Intradermal Injection of Hybrid Complexes of High- and Low-Molecular-Weight Hyaluronan: Where Do We Stand and Where Are We Headed in Regenerative Medicine?

Hyaluronic acid (HA) is a remarkably multifaceted biomacromolecule, playing a role in regulating myriad biological processes such as wound healing, tissue regeneration, anti-inflammation, and immunomodulation. Crosslinked high- and low-molecular-weight hyaluronic acid hydrogels achieve higher molar concentrations, display slower degradation, and allow optimal tissue product diffusion, while harnessing the synergistic contribution of different-molecular-weight hyaluronans. A recent innovation in the world of hyaluronic acid synthesis is represented by NAHYCO® Hybrid Technology, a thermal process leading to hybrid cooperative hyaluronic acid complexes (HCC). This review summarizes the current literature on the in vitro studies and in vivo applications of HCC, from facial and body rejuvenation to future perspectives in skin wound healing, dermatology, and genitourinary pathologies.

Efficacy and Tolerability of Hybrid Complexes of High- and Low-Molecular-Weight Hyaluronan Intradermal Injections for the Treatment of Skin Roughness and Laxity of the Neck.

This study aimed to evaluate the efficacy of a well-characterized formulation of hyaluronic acid (HA), Profhilo®, in the treatment of roughness and laxity of the neck skin. The study was performed on 25 subjects ranging in age from 40 to 65 years. Two injections of the studied product at 30-day intervals were performed, with evaluations conducted 1 and 4 months after the first injection. The efficacy was determined by clinical and multilevel instrumental evaluations. In addition, at the end of the study, the subjects completed a questionnaire related to the efficacy and tolerability of the product. The studied product was shown to induce a clear and statistically significant improvement in the skin of the neck in all the subjects, with concordant results between the clinical, instrumental, and subjects' evaluations. The positive effects, present after the first injection, were further increased in the second and last evaluation. Notably, the product was reported to have a very high tolerability by both clinicians and subjects. In conclusion, two injections of the studied product safely induced skin amelioration in subjects with mild to moderate neck skin roughness and laxity.

Hyaluronan Hydrogels for Injection in Superficial Dermal Layers: An In Vitro Characterization to Compare Performance and Unravel the Scientific Basis of Their Indication.

BACKGROUND: Skinboosters represent the latest category of hyaluronan (HA) hydrogels released for aesthetic purposes. Different from originally developed gels, they are intended for more superficial injections, claiming a skin rejuvenation effect through hydration and possibly prompting biochemical effects in place of the conventional volumetric action. Here, three commercial skinboosters were characterized to unravel the scientific basis for such indication and to compare their performances. METHODS: Gels were evaluated for water-soluble/insoluble-HA composition, rheology, hydration, cohesivity, stability and effect, in vitro, on human dermal fibroblasts towards the production of extracellular matrix components. RESULTS: Marked differences in the insoluble-hydrogel amount and in the hydrodynamic parameters for water-soluble-HA chains were evidenced among the gels. Hydration, rigidity and cohesivity also varied over a wide range. Sensitivity to hyaluronidases and Reactive Oxygen Species was demonstrated allowing a stability ranking. Slight differences were found in gels' ability to prompt elastin expression and in ColIV/ColI ratio. CONCLUSIONS: A wide panel of biophysical and biochemical parameters for skinboosters was provided, supporting clinicians in the conscious tuning of their use. Data revealed great variability in gels' behavior notwithstanding the same clinical indication and unexpected similarities to the volumetric formulations. Data may be useful to improve customization of gel design toward specific uses.

The "gender factor" in wearing-off among patients with Parkinson's disease: a post hoc analysis of DEEP study.

BACKGROUND: The early detection of wearing-off in Parkinson disease (DEEP) observational study demonstrated that women with Parkinson's disease (PD) carry an increased risk (80.1%) for wearing-off (WO). This post hoc analysis of DEEP study evaluates gender differences on WO and associated phenomena. METHODS: Patients on dopaminergic treatment for ≥ 1 year were included in this multicenter observational cross-sectional study. In a single visit, WO was diagnosed based on neurologist assessment as well as the use of the 19-item wearing-off questionnaire (WOQ-19); WO was defined for scores ≥ 2. Post hoc analyses were conducted to investigate gender difference for demographic and clinical features with respect to WO. RESULTS: Of 617 patients enrolled, 236 were women and 381 were men. Prevalence of WO was higher among women, according to both neurologists' judgment (61.9% versus 53.8%, P = 0.045) and the WOQ-19 analysis (72.5% versus 64.0%, P = 0.034). In patients with WO (WOQ-19), women experienced ≥ 1 motor symptom in 72.5% versus 64.0% in men and ≥ 1 nonmotor symptom in 44.5% versus 36.7%, in men. CONCLUSIONS: Our results suggest WO as more common among women, for both motor and nonmotor symptoms. Prospective studies are warranted to investigate this potential gender-effect.

Hyaluronan Hybrid Cooperative Complexes Injection as a Biostimulation for Postobese Skin Laxity in the Arm: A Histopathologic Study.

Background: The Hybrid Cooperative Complexes of high and low molecular weight hyaluronic acids (HHCC) improve skin structure and bioactivity. Massive weight loss damages cellular composition and morphological structure of skin. An injective treatment of postobese skin consisting of HHCC may have a role in counteracting these histopathological alterations. Objectives: To analyze the histological effects of HHCC injection in the cutaneous tissues of massive weight loss patients suffering from arm laxity. Methods: Nine ex-obese patients with postweight-loss-related arm laxity and ptosis requiring brachioplasty were prospectively recruited at the first author's department. HHCC injection was performed on only 1 arm, which included 2 injective sessions separated by 30 days. One month posttreatment, patients underwent a bilateral brachioplasty, and the surgical specimens were histologically examined, searching for any variation in the cutaneous connective tissue following injections. Histology on treated specimens showed a statistically significant increased density of elastic fibers along with a lower fragmentation of the same fibers compared to the untreated tissue. Fibroblasts demonstrated a swollen appearance as if involved in a bioactivation process. Results: Treatment with HHCC increases the number of elastin fibers and determines a more regular elastin deposition and architecture, as well as the bioactivation of fibroblasts. The contralateral untreated area showed an irregular structure with elastosis and elastolysis. Conclusions: More studies are necessary, but histologically proven benefits are demonstrated in the HHCC-treated skins when compared with basal controlateral skin. These data support the use of HHCC formulations for the treatment of postobese skin laxity.

Efficacy and tolerability of Profhilo® Structura intended to restore lateral cheek fat compartment: An observational pilot study.

Background and Aims: Hyaluronic acid (HA)-based injections are used worldwide to improve skin defects associated with aging and ultraviolet light/environmental exposure. HA formulations developed according to molecular weight or with additional components, for example, cross-linking reagents, are limited by their low biological activity and concentration limit. NAHYCO™ technology has enabled the production of hybrid cooperative complexes (HCCs) of low and high molecular weight HA. Developed for injection into the fat compartments of the face and previously demonstrating potential benefits for adipose tissue restoration, Profhilo Structura® is a new 2 mL HCC formulation comprising low molecular weight HA (45 mg/mL) and high molecular weight HA (45 mg/mL). To evaluate the efficacy and tolerability of Profhilo Structura® to restore adipose tissue compartments in the lateral cheek fat compartment. Methods: Fifty healthy enrolled subjects received two injections, 1 month apart, and were evaluated 3 months posttreatment. Investigators performed clinical evaluations (Facial Volume Loss Scale [FVLS] and Wrinkle Severity Rating Scale [WSRS]) at different time points. Subjects also completed self-evaluation assessments following treatment. Results: A significant improvement in FVLS and WSRS clinical scores after the first treatment was observed; treatment benefit was maintained 3 months after treatment completion and confirmed by subject self-assessment. Most participants reported an improvement, particularly a marked reduction of wrinkles and increased skin firmness. No serious adverse events were reported, confirming the excellent safety profile of HCC injectable devices. Conclusions: Overall, the study highlighted the efficacy and tolerability of the studied medical device proving its effect on adipose tissue.

Development and Validation of a Composite Skin Quality Scale.

Background: The increasing demand for skin quality interventions in aesthetic medicine underscores the necessity for objective, evidence-based assessment tools that may be used to evaluate novel interventions or devices. Objectives: To develop and validate a 5-point photonumeric rating scale for assessing overall skin quality, including radiance, color evenness, and smoothness. Methods: The IBSA (Institut Biochimique SA) Composite Skin Quality Scale was developed and underwent live validation with 88 real-world patients, chosen to encompass a broad spectrum of skin qualities and Fitzpatrick skin types. Scale validation was performed by board-certified plastic surgeons and dermatologists over 2 rounds, 2 weeks apart. Reliability was assessed through intrarater and interrater agreements, utilizing weighted kappa statistics and intraclass correlation coefficient (ICC). The scale's ability to discern a clinically relevant 1-grade difference was evaluated with 72 photo pairs. Results: Combined intrarater reliability results showed weighted kappa values of 0.812 (right side) and 0.815 (left side) and an ICC of 0.903 for both sides, indicating an almost perfect agreement. Interrater reliability ranged from substantial to almost perfect, with kappa coefficients between 0.654 and 0.853 and ICCs between 0.657 and 0.855 across all rater pairs in both rounds. The ability to detect a clinically relevant 1-point difference using the scale was established. Conclusions: Integrating various key aspects of skin quality, the IBSA Composite Skin Quality Scale is a clinically relevant and highly reliable tool, suitable for skin assessment in clinical studies of new aesthetic technologies and products.

Restoring Adipose Tissue Homeostasis in Response to Aging: Initial Clinical Experience with Profhilo Structura®.

The aim of the case series was to determine the efficacy of a new medical device developed for adipose tissue restoration in the face. The medical device used the patented NAHYCO® Hybrid Technology to deliver 45 mg of high- (1400 ± 200 kDa) and 45 mg of low- (100 ± 20 kDa) molecular-weight hyaluronan, in 2 mL. Patients and methods: Twenty-two volunteers, aged 36-60 years. Two mL of Profhilo® Structura was injected using a 25 G cannula for each hemiface, into superficial fat compartment along the line from the preauricular area to the mandibular angle. Two injections were performed, and Profhilo Structura's effect on restoring adipose tissue was evaluated immediately after treatment, and over a 6-month follow-up. The studied medical device revealed a pseudoplastic behavior and consistency that allowed easy extrusion from a syringe. It showed a lower viscosity compared to dermal fillers, based on crosslinked HA. Clinically, the soft tissue thickness increased immediately after injection, and the clinical improvement persisted across a 6-month follow-up. The self-reported satisfaction with the treatment showed an amelioration in the midface of all the subjects enrolled, with no adverse effects. Profhilo® Structura demonstrated a peculiar fat compartment integration, with a regenerating effect on adipose tissue senescence. The skin thickening and compaction effects were similar to those obtained using chemically crosslinked dermal fillers, while a natural look was preserved, and the use of crosslinking agents was avoided.

An Overview of Soft Tissue Fillers for Cosmetic Dermatology: From Filling to Regenerative Medicine.

Hyaluronic acid (HA)-based injectable filling agents are at the forefront of the current demand for noninvasive dermatological procedures for the correction of age-related soft tissue defects. The present review aims to summarize currently available HA-based products and critically appraise their differences in rheological nature and clinical application. Linear HA (LHA) gels may be supplemented with amino acids, lipoic acid, vitamins, nucleosides, or minerals for synergistic antiaging and antioxidant benefits (polycomponent LHA). HA hydrogels can be generated via chemical or physical crosslinking, which increases their elasticity and decreases viscosity. The performance of crosslinked fillers depends on HA concentration, degree of crosslinking, elastic modulus, cohesivity, and type of crosslinking agent employed. PEG-crosslinked LHA displays improved elasticity and resistance to degradation, and lower swelling rates as compared to BDDE-crosslinked LHA. Physical crosslinking stabilizes HA hydrogels without employing exogenous chemical compounds or altering hyaluronans' natural molecular structure. Thermally stabilized hybrid cooperative HA complexes (HCC) are a formulation of high- and low-molecular-weight (H-HA and L-HA) hyaluronans, achieving high HA concentration, low viscosity with optimal tissue diffusion, and a duration comparable to weakly cross-linked gel. Our critical analysis evidences the importance of understanding different fillers' properties to assist physicians in selecting the most appropriate filler for specific uses and for predictable and sustainable results.

Development and Validation of IBSA Photographic Scale for the Assessment of Neck Laxity.

OBJECTIVE: To describe the development and validation of the 5-grade photographic IBSA Neck Laxity Scale. METHODS: The scale was developed from 2 real images, which led to the creation of 5 morphed images, representing different degrees of severity of laxity of the neck. For validation, a set of 50 images (25 real and 25 morphed) was created and sent for evaluation to 6 trained raters (physicians) in 2 rounds, 1 month apart. Raters had to assess each image according to the 5-image scale. Inter-rater and intra-rater reliability in both rounds was evaluated. RESULTS: As to intra-rater reliability, single rater kappa scores between 0.69 and 0.87, and a global kappa score of 0.78 were observed. Inter-rater agreement was measured by means of the intra-class correlation coefficient and scores higher than 0.85 were reported, indicating excellent reliability. CONCLUSION: IBSA Neck Laxity Scale is a validated and reliable scale.

Development and Validation of IBSA Photographic Scale for the Assessment of Inner Upper Arm Laxity.

OBJECTIVE: To describe the development and validation of the 5-grade photographic IBSA inner upper arm scale. METHODS: From 2 real-life pictures, a scale made up of 5 morphed images showing increasing severity of inner upper arm laxity was created. For validation, a set of 50 images (half of which real and the other morphed) was developed and sent to 5 trained physicians in two rounds 30 days apart. Raters' task was to make a selection of each image according to the given scale. Inter-rater and intra-rater reliability were evaluated in both rounds. RESULTS: As to intra-rater reliability, single-rater kappa scores between 0.74 and 1.00 and a global kappa score of 0.846 were observed, while inter-rater agreement was calculated with intra-class correlation coefficient reporting scores higher than 0.91, which indicate excellent reliability. CONCLUSION: IBSA inner upper arm laxity scale proved to be a validated and reliable tool.

First Use of Thermal Stabilized Hyaluronic Acid Injection in One-Year Follow-Up Patients with Genitourinary Syndrome.

OBJECTIVE: Evaluation of the impact of hyaluronan hybrid cooperative complex (HCC) injections in premenopausal and postmenopausal Italian women affected by vulvar-vaginal atrophy (VVA), one of the symptoms of genitourinary syndrome (GS), on self-reported quality-of-life, vaginal symptoms, and sexual activity, as well as treatment side-effects. METHODS: We surveyed a sample of 26 women affected by VVA with follow-up at 6 and 12 months. Deep intradermal injections of HCC were delivered at 1-month intervals. Evaluation of the treatment impacting the VVA patients was assessed by three international validated questionnaires (Visual Analogic Scale, VAS; health-related quality-of-life test, SF12; Female Sexual Function Index, FSFI). The statistically significant differences between pre- and after-treatment responses have been assessed by Wilcoxon signed-rank test and repeated measures ANOVA test. RESULTS: At 6-12-month follow-up, general quality-of-life (SF12) did not show any significant improvement. On the contrary, VVA patients showed significant improvements of genital symptoms (VAS) and sexual function (FSFI). Global FSFI score increased by 58% and evidenced important satisfaction (P≤0.05). CONCLUSION: Vestibular HCC injection is an office, safe, fast, not expensive, and reproducible procedure effective in vulvar-vaginal atrophy. This study can be used as a pilot for future trials.

Safety Assessment of High- and Low-Molecular-Weight Hyaluronans (Profhilo®) as Derived from Worldwide Postmarketing Data.

BACKGROUND: At present, dermal fillers based on hyaluronic acid (HA) represent the most popular intervention of dermoesthetic medicine for the treatment of skin aging. Recent studies have shown that the combination of HA chains of different lengths and molecular weights improves tissue repair and regeneration through a synergistic mechanism. Profhilo® is a product available that has been on the market since 2015 and is based on stable, hybrid, and cooperative complexes (HyCoCos) produced by means of NAHYCO® Hybrid Technology, which is an innovative thermal process that rules out the use of any chemical reagents. The result is a filler with high biocompatibility and low viscosity that favors optimal diffusion at the tissue level to obtain the target bioremodeling of the facial contour. The objective of this review is to provide data from the overall postmarketing experience after 3 years of use and more than 40,000 patients treated with the medical device. METHODS: All spontaneous postmarketing adverse event (AE) reports received from physicians and healthcare professionals worldwide between February 9, 2015, and February 8, 2018, associated with the use of the studied medical device and sent to the IBSA global safety database were analyzed. RESULTS: In total, 12 adverse event reports were logged in the global database, and none were considered serious. Early-onset injection site reactions, i.e., swelling, edema, redness, ecchymosis, and erythema, were the most frequently observed. Late-onset local reactions (e.g., swelling, nodules) followed. The genesis of these reactions was considered, both by the reporting physician and IBSA, as being local reactions of hypersensitivity and/or due to inappropriate injection techniques. In no case was the product held liable for direct damage. All events resolved without any complications according to the treatment guidelines. Two late-onset reactions were collected. CONCLUSIONS: Although underreporting of minor events cannot be ruled out, the overall number of reports is very low, thereby supporting the high tolerability and safety of the product. After 3 years of postmarketing experience, the safety profile of the studied medical device is favorable and consistent with the product information.

Evaluation of the Volumizing Performance of a New Volumizer Filler in Volunteers with Age-Related Midfacial Volume Defects.

PURPOSE: The primary aim of this study was to evaluate the performance of the study product, in terms of volumizing activity as well as the duration of the effect, in women with age-related midfacial volume defects. In addition, the study allowed the evaluation of the tolerability of the product by both volunteers and investigators. PATIENTS AND METHODS: Twenty-two female volunteers, aged 42-60 years, participated in this study, which was performed under dermatological control in a single center. After an initial visit at baseline to verify adherence to the protocol criteria, volunteers received an injection of Aliaxin® SV (IBSA Farmaceutici Italia Srl), followed 3-4 weeks later by a second touch-up treatment to treat eventual asymmetries. Four subsequent visits, the last performed 9 months from the first injection, were performed to evaluate clinically and instrumentally the efficacy of the treatment. RESULTS: Clinical and statistically significant improvement in cheek volume was recorded after the first postinjection visit, and the effect was maintained until the end of the study period. A clinically measurable amelioration of wrinkle severity was also observed. By 3D picture recording and subsequent quantitative analysis, it was possible to determine the efficacy in terms of increased facial volume, which was already appreciable at the first visit, was further increased at the second and third visits and was maintained at the fourth and last visits. The injections were very well tolerated by the volunteers, as determined by their self-evaluation questionnaires. CONCLUSION: The results of the study confirm the esthetic performance of the study product on age-related midfacial volume defects. The very strong high-volumizing activity of the study product was not only properly determined by the investigators but also confirmed by self-evaluation by the volunteers. These effects were obtained with no appreciable undesired effects.

Evaluation of the efficacy of a new hyaluronic acid gel on dynamic and static wrinkles in volunteers with moderate aging/photoaging.

PURPOSE: Aim of the study was to determine both clinically and by noninvasive instrumental evaluations the efficacy, tolerability and the duration of the effects of a new hyaluronic acid (HA) gel in human volunteers with moderate aging/photoaging. PATIENTS AND METHODS: Eighteen volunteers (35-55 years) were enrolled in this single-center study. The subjects underwent five visits. The first visit was at baseline to determine the adherence to the inclusion criteria, followed by the first injection of the HA-based study product, and the second visit was at 48 hours after the injection. Two months later, a second injection was given (Visit 3) followed by a subsequent visit (Visit 4) after 48 hours. The last visit (Visit 5) was performed 5 months after the first injection. Clinical and instrumental evaluations as well as self-assessment by the subjects were recorded at each visit. RESULTS: A significant improvement of wrinkles' grade around the eyes, vertical lip lines and wrinkles' severity of nasolabial folds was recorded after the first injection and the effect increased after the second injection. Aging/photoaging grade and surface microrelief improved 2 months after the first injection procedure. These clinical improvements were paralleled by amelioration of instrumental skin profilometry and optical colorimetry. The treatments were very well tolerated by the volunteers as determined by the self-grading score. CONCLUSION: The results confirm the good esthetic performance and the duration of the effect of the HA-based study product (Viscoderm® Hydrobooster) on dynamic facial wrinkles and/or static facial lines. These effects were particularly evident after the second injection and were accompanied by a good tolerability of the product.

Positive Effects against UV-A Induced Damage and Oxidative Stress on an In Vitro Cell Model Using a Hyaluronic Acid Based Formulation Containing Amino Acids, Vitamins, and Minerals.

Ultraviolet (UV) radiations are responsible for skin photoaging inducing alteration of the molecular and cellular pathways resulting in dryness and reduction of skin elasticity. In this study, we investigated, in vitro, the antiaging and antioxidant effects of hyaluronan formulations based hydrogel. Skinkò E, an intradermic formulation composed of hyaluronic acid (HA), minerals, amino acids, and vitamins, was compared with the sole HA of the same size. For this purpose, HaCaT cells were subjected to UV-A radiations and H2O2 exposure and then treated with growth medium (CTR) combined with M-HA or Skinkò E to evaluate their protective ability against stressful conditions. Cells reparation was evaluated using a scratch in vitro model and Time-Lapse Video Microscopy. A significant protective effect for Skinkò E was shown with respect to M-HA. In addition, Skinkò E increased cell reparation. Therefore, NF-kB, SOD-2, and HO-1 were significantly reduced at the transcriptional and protein level. Interestingly, γ-H2AX and protein damage assay confirmed the protection by hyaluronans tested against oxidative stress. G6pdΔ ES cell line, highly susceptible to oxidative stress, was used as a further cellular model to assess the antioxidant effect of Skinkò E. Western blotting analyses showed that the treatment with this new formulation exerts marked antioxidant action in cells exposed to UV-A and H2O2. Thus, the protective and reparative properties of Skinkò E make it an interesting tool to treat skin aging.

Efficacy of cyclosporine A as monotherapy in patients with psoriatic arthritis: a subgroup analysis of the SYNERGY Study.

BACKGROUND: The SYNERGY Study is an observational, multicenter Italian study, conducted in patients with diagnosis of psoriatic arthritis (PsA) treated from at least 3 months with cyclosporine and aimed at assessing patients' seropositivity for viral infections and efficacy and safety of cyclosporine, administered as monotherapy or in combination with other systemic drugs in the routine clinical practice. The aim of this subanalysis of the SYNERGY study was to evaluate the effects of CsA as monotherapy only in PsA over 12 months of observation. METHODS: Psoriasis was evaluated by Body Surface Area and the Psoriasis Area Severity Index (PASI). PsA was evaluated by number of swollen and tender joints, painful entheses and fingers with dactylitis, the Bath Ankylosing Spondylitis Activity Index (BASDAI) and by patients' and physicians' global assessment on a 10-point Visual Analogue Scale. RESULTS: Cyclosporine in monotherapy was effective in reducing all the measured disease parameters. The major indexes of cutaneous and spinal involvement, PASI and BASDAI were significantly reduced over the study period, as were the number of swollen and tender peripheral joints, and enthesitis and dactylitis. CONCLUSIONS: Cyclosporine in monotherapy confirmed its efficacy in cutaneous psoriasis and suggested to be effective also on PsA, reducing spinal and peripheral joints' signs and symptoms.

The GENDER ATTENTION Observational Study: Gender and Hormonal Status Differences in the Incidence of Adverse Events During Cyclosporine Treatment in Psoriatic Patients.

INTRODUCTION: Female sex has been shown to be a risk factor for the development of adverse drug reactions; however, this has not been studied for cyclosporine (CsA). The aim of this study was to investigate, in Italian dermatological practice, the influence of gender and menopause and related hormones on the incidence of adverse events (AEs) during CsA treatment in psoriatic patients. METHODS: Multicenter, prospective, observational study conducted from May 2011 to June 2013. Patients with plaque psoriasis, undergoing a new CsA administration course, or about to start it, were enrolled in the outpatient clinics of Italian dermatological centers. During the 2-6 months of study duration, patients had to note all AEs that occurred in a diary that was reviewed by the investigators at the follow-up visit. Sex hormone levels were measured within 7 days from the start date of a menstrual cycle. RESULTS: A total of 969 adult psoriatic patients were enrolled in the study, divided into four cohorts: fertile women and corresponding age-matched men; postmenopausal women and corresponding age-matched men. A significant difference in the percentage of patients with AEs was observed between fertile and postmenopausal women, but not between women and age-matched men. AE incidence rate was about 37% higher in fertile women than in age-matched men and about 18% higher in postmenopausal women than in age-matched men, but differences were not statistically significant. Incidence rate ratio of fertile vs. postmenopausal women was 0.67, reaching statistical significance. AEs were mild or moderate in severity in the great majority of patients of all cohorts and postmenopausal women had significantly less grade 1-2 AEs compared to fertile women, but more grade 3-4 AEs. FSH levels were significantly higher in postmenopausal women reporting no AEs, and DHEA sulfate levels were about 10% higher in men with no AEs, compared to those reporting at least one AE. Cortisol levels were slightly though significantly higher in postmenopausal women with no AE. CONCLUSIONS: A better understanding of sex- and hormone-related influences on drug responses may help to improve drug safety and efficacy, by permitting one to tailor pharmacological treatments to individual subjects or defined patient cohorts. FUNDING: Novartis Farma S.p.A., Italy.

Gender-related differences in chronic urticaria.

Chronic urticaria (CU) is a common skin disorder with important repercussion on the quality of life (QoL) and a relevant socioeconomic impact. CU is included among the skin diseases that exhibit a significant female preponderance, with an average female to male ratio of nearly 2-4/1. In recent years, an ever-growing interest in gender medicine has been registered and the assessment of gender differences has increasingly become an attractive issue in clinical research. Unfortunately, there are only limited data relative to the study of CU in the perspective of gender medicine. However, apart from the predilection for females, an in-depth evaluation of the available literature shows the existence of other interesting gender-related differences in CU. The aim of this article is to review the current knowledge on gender differences in CU under different points of view, including pathophysiology, epidemiology, clinical and prognostic features, association with comorbidities, psychological aspects and QoL.

Gender differences in the adverse events' profile registered in seven observational studies of a wide gender-medicine (MetaGeM) project: the MetaGeM safety analysis.

BACKGROUND: MetaGeM is a wide gender-medicine project comprising post hoc and meta-analyses by gender of clinical outcomes, therapeutic approaches, and safety data from previously conducted observational studies to explore possible gender differences in real-life clinical settings. We report the results of the safety meta-analysis of seven MetaGeM studies, evaluating gender differences in adverse event (AE) incidence and severity. METHODS: Data were collected between February 2002 and July 2013. Male and female patients were compared for the main safety variables, using Student's t-test, χ2 test, or Fisher's exact test as appropriate. As supportive analysis, a logistic regression model was estimated to evaluate associations between gender and outcome. RESULTS: In total, 4,870 patients (46% females, 54% males) were included in the analysis; age was higher for females (mean ± standard deviation 61.2±18.3 years) than males (56.3±16.6 years). Overall, 264 AEs were reported (59.1% in males). There were no significant gender differences in the percentage of patients with at least one AE: 3.0% for females versus 3.9% for males, χ2 test P>0.05. According to the logistic regression model results, no association between gender and AEs occurrence seems to exist. A statistically significant gender difference in the percentage of drug-related AEs emerged (37.6% in females vs 20.8% in males, χ2P=0.0039). Slightly significantly more AEs in females were addressed with treatment compared with males (78.1% vs 66.7%, χ2P=0.0485). Total serious AEs (SAEs) were 47 (72% in males). The frequency of patients with ≥1 SAE was 0.6% in females versus 1.2% in males (χ2 test P=0.0246). CONCLUSION: This safety analysis on a large sample of almost 5,000 patients with different diseases and treated with a wide range of different drugs provides a useful overview on possible gender differences in drug tolerability, which may be helpful in more accurately designing future clinical trials from a gender-specific perspective.