In silico trial for the assessment of givinostat dose adjustment rules based on the management of key hematological parameters in polycythemia vera patients.

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by excessive levels of platelets (PLT), white blood cells (WBC), and hematocrit (HCT). Givinostat (ITF2357) is a potent histone-deacetylase inhibitor that showed a good safety/efficacy profile in PV patients during phase I/II studies. A phase III clinical trial had been planned and an adaptive dosing protocol had been proposed where givinostat dose is iteratively adjusted every 28 days (one cycle) based on PLT, WBC, and HCT. As support, a simulation platform to evaluate and refine the proposed givinostat dose adjustment rules was developed. A population pharmacokinetic/pharmacodynamic model predicting the givinostat effects on PLT, WBC, and HCT in PV patients was developed and integrated with a control algorithm implementing the adaptive dosing protocol. Ten in silico trials in ten virtual PV patient populations were simulated 500 times. Considering an eight-treatment cycle horizon, reducing/increasing the givinostat daily dose by 25 mg/day step resulted in a higher percentage of patients with a complete hematological response (CHR), that is, PLT ≤400 × 109 /L, WBC ≤10 × 109 /L, and HCT < 45% without phlebotomies in the last three cycles, and a lower percentage of patients with grade II toxicity events compared with 50 mg/day adjustment steps. After the eighth cycle, 85% of patients were predicted to receive a dose ≥100 mg/day and 40.90% (95% prediction interval = [34, 48.05]) to show a CHR. These results were confirmed at the end of 12th, 18th, and 24th cycles, showing a stability of the response between the eighth and 24th cycles.

Effects of a novel finasteride 0.25% topical solution on scalp and serum dihydrotestosterone in healthy men with androgenetic alopecia.

OBJECTIVE: The effects on scalp and serum dihydrotestosterone (DHT) of different doses of a novel topical solution of 0.25% finasteride (P-3074), a type 2 5α-reductase, were investigated in men with androgenetic alopecia. METHODS: Two randomized, parallel-group studies were conducted. Study I: 18 men received 1 mL (2.275 mg) P-3074, applied to the scalp once a day (o.d.) or twice a day (b.i.d), or 1 mg oral tablet o.d. for 1 week. Study II: 32 men received P-3074 at the dose of 100 (0.2275 mg), 200 (0.455 mg), 300 (0.6285 mg), or 400 (0.91 mg) µL or the vehicle o.d. for 1 week. Scalp and serum DHT and serum testosterone were evaluated at baseline and treatment end. RESULTS: Change from baseline in scalp DHT was -70% for P-3074 o.d. and approx. -50% for P-3074 b.i.d. and the tablet. Serum DHT decreased by 60 - 70%. The doses of 100 and 200 µL P-3074 resulted in a -47/-52% scalp DHT reduction, similar to the 300 and 400 µL doses (i.e., -37/-54%). A -5.6% inhibition was observed for the vehicle. Serum DHT was reduced by only -24/-26% with 100 and 200 µL P-3074 and by -44/-48% with 300 and 400 µL P-3074. No relevant changes occurred for serum testosterone. CONCLUSIONS: The novel finasteride 0.25% solution applied o.d. at the doses of 100 and 200 µL results in an appropriate inhibition of scalp DHT potentially minimizing the untoward sexual side-effects linked to a systemic DHT reduction.

Nail Psoriasis in Children: Common or Uncommon? Results from a 10-Year Double-Center Study.

PURPOSE OF THE STUDY: Our aim was to perform an extensive search of the literature on the prevalence of nail psoriasis in the pediatric population and to estimate it on our own database. PROCEDURES: Searching the most important databases yielded results of 16 papers published in a 40-year period which reported the prevalence of nail psoriasis in children. Furthermore, data gathered between 2004 and 2013 at two centers specialized in nail disorders were analyzed. RESULTS: The selected papers encompassed a total of 4,853 psoriatic children, of whom 762 (15.7%) had nail involvement. Concerning our data, a total of 68,839 children were seen in pediatric skin consultation in both clinics over a period of 10 years, 0.11% of which had nail involvement. The rate of psoriatic children presenting nail alterations was 19.4% in the Greek and 15.5% in the Italian patient groups. CONCLUSIONS AND MESSAGE: This is the retrospective study including the largest number of cases of nail psoriasis in the pediatric population. Our data are in line with the incidence estimation of the rest of Europe.

A novel finasteride 0.25% topical solution for androgenetic alopecia: pharmacokinetics and effects on plasma androgen levels in healthy male volunteers.

OBJECTIVE: Finasteride, a selective inhibitor of type 2 5-α reductase isoenzyme, inhibits the conversion of testosterone to dihydrotestosterone (DHT) and is indicated in the treatment of male androgenetic alopecia. The study objective was to evaluate a newly developed finasteride 0.25% topical solution in comparison to the marketed finasteride 1 mg tablet, with respect to finasteride pharmacokinetics and suppressive effects on plasma DHT. METHODS: 24 healthy men with androgenetic alopecia were randomized in a single center, open-label, parallel-group, exploratory study, and received either multiple scalp applications of the topical solution b.i.d. or oral doses of the reference tablet o.d. for 7 days. Plasma finasteride, testosterone and DHT concentrations were determined. RESULTS: After multiple doses, mean (± SD) finasteride C(max) and AUC(0-t) corresponded to 0.46 ± 0.28 ng/mL and 6.64 ± 7.50 ng/mL x h for the topical solution and to 6.86 ± 1.78 ng/mL and 57.93 ± 29.38 ng/mL x h for the tablet. Plasma DHT was reduced by ~ 68 - 75% with the topical solution and by ~ 62 - 72% with the tablet. No relevant changes occurred for plasma testosterone with either treatment. No clinically significant adverse events occurred. CONCLUSIONS: A strong and similar inhibition of plasma DHT was found after 1 week of treatment with the topical and tablet finasteride ormulations, albeit finasteride plasma exposure was significantly lower with the topical than with the oral product (p < 0.0001).

Randomized controlled trial of a water-soluble nail lacquer based on hydroxypropyl-chitosan (HPCH), in the management of nail psoriasis.

BACKGROUND: Nail psoriasis occurs in up to 50% of patients affected by psoriasis, with a significant impact on quality of life that leads to a real clinical need for new therapeutic options. AIM: To confirm whether the strengthening and hardening properties of the hydroxypropyl-chitosan (HPCH) nail lacquer could improve the structure of the nail plates on psoriatic nails. MATERIALS AND METHODS: A randomized, double-blind, placebo controlled, parallel-group trial was carried out to evaluate the efficacy and tolerability of a hydrosoluble nail lacquer containing HPCH, Equisetum arvense, and methylsulfonylmethane on nail psoriasis. The test product or a placebo was applied once daily for 24 weeks to all fingernails. Efficacy assessments were performed on the target fingernail by means of the modified Nail Psoriasis Severity Index score. A cut-off score of 4 was considered to define the clinical cure rate (ie, Cure ≤4, Failure >4). RESULTS: After 24 weeks, the clinical cure rate showed the statistically significant superiority of the HPCH nail lacquer compared to placebo in both the intention-to-treat (Fisher's exact test, P=0.0445) and the per protocol population (Fisher's exact test, P=0.0437). This superiority was already present after 16 weeks of treatment. Moreover, the analysis of the modified Nail Psoriasis Severity Index-50 showed a statistically significant clinical improvement after 12 weeks of treatment in comparison to the results obtained after 8 weeks (Fisher's exact test, P<0.05). CONCLUSION: The trial showed that HPCH nail lacquer could be a new, valid, effective, and safe option for decreasing the signs of nail dystrophy in psoriatic patients.

Topical formulations containing finasteride. Part II: determination of finasteride penetration into hair follicles using the differential stripping technique.

The differential stripping technique consists of a tape-stripping phase followed by a cyanoacrylate biopsy. This technique not only allows the quantification of drug retained in the stratum corneum (SC) and in the hair follicles but also differentiates transepidermal from transfollicular penetration. Our study aimed at both validating the differential stripping procedure on hairless rat skin and assessing the role of the hair follicle in the cutaneous penetration of finasteride (FNS) after application of two experimental formulations for 6 or 24 h: P-08-016, a hydroxypropyl chitosan (HPCH)-based formulation and P-10-008, an anhydrous formulation devoid of HPCH. Microscopic and histological evaluation showed that after 15 tape strips both the SC and the viable epidermis were completely removed. A subsequent cyanoacrylate skin surface biopsy led to the removal of the infundibula content. The largest amounts of FNS were found in the epidermis and in the appendages after application of P-08-016, regardless of the time from application. In contrast, smaller and statistically significant amounts of FNS were recovered with P-10-008 6 h after application, compared with that at 24 h. In conclusion, the differential stripping technique allowed determination of the amount of FNS localized in different skin districts, focusing particularly on the follicular contribution.

Efficacy of vitamin C vaginal tablets as prophylaxis for recurrent bacterial vaginosis: a randomised, double-blind, placebo-controlled clinical trial.

BACKGROUND: The aetiology of bacterial vaginosis (BV) is still unclear but it is currently considered to be a synergistic polymicrobial syndrome. BV can often arise as a chronic or recurrent disease. The reason for such recurrences is not well elucidated. Previous studies have suggested that vaginal vitamin C may be a useful treatment in reducing recurrence rate, by increasing vaginal acidification and thereby making up for the decrease in hydrogen peroxide that results from a reduction in the number of lactobacilli present. Based on the above-mentioned consideration, a study was performed that aimed to evaluate the effect of vitamin C in the prophylaxis of BV relapses. METHODS: This was a randomised, double-blind, placebo-controlled, parallel-group clinical trial. One hundred and forty-two women, after having been cured from a recent episode of BV by either metronidazole or clindamycin, were randomised to receive vitamin C (74 patients) or placebo (68 patients) as prophylaxis for six monthly cycles, starting within 24 hours of the determination of 'BV cure'. The patients applied one vaginal tablet once a day for 6 consecutive days per month after menses. RESULTS: The rate of BV recurrence during the first 3 months was considerably lower in the vitamin C group (6.8%) than in the placebo (14.7%) group. Considering a 6-month treatment period, the recurrence rate in the vitamin C group (16.2%) was significantly lower (P = 0.024) than in the placebo group (32.4%). Moreover, at the same time point, the survival analysis of Kaplan Meyer was significant in favour of the vitamin C group compared with the placebo group (P = 0.029). CONCLUSIONS: The study showed that regular use of 250 mg ascorbic acid vaginal tablets on 6 days per month for 6 months after successful treatment of bacterial vaginosis halves the risk of recurrence from 32.4% to 16.2% (P = 0.024).

Assessment of the antidandruff activity of a new shampoo: a randomized, double-blind, controlled study by clinical and instrumental evaluations.

The aim of this randomized, double-blind, controlled study was to evaluate the antidandruff activity exerted by a new shampoo on patients affected by dandruff and/or mild seborrheic dermatitis by means of both D-squame technique coupled with image analysis and clinical assessments. Thirty-four patients were enrolled and 1:1 randomly assigned to either a test shampoo or a comparative shampoo group. Treatment schedule was twice a week for 4 weeks. The D-squame technique was shown to be able to objectively record variations in scalp desquamation both between test and comparative groups and within the same group over time. The results obtained with this instrumental approach showed a statistically significant reduction by 52% vs baseline after 2 weeks of treatment. There was an even greater reduction after 4 weeks (-66%). This reduction was statistically significant compared with the comparative group at the same time points. The analysis of all the other parameters (except Wood's lamp) confirmed the superiority of the test vs the comparative shampoo. The test shampoo proved to be safe, well tolerated, and accepted by the patients for cosmetic acceptability and efficacy. The study confirmed the antidandruff efficacy of the test shampoo and its superiority vs the comparative shampoo.

Clinical and instrumental assessment of the effects of a new product based on hydroxypropyl chitosan and potassium azeloyl diglycinate in the management of rosacea.

BACKGROUND: Rosacea is a chronic inflammatory skin disease affecting mostly facial skin. Its origin is multifactorial. Important steps in its treatment are avoidance of any triggering factor and control of skin inflammation. AIM: To assess the benefit of topical applications of a new product (P-3075). PATIENTS/METHODS: A randomized, multicenter, double-blind, placebo-controlled, parallel-group, pilot study was carried out to evaluate the efficacy and tolerability of a cream (P-3075) based on 5% potassium azeloyl diglycinate (PAD, Azeloglicina(®)) and 1% hydroxypropyl chitosan (HPCH). Forty-two patients (rosacea stages I and II) were enrolled and randomized, 28 in the P-3075 group and 14 in the placebo group. They were asked to apply the cream twice daily for 4 weeks. The main assessments were the objective quantification of erythema and skin hydration using the Mexameter(®) and Corneometer(®) devices, respectively. Clinical signs and symptoms were evaluated on a four-point scale. RESULTS: The P-3075 cream applied for 28 days was effective in skin protection by reducing erythema, evaluated both instrumentally and clinically. In addition, the clinical assessments of other symptoms such as flushing, stinging, and burning supported the beneficial effect of the P-3075 cream. CONCLUSIONS: The anti-inflammatory and moisturizing effects of potassium azeloyl diglycinate combined with the protective properties of HPCH allow the new product to be a good candidate for controlling signs and symptoms of rosacea.

Efficacy of vitamin C vaginal tablets in the treatment of bacterial vaginosis: a randomised, double blind, placebo controlled clinical trial.

A randomised, double blind, parallel groups, placebo controlled clinical trial was conducted to assess the efficacy and safety profile of 250 mg ascorbic acid (Vit. C, Vagi C) in women with bacterial vaginosis (BV). Overall, 277 out-patients with at least three of the following signs (white discharge that smoothly coats the vaginal walls, pH of vaginal fluid > 4.5, a fishy odour of vaginal discharge before or after addition of 10% KOH and presence of clue cells on microscopic examination) were randomised to apply a tablet deeply into the vagina once daily for 6 days. The primary efficacy endpoint was the cure rate, defined as the recovery of all inclusion criteria. In the intent-to-treat (ITT) population, cure was achieved by 55.3% of patients with Vit. C (n=141) and by 25.7% of patients with placebo (n=136). The between-group difference was 29.6% (p < 0.001). In the per-protocol (PP) population, cure rate was 66.4% with Vit. C (n=116) and 27.1% with placebo (n = 118), respectively. Between-group difference was 39.3% (p < 0.001). In a subset of patients with centralised evaluation of the vaginal swab, cure in ITT was achieved by 86.3% of patients with Vit. C (n=51) and by 7.6% of patients with placebo (n=53), the between-group difference was 78.7% (p < 0.0001). Cure rate in PP was 86.0% with Vit. C (n=50) and 6.1% with placebo (n=49), between-group difference was 79.9% (p < 0.0001). Both Vit. C and placebo were well tolerated and no differences in safety profile were evident between groups. The results support an effective and safe use of silicon-coated Vit. C vaginal tablets in the management of BV.

In vitro activity of nifuratel on vaginal bacteria: could it be a good candidate for the treatment of bacterial vaginosis?

Bacterial vaginosis is characterized by a shift of the physiological flora to a diverse spectrum of bacteria, where Gardnerella vaginalis and Atopobium vaginae are the most important markers. In this study, the antimicrobial activity of nifuratel against G. vaginalis, A. vaginae, and lactobacilli was compared with that of the two currently used antibiotics metronidazole and clindamycin. Results suggest that nifuratel has a better spectrum of activity, being highly active against G. vaginalis and A. vaginae without affecting lactobacilli.

Current and future applications of the anti-IgE antibody omalizumab.

IgE antibodies are a pivotal factor in pathophysiology of allergic diseases, and the possibility of reducing their level by anti-IgE has long been envisioned. Following several attempts, an effective biologic agent was obtained with the recombinant humanized mono-clonal antibody (rhuMAb)-E25, known as omalizumab. A number of controlled clinical trials demonstrated its efficacy and safety in the treatment of severe allergic asthma uncontrolled by standard drug treatment with maximal recommended doses, and treatment with omalizumab is currently included in international guidelines on asthma management. Other studies reported a clear effectiveness also in allergic rhinitis, but the cost of the anti-IgE treatment suggests its use in patients with rhinitis concomitant with asthma. Other indications to be further investigated are skin disorders such as atopic dermatitis and IgE-mediated urticaria, as well as adverse reactions to foods, with a particularly important role in preventing food-induced anaphylaxis. Finally, there are data indicating the usefulness of omalizumab when used in combination with allergen specific immunotherapy, in terms of reducing the adverse reactions to treatment and increasing the clinical efficacy.