

Mid-infrared laser ablation of stratum corneum enhances in vitro percutaneous transport of drugs.

The precise removal of stratum corneum from cadaveric swine skin by a mid-infrared erbium:yttrium scandium gallium garnet laser (lambda = 2.79 microns; 250 microseconds pulse width) was assessed by electrical resistance measurements and documented by histology. The effects of stratum corneum removal by laser ablation and by adhesive tape-stripping on the in vitro penetration of 3H-hydrocortisone and 125I-gamma-interferon were determined. Excised swine skin was irradiated with laser (1 J/cm2; 31 mJ/pulse; 1 Hz; 2 mm spot diameter). For skin penetration studies, laser pulses were delivered to discrete 2-mm areas to ablate up to 12.6% of the total 3-cm2 stratum corneum diffusional area. Franz in vitro skin penetration chambers were used to measure the cumulative 48-h penetration of 3H-hydrocortisone and 125I-gamma-interferon in laser-treated and tape-stripped skin. Electrical resistance measurements and histologic studies demonstrated that 10-14 laser pulses at the above energy density were required to abolish skin resistance and selectively ablate stratum corneum without damage to adjacent dermal structures. Laser ablation of 12.6% of the surface area of stratum corneum produced a 2.8 and 2.1-times increase in permeability constant (kp) for 3H-hydrocortisone and 125I-gamma-interferon, respectively. These studies demonstrate that a pulsed mid-infrared laser can reliably and precisely remove the stratum corneum, facilitating penetration of large molecules such as 125I-gamma-interferon that cannot penetrate intact skin. This new technique may be useful for basic and clinical investigation of skin barrier properties.

Administration, Cutaneous↗

PubMed1991

Specificity of human keratinocyte X HeLa cell hybrid murine monoclonal antibodies.

The immunofluorescent staining patterns of three differentiation-specific monoclonals (HLK3, HLK7, HLK20) that display different immunofluorescent (IF) reactivity in normal and psoriatic epidermis, were examined in basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), as well as other human normal epithelial and nonepithelial tissues. Similar staining patterns within epidermis were seen with HLK3 (intercellular) and HLK7 (perinuclear) in psoriasis, SCC, and BCC. HLK20 selectively stained BCC and SCC within epidermis and dermis, and was negative in psoriasis. The monoclonals did not react with nonepithelial tissues, but repetitively displayed positive, granular reactivity with simple epithelia and transitional epithelium. Stratified squamous epithelia showed IF staining similar to normal epidermis for all three monoclonals. These new monoclonal antibodies offer new investigative tools to study abnormalities in keratinocyte differentiation in benign and malignant hyperplastic skin diseases.

Antibodies, Monoclonal↗

PubMed1989

Technical principles of direct innominate artery revascularization: a comparison of endarterectomy and bypass grafts.

Occlusive lesions of the innominate artery that require operation occur infrequently. Direct repair has been performed with low morbidity and mortality. There is debate over the best method of direct reconstruction. Twenty-six patients undergoing transsternal innominate artery repair over a 12-year period were reviewed to determine if either grafting or endarterectomy was superior and what technical factors might be responsible for success or failure. Most of the patients were women. Twenty-four of the patients had atherosclerotic lesions, whereas the other two had Takayasu's arteritis. Either neurologic or right upper extremity symptoms were present in 24 patients. Sixteen patients had grafting, and 10 underwent endarterectomy. There was one death. There were no strokes or transient ischemic attacks. Three patients experienced recurrence of their symptoms; all had failures of reconstruction. The use of a bifurcated graft in one patient was probably responsible for one recurrence of symptoms. Single limb grafts with added side arms are probably preferable to bifurcated grafts. Innominate artery grafting and innominate endarterectomy are equally effective, although grafting is applicable to more patients. Direct transsternal repair is the procedure of choice to correct innominate occlusive disease in patients who are good candidates for correction.

Adult↗

PubMed1989

Topical cyclosporine: effects on allergic contact dermatitis in guinea pigs.

Cyclosporine (CSA) is an effective immunosuppressive agent and is used in tissue transplantation. The present investigation was undertaken to determine the effect of topical delivery of CSA on allergic contact dermatitis in guinea pigs. Topical 15% CSA in an azone (1-dodecylazacycloheptan-2-one)-containing vehicle blocked local elicitation in previously dinitrochlorobenzene (DNCB) sensitized animals that received a single topical application just prior to elicitation. Elicitation was not blocked at a distant site, indicating a local effect of topical CSA. In contrast, topical CSA when applied twice daily for a total of 5 applications during sensitization only, did not block subsequent elicitation. These experiments suggest that cyclosporine may be beneficial in the therapy of human contact dermatitis, as well as other T cell mediated dermatoses.

Administration, Topical↗

PubMed1989

Skin photosensitivity and photodestruction of several potential photodynamic sensitizers.

The major side effect associated with porphyrins (Photofrin II) in clinical photodynamic therapy is skin photosensitivity. In order to avoid this deleterious reaction, patients must remain out of the sunlight for approximately 1 month. A possible procedure to reduce the amount of skin photosensitivity is to photodegrade (photobleach) the compound in the skin. In this study, we report a series of experiments describing the photodegradation rates of two photosensitizers currently receiving attention due to their potential for use in PDT (mono L-aspartyl chlorin e6 and chloroaluminum sulfonated phthalocyanine). These compounds are compared to Photofrin II (PfII). Experiments consisted of determining photodegradation rates and efficiencies of the sensitizers in (i) phosphate buffered saline (PBS), (ii) PBS with fetal calf serum (to enhance absorption and simulate cellular binding or deaggregation), (iii) Chinese Hamster Ovary cells, and (iv) Balb/c mice. We performed two standardized skin sensitivity assays using the Hartely albino guinea pig irradiated with a UV blue point lamp and Balb/c mice irradiated with the therapeutic wavelength of each sensitizer. In addition, we performed a cell clonogenicity assay comparing photodegraded and fresh PfII on CHO cells. The photodegraded PfII exhibited significant phototoxicity, although the fluorescence was bleached by more than 70%. The results show that PfII causes major skin photosensitization and that the other compounds produce no substantial skin sensitivity. Our studies suggest that photodegradation of PfII with 630 nm light has little influence on the phototoxicity of the compound. In addition, skin sensitivity was not alleviated with prior photobleaching with 405 nm light.

Animals↗

PubMed1989

Vasoactive pharmacologic responses of human skin xenografts in ciclosporin-treated rats.

Human skin xenografts in ciclosporin-treated rats have been reported to preserve many of the characteristics of normal human skin. This model was used to study the cutaneous responses of human skin xenografts and host rat skin to intradermal injections of vasoactive agents. The xenograft responses to corticosteroids (blanching), nicotinic acid (erythema), histamine HCl (urticaria), and privine (blanching) all paralleled those of the host rat skin. However, when quantitatively compared to the responses reported for human skin in vivo, the xenografts were less sensitive to these compounds. The large variability seen in the xenograft responses may be due to variable graft revascularization and to structural irregularities in the dermis from the recent grafting procedure. It is concluded that the lower sensitivity and variable responsiveness of the xenografts limit the potential usefulness of this pharmacologic model for evaluating vasoactive agents.

Animals↗

PubMed1989

Topical methotrexate therapy for psoriasis.

In vitro percutaneous penetration of methotrexate is enhanced with 1-dodecylazacycloheptan-2-one (laurocapram [Azone]). Laurocapram-containing methotrexate formulations provide effective local inhibition of epidermal DNA synthesis in the in vivo hairless mouse and minipig models, providing the biochemical rationale for topical use in the treatment of psoriasis. Topical methotrexate (0.1%, 0.5%, and 1%) in a laurocapram-containing formulation was tested in a two-center double-blind pilot clinical study of 42 patients with plaque psoriasis. Drugs were applied twice a day for six weeks, and lesions were scored weekly for erythema, scale, and elevation. An overall improvement of 50% or more in the combined scores for erythema, scale, and elevation was obtained with 0.1% methotrexate (64% of patients), 0.5% methotrexate (59%), and 1% methotrexate (56%) vs the vehicle alone (25%). These preliminary findings suggest that methotrexate preparations that provide adequate percutaneous absorption may have a beneficial effect in the treatment of psoriasis.

Administration, Topical↗