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Multiple sclerosis (MS) pathology features autoimmune-driven neuroinflammation, demyelination, and failed remyelination. Carnosine is a histidine-containing dipeptide (HCD) with pluripotent homeostatic properties that is able to improve outcomes in an animal MS model (EAE) when supplied exogenously. To uncover if endogenous carnosine is involved in, and protects against, MS-related neuroinflammation, demyelination or remyelination failure, we here studied the HCD-synthesizing enzyme carnosine synthase (CARNS1) in human MS lesions and two preclinical mouse MS models (EAE, cuprizone). We demonstrate that due to its presence in oligodendrocytes, CARNS1 expression is diminished in demyelinated MS lesions and mouse models mimicking demyelination/inflammation, but returns upon remyelination. Carns1-KO mice that are devoid of endogenous HCDs display exaggerated neuroinflammation and clinical symptoms during EAE, which could be partially rescued by exogenous carnosine treatment. Worsening of the disease appears to be driven by a central, not peripheral immune-modulatory, mechanism possibly linked to impaired clearance of the reactive carbonyl acrolein in Carns1-KO mice. In contrast, CARNS1 is not required for normal oligodendrocyte precursor cell differentiation and (re)myelin to occur, and neither endogenous nor exogenous HCDs protect against cuprizone-induced demyelination. In conclusion, the loss of CARNS1 from demyelinated MS lesions can aggravate disease progression through weakening the endogenous protection against neuroinflammation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Thermosensitive in situ gels have been around for decades but only a few have been translated into ophthalmic pharmaceuticals. The aim of this study was to combine the thermo-gelling polymer poloxamer 407 and mucoadhesive polymers chitosan (CS) and methyl cellulose (MC) for developing effective and long-acting ophthalmic delivery systems for L-carnosine (a natural dipeptide drug) for corneal wound healing., Methods: The effect of different polymer combinations on parameters like gelation time and temperature, rheological properties, texture, spreading coefficients, mucoadhesion, conjunctival irritation potential, in vitro release, and ex vivo permeation were studied. Healing of corneal epithelium ulcers was investigated in a rabbit's eye model., Results: Both gelation time and temperature were significantly dependent on the concentrations of poloxamer 407 and additive polymers (chitosan and methyl cellulose), where it ranged from <10 s to several minutes. Mechanical properties investigated through texture analysis (hardness, adhesiveness, and cohesiveness) were dependent on composition. Promising spreading-ability, mucoadhesion, transcorneal permeation of L-carnosine, high ocular tolerability, and enhanced corneal epithelium wound healing were recorded for poloxamer 407/chitosan systems., Conclusion: In situ gelling systems comprising combinations of poloxamer-chitosan exhibited superior gelation time and temperature, mucoadhesion, and rheological characteristics suitable for effective long-acting drug delivery systems for corneal wounds.

Background: Activation of the transforming growth factor beta (TGF-β) pathway is a significant contributor to the pathogenesis of diabetic nephropathy. Carnosine is a dipeptide that can inhibit TGF-β synthesis. We tested the hypothesis that carnosine supplement added to standard therapy will result in reduced urinary TGF-β levels among patients with diabetic nephropathy., Methods: We randomly assigned 40 patients with diabetic nephropathy and albuminuria 30-299 mg/day to treatment with carnosine (2 g/day) or placebo for 12 weeks. Urinary TGF-β level was determined using ELISA, urine albumin was ascertained by immunonephelometric assay, and renal function and metabolic profiles were determined at baseline and during 12 weeks of active treatment. Primary outcome was decrease in urinary levels of TGF-β., Results: The 2 groups were comparable for baseline characteristics, blood pressure, urine albumin, urine TGF-β and renal function measurements. Urinary TGF-β significantly decreased with carnosine supplement (- 17.8% of the baseline values), whereas it tended to increase with placebo (+ 16.9% of the baseline values) (between-group difference P < 0.05). However, blood urea nitrogen, serum creatinine, glomerular filtration rate and other biochemical parameters remained unchanged during the study period including urinary albuminuria. Both groups were well tolerated with no serious side-effects., Conclusions: These data indicated an additional renoprotective effect of oral supplementation with carnosine to decrease urinary TGF-β level that serves as a marker of renal injury in diabetic nephropathy., Trial Registration: Thai Clinical Trials, TCTR20200724002 . Retrospectively Registered 24 July 2020.

Autism spectrum disorders (ASD) are an emerging health problem worldwide. So far, no definite cure for ASD exists. L-Carnosine is an amino acid containing β-alanine and L-histidine which has been proposed to have neuroprotective, antioxidant and anti-convulsive properties that may benefit affected children with this disorder. This review aimed to assess the effect of L-Carnosine in the management of ASD in children. We systematically reviewed randomised controlled trials (RCTs) which documented the effect of L-Carnosine in children with ASD. A literature search was performed in PubMed, Cochrane Library, Google Scholar, ClinicalTrials.gov, Clinical Trial Registry-India databases from inception to December 20, 2020. Articles were selected based on pre-set inclusion/exclusion criteria. The primary outcomes were changes in social, communication and behavioural responses and the secondary outcomes were improvement in sleep disorders, gastrointestinal problems, oxidative stress markers and adverse effects. Jadad scale was used to assess the quality of RCTs and modified Cochrane risk of bias tool was used to check the risk of bias of the included studies. The meta-analysis was reported based on the fixed-effects model. Four double-blinded, placebo-controlled, RCTs and one open label trial with a total of 215 participants were selected for the review. All the trials were methodological of high quality according to the Jadad scale. The modified Cochrane risk of bias tool showed a low to high risk of bias. Results from the meta-analysis of three studies showed no significant difference between L-Carnosine and placebo groups in the Gilliam autism rating scale (GARS) (MD = - 2.57; 95% CI - 10.30, 5.16, p = 0.52) and in its socialisation (MD = - 1.51; 95% CI - 6.16, 3.14, p = 0.53), behaviour (MD = - 0.48; 95% CI - 4.82, 3.87, p = 0.83) and communication (MD = - 3.94; 95% CI - 10.00, 2.11, p = 0.20) subscales as well as the childhood autism rating scale (CARS) (MD = - 0.88; 95% CI - 6.96, 5.20; p = 0.78). Current data do not support the use of L-Carnosine in the management of children with ASD due to a low number of studies and sample size available. Further studies are warranted to know the effect of L-Carnosine for ASD management.

L-Carnosine is an amino acid that acts as an anti-oxidant, anti-toxic and neuroprotective agent. There is a paucity of data about the effectiveness of L-Carnosine in the management of autism spectrum disorder (ASD) in children. This study aimed at investigating the effectiveness of L-Carnosine as adjunctive therapy in the management of ASD. This was a randomized controlled trial. Children aged 3-6 years with a diagnosis of mild to moderate ASD were assigned to standard care arm (occupational and speech therapy) and intervention care arm (L-Carnosine, 10-15 mg/kg in 2 divided doses) plus standard care treatment. The children were assessed at the baseline and the end of 2 months for the scores of Childhood Autism Rating Scale, Second Edition-Standard Version (CARS2-ST), Autism Treatment Evaluation Checklist (ATEC), BEARS sleep screening tool and 6-item Gastrointestinal Severity Index (6-GSI). Of the sixty-seven children enrolled, sixty-three children had completed the study. No statistically significant difference (p > 0.05) was observed for any of the outcome measures assessed. Supplementation of L-Carnosine did not improve the total score of CARS2-ST, ATEC, BEARS sleep screening tool and 6-GSI scores of children with ASD. Further investigations are needed with more objective assessments to critically validate the effectiveness of L-Carnosine on ASD children for more decisive results.

Background: Zinc plays an important role in appetite regulation. L-Carnosine, an endogenous dipeptide, may also regulate eating behavior via its histaminergic and antiglutamatergic properties. Polaprezinc (zinc-L-carnosine complex) is a medication for gastric ulcers. A small case series reported successful treatment of binge eating with add-on polaprezinc., Methods: This was an open trial of add-on polaprezinc in patients with binge eating disorder (BED; n = 22) or bulimia nervosa (BN; n = 7) receiving antidepressants. A 4-week baseline period was followed by a 16-week polaprezinc treatment at 150 mg/d (containing 34 mg zinc and 116 mg L-carnosine) in addition to ongoing psychotropic medications. We also assessed their zinc status via a laboratory index and zinc deficiency-related symptoms., Results: At the study end, both conditions showed a significant reduction in the 4-week frequency of combined objective and subjective binge eating episodes, the 4-week frequency of days when at least 1 such episode occurred (only in BED), several aspects of eating disorder psychopathology (rated by the Eating Disorder Examination-Questionnaire), and comorbid depressive symptoms (rated by the 16-item Quick Inventory of Depressive Symptomatology [Self-Report]). Serum copper/zinc ratio decreased from 1.4 to 1.1 on average in both conditions. All patients had multiple zinc deficiency-related symptoms at baseline that substantially improved after polaprezinc treatment. Overall, the effectiveness of polaprezinc was greater in BED patients than in BN patients, with minor adverse effects., Conclusions: These findings offer preliminary evidence for the effectiveness of polaprezinc in treating BED and BN and suggest the involvement of zinc deficiency in these conditions.

Zinc intake is recommended for zinc deficiency. In clinical practice, polaprezinc has been used as a zinc replacement therapy for zinc deficiency. However, the efficacy of polaprezinc has not been established. To confirm the efficacy on zinc deficiency of polaprezinc and provide additional information on an appropriate regimen, we conducted a systematic review using individual patient data (IPD). We searched PubMed, the Japanese database Ichushi, and the database owned by the marketing authorization holder of polaprezinc. Randomized placebo-controlled trials that reported the serum zinc concentration were eligible. The mean difference of the change from baseline in serum zinc concentration was estimated using a fixed-effects model. The linear dose-response relationship and the subgroup effects were also assessed. Out of 54 unique randomized clinical trials (RCTs), four studies met the eligibility criteria, and we could access IPD for all of them. All three doses of polaprezinc (75 mg, 150 mg, and 300 mg) and the placebo group were examined. The dose-combined overall polaprezinc increased the change from baseline by a mean of 9.08 µg/dL (95% confidence interval: 5.46, 12.70; heterogeneity: I2 = 0.61%) compared to the placebo. A significant dose-response relationship was confirmed (p < 0.001). Baseline serum zinc concentration was considered an effect modifier in polaprezinc 300 mg. All doses of polaprezinc were tolerable, but a dose-response relationship with adverse events (AEs) was observed in gastrointestinal disorders. The dose of 300 mg may be useful among patients with baseline serum zinc concentration of less than 70 µg/dL, and 150 mg for 70 µg/dL or more., Competing Interests: K.F. and M.T. are employees of Zeria Pharmaceutical Co., Ltd., T.M., Y.N. and M.S. received consultant fee and travel expenses on this review from Zeria Pharmaceutical Co., Ltd. K.O. received travel expenses on this review from Zeria Pharmaceutical Co., Ltd.

Neurological, neurodegenerative, and psychiatric disorders represent a serious burden because of their increasing prevalence, risk of disability, and the lack of effective causal/disease-modifying treatments. There is a growing body of evidence indicating potentially favourable effects of carnosine, which is an over-the-counter food supplement, in peripheral tissues. Although most studies to date have focused on the role of carnosine in metabolic and cardiovascular disorders, the physiological presence of this di-peptide and its analogues in the brain together with their ability to cross the blood-brain barrier as well as evidence from in vitro, animal, and human studies suggest carnosine as a promising therapeutic target in brain disorders. In this review, we aim to provide a comprehensive overview of the role of carnosine in neurological, neurodevelopmental, neurodegenerative, and psychiatric disorders, summarizing current evidence from cell, animal, and human cross-sectional, longitudinal studies, and randomized controlled trials., Competing Interests: The authors declare no conflict of interest.

Background: Chemotherapy-induced peripheral neuropathy is a common side effect afflicting cancer patients treated with oxalipatin based chemotherapy., Aim: The study investigated the potential prophylactic effect of L-carnosine against acute oxaliplatin neurotoxicity in colorectal cancer patients with emphasis on the redox (Nrf-2, MDA), inflammatory (NF-κB, TNF-α), and apoptotic (caspase-3) parameters., Methods: In this pilot study, 65 patients were recruited using a prospective randomized controlled study design and enrolled randomly into two arms; Arm A, 31 patients received FOLFOX-6 regimen (oxaliplatin, 5FU & leucovorin) and Arm B, 34 patients received FOLFOX-6 regimen and daily oral L-carnosine (500 mg) along the treatment period. Patients were followed up for three months, then both arms were analyzed for neuropathy incidence/grade and any additional toxicities according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTC version 4)., Results: The neuropathy grading evaluation of Arm B vs Arm A revealed that 17 patients (56.7%) vs 11 patients (35.5%) suffered grade 1, one patient (3.3%) vs 19 patients (61.3%) suffered grade 2, while 12 patients (40%) vs one patient (3.2%) were normal. In arm B, the addition of L-carnosine decreased significantly the levels/activity of NF-κB (27%) and TNF-α (36.6%); this anti-inflammatory effect entailed also its anti-oxidative and anti-apoptotic effects, thus MDA level (51.8%) and caspase-3 activity (49%) were also reduced, whereas Nrf-2 was increased (38.7%) as compared to Arm A. In both arms a significant correlation was only evident between TNF-α and the neuropathy grading score (P < .03); the correlation analysis was significantly positive between NF-κB and both Nrf-2 and caspase 3., Conclusion: L-Carnosine exerted a neuroprotective effect against oxaliplatin-induced peripheral neuropathy in colorectal cancer patients by targeting Nrf-2 and NF-κB pathways., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: This study aimed at investigating the efficacy and tolerability of l-carnosine as an add-on to risperidone in the management of children with autism., Methods: This was a 10-week, randomized, double-blind, placebo-controlled study. Seventy drug-free children aged 4-12 years old with a diagnosis of autism spectrum disorder (ASD), according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition. (DSM-5) who had an Aberrant Behavior Checklist-Community (ABC-C) scale irritability subscale score of ≥12, entered the study. The patients were randomly assigned to l-carnosine (800 mg/day in 2 divided doses) or placebo in addition to risperidone titrated up to 2 mg/day (based on body weight) for 10 weeks. The children were assessed by using ABC-C at baseline and weeks 5 and 10 post-baseline. The primary outcome measure was the mean change in the ABC-C irritability subscale score, and other subscale scores were defined as secondary outcomes., Results: Using the general linear model repeated measures, no significant effect was observed for time × treatment interaction on the irritability subscale scores. However, significant effect was detected on the hyperactivity/noncompliance subscale [F (1.62, 64.96) = 3.53, p-value = 0.044]. No significant improvements were obtained on the lethargy/social withdrawal, stereotypic behavior, and inappropriate speech subscale scores. Significantly greater score reduction in the hyperactivity/noncompliance subscale occurred in the l-carnosine group compared with the placebo group at the end of the trial. Extrapyramidal Symptom Rating Scale Scores and its changes did not differ between the two groups. The frequency of other side effects was not significantly different between the two groups., Conclusions: Although no significant difference was detected on the irritability subscale scores, l-carnosine add-on can improve hyperactivity/noncompliance subscales of the ABC-C rating scale in patients with ASD.

Our goal was to determine whether anserine/carnosine supplementation (ACS) suppresses chemokine levels in elderly people. In a double-blind randomized controlled trial, volunteers were assigned to the ACS or placebo group (1:1). Sixty healthy elderly volunteers (active, n = 30; placebo, n = 30) completed the study. The ACS group was administered 1.0 g of anserine/carnosine (3:1) for 3 months. A microarray analysis and subsequent quantitative real-time polymerase chain reaction (qRT-PCR) analysis of peripheral blood mononuclear cells (PBMCs) showed decreased expression of CCL24, an inflammatory chemokine ( p < 0.05). Verbal memory, assessed using the Wechsler memory scale-logical memory, was preserved in the ACS group. An age-restricted sub-analysis showed significant verbal memory preservation by ACS in participants who were in their 60s (active, n = 12; placebo, n = 9; p = 0.048) and 70s (active, n = 7; placebo, n = 11; p = 0.017). The suppression of CCL24 expression was greatest in people who were in their 70s ( p < 0.01). There was a significant correlation between the preservation of verbal memory and suppression of CCL24 expression in the group that was in the 70s (Poisson correlation, r = 0.46, p < 0.05). These results suggest that ACS may preserve verbal episodic memory, probably owing to CCL24 suppression in the blood, especially in elderly participants., Competing Interests: The authors declare no conflict of interest.

Background: Dysregulation of glutamate is implicated in the pathogenesis of obsessive-compulsive disorder (OCD). Consistently, glutamate-modulating agents, such as riluzole and memantine have been used in OCD treatment. Previous research has identified some neuroprotective role for L-carnosine potentially via its modulatory effect on glutamate. Here, we assessed the efficacy of L-carnosine as adjuvant to fluvoxamine in OCD treatment., Methods: Forty-four patients diagnosed with moderate to severe OCD were recruited in a randomized double-blind trial. Patients received either L-carnosine or placebo as adjuvant to fluvoxamine for 10 weeks. The Yale- Brown Obsessive Compulsive Scale (Y-BOCS) was used for assessing the severity of symptoms at baseline and at weeks 4, 8, and 10., Results: General linear model repeated measure showed significant effects for Time × Treatment interaction on total Y-BOCS [F (2.10, 88.42) = 8.66, p < 0.001], obsession [F (1.88, 79.34) = 4.96, p = 0.01] and compulsion [F (1.88, 79.11) = 4.57, p = 0.01]. At week 10, the change from baseline in Y-BOCS scores was 8.86 ± 2.89 (mean ± SD) in the L-carnosine group compared to 5.86 ± 2.88 in the placebo group., Conclusion: L-carnosine results in significant reduction of obsessive-compulsive symptoms when used as an adjuvant to fluvoxamine., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: Visual impairment broadly impacts the ability of affected people to maintain their function and to remain independent during their daily occupations as they grow older. Visual impairment affects survival of older patients, quality of life, can affect a person's self-ranking of health, may be associated with social and functional decline, use of community support services, depression, falls, nursing home placement, and increased mortality. It has been hypothesized that senile cataract may serve as a marker for generalised tissue aging, since structural changes occurring in the proteins of the lens during cataract formation are similar to those which occur elsewhere as part of the aging process. The published analysis revealed a strong age-dependent relationship between undergoing cataract surgery and subsequent mortality., Methods: Nuclear opacity, particularly severe nuclear opacity, and mixed opacities with nuclear were significant predictors of mortality independent of body mass index, comorbid conditions, smoking, age, race, and sex. The lens opacity status is considered as an independent predictor of 2-year mortality, an association that could not be explained by potential confounders. Telomeres have become important biomarkers for aging as well as for oxidative stress-related disease. The lens epithelium is especially vulnerable to oxidative stress. Oxidative damage to the cuboidal epithelial cells on the anterior surface of the lens mediated by reactive oxygen species and phospholipid hydroperoxides can precede and contribute to human lens cataract formation. The erosion and shortening of telomeres in human lens epithelial cells in the lack of telomerase activity has been recognized as a primary cause of premature lens senescence phenotype that trigger human cataractogenesis. In this study we aimed to be focused on research defining the mechanisms that underlie linkages among telomere attrition in human lens epithelial cells associated with oxidative stress, biology of the lens response to oxidative damages, aging and health, cataract versus neuroendocrine regulation and disease. The cumulative results demonstrate that carnosine, released ophthalmically from the patented 1% Nacetylcarnosine prodrug lubricant eye drops, at physiological concentration might remarkably reduce the rate of telomere shortening in the lens cells subjected to oxidative stress in the lack of efficient antioxidant lens protection. Carnosine promotes the protection of normal cells from acquiring phenotypic characteristics of cellular senescence. The data of visual functions (visual acuity, glare sensitivity) in older adult subjects and older subjects with cataract treated with 1% N-acetylcarnosine lubricant eye drops showed significant improvement as compared, by contrast with the control group which showed generally no improvement in visual functions, with no difference from baseline in visual acuity and glare sensitivity readings., Results: N-acetylcarnosine derived from the lubricant eye drops may be transported into the hypothalamic tuberomammillary nucleus (TMN) histamine neurons and gradually hydrolyzed. The resulting L-histidine may subsequently be converted into histamine, which could be responsible for the effects of carnosine on neurotransmission and hormone-like antiaging and anti-cataract physiological function., Conclusion: The research utilizing the N-acetylcarnosine lubricant eye drops powerful therapeutic platform provides the findings related to the intraocular uptake exposure sources as well as a timing dosage and duration systemic absorption of said preparation from the conjunctional sac reaching the hypothalamus with activities transfer into the hypothalamic-neuroendocrine pathways affecting across the hypothalamus metabolic pathway the telomere biology and cataract disease occurrence, reversal and prevention and the average expected lifespan of an individual. Such findings can be translated into clinical practice and may provide a basis for personalized cataract disease and aging prevention and treatment approaches.

Objectives: Ulcerative colitis (UC) is a chronic, relapsing and remitting intestinal inflammatory disorder. Zinc is known to be efficacious for the repair of damaged tissue and has been shown to protect against gastric ulceration. This study focused on Polaprezinc (PZ), N-(3-aminopropionyl)-L-histidinato zinc, which accelerates ulcer healing through actions such as prostaglandin-independent cytoprotection and antioxidative activity., Methods: In this randomized, placebo-controlled, investigator-blinded trial, 28 patients with active UC at The Jikei University Hospital were randomly divided into two groups: one treated with a 150 mg PZ enema (n = 18) and the other not treated with a PZ enema (n = 10). All patients received usual induction therapy. Clinical symptoms, endoscopic findings and histological findings were evaluated at entry and one week later., Results: In the PZ group, modified Matts' endoscopic scores were significantly improved after treatment compared to baseline in the rectum (p = 0.004), sigmoid colon (p = 0.03) and descending colon (p = 0.04). In the non-PZ group, scores were not significantly improved in the rectum (p = 0.14) and descending colon (p = 0.34), but were improved in the sigmoid colon (p = 0.04). In the PZ group, the Mayo scores at baseline and at Day 8 were 9.1 ± 1.6 and 5.8 ± 2.7 (p = 0.00004), respectively, and in the placebo group, the scores were 8.9 ± 1.7 and 7.4 ± 2.1 (p = 0.009), respectively. Clinical response or remission was significantly better in the PZ group (71%) than in the placebo group (10%)., Conclusions: A zinc-carnosine chelate compound, PZ, enema may become a useful new add-on treatment to accelerate mucosal healing in UC.

Background and Purpose: An urgent need exists to develop therapies for stroke that have high efficacy, long therapeutic time windows, and acceptable toxicity. We undertook preclinical investigations of a novel therapeutic approach involving supplementation with carnosine, an endogenous pleiotropic dipeptide., Methods: Efficacy and safety of carnosine treatment was evaluated in rat models of permanent or transient middle cerebral artery occlusion. Mechanistic studies used primary neuronal/astrocytic cultures and ex vivo brain homogenates., Results: Intravenous treatment with carnosine exhibited robust cerebroprotection in a dose-dependent manner, with long clinically relevant therapeutic time windows of 6 hours and 9 hours in transient and permanent models, respectively. Histological outcomes and functional improvements including motor and sensory deficits were sustained on 14th day poststroke onset. In safety and tolerability assessments, carnosine did not exhibit any evidence of adverse effects or toxicity. Moreover, histological evaluation of organs, complete blood count, coagulation tests, and the serum chemistry did not reveal any abnormalities. In primary neuronal cell cultures and ex vivo brain homogenates, carnosine exhibited robust antiexcitotoxic, antioxidant, and mitochondria protecting activity., Conclusions: In both permanent and transient ischemic models, carnosine treatment exhibited significant cerebroprotection against histological and functional damage, with wide therapeutic and clinically relevant time windows. Carnosine was well tolerated and exhibited no toxicity. Mechanistic data show that it influences multiple deleterious processes. Taken together, our data suggest that this endogenous pleiotropic dipeptide is a strong candidate for further development as a stroke treatment.

The application of carnosine in medicine has been discussed since several years, but many claims of therapeutic effects have not been substantiated by rigorous experimental examination. In the present perspective, a possible use of carnosine as an anti-neoplastic therapeutic, especially for the treatment of malignant brain tumours such as glioblastoma is discussed. Possible mechanisms by which carnosine may perform its anti-tumourigenic effects are outlined and its expected bioavailability and possible negative and positive side effects are considered. Finally, alternative strategies are examined such as treatment with other dipeptides or β-alanine.

Quantitative adjuvant zinc therapy using polaprezinc was performed to examine the correlation between zinc concentration and anemia in maintenance hemodialysis patients to propose appropriate treatment. Anemia and serum zinc concentration were measured in 117 patients with chronic renal failure receiving outpatient maintenance hemodialysis at Tsuyama Chuo Kinen Hospital. Two bags of polaprezinc (containing zinc 34 mg/day) were administered to 58 patients with lower than normal zinc levels (Zn < 80 mg/dl) as adjuvant zinc therapy to assess anemia improvement. Zinc concentration and all anemia parameters showed significant positive correlation, indicating that anemia improves in patients with high serum zinc levels. Regarding the effects of adjuvant zinc therapy for improving anemia, hemoglobin levels were found to increase significantly to the highest value at 3 weeks. During treatment, the dosage of erythropoietin was reduced significantly from baseline at all assessment points. No zinc poisoning from therapy was seen, but two patients had diarrhea (1.9%). Zinc-treated patients required iron therapy due to the development of iron deficiency. Most maintenance hemodialysis patients suffer from zinc deficiency anemia, and zinc-based polaprezinc has been confirmed to be an effective and safe adjuvant zinc treatment. Most patients diagnosed as refractory anemia with no response to erythropoietin also suffer from zinc deficiency anemia, many of whom are expected to benefit from zinc therapy to improve their anemia. Possible zinc deficiency anemia should be considered in the treatment of refractory anemia with no response to erythropoietin.

Objective: The exact biological functions of the aminoacyl-histidine dipeptides in ophthalmology are still unknown but they are the subject of intensive research activities at Innovative Vision Products, Inc. (IVP). Numerous studies have demonstrated, both at the tissue and organelle levels, that naturally occuring imidazole containing peptidomimetics possess strong and specific antioxidant properties, by preventing and reducing the accumulation of oxidised products derived from the lipid peroxidation (LPO) of biological membranes. Carnosine has been shown to act as a competitive inhibitor of the non-enzymatic glycosylation of proteins.Thus, carnosine may prevent and reverse (de-link) the formation of the advanced glycation end-products (AGEs), whose accumulation in the ocular tissues has been proposed to play a direct role in the etiology and pathogenesis of cataract and diabetic ocular complications (DOC). Besides, histidine-containing dipeptides are believed to act as cytosolic buffering agents., Aims: To compare the efficacy of L-carnosine and derivatives in inhibiting/reversing oxidative stress-induced reactions relevant for cataract pathogenesis. To assess the transglycation activity of carnosine versus representatives of a new group of synthetic carnosine histidyl-hydrazide analogs. To test the clinical efficacy of N-acetylcarnosine prodrug eye drops, developed by IVP's scientists, in decreasing the symptoms of age-related cataract., Main Methods: Antioxidant activity of L-carnosine and N-acetylcarnosine was studied in liposomes, a model of lipid membranes. Iron/ascorbate was used for induction of LPO and peroxidation products were measured. Second-generation carnosine analogs were synthesized and tested vs. L-carnosine for their ability to reverse the glycation process, ultimately resulting in the formation of the AGEs. Visual acuity and glare sensitivity was measured before and after 9-month of topical administration of N-acetylcarnosine eye drops in a randomized placebo-controlled cohort of patients presenting age-related uncomplicated cataract and non-cataract subjects of the same age range., Key Findings: L-carnosine operates as aldehyde and reactive oxygen species (ROS) scavenger in aqueous and lipid environments, preventing ROS-induced damage to biomolecules. L-carnosine and histidyl-hydrazide analogs present transglycation properties which could be used to decrease the occurrence of long term complications of AGE formation in DOC and age-related cataracts. In the patented ophthalmic formulations, the designed leucyl-histidylhydrazide (not hydrolizable by carnosinase substrate) is endowed with a highly evolved structure optimized for the bioactivation of a N-acetylcarnosine dipeptide prodrug, targeting therapeutics of the main DOC: cataract, diabetic retinopathy, central retinal vein occlusion, central retinal artery occlusion and neovascular glaucoma. Besides, the data support the clinical application of N-acetylcarnosine lubricant eye drops to compensate corneal acidosis. Nine-month treatment with N-acetylcarnosine resulted in improved visual acuity in subjects with cataract. Glare sensitivity was improved in subjects with cataract and in non-cataract older subjects. The results from the matched studies indicate that the N-acetylcarnosine-laden therapeutic contact lenses increasing the intraocular and systemic absorption of the active dipeptide carnosine ingredient, are an effective and well-tolerated bandage lens for anterior segment disease and for post-operative management of LASEK patients.This allows practitioners to prescribe extended wear of therapeutic contact lenses loaded with N-acetylcarnosine during medical treatment of cataracts, ocular complications of diabetes, primary open-angle glaucoma and potentially creates a healthier eye and body environment during healing. A number of clinically developed with alliance groups famous International brands of patented by IVP N-acetylcarnosine lubricant eye drops (Can-C, IVP C and D-Smile) are described with a quick reference guide for completing a vendor official registration in EC countries, U.A.E., Indonesia, Japan for human and veterinary use. In a separate development series of data Carcinine (beta-alanylhistamine) significantly protected photoreceptors against light-induced apoptosis, suggesting that this compound is sufficiently resistant to degradation with enzymatic hydrolysis and can be used in vivo representing new strategies in the anti-apoptotic ophthalmic therapy., Significance: Cataract is a major disease both in terms of number of people involved and economic impact. The research into causative factors and mechanisms to prevent the development of cataract is essential, particularly in developing countries where cataract surgery is often inaccessible. The results of this study provide a substantial basis for further evaluation of N-acetylcarnosine eye drops patented by IVP in the treatment and prevention of visual impairment in the temporal cross-sections of an older population several years apart. In the number of promotion studies this ophthalmic drug showed experimental and clinical potential for the non-surgical treatment of age-related cataracts. Comprehensive studies that investigate clinical, economic, and humanistic outcomes for the patient and society are conducted and will be described with different types of identified pharmacoeconomic evaluations to adequately assess the comparative value of current N-acetylcarnosine eye drops therapeutics for medical care and its place in future ophthalmic practices. Patients and the public expect that safe and cost-effective cataract medical care with N-acetylcarnosine therapeutic platform should be commissioned for them.

The dipeptide carnosine has been observed to exert antiaging activity at cellular and whole animal levels. This review discusses the possible mechanisms by which carnosine may exert antiaging action and considers whether the dipeptide could be beneficial to humans. Carnosine's possible biological activities include scavenger of reactive oxygen species (ROS) and reactive nitrogen species (RNS), chelator of zinc and copper ions, and antiglycating and anticross-linking activities. Carnosine's ability to react with deleterious aldehydes such as malondialdehyde, methylglyoxal, hydroxynonenal, and acetaldehyde may also contribute to its protective functions. Physiologically carnosine may help to suppress some secondary complications of diabetes, and the deleterious consequences of ischemic-reperfusion injury, most likely due to antioxidation and carbonyl-scavenging functions. Other, and much more speculative, possible functions of carnosine considered include transglutaminase inhibition, stimulation of proteolysis mediated via effects on proteasome activity or induction of protease and stress-protein gene expression, upregulation of corticosteroid synthesis, stimulation of protein repair, and effects on ADP-ribose metabolism associated with sirtuin and poly-ADP-ribose polymerase (PARP) activities. Evidence for carnosine's possible protective action against secondary diabetic complications, neurodegeneration, cancer, and other age-related pathologies is briefly discussed.

A 77-year-old man referred to our hospital three months ago presented with dyspnea on effort and chest radiograph abnormalities. Chest computed tomography showed consolidation and irregular thickening of the peribronchovascular interstitium. Bronchoalveolar lavage fluids showed increases in the percentage of lymphocytes and a decrease of the CD4/8 ratio. Transbronchial lung biopsy specimens showed signs of organizing pneumonia. The patient had been given polaprezinc for the treatment of hypogeusia six months before. A lymphocyte-stimulating test for polaprezinc was positive, and so our diagnosis was polaprezinc-induced pneumonitis.

Purpose: To evaluate the effects of 1% N-acetylcarnosine (NAC) solution on lens clarity over 6 and 24 months in patients with cataracts., Trial Design: Randomised, placebo-controlled study., Participants: 49 subjects (76 affected eyes) with an average age of 65.3 +/- 7.0 years with a diagnosis of senile cataract with minimum to advanced opacification in various lens layers., Methods: 26 patients (41 eyes) were allocated to topical NAC 1% eyedrops twice daily. The control group consisted of 13 patients (21 eyes) who received placebo eyedrops and 10 patients (14 eyes) who did not receive eyedrops., Main Outcome Measures: All patients were evaluated at entry and followed up every 2 months for a 6-month period (trial 1), or at 6-month intervals for a 2-year period (trial 2), for best-corrected visual acuity and glare testing. In addition, cataract was measured using stereocinematographic slit-images and retro-illumination examination of the lens. Digital analysis of lens images displayed light scattering and absorbing centres in two- and three-dimensional scales., Results: The overall intra-reader reproducibility of cataract measurements (image analysis) was 0.830, and glare testing 0.998. After 6 months, 90% of NAC-treated eyes showed improvement in best corrected visual acuity (7 to 100%) and 88.9% showed a 27 to 100% improvement in glare sensitivity. Topographic studies indicated fewer areas of posterior subcapsular lens opacity and 41.5% of treated eyes had improvement in image analysis characteristics. The overall ratios of image analysis characteristics at 6 months compared with baseline measures were 1.04 and 0.86 for the control and NAC-treated group, respectively (p < 0.001). The apparent benefits of treatment were sustained after 24 months' treatment. No treated eyes demonstrated worsening of vision. The overall visual outcome in the control group showed significant worsening after 24 months in comparison with both baseline and the 6-month follow-up examination. The overall clinical results observed in the NAC-treated group by the 24-month period of examination differed significantly (p < 0.001) from the control group in the eyes with cortical, posterior subcapsular, nuclear or combined lens opacities. Tolerability of NAC eyedrops was good in almost all patients, with no reports of ocular or systemic adverse effects., Conclusion: Topical NAC shows potential for the treatment and prevention of cataracts.

We evaluated the synergistic effect of zinc supplementation on the response to interferon (IFN) therapy in patients with intractable chronic hepatitis C in a pilot study using natural IFN-alpha with or without zinc. No clinical differences were observed between patients treated with IFN alone (n=40) and IFN with polaprezinc (IFN + Zn, n=35). All patients were positive for HCV genotype Ib and had more than 105 copies of the virus/mL serum. Ten million units of natural IFN-alpha was administered daily for 4 weeks followed by the same dose every other day for 20 weeks. In the IFN + Zn group, patients received an additional dose of 150 mg/day polaprezinc orally throughout the 24-week IFN course. No additional side-effects of polaprezinc were noted but four out of 40 IFN alone treatment and three out of 35 IFN + Zn group withdrew because of side-effects. Complete response (CR) was defined as negative HCV RNA in the serum on PCR and normal aminotransferase level 6 months after therapy. Incomplete response (IR) was normal liver enzyme and positive serum HCV RNA. Both of them were evaluated at the 6 months after the completion of the treatment. Patients with higher levels of serum HCV (more than 5 x 105 copies/mL) had little response in both treatment groups. Patients with moderate amount of HCV (105 to 4.99 x 105/mL) showed high response rates in combination group (CR: 11/27, 40.7%; CR + IR 15/27, 64.3%), better than IFN alone (CR: 2/15, 18.2%; CR + IR: 2/15, 18.2%). Serum zinc levels were higher in patients with IFN + Zn group than in the IFN group. Our results indicate that zinc supplementation enhances the response to interferon therapy in patients with intractable chronic hepatitis C.

Aim: To evaluate the efficacy of polaprezinc, a mucosal protective agent, in combination with a 7-day triple therapy containing lansoprazole, amoxycillin and clarithromycin, as a treatment for Helicobacter pylori., Methods: Sixty-six consecutive patients suffering from dyspeptic symptoms with H. pylori infection were randomly allocated to one of two regimens: one group (LAC; n = 31) received lansoprazole 30 mg b.d., amoxycillin 500 mg b.d. and clarithromycin 400 mg b.d. for 7 days. The other group (LACP; n = 35) received the LAC regimen plus polaprezinc 150 mg b.d. for 7 days. H. pylori status was evaluated by rapid urease test, histology and culture at entry and 4 weeks after treatment., Results: Five patients did not complete the treatment: no follow-up endoscopy was performed on two patients in the LAC group; one patient in the LAC group and two in the LACP group had their treatment stopped due to severe diarrhoea. By per protocol analysis, H. pylori eradication was achieved in 24 of the 28 evaluable patients (86%; 95% CI: 72-100%) after LAC therapy, and in 33 of the 33 evaluable patients (100%) after LACP therapy (P < 0.05). On intention-to-treat analysis, the rates of eradication were 24 of 31 patients (77%; 95% CI: 62-93%) in the LAC group, and 33 of 35 patients (94%; 95% CI: 86-100%) in the LACP group (P < 0.05)., Conclusion: A 7-day triple therapy with lansoprazole, amoxycillin and clarithromycin is effective in H. pylori eradication, but this regimen is significantly improved by the addition of polaprezinc.

Stable eye drops of 5% carnosine have been developed. Trials of the drug on mice, rats, rabbits, and dogs showed it to be well tolerated at both total and local levels. In animals the eye drops did not affect the diameter of the pupil, nor did they increase the intraocular pressure. Clinical trials were carried out in 109 patients. Carnosine eye drops exerted a good therapeutic effect in corneal erosion, trophic keratitis, postherpetic epitheliopathy, primary and secondary corneal dystrophy, and bullous keratopathy. Used in combined treatment, the eye drops accelerated healing of corneal ulcers in herpesvirus and bacterial infection or dry keratoconjunctivitis. The Pharmacological Committee of the Ministry of Health and Medical Industry of the Russian Federation permitted 5% carnosine eye drops for medical use.