Betamethasone dipropionate spray 0.05% alleviates troublesome symptoms of plaque psoriasis.

Patients consider pruritus and scaling to be the most bothersome symptoms of psoriasis. Psoriatic plaques on the knees and elbows are widely considered difficult to treat because of the thicker stratum corneum, which reduces skin hydration and topical absorption. Betamethasone dipropionate (BD) spray 0.05% is a topical steroid with demonstrated efficacy in treating plaque psoriasis. Post hoc analyses of 2 phase 3 trials were done to assess the efficacy of BD spray in relieving the symptom of itching and improving the signs of erythema, scaling, and plaque elevation on plaques located on the knees and elbows vs its vehicle and an augmented BD (AugBD) lotion 0.05%. Betamethasone dipropionate spray reduced the incidence of pruritus, with approximately half of patients who reported itching at baseline showing complete itch relief by day 4. Betamethasone dipropionate spray also reduced the signs of psoriasis on knee and elbow plaques in more patients than AugBD lotion at day 4, though the differences were not statistically significant. Efficacy was similar between the 2 formulations on days 8 and 15. Betamethasone dipropionate spray rapidly relieved2 of the most bothersome symptoms of psoriasis and improved psoriatic signs in hard-to-treat knee and elbow plaques.

Bioavailability, Pharmacokinetics, and Transepidermal Water Loss of Short Contact Tazarotene Lotion 0.1% Versus Tazarotene (Tazorac®) Cream 0.1.

Objective: Two clinical studies were conducted to 1) assess the pharmacokinetic (PK) properties of tazarotene and tazarotenic acid in DFD-03 lotion (a 1-minute, short-contact formulation for the topical treatment of acne vulgaris) and tazarotene cream 0.1% and 2) to evaluate transepidermal water loss (TEWL) with DFD-03 lotion, tazarotene gel (0.1%), or vehicle. Design: The PK study included a single-center, randomized, multiple-dose, laboratory-blinded, open-label, parallel-design, and the TEWL study included a multiple-dose, within-subject comparison design. Participants: The PK study included healthy adult men aged 18 to 40 years (n=43), and the TEWL study included healthy adults, male or female, aged 18 to 40 years (n=24). Measurements: PK was assessed via Cmax, AUC0-12, AUC0-24, Tmax, Cmin, Tmin, and fluctuation. TEWL was assessed via evaporimetry. Results: Tazarotene levels were very low due to rapid esterase hydrolysis to the primary active metabolite, tazarotenic acid. Tazarotenic acid AUC0-24 ratios (%) were at least two times higher when the test product was applied twice daily (Treatment-1) versus once daily (Treatment-2) on Days 7 and 14 (268.73% and 254.42%, respectively). Tazarotenic acid AUC0-24 ratios (%) were nearly 100 percent for Treatment-1 versus once-daily tazarotene cream 0.1% (Treatment-3) (99.36% and 83.21%, on Days 7 and 14, respectively). Starting on Day 7, DFD-03 lotion TEWL readings were significantly greater than vehicle (p≤0.05), except for on one study day. DFD-03 lotion TEWL readings were numerically greater (nonsignificant) than tazarotene gel. Conclusion: DFD-03 lotion was well-tolerated, increased TEWL when applied twice daily for one minute, and had a PK profile with similar overall exposure as compared with commercially available tazarotene formulations applied once daily for 12 hours.

Effect of a New Head Lice Treatment, Abametapir Lotion, 0.74%, on Louse Eggs: A Randomized, Double-Blind Study.

Few head lice treatments have demonstrated effectiveness against louse eggs. Abametapir, a metalloproteinase inhibitor, is able to target metalloproteinases critical to egg hatching and louse development. In this double-blind, phase 2 study, 50 subjects aged ≥3 years with active head lice infestation were randomized to receive a single treatment of abametapir lotion, 0.74%, or vehicle (control), applied to scalp and hair for 10 minutes. Ovicidal efficacy was measured by recording the hatch rate of eggs collected from each subject's hair before and after treatment and incubated for 14 days. With abametapir, 100% of treated eggs remained unhatched compared with 64.0% for vehicle. Accounting for pretreatment hatch rates, the absolute reduction in egg hatching was 92.9% for abametapir versus 42.3% for vehicle (P < .0001). The most frequently reported adverse event was rash (16%). Abametapir lotion, 0.74%, demonstrated significant ovicidal activity against head lice eggs with a single application.

Clinical studies evaluating abametapir lotion, 0.74%, for the treatment of head louse infestation.

BACKGROUND: There is a need for better control of head louse infestations. Abametapir is an inhibitor of metalloproteinases critical for louse survival and egg development. The efficacy of abametapir lotion, 0.74%, was assessed for its ability to clear head louse infestations after a single application. METHODS: Two randomized, double-blind, multicenter, vehicle-controlled studies were conducted in subjects aged 6 months and older to compare the effectiveness of abametapir lotion versus vehicle control for eliminating head louse infestations without nit combing. Abametapir lotion was applied to dry hair for 10 minutes on day 0 and then rinsed with water. The primary endpoint was the proportion of index subjects (youngest household member with ≥ 3 live lice at screening) in the intent-to-treat population who were louse free at all follow-up visits through day 14. Older household members with one or more live lice at screening were designated as nonindex subjects and treated as per the index subject within their household. RESULTS: In the intent-to-treat population (index subjects, N = 216), 81.5% of subjects treated with abametapir lotion were louse free through day 14 after a single treatment, versus 49.1% with vehicle (P < 0.001). For the combined index and nonindex population (N = 704), 85.9% were louse free through day 14 in the abametapir group, versus 61.3% in the vehicle group (P < 0.001). The most frequently reported adverse events were erythema (4.0%), rash (3.2%), and skin burning sensation (2.6%). CONCLUSION: Abametapir lotion, 0.74%, was effective at clearing active head louse infestations through day 14 in subjects aged 6 months and older. All adverse events (including one serious but unrelated to study drug) resolved uneventfully.

Efficacy, Safety, and Potency of Betamethasone Dipropionate Spray 0.05%: A Treatment for Adults with Mild-to-moderate Plaque Psoriasis.

Objective: A spray formulation of betamethasone dipropionate 0.05% (BD spray 0.05%; Sernivo™ [betamethasone dipropionate] Spray 0.05%; Promius Pharma, LLC; Princeton, New Jersey, USA) has been developed for the topical treatment of psoriasis. The objective of these studies was to evaluate the efficacy, safety, and potency of BD spray 0.05%. Design, Setting, Participants, and Measurements: Efficacy and safety were assessed in a randomized, vehicle-controlled, double-blind study in adults with moderate plaque psoriasis (ClinicalTrials.gov identifier: NCT01947491). Additionally, the potential for adrenal suppression and systemic absorption was evaluated in a randomized, open-label study in healthy adults (ClinicalTrials.gov identifier: NCT02070965). Potency was measured in two single-point, randomized, evaluator-blinded studies in healthy adults. Results: BD spray 0.05% was significantly more effective than the vehicle spray in subjects with moderate plaque psoriasis after three, 14, and 28 days of twice-daily treatment. The efficacy of BD spray 0.05% was similar to augmented BD lotion 0.05% after 14 days of treatment. The safety of BD spray 0.05% was similar to that of the vehicle spray over 28 days and to that of augmented BD lotion 0.05% over 14 days. Under maximal use conditions for up to 29 days, the potential for adrenal suppression was no greater with BD spray 0.05% than with a 15-day regimen of augmented BD lotion 0.05%. There was less systemic absorption of BD from BD spray 0.05% than from augmented BD lotion 0.05%. Studies classify BD spray 0.05% as a midpotent corticosteroid. Conclusions: BD spray 0.05%, a midpotent corticosteroid, is an effective and well-tolerated treatment for adults with mild to moderate plaque psoriasis.

DFD-01 Reduces Transepidermal Water Loss and Improves Skin Hydration and Flexibility.

INTRODUCTION: In plaque psoriasis, the benefit of topical steroids is well established. The vehicle formulation of topical steroids may also provide benefit in addition to the effects of the steroid itself. DFD-01 (betamethasone dipropionate spray, 0.05%) is a formulation composed of a topical steroid in an emollient-like vehicle that enhances penetration to the target site of inflammation in the skin. The aim of this study was to assess the effect of DFD-01 and its vehicle on skin hydration and barrier function in compromised skin and to evaluate its effect on flexibility in healthy skin. METHODS: Eighteen healthy white volunteers were enrolled in each of two studies. In Study 1, dry shaving of volar forearms created a compromised skin barrier, through which transepidermal water loss (TEWL) was measured using an evaporimeter. Capacitance, a measure of epidermal hydration, was also measured at baseline and at 1, 2 and 4 h after application of DFD-01 or its vehicle formulation. In Study 2, intact skin flexibility was tested with a cutometer before and at 1, 2 and 4 h after application of DFD-01 or vehicle. RESULTS: In Study 1, both DFD-01 and its vehicle were effective at reducing TEWL through the compromised stratum corneum. Capacitance measurements confirmed this finding; razor-chafed skin treated with either DFD-01 or vehicle exhibited levels of skin hydration similar to unshaved control skin. Study 2 found softening and greater flexibility of normal skin treated with either DFD-01 or vehicle compared with nontreated control skin samples. CONCLUSIONS: These tests suggest that the DFD-01 formulation and its vehicle are each effective at retaining moisture within a damaged skin barrier and for softening and increasing the flexibility of intact skin. FUNDING: Dr. Reddy's Laboratories.

A multicenter, open-label, long-term safety and tolerability study of DFN-02, an intranasal spray of sumatriptan 10 mg plus permeation enhancer DDM, for the acute treatment of episodic migraine.

BACKGROUND: DFN-02 is a novel intranasal spray formulation composed of sumatriptan 10 mg and a permeation-enhancing excipient comprised of 0.2% 1-O-n-Dodecyl-ß-D-Maltopyranoside (DDM). This composition of DFN-02 allows sumatriptan to be rapidly absorbed into the systemic circulation and exhibit pharmacokinetics comparable to subcutaneously administered sumatriptan. Rapid rate of absorption is suggested to be important for optimal efficacy. The objective of this study was to evaluate the safety and tolerability of DFN-02 (10 mg) in the acute treatment of episodic migraine with and without aura over a 6-month period based on the incidence of treatment-emergent adverse events and the evaluation of results of clinical laboratory tests, vital signs, physical examination, and electrocardiograms. METHODS: This was a multi-center, open-label, repeat-dose safety study in adults with episodic migraine with and without aura. Subjects diagnosed with migraine with or without aura according to the criteria set forth in the International Classification of Headache Disorders, 2nd edition, who experienced 2 to 6 attacks per month with fewer than 15 headache days per month and at least 48 headache-free hours between attacks, used DFN-02 to treat their migraine attacks acutely over the course of 6 months. RESULTS: A total of 173 subjects was enrolled, 167 (96.5%) subjects used at least 1 dose of study medication and were evaluable for safety, and 134 (77.5%) subjects completed the 6-month study. A total of 2211 migraine attacks was reported, and 3292 doses of DFN-02 were administered; mean per subject monthly use of DFN-02 was 3.6 doses. Adverse events were those expected for triptans, as well as for nasally administered compounds. No new safety signals emerged. Dysgeusia and application site pain were the most commonly reported treatment-emergent adverse events over 6 months (21% and 30.5%, respectively). Most of the treatment-emergent adverse events were mild. There were 5 serious adverse events, all considered unrelated to the study medication; the early discontinuation rate was 22.5% over the 6-month treatment period. CONCLUSION: DFN-02 was shown to be well tolerated when used over 6 months to treat episodic migraine acutely.

A randomized, blinded, multicenter trial of a gentamicin vancomycin gel (DFA-02) in patients undergoing abdominal surgery.

BACKGROUND: SI is a significant medical problem. DFA-02 is an investigational bioresorbable modified release gel consisting of both gentamicin (16.8 mg/mL) and vancomycin (18.8 mg/mL). A Phase 2a study, where the drug was applied during surgical incision closure, suggested safety and tolerability but was not designed to assess its efficacy. STUDY DESIGN: In a Phase 2b randomized, blinded trial patients undergoing abdominal, primarily colorectal, surgery were randomized (4:1:1) to one of three study arms: DFA-02, matching placebo gel, or standard of care (SOC) involving irrigation of the wound with normal saline. The DFA-02 and placebo gel groups received up to 20 mL of study drug inserted above the fascia during wound closure, and were treated in a double-blind manner; the SOC group was treated in a single-blind manner. The primary endpoint was SSI (adjudicated centrally by a blinded committee) through postoperative day 30. RESULTS: Overall, 445 subjects (intention-to-treat) were randomized at 35 centers with 425 subjects completing the study and being evaluable. There were 67 SSIs (15.8%): 64.2% superficial, 7.5% deep, and 28.4% organ space. The incidence of SSI was not statistically significantly different between the DFA-02 and the placebo gel/SOC arms combined, 42/287 = 14.6% vs 25/138 = 18.1% (p = 0.36), respectively. Rehospitalization within 30 days was also similar between study groups (DFA-02 28.6%, placebo gel 21.4%, SOC 27.3%). CONCLUSION: In this multicenter, blinded, randomized trial with central adjudication, the gentamicin/vancomycin gel was not associated with a significant reduction in SSI. SUMMARY: Patients undergoing abdominal surgery were randomized to one of three study arms: DFA-02 gel consisting of both gentamicin and vancomycin, matching placebo gel, or standard of care (SOC). Of 425 patients completing the study at 35 sites the gentamicin/vancomycin gel was not associated with a significant reduction in SSI.

A Randomized Trial Comparing the Pharmacokinetics, Safety, and Tolerability of DFN-02, an Intranasal Sumatriptan Spray Containing a Permeation Enhancer, With Intranasal and Subcutaneous Sumatriptan in Healthy Adults.

OBJECTIVE/BACKGROUND: Intranasal sumatriptan (Imitrex® ) may be an alternative for patients who refuse injections and cannot tolerate oral agents, but due to low bioavailability and slow absorption, the clinical utility of the currently marketed formulation is limited, highlighting an unmet need for an effective non-oral migraine medication with a rapid onset of action. To overcome the slow absorption profile associated with intranasal administration, we evaluated the impact of 1-O-n-Dodecyl-ß-D-Maltopyranoside (DDM, Intravail A-3™), a permeation enhancer, on sumatriptan's pharmacokinetic profile by comparing the pharmacokinetic characteristics of two commercial sumatriptan products, 4 mg subcutaneous and 6 mg subcutaneous in healthy adults, with DFN-02 - a novel intranasal agent comprised of sumatriptan 10 mg plus 0.20% DDM. We also determined the pharmacokinetic characteristics of DDM and evaluated its safety and tolerability. METHODS: We conducted two studies: a randomized, three-way crossover study comparing monodose and multidose devices for delivery of single doses of DFN-02 with commercially available intranasal sumatriptan 20 mg in 18 healthy, fasted adults, and an open-label, randomized, single-dose, three-way crossover bioavailability study comparing DFN-02 with 4 mg and 6 mg subcutaneous sumatriptan in 78 healthy, fasted adults. In the study comparing DFN-02 with IN sumatriptan, subjects received a single dose of DFN-02 (sumatriptan 10 mg plus DDM 0.20%) via monodose and multidose delivery systems with at least 5 days between treatments. In the comparison with SC sumatriptan, subjects received a single dose of each treatment with at least 3 days between treatments. In both studies, blood was sampled for pharmacokinetic evaluation of sumatriptan and DDM through 24 hours post-dose; safety and tolerability were monitored throughout. RESULTS: In the comparison with commercially available intranasal sumatriptan 20 mg, DFN-02 had a more rapid absorption profile; tmax was 15 minutes for DFN-02 monodose, 10.2 minutes for DFN-02 multidose, and 2.0 hours for commercially available intranasal sumatriptan 20 mg. Compared with 4 and 6 mg subcutaneous sumatriptan, DFN-02's median tmax (10 minutes) was significantly earlier (15 minutes; P < .0001). Mean sumatriptan exposure metrics were similar for DFN-02 and 4 mg sumatriptan: AUC0-2 : 35.12 and 44.82 ng*hour/mL, respectively; AUC0-∞ : 60.70 and 69.21 ng*hour/mL, respectively; Cmax : 51.79 and 49.07 ng/mL, respectively. With 6 mg subcutaneous sumatriptan, these exposure metrics were about 50% larger (AUC0-2 : 67.17 ng*hour/mL; AUC0-∞ : 103.78 ng*hour/mL; Cmax : 72.75 ng/mL). Inter-subject variability of AUC0-2 , AUC0-∞ , and Cmax was 42-58% for DFN-02, 15-22% for 4 mg subcutaneous sumatriptan, and 15-25% for 6 mg subcutaneous sumatriptan. DDM exposure was low (mean Cmax : 1.63 ng/mL), tmax was 30 minutes, and it was undetectable by 4 hours. There were no serious adverse events, discontinuations due to adverse events, or remarkable findings for vital signs, physical examinations (including nasal and injection site examinations), or clinical laboratory assessments. The overall incidence of adverse events was comparable across treatments, and all treatment-related events were mild in severity. Adverse events occurring in ≥10% of subjects were dysgeusia (19%), headache (18%), nausea (15%), paresthesia (15%), and dizziness (12%). CONCLUSIONS: In healthy subjects, DFN-02, an intranasal spray containing 10 mg sumatriptan plus DDM, had a more rapid absorption profile than commercially available intranasal sumatriptan 20 mg, and systemic exposure from a single-dose administration of DFN-02 was similar to 4 mg SC sumatriptan and two-thirds that of 6 mg SC sumatriptan. With DFN-02, plasma sumatriptan peaked 5 minutes earlier than with both subcutaneous formulations. Systemic exposure to sumatriptan was similar with DFN-02 and 4 mg subcutaneous sumatriptan; both yielded lower systemic exposure than 6 mg subcutaneous sumatriptan. Systemic exposure to DFN-02's excipient DDM was short-lived. DFN-02's safety and tolerability appear to be comparable to subcutaneous sumatriptan. Addition of a permeation enhancer improved the absorption profile compared with commercially available intranasal sumatriptan 20 mg.

A randomized, double-blind, placebo controlled safety, tolerability, and pharmacokinetic dose escalation study of a gentamicin vancomycin gel in patients undergoing colorectal surgery.

BACKGROUND: Despite numerous interventions promulgated by the Surgical Care Improve Project (SCIP) and other organizations, surgical site infection (SSI) continues to be a significant medical problem. DFA-02 is a novel bioresorbable modified-release gel consisting of both gentamicin (16.8 mg/mL) and vancomycin (18.8 mg/mL) to be applied during surgical incision closure for the prevention of SSIs. The following double-blind phase 2a trial was designed to test the safety and tolerability of DFA-02. METHODS: At six US sites, the study planned to randomize 40 subjects undergoing colorectal surgery (30 with DFA-02, and eight with placebo gel) in four ascending dose cohorts (10-, 20-, 30-, and 40-mL study drug per wound). Safety was ascertained and serum pharmacokinetics (PK) was determined. RESULTS: Study enrollment was discontinued after the first three dose cohorts (10, 20, and 30 mL) as even very large incisions could not accommodate more than 20 mL of gel, leaving no scientific justification for the 40-mL cohort. DFA-02 was well tolerated and showed no evidence of local tissue reaction or impairment of wound healing. No serious AEs were deemed related to study drug. Systemic exposure to gentamicin and vancomycin remained well below levels considered to be at higher risk for oto- or nephrotoxicity. The maximal gentamicin and vancomycin levels observed were 2.36 and 0.684 µg/mL at 6 h, which were well below the prespecified stopping criteria of 12 and 20 µg/mL, respectively. CONCLUSIONS: In this small phase 2a study, the study drug was well tolerated and appeared to be free of serious adverse effects. Consistent with these findings, the PK values were consistent with gradual release of the antibiotics from the gel in the surgical site. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01496352.

Safety and pharmacokinetics of single and multiple intravenous bolus doses of diclofenac sodium compared with oral diclofenac potassium 50 mg: A randomized, parallel-group, single-center study in healthy subjects.

In a randomized, parallel-group, single-center study in 42 healthy adults, the safety and pharmacokinetic parameters of an intravenous formulation of 18.75 and 37.5 mg diclofenac sodium (DFP-08) following single- and multiple-dose bolus administration were compared with diclofenac potassium 50 mg oral tablets. Mean AUC0-inf values for a 50-mg oral tablet and an 18.75-mg intravenous formulation were similar (1308.9 [393.0]) vs 1232.4 [147.6]). As measured by the AUC, DFP-08 18.75 mg and 37.5 mg demonstrated dose proportionality for extent of exposure. One subject in each of the placebo and DFP-08 18.75-mg groups and 2 subjects in the DFP-08 37.5-mg group reported adverse events that were considered by the investigator to be related to the study drug. All were mild in intensity and did not require treatment. Two subjects in the placebo group and 1 subject in the DFP-08 18.75-mg group reported grade 1 thrombophlebitis; no subjects reported higher than grade 1 thrombophlebitis after receiving a single intravenous dose. The 18.75- and 37.5-mg doses of intravenous diclofenac (single and multiple) were well tolerated for 7 days. Additional efficacy and safety studies are required to fully characterize the product.

Esmolol in acute ischemic syndromes.

BACKGROUND: beta-Blockers have been shown to reduce both morbidity and mortality rates in patients with acute coronary syndromes. However, because of potential side effects, their use is limited in patients who might benefit the most from such therapy. It was thought that the use of an ultra-short-acting intravenous beta-blocker might produce similar results with fewer complications in those patients with relative contraindications to beta-blocker therapy. METHODS: Accordingly, we evaluated the use of esmolol in patients with acute coronary syndromes and relative contraindication to beta-blocker therapy in a prospective randomized trial. One hundred eight patients at 21 sites received an infusion of intravenous esmolol or standard therapy on admission and were followed for 6 weeks from the day of admission. The primary efficacy outcome was a composite event consisting of any of the following that occurred during the index hospitalization: death, myocardial (re)infarction, recurrent ischemia, or arrhythmia as well as silent myocardial ischemia assessed by ambulatory electrocardiographic monitoring. Safety end points including hypotension, bradyarrhythmias, new or worsening congestive heart failure, and bronchospasm were also recorded. RESULTS: Event rates for primary end points were similar in the 2 groups: death (2% in the standard care group vs 4% in the group receiving esmolol), myocardial (re)infarction (4% standard vs 7% esmolol), ischemia (12% vs 13%), arrhythmias (4% vs 2%), and silent ischemia (13% vs 15%). There was a higher incidence of transient hypotension in the group receiving esmolol (2% vs 16%), but all such events were noted to resolve after discontinuation of the esmolol infusion. There were no additional differences in safety end points: bradycardia (2% for those receiving standard care vs 9% receiving esmolol), new congestive heart failure (10% vs 16%), bronchospasm (0% vs 7%), and heart block (2% vs 2%). CONCLUSIONS: The use of an ultra-short-acting beta-blocker such as esmolol might offer an alternative to patients with contraindications to standard beta-blocker therapy. Although this trial had limited power to detect safety and efficacy differences between the 2 therapies, it was observed that safety end points, which occurred during esmolol administration, resolved readily when the infusions were decreased or discontinued. Additional testing is needed to substantiate these findings.