Safety and efficacy of eblasakimab, an interleukin 13 receptor α1 monoclonal antibody, in adults with moderate-to-severe atopic dermatitis: A phase 1b, multiple-ascending dose study.

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.

Calcipotriene Plus Betamethasone Dipropionate Foam for Mild Psoriasis: Pooled Results from Three Randomized Trials.

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.

Calcipotriol/betamethasone dipropionate aerosol foam for the treatment of psoriasis vulgaris: a review of real-world evidence (RWE).

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.

Efficacy of Fixed-combination Calcipotriene 0.005% and Betamethasone Dipropionate 0.064% Foam for Scalp Plaque Psoriasis: Additional Analysis of a Phase II, Randomized Clinical Study.

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.

Real-World Effectiveness and Safety of Field- and Lesion-Directed Treatments for Actinic Keratosis.

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.

PGAxBSA composite versus PASI: Comparison across disease severities and as therapeutic response measure for Cal/BD foam in plaque psoriasis.

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.

Effect of Calcipotriene/Betamethasone Dipropionate 0.005%/0.064% Foam on Target Lesions in Plaque Psoriasis: A Post-Hoc Analysis

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

Effectiveness comparison and incremental cost-per-responder analysis of calcipotriene 0.005%/betamethasone dipropionate 0.064% foam vs. halobetasol 0.01%/tazarotene 0.045% lotion for plaque psoriasis: a matching-adjusted indirect comparative analysis.

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.

Real-world experience of calcipotriene and betamethasone dipropionate foam 0.005%/0.064% in the treatment of adults with psoriasis in the United States.

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.

The journey for US psoriasis patients prescribed a topical: a retrospective database evaluation of patient progression to oral and/or biologic treatment.

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.

Patient-Reported Satisfaction With the Fixed Combination Calcipotriene/Betamethasone Dipropionate Foam for Plaque Psoriasis.

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.

Absorption, distribution, metabolism and excretion of the novel SARM GTx-024 [(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide] in rats.

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 ∼70% 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.

Role and pharmacologic significance of cytochrome P-450 2D6 in oxidative metabolism of toremifene and tamoxifen.

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.

Preclinical characterization of a novel diphenyl benzamide selective ERα agonist for hormone therapy in prostate cancer.

Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. ADT improves overall and disease-free survival rates, but long-term therapy is associated with severe side effects of androgen and estrogen depletion including hot flashes, weight gain, depression, and osteoporosis. Effective hormone reduction can be achieved without estrogen deficiency-related side effects by using therapy with estrogenic compounds. However, cardiovascular complications induced by estrogens coupled with the availability of LHRH agonists led to discontinuation of estrogen use for primary androgen deprivation therapy in the 1980s. New treatments for prostate cancer that improve patient outcomes without the serious estrogen deficiency-related toxicities associated with ADT using LHRH analogs are needed. Herein we describe a novel nonsteroidal selective estrogen receptor-α agonist designed for first-line therapy of advanced prostate cancer that in animal models induces medical castration and minimizes many of the estrogen deficiency-related side effects of ADT. The present studies show that orally administered GTx-758 reversibly suppressed testosterone to castrate levels and subsequently reduced prostate volume and circulating prostate-specific antigen in relevant preclinical models without inducing hot flashes, bone loss, thrombophilia, hypercoagulation, or increasing fat mass.

Drug interaction potential of toremifene and N-desmethyltoremifene with multiple cytochrome P450 isoforms.

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.

Estrogen receptor-{beta}-selective ligands alleviate high-fat diet- and ovariectomy-induced obesity in mice.

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.

Toremifene--a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy.

Deregulation of the estrogen axis in humans prompts a series of tissue-specific events. In the breast and prostate, alterations in estrogen signalling lead to genotypic and phenotypic molecular alterations that result in dysplastic cellular appearance, deregulated cell growth and carcinoma. In bone, decreased estrogen leads to increased osteoclastogenesis and bone resorption, decreased bone mineral density and a significant fracture risk. Toremifene is a selective estrogen receptor modulator that exerts pharmacological activity in the breast, bone and prostate. An intense interest in developing this agent for prostate cancer chemoprevention is based on the reduction of premalignant and malignant prostate lesions in a transgenic model of prostate cancer. Biological and clinical activity was demonstrated in Phase II trials by the prevention of progression to prostate cancer in men with high-grade prostate intraepithelial neoplasia and through suppression of bone turnover biomarkers and increased bone mineral density in men on androgen deprivation therapy for prostate cancer.

Pharmacodynamics of selective androgen receptor modulators.

The present study aimed to identify selective androgen receptor modulators (SARMs) with in vivo pharmacological activity. We examined the in vitro and in vivo pharmacological activity of four chiral, nonsteroidal SARMs synthesized in our laboratories. In the in vitro assays, these compounds demonstrated moderate to high androgen receptor (AR) binding affinity, with K(i) values ranging from 4 to 37 nM, and three of the compounds efficaciously stimulated AR-mediated reporter gene expression. The compounds were then administered subcutaneously to castrated rats to appraise their in vivo pharmacological activity. Androgenic activity was evaluated by the ability of these compounds to maintain the weights of prostate and seminal vesicle, whereas levator ani muscle weight was used as a measure of anabolic activity. The maximal response (E(max)) and dose for half-maximal effect (ED(50)) were determined for each compound and compared with that observed for testosterone propionate (TP). Compounds S-1 and S-4 demonstrated in vivo androgenic and anabolic activity, whereas compounds S-2 and S-3 did not. The activities of S-1 and S-4 were tissue-selective in that both compounds stimulated the anabolic organs more than the androgenic organs. These two compounds were less potent and efficacious than TP in androgenic activity, but their anabolic activity was similar to or greater than that of TP. Neither S-1 nor S-4 caused significant luteinizing hormone or follicle stimulating hormone suppression at doses near the ED(50) value. Thus, compounds S-1 and S-4 were identified as SARMs with potent and tissue-selective in vivo pharmacological activity, and represent the first members of a new class of SARMs with selective anabolic effects.