Tretinoin Gel Research Articles

A Comparative Study of the Efficacy of Platelet-rich Plasma Therapy versus Topical Application of 0.1% Tretinoin Gel in the Management of Striae Gravidarum

Abstract Aim: To determine the relative efficacy of platelet rich plasma therapy versus topical 0.1% tretinoin gel in the management of striae gravidarum. Objectives: To determine the degree of response to platelet rich plasma therapy in comparison with topical 0.1% tretinoin gel in striae gravidarum and to determine the treatment of choice amongst platelet rich plasma and topical 0.1% tretinoin gel. Material and Methods: Study design - A randomised control cross sectional comparative study among the female patients with striae gravidarum was carried out at department of Dermatology, Venereology & Leprosy, Base Hospital, Delhi Cantt, New Delhi. Results: There was early and fast clinical improvement in PRP group with continuous clinical improvement noticed in successive sittings although degree of improvement was lower in 5th and 6th sittings. There was also an earlier plateau of response, in tretinion group after 04 sittings with mild or little improvement in the last 02 sittings in comparison to the PRP group. Conclusion: Platelet Rich Plasma therapy was effective as compared to topical 0.1% Tretinoin gel in the management of Striae gravidarum. PRP had better treatment outcome as well as patient satisfaction.

Topical Tretinoin in the Management of Thick-skinned Rhinoplasty Patients.

Despite the increasing popularity of cosmetic surgeries, some patients still experience skin problems, particularly those with thick nasal skin. Isotretinoin is a commonly used drug for severe acne, and its effects on rhinoplasty aesthetic results have recently been studied. This placebo-controlled clinical trial aimed to investigate the effects of topical tretinoin gel on the cosmetic outcomes of rhinoplasty in patients with thick nasal skin. Forty-nine individuals were randomly allocated to either the treatment group or the control group in Mashhad, Iran from 2019 to 2021. The treatment group received topical tretinoin gel (0.05%) beginning on the 31st postoperative day and continued for six months, while the control group received a usual dermatological recommendation as a placebo. Patients were assessed during the first, third, and sixth months after the intervention, and their cosmetic results were evaluated by an expert surgeon and dermatologist. There were no significant differences in baseline features between the two groups. The median score given by the surgeon was not significantly different between the groups. However, the median score given by the dermatologist was significantly higher in the treatment group during the first, third, and sixth months (P<0.001). Patient satisfaction scores were also significantly higher in the treatment group during the third and sixth months compared to the control group. (P=0.02 and 0.01, respectively). Topical tretinoin gel could effectively reduce acne in patients with thick nasal skin after rhinoplasty and increase patient satisfaction in the early months following surgery. However, it did not significantly affect final cosmetic outcomes.

Benefits of the Dermocosmetic Mineral 89 Probiotic Fractions Adjunct to Topical Retinoids for Anti-Aging Benefits.

Tretinoin is a topical gold standard for photoaging treatment. However, patient adherence can be impaired by local tolerability in the first 1-2 weeks of treatment. Mineral 89 Probiotic Fractions® (M89PF) containing Vichy volcanic mineralizing water®, probiotic fractions, hyaluronic acid, niacinamide and tocopherol was developed to fulfill the need for adjunctive products that can reinforce skin barrier and manage retinoid induced irritation. The study included 38 women, aged 44-60 years, phototype II-VI, applying 0.025% tretinoin gel once nightly for 84 days. For 28 days, one hemi face was treated with M89PF and sunscreen SPF 50+ while other hemi face received sunscreen only. Then, M89PF application was changed to full face. Evaluations were performed at days 0, 7, 28 and 84. Erythema, dryness, fine lines, skin tone, radiance and pore appearance were assessed by a dermatologist. Tolerability was evaluated through self-assessment questionnaire. Skin hydration levels, inflammatory and oxidative stress biomarkers were analyzed by immunological assay: Interleukin(IL)-8, IL1-alpha, IL1-Receptor Antagonist (IL-1Ra), Prostaglandin E2 (PGE2), Catalase and Superoxide Dismutase (SOD). Hemiface analysis showed that erythema, fine lines, skin tone, radiance, pore appearance, hydration, tightness, dryness, burning, itching and stinging sensations were improved (p<0.05) on the M89PF side. At full face analysis on D84, erythema, fine lines, skin tone, radiance and pore appearance were improved compared to D0 (p<0.001). Tightness, dryness, burning, itching and stinging were reduced when compared to D7 (p<0.05). Dermatology Life Quality Index (DLQI) and Skindex 16 showed improvement in quality of life (p<0.05). IL-1RA increased at D28 (p=0.003) and PGE2 decreased at D28 and D84 compared to D0 (p<0.01). M89PF reduced retinoid induced irritation with a good tolerability profile and, used as an adjunct to topical tretinoin, significantly improved skin hydration, erythema, fine lines, skin tone, radiance and pore appearance.

Topical tretinoin treatment for burning mouth syndrome: a pilot study.

Burning mouth syndrome is an intraoral chronic pain condition characterized by a moderate to severe sensation of burning from the oral mucosa. No clinical signs are found and there is no efficient treatment. This pilot study included 10 women that were resistant to other previous treatments or noncompliant to systemic medications. Patients were asked to apply tretinoin gel 0.05% on their tongues twice daily for 14 days. Treatment effectiveness was assessed by completing a pre-study psychologic questionnaire and recording a daily wellbeing and pain log. Significant pain-score decrease in 50% of the patients (delta numerical rating score -3.15 ± 3.02, P value = .005) was recorded. This finding was in concordance with the verbal statements including major quality-of-life improvement (P value = .05), without any treatment positive or negative predictive factors. Topical tretinoin exhibits potential efficacy in patients with treatment resistant burning mouth syndrome and may also be used as a primary treatment modality.

Review on Optimization base Emulgel Formulation

The aim of the present research work is to decrease the systemic side effects and to create a more pronounced effect of emulgel of tretinoin with lower doses of the drug. Emulgel emerged as one of the most interesting topical drug delivery system as it has dual release control system. Also the stability of emulsion is increased when it is incorporated into gel. The emulgel was developed using polymers like carbopol 940 (1: 1) of gel and emulsion. Drug-excipients interaction was characterized by FTIR studies. The topical emulgel was prepared by preparing emulsion and gel separately and incorporation emulsion into the gel. The emulgel was evaluated for their physical appearance, pH evaluation, Spreadability, rheological study, drug content, in vitro permeation study and stability study. After all evaluation it can be concluded that tretinoin emulgel could increase the drug permeability across the membrane and fast release of the drug could be achieved successfully. Objective and aim-The aim of present study was to develop an emulgel formulation of Tretinoin gel using Carbopol 940 or HPMC as a gelling agent. The influence of the type of gelling agent and the concentration of both the oil phase and emulsifying agent on the release of the drug and its microbial activity were investigate using 23 factorial design in addition, rheological properties were also evaluated. Conclusion-The present work is to develop tretinoin emulgel adaptable topical drug delivery systems which provide protection against oxidation, fast absorption, and prolonged release and enables reduction in dose and evaluate the emulgel using an ideal topical drug candidate of Tretinoin by suitable method with its release. Tretinoin is widely used in topical acne treatment at 0.025% and 0.05% concentrations. Tretinoin is very effective in 0.05% strength but it cause skin erythema on the applied area.

Nanostructured lipid carriers for the topical delivery of tretinoin

Cosmetic skin care products currently in the market demonstrate an increasing trend toward antiaging products. Selection of the right formulation approach is the key to successful consumer acceptance. Nanostructured lipid carriers (NLCs) for dermal application can render added benefits to the formulation. Tretinoin a derivative of vitamin A, is a retinoid with anti-aging and anti-acne potential. The present study was aimed at formulating NLCs of tretinoin for reducing the skin irritation potential, increasing the drug loading capacity and prolonging the duration of action. The NLCs were optimized using the response surface methodology based on the particle size. Preliminary study, suggested the use of stearic acid, oleic acid, Tween 80 and Span 60 as solid lipid, liquid lipid and surfactants respectively formed a stable dispersion. NLCs of tretinoin were prepared by hot melt microemulsion and hot melt probe sonication methods. The properties of the optimized NLCs such as morphology, size, Zeta potential, stability and in vitro drug release were investigated. Tretinoin loaded NLCs in carbopol gel showed a sustained release pattern with isopropyl alcohol as the receptor fluid compared to the marketed gel using Franz diffusion cells. Eight prepared gel formulations tested were found to follow the Higuchi model of drug release. Stability studies indicated that the formulations stored at refrigeration and room temperature showed no noticeable differences in the drug content and release profiles in vitro, after a period of 4 weeks. In vivo skin irritation test on male Wister rats indicated no irritation or erythema after application of the NLCs loaded gel repeated for a period of 7 days compared to the application of marketed tretinoin gel which showed irritation and slight erythema within 3 days. The results showed that the irritation potential of tretinoin was reduced, the drug loading was increased and the drug release was prolonged by the incorporation into the NLCs.

The Effectiveness of Benzoyl Peroxide 5% Gel with 0.05% Tretinoin Gel in Patients with Mild Acne Vulgaris (Identification of P. Acnes)

Topical tretinoin is used by the dermatolovenereologist and aesthetic physicians in patients with mild acne vulgaris, so it is necessary to be investigated. The aim of the study was to assess the effectiveness of benzoyl peroxide gel compared to tretinoin gel on persons with mild acne vulgaris and identify Propionibacterium acnes in patients with mild acne vulgaris. The research method was a clinical trial, double blind randomization. Patients with mild acne vulgaris were randomized in to 2 groups, each group was examined for clinical manifestations (comedone, papules or pustules) examination with sebumeter 815 and Polymerase Chain Reaction, every night each group was treated with benzoyl peroxide 5% gel and tretinoin 0.05% gel in the application, and followed-up in the days of the week 2, 4 and 6. Data were processed with Mann-Whitney test and Chi-Square Test. The results indicated benzoyl peroxide 5% gel and tretinoin 0.05% gel have the same effectiveness in patients with mild acne vulgaris. But, benzoyl peroxide 5% gel decreased blackheads faster compared to papules or pustules with 0.05% tretinoin gel. of sebum. There was no difference in levels of decrease between benzoyl peroxide 5% gel and tretinoin 0.05% gel. Propionibacterium acnes were found in patients with mild acne vulgaris before the treatment of benzoyl peroxide 5% gel and tretinoin 0.05% gel, although not found in all samples.

Comparison of the Effectiveness of Tretinoin 0.05% Gel and Adapalene 0.1% Gel Based on Clinical Manifestations, and Sebum Levels in Mild Acne Vulgaris Patients

This study aimed to compare the effectiveness of tretinoin 0.05% gel and adapalene 0.1% gel by observing any changes in clinical manifestations and sebum levels before, during and after treatment. This study was carried out in public hospitals and network hospitals in the city of Makassar with double-blind prospective cohort of pre and post treatment. The research sample were thirty-eight patients with mild acne vulgaris who have been observed for the change in the clinical manifestations, measured levels of sebum with sebumeter. The results showed no significant difference between the use of tretinoin 0.05% gel and adapalene 0.1% gel in patients with mild acne vulgaris. There were significant changes of clinical manifestations of two treatment on day 7 and day 14. Levels of sebum by the administration of adapalene 0.1% gel decreased significantly (p <0.05) at day 42, faster than the 0.05% tretinoin gel.

A comparison study of the clinical efficacy and safety of topical adapalene gel (0.1%) and tretinoin cream (0.025%) in the treatment of acne vulgaris

Background: Adapalene a synthetic retinoid analogue, is an addition to the arsenal of topical retinoids developed for the topical treatment of acne vulgaris. The study was designed to compare the clinical efficacy and safety of topical adapalene gel 0.1% and tretinoin cream 0.025% in the treatment of acne vulgaris. Methods: A total of 80 patients with grade I-III acne vulgaris seen in the out-patient department of a tertiary care center were randomized to 8 weeks of daily treatment with either adapalene gel 0.1% or tretinoin gel 0.025%. Counts of total lesions, inflammatory lesions and non-inflammatory lesions were made at baseline and again at treatment weeks 2, 4, 6 and 8. Global assessment ratings, based on percent lesion reduction from baseline were also made. Side-effects like erythema, burning, pruritus, scaling and dryness were rated on a 0-3 severity scale. Results: Out of 80 patients there were 8 dropouts in the study; the 72 patients who completed the study were evaluated for efficacy and safety. Both adapalene and tretinoin produce dramatic reductions in total, inflammatory and non-inflammatory lesion counts, on an average. Cutaneous side-effects were limited to a mild retinoid dermatitis occurring in both treatment groups however patients treated with adapalene gel tolerated this therapy significantly better than those treated with tretinoin cream. Conclusions: Adapalene gel 0.1% offers comparable efficacy to tretinoin cream 0.025 % cream, but is less irritating. Adapalene gel 0.1% is a safe and effective topical agent in the treatment of mild to moderate acne vulgaris in Indian patients.

Evaluation of Various Therapeutic Measures in Striae Rubra.

Background:Striae are linear atrophic depressions that form in areas of dermal damage in the skin. As on date, no consensus or protocol exists for the treatment of stria rubra. Topical retinoids, chemical peels, microdermabrasion, radiofrequency, photothermolysis, intense pulsed light and lasers are some of the modalities used.Aims and Objective:To compare the efficacy of various therapeutic modalities in striae rubra.Methods:This prospective cohort study comprised of a total of fifty patients from August-2012 to October-2013 in a tertiary care center in Western India, Gujarat having striae rubra. They were randomly divided into five groups of ten patients each. Patients were evaluated on the basis of visual assessment, both by doctor as well as the patient. Group I was given topical tretinoin (0.1% w/w) gel applied once at night, Group II-microdermabrasion (MDA) combined with trichloroacetic acid (TCA) (30%) peel, Group III-mesotherapy, Group IV-Q-switched Nd: YAG laser, and Group V-combination treatment of microdermabrasion, salicylic acid peel and retinol (yellow) peel. Patients were treated at an interval of 15 days for 2 months and then at monthly intervals. Objective assessment was done at 2nd month, 6th month, and at the end of 1st year.Results:Patients in Group I treated with topical tretinoin showed the least response with 80% (8) of them showing minimal clinical improvement (0–25%) as compared to patients in Group V in which 60% (6) patients showed moderate clinical improvement (50–75%). While majority of the patients in Group II, III, and IV showed mild clinical improvement (25–50%).Conclusions:Striae rubra is a common cause of concern for adolescent population. Combination treatment with microdermabrasion, salicylic acid and retinol yellow peel gave superior results as compared to other therapeutic options. Mild to moderate improvement was seen with Nd: YAG laser, mesotherapy and MDA + TCA whereas minimal improvement were seen with topical tretinoin.

Effect of tretinoin gel sheeting on early-stage hyperplastic scars in rabbit ears

Objective To estimate the effect of tretinoin gel sheeting on early-stage hyperplastic scars in rabbit ears,and to evaluate the feasibility to prevent and treat hyperplastic scars with it.Methods The ears of 24 rabbits were used to establish a model of hyperplastic scar according to previously reported methods.Then,the rabbit ears were randomly divided into four groups:control group receiving no treatment,gel sheeting group treated with the vehicle of the tretinoin gel sheeting,0.05％ tretinoin group treated with 0.05％ tretinoin gel sheeting,0.1％ tretinoin group treated with 0.1％ tretinoin gel sheeting.All the gel sheetings were topically used twice daily for six consecutive weeks.During the treatment,the size,thickness,color and texture of scars were estimated.After six weeks of treatment,all the scar tissues were resected from the rabbit ears and subjected to hematoxylin and eosin (HE) staining and van Gieson (VG) staining.Statistical analysis was carried out by analysis of variance and rank sum test.Results The scars were deeply colored,thickened,hard and elevated with an uneven surface in the control group,but lightly colored,thinned and soft with the presence of small subcutaneous nodules in the other three groups.The surface of scars in the two tretinoin groups was similar to that of adjacent normal skin,and scaling was observed on the scar surface in the 0.1％ tretinoin group.HE and VG staining showed a disarrangement of collagen fibers with the formation of vortex-like structures in the control group.A significant decrease was noted in the number of fibroblasts and microvessels as well as amount of collagen deposition per unit cross-sectional area in the two tretinoin groups compared with the control group and gel sheeting group.Additionally,the collagen fibers were regularly arranged and parallel to the long axis of scars in the two tretinoin groups.The scar hyperplasia index (HI) was 3.173 ± 0.26,2.465 ± 0.19,1.906 ± 0.21 and 1.903 ± 0.23 in the control group,gel sheeting group,0.05％ tretinoin group and 0.1％ tretinoin group respectively,the fibroblast density (NA) was 5836.7 ± 527.03,4128.73 ± 387.66,3207.59 ± 439.17 and 3200.28 ± 421.48 respectively,and the area density of collagen fiber (AA) was 45.38 ± 5.83,36.57 ± 6.84,28.09 ± 3.82 and 28.07 ± 3.47 respectively.As far as HI,NA and AA were concerned,the control group differed significantly from the other three groups (all P ＜ 0.01),and the gel sheeting group from the two tretinoin groups (all P ＜ 0.01),but no significant difference was observed between the two tretinoin groups (all P ＞ 0.05).Conclusions Topical tretinoin gel sheeting can inhibit scar proliferation at early stage in rabbit ears,and may provide a new choice for the prevention and treatment of hyperplastic scars. Key words: Cicatrix, hypertrophic; Retinoids; Disease models, animal

Efficacy and safety of adapalene gel 0.1% and 0.3% and tretinoin gel 0.05% for acne vulgaris: results of a single‐center, randomized, double‐blinded, placebo‐controlled clinical trial on Mexican patients (skin type III–IV)

The efficacy of topical retinoids is well known according to several clinical studies conducted predominantly among Caucasian patients. This study aimed to evaluate the efficacy and safety profile of adapalene and tretinoin among Mexican patients. To compare adapalene 0.1 and 0.3% and tretinoin 0.05% in Mexican subjects with acne vulgaris. We enrolled 171 patients in this single-center, randomized, double-blinded, placebo-controlled clinical trial. The patients applied on the face either adapalene 0.1%, adapalene 0.3%, tretinoin 0.05%, or placebo for 90days and were evaluated for the reduction in total lesion counts and for the level of irritation. Tretinoin 0.05% and adapalene 0.3% were more effective than adapalene 0.1% and placebo in the reduction of both inflammatory and noninflammatory lesions. Most of adverse events to adapalene and many on tretinoin group were related to skin irritation, dry skin, scaling, pruritus, burning, and postinflammatory hyperpigmentation. Adapalene 0.3% and tretinoin 0.05% are comparable in efficacy, and adapalene 0.1% offers a better safety profile in Mexican patients.

Assessing the Bioequivalence of Topical Retinoid Products by Pharmacodynamic Assay

Purpose: To develop a simple pharmacodynamic (PD) assay for the evaluation of the bioequivalence of topically applied retinoid products. Methods: Daily applications of products containing tretinoin or adapalene were made to the forearms of human subjects for up to 21 days. Percutaneous absorption was enhanced through the use of polyethylene film occlusion (5 h). Pharmacologic activity was assessed through the daily measurement of three cutaneous responses intimately linked to retinoid-induced changes in epidermal differentiation: (1) erythema; (2) exfoliation (scaling/peeling), and (3) increased transepidermal water loss. Results: The PD model exhibited the sensitivity and specificity required to function as a bioequivalence surrogate. It was possible to differentiate between: (1) three concentrations of tretinoin in a commercial cream product line; (2) two concentrations of tretinoin in a commercial gel product line; (3) different vehicles (gel vs. cream) containing the same concentration of tretinoin, and (4) tretinoin and adapalene at the same concentration. The applicability of this model for bioequivalence testing was established by showing that it had sufficient power to determine that three test tretinoin cream products and two approved generic tretinoin gel products were equivalent to their corresponding reference products. Conclusions: A surrogate PD model to assess retinoid bioequivalence has been developed.

Assessment of efficacy of a new tretinoin plus clindamycin gel: Treatment of acne patients from Brazil

Assessment of efficacy of a new tretinoin plus clindamycin gel: Treatment of acne patients from Brazil

Valeant Continues its Acquisition Spree with Agreement to Buy Janssen’s Ortho Dermatologics Division

With the aim of becoming the leading player in the fragmented dermatology market within 5 years, Valeant Pharmaceuticals has continued its deal making in this area by agreeing to acquire the assets of the Ortho Dermatologics division of Johnson & Johnson’s Janssen Pharmaceuticals for US$345 M. The division reported revenues of approximately US$150 M in 2010 from sales of prescription drugs such as Retin-A-Micro® (tretinoin gel), Ertaczo® (sertaconazole nitrate) and Renova® (tretinoin cream).

Effect of tretinoin inclusion in dimethyl-beta-cyclodextrins on release rate from a hydrogel formulation

The aim of this work was to study the release, permeation and skin retention profiles of 0.05% tretinoin hydrogel formulations in which tretinoin was in free form or complexed with dimethyl-beta-cyclodextrin in a stoichiometry of 1:4. Theoretically, this complexation will mainly allow to: overcome drug’s low water solubility and low stability; enhance the drug permeation by promoting skin absorption and alleviate drug inducing local irritation. In vitro release, permeation and skin retention tests were performed in both formulations in order to compare the main advantages of this complexation. The influence of the thermodynamic activity on the drug release profile was also investigated. This study proved that tretinoin inclusion complexes formulation with excess of cyclodextrins had better release profile than the free tretinoin formulation. It was concluded that in this study, thermodynamic activity was not the driving force for the release rate improvement observed with cyclodextrins. Probably, this improvement was due to the increased availability of tretinoin near the membrane surface. In fact, the percentage of total drug that had been retained in the skin was 0.41 ± 0.08% for complexed tretinoin gel and 0.17 ± 0.04% for the free tretinoin gel.

Retinoid plus antimicrobial combination treatments for acne

Background:Acne vulgaris is a chronic disease with several pathogenic factors. Multiple medications are typically used that can lead to nonadherence and treatment failure. Combination medications target multiple pathways of acne formation and may offer therapeutic benefit.Purpose:To explore the efficacy and tolerability of combination retinoid plus antimicrobial treatments in acne vulgaris.Methods:A PubMed and Google search was conducted for combination therapies of clindamycin and tretinoin, with secondary analysis of related citations and references. Similar searches were completed for the combination medications of benzoyl peroxide plus clindamycin or erythromycin, and for the combination therapy of adapalene and benzoyl peroxide.Results:Combination clindamycin phosphate and tretinoin gel was found to be more efficacious than monotherapy of either drug or its vehicle for acne, including inflammatory acne, and has a greater onset of action than either drug alone. Clindamycin phosphate and tretinoin gel was well-tolerated, and adherence to its use exceeded that of using both medications in separate formulations. Benzoyl peroxide-containing combination medications with clindamycin or erythromycin were both more effective in the treatment of acne than either drug alone. Both medications were well-tolerated, with dry skin being the most common adverse effect.Conclusions:Combination medications have superior efficacy and adherence, and have a similar tolerability profile compared with monotherapy of its components. Several studies have found antibiotic-containing combination products with a retinoid effective for acne. The use of antibiotic-containing combination medications for acne can lead to bacterial resistance. Due to this potential for bacterial resistance, benzoyl peroxide treatments are also recommended in combination with a retinoid.

A pilot methodology study for the photographic assessment of post‐inflammatory hyperpigmentation in patients treated with tretinoin

Post-inflammatory hyperpigmentation (PIH) is a common occurrence in patients with acne vulgaris, particularly in those with skin of colour. A previous study has demonstrated the benefit of tretinoin (retinoic acid) in the treatment of PIH; however, there is currently no standard protocol to evaluate change in PIH following treatment. Based on these findings, we performed a pilot, exploratory, blinded, intraindividual-controlled methodology study that consisted of a photographic assessment protocol with facial mapping. The study was based on a secondary analysis of a phase 4, community-based trial of 544 acne patients who were treated with tretinoin gel microsphere 0.04% or 0.1%. Only patients with Fitzpatrick types III-V (skin of colour) were included in the study; subjects with Fitzpatrick skin type VI were excluded because the photographic assessment did not allow for proper evaluation. Despite the small number of subjects evaluated (n=25), the results revealed consistent assessment of improvement in PIH between two independent graders (weighted κ=0.84). Further study with a larger population is recommended to validate the accuracy of this method.

No benzoyl peroxide–induced degradation of tretinoin when benzoyl peroxide is combined with an optimized formulation of tretinoin gel (0.05%)

No benzoyl peroxide–induced degradation of tretinoin when benzoyl peroxide is combined with an optimized formulation of tretinoin gel (0.05%)

Managing mild to moderate acne in adolescents: Cutaneous tolerability benefits of tretinoin gel (0.05%) in a study subpopulation of 983 subjects aged 10 to

Managing mild to moderate acne in adolescents: Cutaneous tolerability benefits of tretinoin gel (0.05%) in a study subpopulation of 983 subjects aged 10 to <18 years