Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 9 de 9
Filter
1.
Sci Adv ; 10(18): eadk4946, 2024 May 03.
Article in English | MEDLINE | ID: mdl-38691597

ABSTRACT

This phase 2a trial investigated the efficacy of NFX-179 Topical Gel, a metabolically labile MEK inhibitor, in the treatment of cutaneous neurofibromas (cNFs) in neurofibromatosis type 1. Forty-eight participants were randomized to four treatment arms: NFX-179 Topical Gel 0.05%, 0.15%, and 0.5% or vehicle applied once daily to five target cNFs for 28 days. Treatment with NFX-179 Topical Gel resulted in a dose-dependent reduction in p-ERK levels in cNFs at day 28, with a 47% decrease in the 0.5% NFX-179 group compared to the vehicle (P = 0.0001). No local or systemic toxicities were observed during the treatment period, and systemic concentrations of NFX-179 remained below 1 ng/ml. In addition, 20% of cNFs treated with 0.5% NFX-179 Topical Gel showed a ≥50% reduction in volume compared to 6% in the vehicle group by ruler measurement with calculated volume (P = 0.021). Thus, NFX-179 Topical Gel demonstrated significant inhibition of MEK in cNF with excellent safety and potential therapeutic benefit.


Subject(s)
Neurofibromatosis 1 , Protein Kinase Inhibitors , Skin Neoplasms , Humans , Neurofibromatosis 1/drug therapy , Female , Male , Adult , Middle Aged , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/adverse effects , Skin Neoplasms/drug therapy , Skin Neoplasms/pathology , Neurofibroma/drug therapy , Neurofibroma/pathology , Neurofibroma/metabolism , Young Adult , Adolescent , Treatment Outcome , Administration, Topical , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinase Kinases/metabolism
2.
Sci Transl Med ; 15(717): eade1844, 2023 10 11.
Article in English | MEDLINE | ID: mdl-37820007

ABSTRACT

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. Although cSCC contributes to substantial morbidity and mortality in high-risk individuals, deployment of otherwise effective chemoprevention of cSCC is limited by toxicities. Our systematic computational drug repurposing screen predicted that selumetinib, a MAPK (mitogen-activated protein kinase) kinase inhibitor (MEKi), would reverse transcriptional signatures associated with cSCC development, consistent with our genomic analysis implicating MEK as a chemoprevention target. Although systemic MEKi suppresses the formation of cSCC in mice, systemic MEKi can cause severe adverse effects. Here, we report the development of a metabolically labile MEKi, NFX-179, designed to potently and selectively suppress the MAPK pathway in the skin before rapid metabolism in the systemic circulation. NFX-179 was identified on the basis of its biochemical and cellular potency, selectivity, and rapid metabolism upon systemic absorption. In our ultraviolet-induced cSCC mouse model, topical application of NFX-179 gel reduced the formation of new cSCCs by an average of 60% at doses of 0.1% and greater at 28 days. We further confirmed the localized nature of these effects in an additional split-mouse randomized controlled study where suppression of cSCC was observed only in drug-treated areas. No toxicities were observed. NFX-179 inhibits the growth of human SCC cell lines in a dose-dependent manner, and topical NFX-179 application penetrates human skin and inhibits MAPK signaling in human cSCC explants. Together, our data provide a compelling rationale for using topical MEK inhibition through the application of NFX-179 gel as an effective strategy for cSCC chemoprevention.


Subject(s)
Carcinoma, Squamous Cell , Skin Neoplasms , Animals , Humans , Mice , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/genetics , Cell Proliferation , Chemoprevention , Mitogen-Activated Protein Kinase Kinases , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Skin Neoplasms/drug therapy , Skin Neoplasms/prevention & control , Skin Neoplasms/genetics
3.
Dermatol Surg ; 44(3): 330-340, 2018 Mar.
Article in English | MEDLINE | ID: mdl-28902028

ABSTRACT

BACKGROUND: Seborrheic keratosis (SK) is a common benign skin tumor, yet no topical treatments are approved in the United States. OBJECTIVE: To evaluate the proprietary, stabilized, high-concentration hydrogen peroxide-based topical solution A-101 (32.5% and 40% concentrations) for treatment of facial SK lesions. MATERIALS AND METHODS: In this multicenter, double-blind, vehicle-controlled study, eligible subjects were randomly assigned to receive up to 2 treatments of A-101 40%, A-101 32.5%, or vehicle solution applied to a single facial SK lesion. The primary efficacy assessment was the Physician's Lesion Assessment (PLA), a validated 4-ordinal scale. RESULTS: The primary end point, the mean reduction in PLA grade from baseline to Day 106 was 1.7 for A-101 40%, 1.4 for A-101 32.5%, and 0.1 for vehicle (p < .001, both concentrations vs vehicle). Lesions for 68%, 62%, and 5% of subjects, respectively, were judged to be clear or near clear (p < .001, both concentrations vs vehicle). Local skin reactions were predominantly mild and transient. No subjects discontinued because of treatment-related adverse events. CONCLUSION: A-101 solution demonstrated efficacy in treating SKs on the face. Greater magnitude of effect was seen with the 40% concentration than the 32.5% concentration. A-101 solution had a favorable safety and tolerability profile at both concentrations.


Subject(s)
Dermatologic Agents/administration & dosage , Hydrogen Peroxide/administration & dosage , Keratosis, Seborrheic/drug therapy , Administration, Topical , Aged , Dose-Response Relationship, Drug , Double-Blind Method , Face , Female , Humans , Male , Middle Aged
4.
J Periodontol ; 79(1): 33-41, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18166090

ABSTRACT

BACKGROUND: Previous studies showed that host modulation therapy (HMT) or topical antimicrobial therapy (TAT) provided significant adjunctive benefits to scaling and root planing (SRP) in the treatment of chronic periodontitis (CP). The purpose of this study was to evaluate a combination therapy involving SRP, HMT, and TAT in the treatment of moderate to severe CP. METHODS: A 6-month, randomized, multicenter, placebo-controlled, examiner-masked study was undertaken to evaluate the clinical usefulness of a combination treatment of systemically delivered doxycycline hyclate (HMT; 20 mg, twice a day) plus locally delivered doxycycline hyclate gel (TAT; 10%, in pockets > or =5 mm) in combination with SRP versus SRP plus placebo. Clinical outcomes included mean changes in probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), and gingival index (GI) at baseline and at 3 and 6 months. RESULTS: In 171 subjects, combination therapy provided significantly greater clinical benefits than control therapy for all clinical measures at 3 and 6 months. In moderate CP (PD of 4 to 6 mm), combination therapy provided significant benefits over control for PD (3 and 6 months: P <0.01), CAL (3 months: P <0.01; 6 months: P <0.03), BOP (3 months: P <0.02; 6 months: P <0.05), and GI (3 months: P <0.01; 6 months: P <0.03). In severe CP (PD > or =7 mm), combination therapy provided significant benefits over control for PD (3 and 6 months: P <0.01), CAL (3 months: P <0.01; 6 months: P <0.02), BOP (3 months: P <0.01; 6 months: P >0.05), and GI (3 months: P <0.01; 6 months: P <0.01). CONCLUSION: Combination therapy, including SRP, HMT, and TAT, provided significantly greater clinical benefits than SRP alone in the treatment of moderate to severe CP.


Subject(s)
Anti-Bacterial Agents/administration & dosage , Dental Scaling , Doxycycline/administration & dosage , Periodontitis/therapy , Root Planing , Administration, Oral , Administration, Topical , Adolescent , Adult , Aged , Chronic Disease , Combined Modality Therapy , Female , Follow-Up Studies , Gingival Hemorrhage/drug therapy , Gingival Hemorrhage/therapy , Humans , Male , Middle Aged , Periodontal Attachment Loss/drug therapy , Periodontal Attachment Loss/therapy , Periodontal Index , Periodontal Pocket/drug therapy , Periodontal Pocket/therapy , Periodontitis/drug therapy , Placebos , Single-Blind Method , Treatment Outcome
5.
J Clin Periodontol ; 32(11): 1163-9, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16212578

ABSTRACT

AIM: The purpose of this study was to determine if a 9-month regimen of sub-antimicrobial doxycycline (20 mg, bid) had an effect on either the intestinal or the vaginal microflora. MATERIAL AND METHODS: A total of 69 periodontally diseased subjects were randomized to receive drug or placebo control for a 9-month period. Stool specimens and vaginal swabs were collected at baseline and after 3 and 9 months of therapy. Samples were examined for total anaerobic counts, opportunistic pathogens, and doxycycline-resistant (>or=4 microg/ml) bacteria. All isolates that survived sub-culture were identified and their susceptibilities determined to six antibiotics. Analyses were performed to determine if treatment differences were present. RESULTS: The only statistically significant differences (p<0.05) between the two treatment groups occurred in the doxycycline-resistant counts at the baseline sample period for the faecal samples. This imbalance was before treatment initiation and the administration of the study drug. No between-treatment differences were detected at either the 3- or 9-month sample period either in the predominant bacterial taxa present or in their antibiotic susceptibilities. CONCLUSIONS: There was no evidence that sub-antimicrobial doxycycline treatment exerted an effect on the composition or doxycycline resistance level of either the faecal or the vaginal microflora.


Subject(s)
Anti-Bacterial Agents/pharmacology , Doxycycline/pharmacology , Intestines/microbiology , Periodontitis/drug therapy , Vagina/microbiology , Adult , Aged , Anti-Bacterial Agents/administration & dosage , Doxycycline/administration & dosage , Female , Humans , Longitudinal Studies , Middle Aged , Statistics, Nonparametric
6.
J Am Acad Dermatol ; 53(5): 791-7, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16243127

ABSTRACT

BACKGROUND: Subantimicrobial doses of doxycycline may improve outcomes in rosacea when combined with topical metronidazole and used as maintenance monotherapy. OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of doxycycline hyclate 20 mg (subantimicrobial dose doxycycline) administered twice daily as an adjunct to metronidazole 0.75% topical lotion in the treatment of rosacea. METHODS: Patients received subantimicrobial doses of doxycycline twice daily plus metronidazole (n = 20) or placebo plus metronidazole (n = 20) for 12 weeks. Subantimicrobial-dose doxycycline or placebo monotherapy continued for 4 weeks. The primary efficacy measure was change from baseline in total inflammatory lesions at weeks 2 and 16. RESULTS: Total inflammatory lesions were reduced significantly (P =.048) by week 4 and by all subsequent visits in the subantimicrobial-dose doxycycline/metronidazole group compared with placebo/metronidazole. Changes from baseline increased over time and were maintained during subantimicrobial-dose doxycycline monotherapy. CONCLUSION: Adjunctive use of subantimicrobial dose doxycycline significantly reduced the clinical signs of rosacea compared with metronidazole alone and may be useful maintenance monotherapy.


Subject(s)
Anti-Infective Agents/administration & dosage , Doxycycline/analogs & derivatives , Metronidazole/administration & dosage , Rosacea/drug therapy , Administration, Topical , Adult , Double-Blind Method , Doxycycline/administration & dosage , Drug Therapy, Combination , Female , Humans , Male , Tablets
7.
Gerodontology ; 22(1): 37-43, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15747897

ABSTRACT

OBJECTIVE: To assess the efficacy of subantimicrobial dose doxycycline (SDD; 20 mg doxycycline twice daily) as an adjunct to scaling and root planing (SRP) in the treatment of moderate-severe chronic periodontitis (CP) in institutionalised elderly patients aged 65 years or older. BACKGROUND: Previous studies have shown that SDD is of clinical benefit in the treatment of CP. However, the benefits of SDD in geriatric populations (65+ years) have not been determined. MATERIAL AND METHODS: A 9-month, double-blind, randomised, placebo-controlled pilot study was conducted. 24 institutionalised geriatric patients (65 years or older) with evidence of CP manifested by baseline clinical attachment levels (CAL) 5-9 mm, probing depths (PD) 4-9 mm and bleeding on probing (BOP) were recruited. At baseline, patients were treated by a standardised episode of SRP, and randomised to receive either adjunctive SDD or placebo. Full mouth PD and CAL were measured using the manual UNC-15 periodontal probe at 3, 6, and 9 months post-baseline to assess the response to treatment. Periodontal sites were stratified by baseline PD value: sites with PD 4-5 mm were considered moderately diseased and sites with PD > or = 6 mm severely diseased. RESULTS: The SRP + placebo resulted in PD reductions similar to those reported previously in the literature. At all time-points and in both moderate and deep sites, SRP + SDD resulted in significantly greater PD reductions relative to baseline than SRP + placebo. At month 9, in moderate sites, mean PD reductions of 1.57 +/- 0.11 mm were reported in the adjunctive SDD group, compared with 0.63 +/- 0.11 mm in the adjunctive placebo group (p < 0.001). In deep sites at month 9, mean PD reductions of 3.22 +/- 0.29 mm were reported in the adjunctive SDD group, compared with 0.98 +/- 0.31 mm in the adjunctive placebo group (p < 0.05). Similar improvements were observed for CAL in the SDD group compared with the placebo group. Significantly lower BOP scores were also recorded at month 9 in the SDD group (7.5%) compared with the placebo group (71.2%) (p < 0.01). CONCLUSION: SDD used as an adjunct to SRP provides significant benefit for elderly patients with CP compared with SRP alone.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Doxycycline/therapeutic use , Institutionalization , Nursing Homes , Periodontitis/drug therapy , Aged , Aged, 80 and over , Analysis of Variance , Anti-Bacterial Agents/administration & dosage , Chronic Disease , Double-Blind Method , Doxycycline/administration & dosage , Female , Humans , Male , Pilot Projects
8.
Article in English | MEDLINE | ID: mdl-12888200

ABSTRACT

An accurate and reliable liquid chromatographic-tandem mass spectrometric (LC-MS-MS) method has been developed and validated for the determination of 6-deoxy-6-demethyl-4-dedimethylaminotetracycline (COL-3) in human plasma. The assay used chrysin as an internal standard (I.S.). The analyte and the I.S. were extracted from acidified plasma by methyl-t-butyl ether. Separation was achieved on a YMCbasic column using acetonitrile-water-formic acid mobile phase. The MS-MS detection was by monitoring fragmentation 372.1-->326.2 (m/z) for COL-3 and 255.1-->153.1 (m/z) for the I.S. on a Sciex API 365 using a Turbo Ionspray in positive ion mode. The retention times were approximately 1.7 min for COL-3 and 1.8 min for the I.S. The validated dynamic range was 0.03-10.0 microg/ml using 0.25-ml plasma with correlation coefficients of >or=0.9985. The precision and accuracy for the calibration standards (n=3) were RSD

Subject(s)
Chromatography, High Pressure Liquid/methods , Spectrometry, Mass, Electrospray Ionization/methods , Tetracyclines/blood , Calibration , Humans , Reference Standards , Reproducibility of Results , Sensitivity and Specificity
9.
Arch Dermatol ; 139(4): 459-64, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12707093

ABSTRACT

OBJECTIVE: To determine if treatment with subantimicrobial-dose (SD) doxycycline hyclate (20-mg tablets taken twice daily) improved clinical outcome, had any detectable effect on skin flora, led to overgrowth or colonization of skin by opportunistic pathogens, or resulted in an increase in antibiotic resistance by the surface skin microflora in patients with moderate acne compared with placebo. DESIGN: Multicenter, double-blind, randomized, placebo-controlled, parallel-group trial. SETTING: Two university-based clinics. SUBJECTS: Adults (N = 51) with moderate facial acne. INTERVENTIONS: Patients were randomized to receive SD doxycycline (Periostat; CollaGenex Pharmaceuticals Inc, Newtown, Pa) or placebo twice daily for 6 months. MAIN EFFICACY OUTCOMES: Primary: changes from baseline in numbers of inflammatory, noninflammatory, and total lesions. Secondary: changes from baseline of individual counts of papules, pustules, and nodules and global assessments of clinical improvement by patient and physician. RESULTS: Forty patients completed 6 months of treatment. At 6 months, the SD doxycycline group had a significantly greater percent reduction in the number of comedones (P<.01), inflammatory and noninflammatory lesions combined (P<.01), and total inflammatory lesions (P<.05) than did the placebo group. They also had significantly greater improvement according to the clinician's global assessment (P =.03). There were no significant differences in microbial counts between groups and no evidence of change in antibiotic susceptibility or colonization by potential pathogens. The treatment was well tolerated. CONCLUSIONS: Twice-daily SD doxycycline treatment significantly reduced the number of inflammatory and noninflammatory lesions in patients with moderate facial acne, was well tolerated, had no detectable antimicrobial effect on the skin flora, and did not result in any increase in the number or severity of resistant organisms.


Subject(s)
Acne Vulgaris/drug therapy , Anti-Bacterial Agents/administration & dosage , Doxycycline/analogs & derivatives , Doxycycline/administration & dosage , Acne Vulgaris/microbiology , Acne Vulgaris/pathology , Administration, Oral , Adolescent , Adult , Anti-Bacterial Agents/adverse effects , Double-Blind Method , Doxycycline/adverse effects , Female , Humans , Male , Skin/microbiology
SELECTION OF CITATIONS
SEARCH DETAIL
...