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Biomedical subjects

A G Martin

Publications and source records attributed to A G Martin.

At least 19 recordsLinked to original sources
PubMed2001

Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results.

PURPOSE: Cutaneous T-cell lymphomas (CTCL) are malignancies of T cells appearing as skin lesions and are responsive to retinoid therapy. Safety and efficacy of a novel RXR-selective retinoid (rexinoid) bexarotene (Targretin, LGD1069; Ligand Pharmaceuticals Inc, San Diego, CA) was evaluated as a single-agent oral therapy administered once daily in an open-label study in patients with refractory advanced-stage CTCL. PATIENTS AND METHODS: Ninety-four patients with biopsy-confirmed CTCL in advanced stages (IIB-IVB) were enrolled at 26 centers. Fifty-six patients received an initial dose of 300 mg/m2/d oral bexarotene and 38 started at more than 300 mg/m2/d. RESULTS: Clinical complete and partial responses were reported by Primary End point Classification for the study in 45% (25 of 56) of patients enrolled at 300 mg/m2/d dosing. At more than 300 mg/m2/d, 55% (21 of 38) of patients responded, including 13% (five of 38) clinical complete. For the 300 mg/m2/d initial dose group, the rate of relapse after response was 36% and the projected median duration of response was 299 days. Improvements were also seen in overall body-surface area involvement, median index lesion surface area, adenopathy, cutaneous tumors, pruritus, and CTCL-specific quality of life. The most frequent drug-related adverse events included hypertriglyceridemia (associated rarely with pancreatitis), hypercholesterolemia, hypothyroidism, and headache. CONCLUSION: Bexarotene is the first in a novel class of pharmacologic agents, the RXR-selective retinoids, or rexinoids. Bexarotene is orally administered, safe, and generally well tolerated with reversible side effects, and is effective for the treatment of advanced, refractory CTCL.

Adult↗
PubMed2001

Regulation of nuclear factor kappa B transactivation. Implication of phosphatidylinositol 3-kinase and protein kinase C zeta in c-Rel activation by tumor necrosis factor alpha.

Transactivation by c-Rel (nuclear factor kappaB) was dependent on phosphorylation of several serines in the transactivation domain, indicating that it is a phosphorylation-dependent Ser-rich domain. By Ser --> Ala mutational and deletion analysis, we have identified two regions in this domain: 1) a C-terminal region (amino acids 540-588), which is required for basal activity; and 2) the 422-540 region, which responds to external stimuli as tumor necrosis factor (TNF) alpha or phorbol myristate acetate plus ionomycin. Ser from 454 to 473 were shown to be required for TNFalpha-induced activation, whereas Ser between 492 and 519 were required for phorbol myristate acetate plus ionomycin activation. Phosphatidylinositol 3-kinase (PI3K) and protein kinase C (PKC) zeta were identified as downstream signaling molecules of TNFalpha-activation of c-Rel transactivating activity. Interestingly, dominant negative forms of PI3K inhibited PKCzeta activation and dominant negative PKCzeta inhibited PI3K-mediated activation of c-Rel transactivating activity, indicating a cross-talk between both enzymes. We have identified the critical role of different Ser for PKCzeta- and PI3K-mediated responses. Interestingly, those c-Rel mutants not only did not respond to TNFalpha but also acted as dominant negative forms of nuclear factor kappaB activation.

Amino Acid Sequence↗
PubMed2001

A comparative trial of two retinoids commonly used in the treatment of acne vulgaris.

BACKGROUND: Topical retinoids are highly effective treatments for acne vulgaris. The various formulations and concentrations available allow physicians to tailor therapies to individual patient's needs and minimize the cutaneous irritation that is often observed with the use of these drugs. OBJECTIVE: To compare the efficacy and safety of tretinoin gel microsphere 0.1% with adapalene gel 0.1% in the treatment of acne vulgaris. METHODS: A 12-week double-blind study was conducted, and patients were evaluated at baseline and at weeks 2, 3, 4, 6, 8, 10, and 12. RESULTS: Although the two drugs displayed similar efficacy in the resolution of acne lesions at 12 weeks, a significantly greater reduction in the number of comedones was seen at week 4 among patients treated with tretinoin gel microsphere (p = 0.047). Patients receiving tretinoin gel microsphere had an increased incidence of dryness (weeks 8 and 10) and peeling (weeks 3, 6, 8, and 10) compared with those patients treated with adapalene gel, but the two groups were comparable with respect to erythema, burning/stinging, and itching. CONCLUSION: Both drugs have similar efficacy in the resolution of acne lesions but tretinoin gel microsphere may result in a faster onset of action in the reduction of comedones compared to adapalene.

Acne Vulgaris↗
PubMed2001

Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or persistent early-stage cutaneous T-cell lymphoma.

OBJECTIVES: To determine the safety and efficacy of oral bexarotene (Targretin capsules; Ligand Pharmaceuticals Incorporated, San Diego, Calif). DESIGN: The effects of 2 randomized doses of 6.5 mg/m(2) per day (with crossover for progression) vs 650 mg/m(2) per day (later modified to 300 mg/m(2) per day) were evaluated in an open-label, multicenter, phase 2 and 3 study conducted between February 1997 and November 1998. SETTING: Eighteen international cutaneous T-cell lymphoma clinics at academic referral centers. PATIENTS: Fifty-eight patients with biopsy-proven stage IA through IIA cutaneous T-cell lymphoma that was refractory to (or patients were intolerant of) treatment or had reached at least a 6-month response plateau under at least 2 forms of prior therapy (median of 3.5 prior therapies). INTERVENTION: Bexarotene (Targretin capsules) administered once daily with meal for 16 weeks or longer. MAIN OUTCOME MEASURES: Primary end point classification of overall response rate of complete and partial remissions determined by either the Physician's Global Assessment of Clinical Condition or the objective Composite Assessment of Index Lesion Severity. Body surface area, time to response, duration of disease control, time to disease progression, individual index lesion signs and symptoms, and quality of life parameters were secondary outcomes. RESULTS: Responses (> or = 50% improvement) were seen in 3 (20%) of 15 patients with an initial dose at 6.5 mg/m(2) per day (95% confidence interval [CI], 0%-40%), 15 (54%) of 28 patients at 300 mg/m(2) per day (95% CI, 35%-72%), and 10 (67%) of 15 patients at above 300 mg/m(2) per day (95% CI, 43%-91%). The rate of progressive disease was 47%, 21%, and 13% at the same dose levels, respectively. Eight (73%) of 11 patients crossing over from 6.5 mg/m(2) per day to higher doses subsequently responded. The median duration of response from start of therapy could not be estimated for the 15 patients at 300 mg/m(2) per day owing to low relapse rates in 2 patients (13%); at higher doses it was 516 days. The following drug-related adverse effects were reversible and treatable: hypertriglyceridemia (46 patients [79%]), hypercholesterolemia (28 patients [48%]), headache (27 patients [47%]), central hypothyroidism (23 patients [40%]), asthenia (21 patients [36%]), and leukopenia (16 patients [28%]). No cases of drug-related neutropenic fever, sepsis, or death occurred. Pancreatitis occurred in 3 patients with triglyceride levels higher than 14.69 mmol/L (1300 mg/dL), all of whom were taking 300 mg/m(2) or more of oral bexarotene per day. CONCLUSIONS: Bexarotene (Targretin capsules) (the first retinoid X receptor-selective rexinoid) was well tolerated and effective as an oral treatment for 15 (54%) of 28 patients with refractory or persistent early-stage cutaneous T-cell lymphoma at doses of 300 mg/m(2) per day. Hypertriglyceridemia and hypothyroidism require monitoring but are reversible and manageable with concomitant medication.

Administration, Oral↗
PubMed2000

Tumor necrosis factor-alpha activation of NF-kappa B requires the phosphorylation of Ser-471 in the transactivation domain of c-Rel.

Activation of the transcription factor NF-kappaB is controlled at two levels in resting T cells: an initial activation induced by the triggering of the TcR.CD3 complex and a second phase controlled by paracrine- or autocrine-secreted TNFalpha. The initial phase is regulated by p65 (RelA), whereas the second one is mainly dependent on c-Rel. We describe here a mutant clone, D6, derived from the parental T lymphoblastic line Jurkat that fails to activate NF-kappaB upon TNFalpha stimulation. This clone had no alteration in tumor necrosis factor-alpha (TNFalpha) signaling pathways nor in IkappaBalpha, -beta, or -epsilon expression and degradation. However, TNFalpha induced an exacerbated apoptotic response in this clone compared with Jurkat cells. This mutant clone showed a defect in the intermediate-late translocation of c-Rel to the nucleus promoted by TNFalpha stimulation, whereas early translocation is not affected. Activation or translocation of p65-containing complexes was not altered in this mutant clone. Sequencing of the c-Rel gene from this clone revealed a mutation of Ser-471 to Asn in the transactivation domain. The mutant S471N transactivation domain fused to the Gal4 DNA binding domain could not be activated by TNFalpha, unlike the wild type. Moreover, the overexpression of the mutant protein c-Rel S471N into Jurkat cells abolished TNFalpha-induced NF-kappaB activity, thus demonstrating that this mutation is responsible for the failure of TNFalpha stimulation of NF-kappaB. Moreover, extracts from TNFalpha-stimulated Jurkat cells phosphorylated in vitro recombinant wild type GST-c-Rel 464-481 but not the GST-c-Rel mutant. Thus, TNFalpha-induced phosphorylation of Ser-471 seems to be absolutely necessary for TNFalpha activation of c-Rel.

Amino Acid Sequence↗
PubMed1998

Once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the fingernail.

BACKGROUND: Onychomycosis is a prevalent infection of the nail caused primarily by dermatophytes. Fluconazole is active in vitro against the most common pathogens, penetrates into the nail bed, and is clinically effective in the treatment of a wide variety of fungal infections. OBJECTIVE: The purpose of this study was to assess the safety and efficacy of oral fluconazole 150, 300, and 450 mg administered once weekly compared with placebo in the treatment of distal subungual onychomycosis of the fingernail caused by dermatophytes. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study enrolling 349 patients with onychomycosis of the fingernails. Clinical and mycologic efficacy as well as measures of safety were assessed monthly for a maximum of 9 months of treatment, with additional safety visits occurring at weeks 2 and 6. For inclusion, patients were required to have clinically and mycologically documented onychomycosis of the fingernail caused by dermatophytes with at least 25% involvement of the target fingernail. After end of therapy, patients with improved or cured fingernails entered a blinded 6-month follow-up without drug treatment during which efficacy was assessed every 2 months. Efficacy was assessed by clinical (visual) and mycologic (microscopic and culture) measures. Clinical measures included assessments of the percentage of target nail involvement, measurement of the distance from the nail fold to the proximal onychomycotic border, and signs and symptoms of onychomycosis. RESULTS: Fluconazole was significantly superior to placebo in eradicating clinical and mycologic symptoms of onychomycosis, both at the end of active treatment and at 6 months after treatment (p=0.0001 for all efficacy measures). At the end of therapy, 91% to 100% of patients in the fluconazole groups were judged clinical successes, defined as reduction of the affected area of the target nail to less than 25% or cure, compared with 8% for placebo. Clinical cure rates at end of therapy were 76%, 85%, and 90% for fluconazole 150, 300, and 450 mg, respectively, compared with 3% for placebo. These clinical success and cure rates were largely maintained or improved during follow-up. Clinical relapse in cured patients during the follow-up period was very low (1.5% to 3.3%). Fluconazole demonstrated mycologic eradication rates of 89% to 100% at the end of treatment and 90% to 99% at the end of follow-up; for placebo the rates were 8% and 12%, respectively. CONCLUSION: Fluconazole administered once weekly is safe and effective in eradicating distal subungual onychomycosis of the fingernail caused by dermatophytes.

Adolescent↗
PubMed1998

Once-weekly fluconazole (450 mg) for 4, 6, or 9 months of treatment for distal subungual onychomycosis of the toenail.

BACKGROUND: Fluconazole is a bis-triazole antifungal agent approved for the treatment of oropharyngeal, esophageal, and vaginal candidiasis, serious systemic candidal infections, and cryptococcal meningitis. OBJECTIVE: The purpose of this study was to evaluate three different durations of once-weekly fluconazole for the treatment of onychomycosis of the toenail caused by dermatophytes. METHODS: In a multicenter, randomized, double-blind, parallel, placebo-controlled trial, 384 patients with distal subungual onychomycosis of the toenail received fluconazole, 450 mg once weekly, or placebo for 4, 6, or 9 months. For inclusion, patients were required to have mycologically confirmed distal subungual onychomycosis of the toenail with a large toenail at least 25% clinically affected but having at least 2 mm of healthy nail between the nail fold and the proximal onychomycotic border. Efficacy was assessed by clinical and mycologic (microscopic and microbiologic) measures at screening, at every treatment visit starting at month 3, and at months 2, 4, and 6 after therapy. Observed or volunteered adverse events were recorded and classified at all visits. RESULTS: At the end of treatment, very significantly superior clinical and mycologic results were achieved in all fluconazole groups compared with placebo (p=0.0001). This superiority was largely maintained over 6 months of follow-up. The clinical and mycologic responses of the 9-month treatment duration were significantly superior to the 4- and 6-month durations. Similar percentages of patients in the fluconazole and placebo groups reported adverse experiences for all three durations of the study. CONCLUSION: Results of this study support the efficacy and safety of fluconazole in the treatment of distal subungual onychomycosis of the toenail.

Adolescent↗
PubMed1998

Pharmacokinetics of three once-weekly dosages of fluconazole (150, 300, or 450 mg) in distal subungual onychomycosis of the fingernail.

BACKGROUND: Fluconazole has proven to be safe and effective for a variety of superficial and systemic fungal infections. Preliminary analysis of extensive Phase III studies suggests that it is very effective for the treatment of onychomycosis. Its pharmacokinetic properties, including low molecular weight and high water-solubility, suggest a unique ability to penetrate the nail. This feature is likely to account in part for fluconazole's effectiveness in the treatment of onychomycosis. OBJECTIVE: Determinations of plasma and fingernail concentrations of fluconazole were performed as part of a larger study comparing the safety and efficacy of once-weekly fluconazole (150, 300, and 450 mg) to placebo in the treatment of distal subungual onychomycosis of the fingernails caused by dermatophytes. The relationship between fluconazole concentrations and efficacy was also examined. METHODS: Pharmacokinetic studies were performed by means of plasma and fingernail samples from 133 patients, a subset of 349 patients participating in a double-blind, placebo-controlled clinical trial of fluconazole administered in once-weekly doses of 150, 300, or 450 mg until cure of onychomycosis or for a maximum of 9 months. Blood and fingernail samples for pharmacokinetic analysis were taken at baseline, at week 2, and at monthly intervals during the treatment phase of the study. Patients considered clinically cured or improved also participated in a 6-month follow-up study. During this phase, patients were monitored and samples taken every 2 months. RESULTS: Significant amounts of fluconazole were detected in the earliest fingernail samples taken (after 2 weeks of treatment). After two weekly doses, 30% to 33% of steady-state concentrations had been achieved in healthy nails and 22% to 29% in affected nails. Steady state was achieved in 3 to 5 months. Fluconazole concentration in nails as well as plasma followed dose-proportional pharmacokinetics. Nail:plasma ratios in affected nails were 0.4 to 0.6 at 2 weeks and 1.7 to 1.8 at 6 months. Fluconazole concentrations fell slowly after drug discontinuation and were still detectable 4 months after end of treatment. A statistically significant correlation was found between steady-state concentration and clinical and global outcomes. CONCLUSION: Fluconazole rapidly penetrates the fingernail, where it is retained at detectable levels for at least 4 months after drug discontinuation. A significant correlation exists between fluconazole concentration in the fingernails and clinical and global outcomes.

Adult↗
PubMed1997

Analysis of immunological cross-protection and sensitivities to anticoccidial drugs among five geographical and temporal strains of Eimeria maxima.

Two laboratory strains (USDA strain No. 68 isolated from the eastern shore of Maryland 15 years ago and a University of Guelph strain isolated from an Ontario broiler house 23 years ago) and 3 recent field strains of Eimeria maxima [isolated in Maryland (MD), North Carolina (NC) and Florida (FL)] were tested for their ability to induce cross-protective immunity and their sensitivities to a variety of anticoccidial compounds. To assess immunological cross-protection, 1-day-old chicks were inoculated and subsequently challenged at 10 days of age, testing all possible combinations of initial inoculating (immunizing) and subsequent challenge strain. Six days post-challenge, chicks were killed and weight gains and lesion scores were determined and compared to sham inoculated and challenged, and sham challenged age-matched controls. The 2 laboratory strains and the NC strain were fully cross-protective against each other by both these measures. In contrast, the MD and FL strains induced complete protection only against the homologous strain. Reciprocally, no other strains protected chicks completely against the FL and MD strains. Drug sensitivity studies using 10 different anticoccidial formulations at prescribed drug levels showed significant differences between the 2 laboratory strains and the 3 recently isolated field strains; more recent isolates from commercial broiler houses demonstrated complete or partial resistance to a wider range of anticoccidial compounds. No correlation was seen between cross-protection and sensitivities to anticoccidials.

Animals↗
PubMed1996

Clinical sequelae associated with squaric acid dibutylester topical sensitization.

BACKGROUND: Squaric acid dibutylester (SADBE) is a potent topical sensitizer used in the treatment of various cutaneous conditions. Currently, there are no standardized protocols defining safe sensitization methods or treatment regimens following sensitization. OBJECTIVE: This is a literature review of the clinical use of SADBE and a report of our experience with SADBE therapy and its potential hazards. METHODS: SADBE was applied with a cotton swab to the forearm of 14 patients to induce contact dermatitis. RESULTS: Ten of 14 patients (71%) had severe eczematous reactions at the site of sensitization, and 9 of 14 (64%) developed disseminated reactions. CONCLUSION: Standard protocols delineating safe methods of sensitization and treatment with SADBE need further development.

Administration, Topical↗
PubMed1994

Management of a young patient with xeroderma pigmentosum.

Xeroderma pigmentosum is a group of rare autosomal recessive disorders with defective DNA repair that provide insight into the basic mechanism of carcinogenesis. It is the best human model linking clinical abnormalities and neoplasia to carcinogen exposure. We describe a patient with xeroderma pigmentosum and numerous basal cell carcinomas, squamous cell carcinomas, and melanomas treated with radiation therapy, Mohs micrographic surgery, dermabrasion, and isotretinoin prophylaxis.

Adolescent↗
PubMed1994

Measurement of femoral vein blood flow during total hip replacement. Duplex ultrasound imaging with and without the use of a foot pump.

We examined ten femoral veins with duplex ultrasound during total hip replacement to demonstrate the operative manoeuvres which cause venous obstruction and to assess prophylactic measures which may overcome it. Exposure of the acetabulum by distraction of the femur with a hook was less likely to occlude flow than retraction with bone levers. Adequate exposure of the femoral shaft by adduction, flexion and either internal or external rotation caused cessation of flow in all cases. In four cases an A-V Impulse System foot pump was activated during periods of stasis. In each case it overcame the obstruction and produced peak velocities which were twice that of the resting state. In five cases, towards the end of the procedure, debris was seen travelling proximally through the femoral vein.

Blood Flow Velocity↗
PubMed1992

Pityriasis rubra pilaris in the setting of HIV infection: clinical behaviour and association with explosive cystic acne.

The development of pityriasis rubra pilaris (PRP) in three patients with human immunodeficiency virus (HIV) infection is described. Two of the patients had onset of severe generalized cystic acne concomitant with their development of PRP. PRP and acne conglobata should be added to the group of cutaneous disorders that can present in a more virulent manner in the setting of HIV infection. The association of cystic acne with PRP and their response to treatment are discussed.

Acne Vulgaris↗
PubMed1986

Immunohistologic identification of antigen-presenting cells in cutaneous sarcoidosis.

Considerable evidence exists to show that activated T lymphocytes preferentially accumulate at sites of disease activity in sarcoidosis. Langerhans cells, which can be recognized by reactivity with an antibody to the T6 antigen are thought to play a primary role in T-lymphocyte activation by the skin, a tissue frequently involved in sarcoidosis. This immunohistologic study examined the distribution of OKT6-positive cells and surface expression of HLA-DR antigen in cutaneous sarcoid lesions. Skin specimens stained with an anti-HLA-DR antibody demonstrated diffuse staining of the granulomas. In addition, keratinocytes, which do not normally express HLA-DR antigens, were found to stain with monoclonal antibody to HLA-DR in an intercellular pattern. Examination of specimens for OKT6-reactive Langerhans cells revealed significantly greater concentrations in the epidermis overlying sarcoidal granulomas (33 +/- 7 cells/mm) than in the epidermis of age-, sex-, and race-matched controls (11 +/- 3 cells/mm, p less than 0.001). Of greater importance was the demonstration that significant numbers of OKT6-positive cells were present within the dermal sarcoid granulomas (19-208/mm2) in a distribution that paralleled that of Leu-3a-positive T lymphocytes. These data suggest that the epidermis may participate in activation of lymphocytes in cutaneous sarcoidosis, and implicate OKT6-positive cells in granuloma formation.

Adult↗
PubMed1978

Augmentation of fetal hemoglobin (HbF) synthesis in culture by human erythropoietic precursors in the marrow and peripheral blood: studies in sickle cell anemia and nonhemoglobinopathic adults.

We cultured marrow and peripheral blood erythropoietic precrusors in methylcellulose clonal assay and measured the synthetic rates of HbA, A2, F, and S in patients with and without sickle cell anemia. Hb was labeled with 14C-amino acid in culture, separated by slab gel isoelectric focusing techniques, and quantitated by autoradiographic methods. Comparison of marrow late (CFU-E) and early (BFU-E) precursors from patients without hemoglobinopathies showed that preferential synthesis of HbF is limited to early precursors. Simultaneous examinations of Hb synthesis by blood and marrow early erythropoietic precursors confirmed the similarity of the biosynthetic capabilities of the precursors from the two sources. Increasing concentrations of erythropoietin (Ep) in culture corresponded with increases in the percentages of HbF synthesized by blood BFU-E of normal individuals. HbF biosynthesis by blood BFU-E from sickle cell anemia patients was significantly higher than that synthesized by nonanemic individuals and showed significant individual variations. HbF synthesis in patients with sickle cell anemia was partially dependent on Ep concentrations in culture. Cell culture of circulating erythropoietic precursors in man appears to provide a unique tool for studying the control mechanisms of Hb synthesis in man.

Anemia, Sickle Cell↗