RESUMO
BACKGROUND: Eblasakimab, an interleukin (IL)-13 receptor α1 antagonist, blocks IL-4 and IL-13 signaling through the type 2 receptor. OBJECTIVE: The safety and efficacy of eblasakimab was evaluated in adults with moderate-to-severe atopic dermatitis (AD). METHODS: In this phase 1b randomized, double-blinded study, 52 patients with moderate-to-severe AD received weekly subcutaneous injections of eblasakimab 200, 400, or 600 mg, or placebo for 8 weeks. Primary outcome was the incidence of treatment-emergent adverse events. Secondary outcomes included percentage change in the Eczema Area and Severity Index from baseline; Eczema Area and Severity Index improvement of at least 50%, 75%, or 90% from baseline; and percentage change in the peak-pruritus numeric rating scale score from baseline. RESULTS: Treatment-emergent adverse events were reported in 47% placebo and 71% eblasakimab patients; most were considered mild or moderate and did not lead to study discontinuation. At week 8 eblasakimab 600 mg showed statistically significant improvement in mean percentage change in Eczema Area and Severity Index versus placebo (-65% vs -27%, P = .014). Other key secondary physician- and patient-reported end points were met. LIMITATIONS: Longer studies are required to confirm eblasakimab safety and efficacy in AD patients. CONCLUSIONS: Treatment of adults with moderate-to-severe AD with eblasakimab was well-tolerated and associated with significant clinical improvements versus placebo.
Assuntos
Dermatite Atópica , Eczema , Adulto , Humanos , Dermatite Atópica/diagnóstico , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/induzido quimicamente , Anticorpos Monoclonais/efeitos adversos , Receptores de Interleucina-13/uso terapêutico , Resultado do Tratamento , Índice de Gravidade de Doença , Método Duplo-Cego , Eczema/tratamento farmacológicoRESUMO
Eblasakimab is a first-in-class monoclonal antibody under investigation for the treatment of atopic dermatitis (AD), which targets IL-13Rα1, a subunit of the Type 2 receptor complex. IL-13Rα1 stimulates phosphorylation of signal transducer and activator of transcription 6 (STAT6) to drive inflammation. This brief report investigates the mechanistic basis of eblasakimab and its effects on IL-13Rα1 signaling as part of a phase 1a, open-label, single ascending dose study. Single ascending doses of eblasakimab were administered by intravenous or subcutaneous injection to healthy male volunteers. The impact of eblasakimab on IL-13Rα1 receptor occupancy and STAT6 phosphorylation was assessed in participant blood monocytes. No serious treatment emergent adverse events were reported. Eblasakimab effectively blocked the IL-13Rα1 receptor and inhibited STAT6 phosphorylation with single doses of 3 mg/kg intravenously and 300 mg subcutaneously. Results support further clinical development of eblasakimab as a novel biologic for AD, with potential for 2- to 4-week dosing regimens.
Assuntos
Anticorpos Monoclonais , Interleucina-13 , Humanos , Masculino , Receptores de Interleucina-13 , Fosforilação , Fator de Transcrição STAT6 , Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Voluntários SaudáveisRESUMO
BACKGROUND: Psoriasis vulgaris is not easy to manage, even when mild. Knowledge of the efficacy of most topical therapies in this population is limited. OBJECTIVE: To assess the efficacy of calcipotriene 0.005% plus betamethasone dipropionate 0.064% (Cal/BD) foam in patients with mild psoriasis. METHODS: Post hoc analysis was performed on pooled data for subjects with mild psoriasis at baseline from 2 Phase 3 and 1 Phase 2 clinical trials. All subjects applied Cal/BD foam or vehicle foam once daily for at least 4 weeks. Efficacy assessments included treatment success (defined as IGA=0), mPASI, BSA, and the composite IGA BSA score. RESULTS: Of the 848 subjects, 164 had mild psoriasis at baseline. Within this subpopulation of mild subjects, Cal/BD foam demonstrated significant efficacy over vehicle at week 4 in terms of the proportion of subjects achieving complete clearance of visible lesions (IGA=0). Significant improvements were also observed for mPASI, BSA, and IGA BSA score. LIMITATIONS: These post hoc analyses need to be confirmed with prospective studies. CONCLUSION: Once-daily Cal/BD foam for 4 weeks demonstrated effectiveness in treating subjects with mild psoriasis, a population in which demonstration of treatment success can be difficult, because of the requirement for complete clearance of visible disease. Clinicaltrials.gov: NCT02132936, NCT01866163, and NCT01536938 J Drugs Dermatol. 2021;20(8):822-828. doi:10.36849/JDD.5743.
Assuntos
Betametasona/análogos & derivados , Calcitriol/análogos & derivados , Psoríase , Betametasona/uso terapêutico , Calcitriol/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Formas de Dosagem , Combinação de Medicamentos , Humanos , Estudos Prospectivos , Psoríase/diagnóstico , Psoríase/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
BACKGROUND: The product of the Physician Global Assessment and body surface area (PGA×BSA) is simpler to use than the Psoriasis Area and Severity Index (PASI), which lacks sensitivity in patients with mild psoriasis. OBJECTIVE: To compare the PGA×BSA versus the modified PASI (mPASI) for assessing disease severity and therapeutic response to calcipotriol/betamethasone dipropionate (Cal/BD) foam. METHODS: This post hoc analysis evaluated the efficacy of Cal/BD foam in mild, moderate, and severe psoriasis, as assessed by the PGA×BSA and mPASI, using data from 3 randomized controlled trials (NCT01536886, NCT01866163, NCT02132936). Spearman correlation and Bland-Altman plots were used to compare the PGA×BSA with the mPASI. RESULTS: Proportions of patients receiving Cal/BD foam achieving 75% response for PGA×BSA and mPASI at weeks 1, 2, and 4 were similar and significantly greater than with vehicle (P ≤ .002 at all timepoints); at week 4, mean improvements were 51.0% and 50.7%, respectively. Spearman correlations for mild, moderate, and severe psoriasis were moderate to high between PGA×BSA and mPASI at baseline (r = .51, .72, and .86, respectively; n = 126, 465, and 58, respectively) and high at week 4 (r = .80, .81, and .89, respectively; n = 121, 452, and 58, respectively) (P < .001). LIMITATIONS: Pooled data from different trials were not prespecified for post hoc analysis. Interrater reliability was not assessed. CONCLUSION: Pooled data analysis showed that the PGA×BSA and mPASI correlation was higher with increasing psoriasis severity.
Assuntos
Anti-Inflamatórios/uso terapêutico , Betametasona/análogos & derivados , Superfície Corporal , Calcitriol/análogos & derivados , Fármacos Dermatológicos/uso terapêutico , Psoríase/diagnóstico , Psoríase/tratamento farmacológico , Índice de Gravidade de Doença , Adulto , Idoso , Betametasona/uso terapêutico , Calcitriol/uso terapêutico , Interpretação Estatística de Dados , Feminino , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Objective: Investigate the effect of fixed-combination calcipotriene 0.005% plus betamethasone dipropionate 0.064% (Cal/BD) foam on target lesion severity in plaque psoriasis. Design: Post-hoc analysis was conducted on data from a Phase 3, randomized, double-blind, multicenter clinical study of Cal/BD foam in the treatment of psoriasis vulgaris for 4 weeks (PSO-FAST; NCT01866163). Participants: In PSO-FAST, 426 patients (≥18 years) with psoriasis vulgaris (≥mild severity) were randomized 3:1 to Cal/BD foam (n=323) or vehicle foam (n=103), applied once daily. Measurements: Assessments included (1) target lesion severity (redness, scaliness, and thickness) at baseline and weeks 1, 2, and 4; and (2) the proportion of patients with ≥50% reduction in total sign score (TSS-50) from baseline at weeks 1, 2, and 4. Results: A greater proportion of patients achieved considerable improvement (a score of 0 or 1) in the severity of target lesions after 4 weeks of treatment with Cal/BD foam vs vehicle foam at week 4 (redness: 76.2% vs 21.4%; P<.001; scaliness: 91.3% vs 61.2%; P<.001; and thickness: 83.3% vs 35.0%; P<.001, respectively). Rapid onset of efficacy was observed as early as week 1. Significantly more patients also achieved TSS-50 at week 4 with Cal/BD foam vs vehicle foam for their target lesions regardless of treatment area, including the elbows and knees (P<.05 for all). Conclusions: Significant improvements in target lesion severity were achieved with up to 4 weeks of treatment with once-daily Cal/BD foam for adults with plaque psoriasis versus vehicle foam, with rapid onset of efficacy observed at week 1. J Drugs Dermatol. 2020;19(2)121-126. doi:10.36849/JDD.2020.4750
Assuntos
Betametasona/análogos & derivados , Calcitriol/análogos & derivados , Psoríase/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Betametasona/administração & dosagem , Calcitriol/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Background: Real-world data for actinic keratosis treatment in the United States is lacking. Objectives: To understand real-world treatment patterns for actinic keratosis by type and modality, and compare effectiveness and safety of therapies, either alone or in combination. Methods: Medical charts of 429 patients were identified; clinical and outcome data were analyzed. Results: The first treatment after the index diagnosis was most frequently a procedure, followed by a topical agent. Treatment with 5-fluorouracil, ingenol mebutate, imiquimod, cryotherapy, or cryotherapy plus one topical (CRYO+One Topical) reduced actinic keratoses by 66.0%, 69.3%, 72.5%, 72.9%, and 73.0%, respectively; ≥75% clearance (AKCLEAR 75) was achieved in 57.1%, 72.7%, 57.1%, 62.4%, and 62.0% of those patients. Treatment effectiveness was positively correlated with the number of baseline actinic keratoses for topical and for procedural plus topical combination treatments, but not for procedural treatments alone. Adverse reactions (ARs) were more common with cryotherapy (9.7%); local skin responses (LSRs) were more common with field-directed (18.5%-43.1%) and CRYO+One Topical therapy (21.3%). Limitations: This was a retrospective study of limited duration and population size. Conclusions: The most commonly used treatments for patients with 6 or more actinic keratoses were topicals and a procedure plus topical combination, which also achieved higher rates of complete clearance than a procedure alone. ARs and LSRs were few in frequency and type.
Assuntos
Antineoplásicos/administração & dosagem , Crioterapia/métodos , Ceratose Actínica/terapia , Administração Cutânea , Idoso , Antineoplásicos/efeitos adversos , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Crioterapia/efeitos adversos , Diterpenos/administração & dosagem , Diterpenos/efeitos adversos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Imiquimode/administração & dosagem , Imiquimode/efeitos adversos , Ceratose Actínica/diagnóstico , Ceratose Actínica/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Pele/efeitos dos fármacos , Pele/patologia , Resultado do Tratamento , Estados UnidosRESUMO
Psoriasis is a chronic, immune-mediated inflammatory disease characterized by localized scaling and plaques associated with itching and pain. In some cases, topical therapies are effective to treat mild to moderate psoriasis. Topical agents can be used concomitantly with other treatments for moderate and severe or treatment-resistant psoriasis. Patient adherence to medication regimens remains a major challenge in therapy, especially with topical agents, for which adherence can be affected by the amount of time needed for application, the treatment formulation, cost, and cosmetic characteristics. This study was conducted to obtain feedback from patients clinically diagnosed with psoriasis regarding their satisfaction following once-daily topical application of the fixed combination calcipotriene (Cal) 0.005% and betamethasone dipropionate (BD) 0.064% foam for 15 days. Patients completed a 13-question online survey. In this community-based setting of patients with mild to severe psoriasis, patients were satisfied with Cal/BD foam after 15 days of use; 94% were satisfied or highly satisfied with symptom relief. Most of the patients (88%) were satisfied with how Cal/BD foam felt on their skin. After 15 days of use, 94% of patients would recommend Cal/BD foam to other patients with psoriasis, with 73% being very likely to do so. These findings may have important implications for optimizing medical decision-making, treatment adherence, and health outcomes in clinical practice. The cosmetic acceptability of the fixed combination Cal/BD foam formulation and patient satisfaction may make Cal/BD aerosol foam a more acceptable topical treatment than other currently available vehicles for patients with plaque psoriasis. J Drugs Dermatol. 2018;17(8):880-884.
Assuntos
Anti-Inflamatórios/administração & dosagem , Betametasona/análogos & derivados , Calcitriol/análogos & derivados , Fármacos Dermatológicos/administração & dosagem , Satisfação do Paciente , Psoríase/tratamento farmacológico , Adolescente , Adulto , Idoso , Betametasona/administração & dosagem , Calcitriol/administração & dosagem , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/diagnóstico , Psoríase/psicologia , Autorrelato/normas , Resultado do Tratamento , Adulto JovemRESUMO
We investigated the in vitro metabolism and estrogenic and antiestrogenic activity of toremifene (TOR), tamoxifen (TAM) and their metabolites to better understand the potential effects of cytochrome P-450 2D6 (CYP2D6) status on the activity of these drugs in women with breast cancer. The plasma concentrations of TOR and its N-desmethyl (NDM) and 4-hydroxy (4-OH) metabolites during steady-state dosing with TOR were also determined. Unlike TOR, TAM and its NDM metabolite were extensively oxidized to 4-OH TAM and 4-OH-NDM TAM by CYP2D6, and the rate of metabolism was affected by CYP2D6 status. 4-OH-NDM TOR concentrations were not measurable at steady state in plasma of subjects taking 80 mg of TOR. Molecular modeling provided insight into the lack of 4-hydroxylation of TOR by CYP2D6. The 4-OH and 4-OH-NDM metabolites of TOR and TAM bound to estrogen receptor (ER) subtypes with fourfold to 30-fold greater affinity were 35- to 187-fold more efficient at antagonizing ER transactivation and had antiestrogenic potency that was up to 360-fold greater than their parent drugs. Our findings suggest that variations in CYP2D6 metabolic capacity may cause significant differences in plasma concentrations of active TAM metabolites (i.e., 4-OH TAM and 4-OH-NDM TAM) and contribute to variable pharmacologic activity. Unlike TAM, the clinical benefits in subjects taking TOR to treat metastatic breast cancer would not likely be subject to allelic variation in CYP2D6 status or affected by coadministration of CYP2D6-inhibiting medications.
Assuntos
Citocromo P-450 CYP2D6/fisiologia , Moduladores Seletivos de Receptor Estrogênico/metabolismo , Tamoxifeno/metabolismo , Toremifeno/metabolismo , Adulto , Humanos , Masculino , Oxirredução , Relação Estrutura-Atividade , Tamoxifeno/análogos & derivados , Tamoxifeno/sangueRESUMO
1. GTx-024, a novel selective androgen receptor modulator, is currently being investigated as an oral treatment for muscle wasting disorders associated with cancer and other chronic conditions. 2. Absorption of GTx-024 was rapid and complete, with high oral bioavailability. A wide tissue distribution of [(14)C]GTx-024 derived radioactivity was observed. [(14)C]GTx-024-derived radioactivity had a moderate plasma clearance (117.7 and 74.5 mL/h/kg) and mean elimination half-life of 0.6 h and 16.4 h in male and female rats, respectively. 3. Fecal excretion was the predominant route of elimination, with â¼70% of total radioactivity recovered in feces and 21-25% in urine within 48 h. Feces of intact rats contained primarily unchanged [(14)C]GTx-024 (49.3-64.6%). Metabolites were identified in urine and feces resulting from oxidation of the cyanophenol ring (M8, 17.6%), hydrolysis and/or further conjugation of the amide moiety (M3, 8-12%) and the cyanophenol ring (M4, 1.3-1.5%), and glucuronidation of [(14)C]GTx-024 at the tertiary alcohol (M6, 3.5-3.7%). There was no quantifiable metabolite in plasma. 4. In summary, in the rat GTx-024 is completely absorbed, widely distributed, biotransformed through several metabolic pathways, and eliminated in feces primarily as an unchanged drug.
Assuntos
Amidas/metabolismo , Amidas/urina , Absorção , Administração Oral , Amidas/química , Amidas/farmacocinética , Anilidas , Animais , Autorradiografia , Biotransformação , Fezes/química , Feminino , Masculino , Espectrometria de Massas , Metabolômica , Radioatividade , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Padrões de Referência , Fatores de Tempo , Distribuição TecidualRESUMO
Obesity is an epidemic problem affecting millions of people in the Western hemisphere and costs the United States economy more than $200 billion annually. Currently, there are no effective treatments to combat obesity. Recent studies have implicated the constitutive activity of estrogen receptor (ER) ß as an important regulator of metabolic diseases. However, the potential of ER-ß-selective ligands to offset obesity is not clear. We evaluated the pharmacological effect of ER-ß-selective ligands (ß-LGNDs) in animal models of high-fat diet- and ovariectomy-induced obesity. Ligand binding, transactivation, and uterotrophic studies with ß-LGNDs demonstrated selectivity for ER-ß over ER-α. Animals fed a high-fat diet showed a significant increase in body weight, and this weight gain was attenuated by ß-LGNDs. High-fat diet-mediated increases in serum cholesterol, leptin, glucose, and fat accumulation in organs were also reduced by ß-LGNDs. In addition, MRI scanning indicated that ß-LGNDs altered body composition by reducing fat mass and increasing lean body mass. Organ weights and gene expression analyses demonstrated that adipose tissue is the center of action for ß-LGNDs, and the reduction in body weight is likely due to increased energy expenditure. In vitro and in vivo mechanistic studies indicated that the anti-obesity effects of ß-LGNDs were due to indirect peroxisome proliferator-activated receptor γ antagonistic actions requiring the ligand binding domain of ER-ß and through abrogation of the ability of PGC-1 to coactivate peroxisome proliferator-activated receptor γ. In conclusion, these studies indicate that ligand-activated ER-ß is a potential therapeutic target to combat obesity and obesity-related metabolic diseases.
Assuntos
Gorduras na Dieta/efeitos adversos , Receptor beta de Estrogênio/agonistas , Isoquinolinas/farmacologia , Ligantes , Obesidade/tratamento farmacológico , Ovariectomia , Animais , Glicemia/metabolismo , Colesterol/sangue , Gorduras na Dieta/administração & dosagem , Modelos Animais de Doenças , Receptor beta de Estrogênio/metabolismo , Feminino , Leptina/sangue , Masculino , Camundongos , Obesidade/sangue , Obesidade/etiologia , Tamanho do Órgão , PPAR gama/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição/metabolismoRESUMO
Toremifene is an effective agent for the treatment of breast cancer in postmenopausal women and is being evaluated for its ability to prevent bone fractures in men with prostate cancer taking androgen deprivation therapy. Due to the potential for drug-drug interactions, the ability of toremifene and its primary circulating metabolite N-desmethyltoremifene (NDMT) to inhibit nine human cytochrome P450 (CYP) enzymes was determined using human liver microsomes. Induction of CYP1A2 and 3A4 by toremifene was also investigated in human hepatocytes. Toremifene did not significantly inhibit CYP1A2 or 2D6. However, toremifene is a competitive inhibitor of CYP3A4, non-competitive inhibitor of CYP2A6, 2C8, 2C9, 2C19 and 2E1 and mixed-type inhibitor of CYP2B6. CYP inhibition by NDMT was similar in magnitude to toremifene. Toremifene did not induce CYP1A2 but increased CYP3A4 monooxygenase activity and gene expression in drug-exposed human primary hepatocytes. Although clinical doses of toremifene produce steady state exposures to toremifene and NDMT that may be sufficient to cause pharmacokinetic drug-drug interactions with other drugs metabolised by CYP2B6, CYP2C8, CYP3A4, CYP2C9 and CYP2C19, these data indicate that toremifene is unlikely to play a role in clinical drug-drug interactions with substrate drugs of CYP1A2 and CYP2D6.
Assuntos
Inibidores das Enzimas do Citocromo P-450 , Tamoxifeno/análogos & derivados , Toremifeno/farmacologia , Células Cultivadas , Sistema Enzimático do Citocromo P-450/química , Interações Medicamentosas , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Humanos , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Tamoxifeno/química , Tamoxifeno/farmacologia , Toremifeno/química , Toremifeno/metabolismoRESUMO
BACKGROUND: Randomized controlled trials (RCTs) demonstrated the advantages of an aerosol foam formulation of calcipotriol/betamethasone dipropionate (Cal/BD) in patients with psoriasis. In this review, we investigated whether such benefits could also be obtained in real-world clinical practice. METHODS: PubMed was searched for studies reporting real-world data in patients with psoriasis treated with Cal/BD aerosol foam. RESULTS: Three large real-world studies with Cal/BD aerosol foam were identified: a prospective non-interventional study from Germany, a medical chart review from the US, and a retrospective non-interventional study from Spain. Some key findings included the following: high levels of adherence to treatment (82-93%); after 4 weeks, about 50% of patients achieved complete/almost complete responses; at final assessment, 85-95% of patients were extremely satisfied/very satisfied/satisfied with Cal/BD aerosol foam; all healthcare providers were satisfied or somewhat satisfied with the efficacy of Cal/BD foam and they reported similar findings for symptom improvements (itch, pain, erythema/redness, flaking, and plaque thickness). Global ratings by investigators/healthcare providers for symptom control, overall efficacy and the emotional status of patients were also very high (75-100%). CONCLUSION: The results from real-world studies undertaken in diverse healthcare systems reinforce the positive findings reported in RCTs with Cal/BD aerosol foam in patients with psoriasis.
Assuntos
Fármacos Dermatológicos , Psoríase , Aerossóis , Betametasona/análogos & derivados , Betametasona/uso terapêutico , Calcitriol/análogos & derivados , Fármacos Dermatológicos/uso terapêutico , Combinação de Medicamentos , Humanos , Psoríase/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: There are a variety of treatment options currently available for plaque psoriasis affecting the scalp, yet scalp psoriasis remains one of the most frustrating and difficult-to-manage forms of the disease. OBJECTIVE: We investigated the efficacy of fixed-combination calcipotriene 0.005% plus betamethasone dipropionate 0.064% (Cal/BD) foam for the treatment of scalp psoriasis. METHODS: Additional (including post-hoc) analysis was conducted on data from a Phase II, randomized, double-blind, multicenter study of Cal/BD foam for the treatment of psoriasis vulgaris (NCT01536938). A total of 302 patients, ages 18 years or older, with psoriasis vulgaris of at least mild severity (scalp involvement of at least 10%) were included; 100, 101, and 101 patients were randomized to once-daily Cal/BD foam, Cal foam, or BD foam, respectively. Assessments included a severity score for lesion redness, scaliness, and plaque thickness, modified Psoriasis Area and Severity Index (mPASI) score, proportion of patients with reduction of 50 percent or greater in total sign score (TSS-50), and proportion of patients with at least a 75-percent reduction in mPASI score (mPASI-75). RESULTS: Patients achieved greater improvements in their scalp psoriasis with Cal/BD foam versus BD or Cal foam alone at Week 4 considering mPASI, mPASI-75, and TSS-50 outcomes. After four weeks of treatment, more patients receiving Cal/BD foam had a severity score for redness, scaliness, and thickness indicating "none" or "mild" versus BD foam or Cal foam alone. Improvements on the scalp appear to be consistent with those on the trunk and limbs. CONCLUSION: Scalp lesion severity improved considerably and rapidly with a four-week regimen of Cal/BD foam, suggesting that Cal/BD foam is an effective topical treatment option for scalp psoriasis.
RESUMO
Background: The fixed-dose combination foam formulation of calcipotriene 0.005% plus betamethasone dipropionate 0.064% (Cal/BD) has demonstrated efficacy and a favorable safety profile for the treatment of plaque psoriasis. Recently, a topical lotion of the combination of halobetasol 0.01% plus tazarotene 0.045% (HP/TAZ) was approved for treating adult plaque psoriasis. Currently, no head-to-head studies have compared Cal/BD foam with HP/TAZ lotion.Objective: Compare the effectiveness and drug incremental cost per responder (ICPR) of Cal/BD foam vs. HP/TAZ lotion in moderate-to-severe plaque psoriasis.Methods: An anchor-based, matching-adjusted indirect comparison was conducted for PGA treatment success (Physician's Global Assessment of "clear" or "almost clear," [PGA 0/1] with at least a 2-point improvement) using individual patient data from 3 randomized clinical studies of Cal/BD foam and published data from 2 randomized, Phase 3 clinical studies of HP/TAZ lotion. The number needed to treat and ICPR were also calculated.Results: After reweighting of patients in the Cal/BD foam studies to match summary baseline characteristics of the HP/TAZ lotion study patients and anchoring to vehicle effect, 4 weeks of Cal/BD foam produced a significantly greater rate of treatment success than 8 weeks of HP/TAZ lotion treatment (51.4 vs. 30.7%; treatment difference = 20.7%, p < .001). The number needed to treat with Cal/BD foam was also less than HP/TAZ lotion (1.9 vs. 3.3). Using US wholesale acquisition costs and equal weekly consumption rates, the incremental cost per PGA 0/1 responder relative to vehicle for Cal/BD foam was $3,988 and was 37% lower compared with HP/TAZ lotion ($6,294).Conclusions: The indirect comparison analyses showed that Cal/BD foam was associated with a greater rate of treatment success, lower ICPR, and quicker treatment response than HP/TAZ lotion in adult patients with moderate-to-severe plaque psoriasis.
Assuntos
Fármacos Dermatológicos/economia , Fármacos Dermatológicos/uso terapêutico , Psoríase/tratamento farmacológico , Administração Cutânea , Adulto , Idoso , Betametasona/análogos & derivados , Betametasona/economia , Betametasona/uso terapêutico , Calcitriol/análogos & derivados , Calcitriol/economia , Calcitriol/uso terapêutico , Clobetasol/análogos & derivados , Clobetasol/economia , Clobetasol/uso terapêutico , Fármacos Dermatológicos/administração & dosagem , Combinação de Medicamentos , Humanos , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Ácidos Nicotínicos/economia , Ácidos Nicotínicos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de DoençaRESUMO
Background: Clinical trials have established calcipotriene 0.005%/betamethasone dipropionate 0.064% (Cal/BD) foam as a well-tolerated and efficacious topical therapy for psoriasis. Methods: A chart review of 24 US healthcare providers gathered real-world information (clinical characteristics and outcomes, safety, and resource utilization) for patients (≥18 years old) prescribed Cal/BD foam between January 1 and October 31, 2016, along with healthcare provider characteristics and perceptions of Cal/BD foam. Results: Data were reported from 105 patients and 177 active psoriatic lesions. Cal/BD foam was applied once-daily; the prescription was 4 weeks for 69/177 (39%) lesions (median 4, range 1-26 weeks). Knees (n = 41; 23%) and elbows (n = 37; 20%) were the most frequently treated areas. Among 114 lesions, severity improved from "mild"/"moderate"/"severe" to "clear"/"almost clear" in 71%, and 54% had a clinically significant improvement (two-step/greater improvement) in lesion severity from baseline. Of 128 lesions with baseline itch, 90% were not itchy at the best treatment response. Most healthcare providers reported prescribing Cal/BD foam because of its overall efficacy (n = 20/23; 87%). Adverse events were reported in 1/105 patients (1%). Conclusion: Data from real clinical practice demonstrate that Cal/BD foam improves psoriasis disease severity and associated itch in patients and further extend results of clinical trials.
Assuntos
Betametasona/análogos & derivados , Calcitriol/análogos & derivados , Fármacos Dermatológicos/administração & dosagem , Psoríase/tratamento farmacológico , Adolescente , Adulto , Aerossóis , Anti-Inflamatórios/administração & dosagem , Betametasona/administração & dosagem , Calcitriol/administração & dosagem , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Padrões de Prática Médica/estatística & dados numéricos , Prurido/tratamento farmacológico , Prurido/etiologia , Psoríase/complicações , Resultado do Tratamento , Estados UnidosRESUMO
Background: A specific sequence for psoriasis (PsO) therapy has not been defined. Objectives: This retrospective, observational cohort study characterized pathways of PsO treatment over 3 years for newly diagnosed patients initially treated with a topical medication. Methods: Adult PsO patients from the Explorys database (March 1 2011 to June 30 2015) were grouped according to medication-use patterns: 1) discontinued therapy; 2) topical therapy only; 3) switched/added an oral agent; and 4) switched/added a biologic agent. Results: Of 6875 patients, 907 (13.2%) discontinued treatment; 2544 (37.0%) used topical only, and 3319 (45.7%) and 819 (11.9%) switched/added-on an oral and/or biologic agent, respectively. Patients progressed to biologic treatment faster than to oral agents (median 254 vs. 378 d; p < .0001). Using an oral agent before a biologic significantly delayed biologic initiation compared to progressing to biologic directly from topical (median 456 vs. 90 d; p < .0001). Limitations: Disease severity and the reason for treatment transitions were not assessed. Conclusions: Patients initiating topical PsO treatment progressed to biologics faster than to oral agent using an oral agent prior to a biologic significantly delayed biologic initiation. Maintaining patients on an effective topical treatment may minimize the need for a switch to oral and biologics.
Assuntos
Anti-Inflamatórios/administração & dosagem , Produtos Biológicos/uso terapêutico , Psoríase/tratamento farmacológico , Administração Oral , Administração Tópica , Adulto , Idoso , Estudos de Coortes , Bases de Dados como Assunto , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Estados UnidosRESUMO
PURPOSE: To develop a urine diagnostic test for preneoplastic intraepithelial neoplasia of the prostate. EXPERIMENTAL DESIGN: We have used a DNA-binding assay and electrophoretic mobility shift assays (EMSA) to screen for novel duplexed DNA-binding sequences, which bind protein(s) overexpressed in crude protein extracts from high-grade prostatic intraepithelial neoplasia (HGPIN). EMSAs, immunohistochemistry, and ELISAs were used to measure expression of the ABCA5 protein identified as a specific marker in prostate tissue and patient urine. RESULTS: Following screening of 4,096 sequences, an 8-bp dsDNA sequence (i.e., TCCAGCGA) was identified, which binds the ABCA5 protein, a member of the ATP-binding cassette multidrug resistant family. EMSAs showed that ABCA5 was overexpressed in HGPIN tissue (n=11/11) and in the urine of patients with HGPIN (n=18/18) but was not expressed in prostate cancer, benign prostatic hyperplasia, or stroma. Immunohistochemistry indicated that ABCA5 was overexpressed in foci of intermediate basal cells in normal glands and in HGPIN. ABCA5 was faintly expressed in prostate cancer glands. ELISAs showed in 'blinded studies' that ABCA5 was a highly sensitive (>98% sensitivity) urine diagnostic marker for HGPIN in biopsy-positive patients (n=107) at a 'cutoff' of 25 ng/mL. ABCA5 was present at very low levels (i.e., <25 ng/mL) in the urine of patients diagnosed with benign prostatic hyperplasia (n=79) or prostatitis or kidney and bladder cancer (>86% specificity). CONCLUSIONS: The data indicate that ABCA5 might be a specific urine marker for diagnosis of patients with HGPIN.
Assuntos
Transportadores de Cassetes de Ligação de ATP/urina , Regulação Neoplásica da Expressão Gênica , Neoplasia Prostática Intraepitelial/urina , Biópsia , Clonagem Molecular , DNA de Neoplasias/química , Ensaio de Imunoadsorção Enzimática , Humanos , Imuno-Histoquímica , Masculino , Próstata/metabolismo , Neoplasia Prostática Intraepitelial/diagnóstico , Ligação Proteica , Sensibilidade e EspecificidadeRESUMO
The mTOR inhibitor rapamycin induces G1 cell cycle accumulation and p53-independent apoptosis of the human rhabdomyosarcoma cell line Rh1. Insulin-like growth factor I (IGF-I) and insulin, but not epidermal growth factor or platelet-derived growth factor, completely prevented apoptosis of this cell line. Because the Ras-Erk1-Erk2 and phosphatidylinositol 3'-kinase (PI3K)-Akt pathways are implicated in the survival of various cancer cells, we determined whether protection from rapamycin-induced apoptosis by IGF-I requires one or both of these pathways. Despite the blocking of Ras-Erk signaling by the addition of PD 98059 (a MEK1 inhibitor) or by the overexpression of dominant-negative RasN17, IGF-I completely prevented rapamycin-induced death. Inhibition of Ras signaling did not prevent Akt activation by IGF-I. To determine the role of the PI3K-Akt pathway in rescuing cells from apoptosis caused by rapamycin, cells expressing dominant-negative Akt were tested. This mutant protein inhibited IGF-I-induced phosphorylation of Akt and blocked phosphorylation of glycogen synthase kinase 3. The prevention of rapamycin-induced apoptosis by IGF-I was not inhibited by expression of dominant-negative Akt either alone or under conditions in which LY 294002 inhibited PI3K signaling. Furthermore, IGF-I prevented rapamycin-induced apoptosis when the Ras-Erk1-Erk2 and PI3K-Akt pathways were blocked simultaneously. Similar experiments in a second rhabdomyosarcoma cell line, Rh30, using pharmacological inhibitors of PI3K or MEK1, alone or in combination, failed to block IGF-I rescue from rapamycin-induced apoptosis. Therefore, we conclude that a novel pathway(s) is responsible for the IGF-I-mediated protection against rapamycin-induced apoptosis in these rhabdomyosarcoma cells.