Sarcosine as an add-on treatment to antipsychotic medication for people with schizophrenia: a systematic review and meta-analysis of randomized controlled trials.

Background: N-methyl-glycine (sarcosine) may improve symptoms of schizophrenia via NMDA-receptor modulation. We undertook a systematic review and meta-analysis to determine the short- and long-term effectiveness of sarcosine for schizophrenia.Research design and methods: The databases Medline, Scopus, EMBASE, Cochrane Library, and PsycINFO were searched. We included six independent randomized controlled trials of sarcosine as add-on treatment to current antipsychotic medication, involving 234 adult participants with schizophrenia, and reporting data on symptom severity. Standardized mean differences (SMDs) were used to assess continuous outcomes.Results: In all of the trials, sarcosine was administered orally at 2 g/day. Treatment with sarcosine did not show a significant effect size at any of the pre-established time points (2, 4, 6, or >6 weeks), due to marked quantitative heterogeneity. However, sarcosine was associated with significant reductions of symptom severity in the subgroups of people with chronic schizophrenia and no treatment resistance (namely, without added-on clozapine) in relation to the SMD after 6 weeks treatment at -0.36 and -0.31, respectively.Conclusions: People with chronic and non-refractory schizophrenia may benefit from the use of sarcosine as an add-on treatment to antipsychotic medication. Due to the good tolerability of this compound, future trials with larger sample sizes appear worthwhile.

Epidemiology and Co-Reactivity of Novel Surfactant Allergens: A Double-Blind Randomized Controlled Study.

BACKGROUND: Surfactants are cleansing agents used in products such as shampoos and soaps. OBJECTIVES: The aims of this study were to identify positivity rates to 3 novel amide-containing surfactants (sodium lauroyl sarcosinate, isostearamidopropyl morpholine lactate, and disodium lauroamphodiacetate) and evaluate co-reactivity with other surfactants in patients with known surfactant sensitivity. METHODS: Previously patch-tested, surfactant-positive patients were identified via chart review and invited to participate. Participants were patch tested to screening surfactants (cocamidopropyl betaine, amidoamine, dimethylaminopropylamine, cocamide diethanolamine [DEA], oleamidopropyl dimethylamine, and decyl glucoside), as well as 3 novel surfactants: sodium lauroyl sarcosinate 0.5% and 1.0% aq, isostearamidopropyl morpholine lactate 0.5% and 1.0% aq, disodium lauroamphodiacetate 1.0 and 2.0% aq, and a hypoallergenic liquid cleanser (tested semiopen). Participants and clinicians were blinded. The order of tested allergens was randomized. RESULTS: Forty-seven participants completed the study. Excluding doubtful reactions, positive reactions were most common to oleamidopropyl dimethylamine (34%) and dimethylaminopropylamine (34%), followed by isostearamidopropyl morpholine lactate (23%). Reactivity was not associated with history of childhood eczema. Co-reactivity was high among oleamidopropyl dimethylamine, dimethylaminopropylamine, cocamidopropyl betaine, amidoamine, and isostearamidopropyl morpholine lactate. None of the participants who reacted to cocamide DEA reacted to an additional surfactant. CONCLUSIONS: Isostearamidopropyl morpholine lactate may be an important emerging allergen with sensitivity rates comparable with those of oleamidopropyl dimethylamine and dimethylaminopropylamine. Co-reactivity among surfactants was frequent except for cocamide DEA.

Contact Allergy to Surfactants in a Hypoallergenic Liquid Cleanser.

: Surfactants are a relatively rare cause of allergic contact dermatitis (ACD) and testing patients to personal care products containing these ingredients has historically been difficult given their irritant properties. Using the semiopen technique, we were able to identify ACD to a hypoallergenic liquid cleanser in 2 patients who presented to our patch test clinic only months apart. Additional patch testing to individual ingredients led to subsequent identification of 3 novel surfactant allergens (sodium lauroyl sarcosinate, isostearamidopropyl morpholine lactate, and disodium lauroamphodiacetate). Only one of these allergens, sodium lauroyl sarcosinate, has previously been reported as a cause of ACD.

Safety, tolerability and pharmacokinetics of open label sarcosine added on to anti-psychotic treatment in schizophrenia - preliminary study.

BACKGROUND: Hypofunction of NMDA receptor-mediated neurotransmission might play a critical role in schizophrenia. Sarcosine, N- methylglycine and inhibitor of the glycine transporter-1 (Gly-T1), has been suggested as a novel treatment for schizophrenia. METHODS: Open label sarcosine was added to 22 stabilized patients: 5 patients received 2 gm/d, and 17 received 4gm/d. Pharmacokinetics samples, clinical and cognitive parameters using PANSS, CGI and MCCB were collected for all patients. RESULTS: Significant improvement was observed after one week of treatment on PANSS sub-scale of 'positive symptoms' (Z= -2.68; P=0.007) and 'general psychopathology' (Z= -3.02; P=0.003), an improvement in PANSS total score and CGI-S showed a trend (Z= -2.72; P=0.06; Z=-2.69; P=0.08). Speed of processing (MCCB subscale) improved significantly (Z=-2.13; P=0.03). Sarcosine exhibited linear kinetics, with a Tmax and t½ of ~1½- 2½ hr and ~1hr, respectively. LIMITATIONS: This was a short period, open label pilot study with small sample size per dosage group. CONCLUSIONS: Sarcosine is a safe compound and might be efficacious in the treatment of schizophrenia.

Involvement of the strychnine-sensitive glycine receptor in the anxiolytic effects of GlyT1 inhibitors on maternal separation-induced ultrasonic vocalization in rat pups.

Several studies have shown that glycine transporter 1 (GlyT1) inhibitors have anxiolytic actions. There are two types of glycine receptor: the strychnine-sensitive glycine receptor (GlyA) and the strychnine-insensitive glycine receptor (GlyB); however, which receptor is the main contributor to the anxiolytic actions of GlyT1 inhibitors is yet to be determined. Here, we clarified which glycine receptor is the main contributor to the anxiolytic effects of GlyT1 inhibitors by using maternal separation-induced ultrasonic vocalization (USV) by rat pups as an index of anxiety. We confirmed that administration of the benzodiazepine diazepam or the selective serotonin reuptake inhibitor escitaloplam, which are both clinically proven anxiolytics, or the GlyT1 inhibitor SSR504734 (2-chloro-N-[(S)-phenyl[(2S)-piperidin-2-yl] methyl]-3-trifluoromethyl benzamide), decreases USV in rat pups. In addition, we showed that another GlyT1 inhibitor, ALX5407 ((R)-N-[3-(4'-fluorophenyl)-3(4'-phenylphenoxy)propyl]sarcosine) also decreases USV in rat pups. SSR504734- or ALX5407-induced decreases in USV were dose-dependently reversed by administration of the GlyA antagonist strychnine, whereas the diazepam- or escitalopram-induced decreases in USV were not. Furthermore, GlyT1-induced decreases in USV were not reversed by administration of the GlyB antagonist L-687,414. Together, these results suggest that GlyA activation is the main contributor to the anxiolytic actions of GlyT1 inhibitors and that the anxiolytic actions of diazepam and escitalopram cannot be attributed to GlyA activation. Our findings provide new insights into the importance of the activation of GlyA in the anxiolytic effects of GlyT1 inhibitors.

Long-term application of glycine transporter inhibitors acts antineuropathic and modulates spinal N-methyl-D-aspartate receptor subunit NR-1 expression in rats.

BACKGROUND: Dysfunction of spinal glycinergic neurotransmission is a major pathogenetic factor in neuropathic pain. The synaptic glycine concentration is controlled by the two glycine transporters (GlyT) 1 and 2. GlyT inhibitors act antinociceptive in various animal pain models when applied as bolus. Yet, in some studies, severe neuromotor side effects were reported. The aim of the current study was to elucidate whether continuous inhibition of GlyT ameliorates neuropathic pain without side effects and whether protein expression of GlyT1, GlyT2, or N-methyl-D-aspartate receptor subunit NR-1 in the spinal cord is affected. METHODS: In the chronic constriction injury model of neuropathic pain, male Wistar rats received specific GlyT1 and GlyT2 inhibitors (ALX5407 and ALX1393; Sigma-Aldrich, St. Louis, MO) or vehicle for 14 days via subcutaneous osmotic infusion pumps (n = 6). Mechanical allodynia and thermal hyperalgesia were assessed before, after chronic constriction injury, and every 2 days during substance application. At the end of behavioral assessment, the expression of GlyT1, GlyT2, and NR-1 in the spinal cord was determined by Western blot analysis. RESULTS: Both ALX5407 and ALX1393 ameliorated thermal hyperalgesia and mechanical allodynia in a time- and dose-dependent manner. Respiratory or neuromotor side effects were not observed. NR-1 expression in the ipsilateral spinal cord was significantly reduced by ALX5407, but not by ALX1393. The expression of GlyT1 and GlyT2 remained unchanged. CONCLUSIONS: Continuous systemic inhibition of GlyT significantly ameliorates neuropathic pain in rats. Thus, GlyT represent promising targets in pain research. Modulation of N-methyl-D-aspartate receptor expression might represent a novel mechanism for the antinociceptive action of GyT1 inhibitors.

Topical surfactant-induced pruritus: involvement of histamine released from epidermal keratinocytes.

Surfactants, an important component of cleansers, often cause itch in humans. Topical application of sodium laurate and N-lauroylsarcosine sodium salt to the skin of mice immediately (for 1-1.5 hours) increased scratching, and the former increased scratching again between 2 and 3 hours after application. Thus, we examined the mechanisms of sodium laurate-induced delayed scratching. Sodium laurate (0.1%-10%) increased delayed scratching and skin surface pH in a concentration-dependent manner. N-lauroylsarcosine sodium salt had no effect on these parameters, and sodium hydroxide solution did not increase delayed scratching. Sodium laurate-induced delayed scratching was markedly inhibited by the H(1) histamine receptor antagonist terfenadine, but it was not affected by mast cell deficiency. Sodium laurate application had no effect on the number of total and degranulated mast cells, and did not induce plasma extravasation or the infiltration of inflammatory cells in the skin. Sodium laurate application increased the histamine content of the epidermis, but not that of the dermis, in normal and mast cell-deficient mice. Sodium laurate application increased the ratio of 53-kDa l-histidine decarboxylase (HDC, a key enzyme for histamine production) to 74-kDa HDC in the mouse epidermis and in a human keratinocyte culture. Sodium laurate increased histamine in the human keratinocyte culture, without affecting cell viability. The present results suggest that sodium laurate induced delayed scratching at an alkaline pH through the increased production of histamine in keratinocytes, which may be due to enhanced processing of 74-kDa to 53-kDa HDC.

Tolerance and safety evaluation of N,N-dimethylglycine, a naturally occurring organic compound, as a feed additive in broiler diets.

N,N-Dimethylglycine (DMG) is a tertiary amino acid that naturally occurs as an intermediate metabolite in choline-to-glycine metabolism. The objective of the present trial was to evaluate tolerance, safety and bioaccumulation of dietary DMG in broilers when supplemented at 1 g and 10 g Na-DMG/kg. A feeding trial was conducted using 480 1-d-old broiler chicks that were randomly allocated to twenty-four pens and fed one of three test diets added with 0, 1 or 10 g Na-DMG/kg during a 39 d growth period. Production performance was recorded to assess tolerance and efficacy of the supplement. At the end of the trial, toxicity was evaluated by means of haematology, plasma biochemistry and histopathology of liver, kidney and heart (n 12), whereas bioaccumulation was assessed on breast meat, liver, blood, kidney and adipose tissue (n 8). Carcass traits were similar between the control and 1 g Na-DMG/kg feed groups (P>0·05), but the feed:gain ratio was significantly improved at 1 g Na-DMG/kg feed compared with the control or the 10-fold dose (P=0·008). Histological examinations showed no pathological effects and results of haematology and plasma biochemistry revealed similar values between the test groups (P>0·05). Bioaccumulation occurred at the 10-fold dose, but the resulting DMG content in breast meat was comparable with, for instance, wheat bran and much lower than uncooked spinach. In conclusion, DMG at 1 g Na-DMG/kg improved the feed:gain ratio in broilers without DMG being accumulated in consumer parts. Furthermore, dietary supplementation with DMG up to 10 g Na-DMG/kg did not induce toxicity or impaired performance in broilers.

First-time-in-human study of GSK923295, a novel antimitotic inhibitor of centromere-associated protein E (CENP-E), in patients with refractory cancer.

PURPOSE: GSK923295 is an inhibitor of CENP-E, a key cellular protein important in the alignment of chromosomes during mitosis. This was a Phase I, open-label, first-time-in-human, dose-escalation study, to determine the maximum-tolerated dose (MTD), safety, and pharmacokinetics of GSK923295. PATIENTS AND METHODS: Adult patients with previously treated solid tumors were enrolled in successive cohorts at GSK923295 doses ranging from 10 to 250 mg/m(2). GSK923295 was administered by a 1-h intravenous infusion, once weekly for three consecutive weeks, with treatment cycles repeated every 4 weeks. RESULTS: A total of 39 patients were enrolled. The MTD for GSK923295 was determined to be 190 mg/m(2). Observed dose-limiting toxicities (all grade 3) were as follows: fatigue (n = 2, 5%), increased AST (n = 1, 2.5%), hypokalemia (n = 1, 2.5%), and hypoxia (n = 1, 2.5%). Across all doses, fatigue was the most commonly reported drug-related adverse event (n = 13; 33%). Gastrointestinal toxicities of diarrhea (n = 12, 31%), nausea (n = 8, 21%), and vomiting (n = 7, 18%) were generally mild. Frequency of neutropenia was low (13%). There were two reports of neuropathy and no reports of mucositis or alopecia. GSK923295 exhibited dose-proportional pharmacokinetics from 10 to 250 mg/m(2) and did not accumulate upon weekly administration. The mean terminal elimination half-life of GSK923295 was 9-11 h. One patient with urothelial carcinoma experienced a durable partial response at the 250 mg/m(2) dose level. CONCLUSIONS: The novel CENP-E inhibitor, GSK923295, had dose-proportional pharmacokinetics and a low number of grade 3 or 4 adverse events. The observed incidence of myelosuppression and neuropathy was low. Further investigations may provide a more complete understanding of the potential for GSK923295 as an antiproliferative agent.

Sodium hydroxymethylglycinate.

Sodium hydroxymethylglycinate (SHMG) is a preservative used in many commercially available products, including shampoos, conditioners, soaps, moisturizers, body sprays, baby wipes, room sprays, cleaning agents, and pesticides. It is in a class of chemicals known as formaldehyde-releasing preservatives. Notably, members of this class have been associated with allergic contact dermatitis, possibly due to the agents themselves, the formaldehyde they release, or both. Studies on SHMG in animals have demonstrated potential for sensitization and dermatitis, and formaldehyde-allergic patients have been reported to improve when products containing SHMG are avoided. Patients and providers need to be aware of this preservative.

Formaldehyde-releasers in cosmetics: relationship to formaldehyde contact allergy. Part 1. Characterization, frequency and relevance of sensitization, and frequency of use in cosmetics.

In this part of a series of review articles on formaldehyde-releasers and their relationship to formaldehyde contact allergy, formaldehyde-releasers in cosmetics are discussed. In this first part of the article, key data are presented including frequency of sensitization and of their use in cosmetics. In Europe, low frequencies of sensitization have been observed to all releasers: 2-bromo-2-nitropropane-1,3-diol 0.4-1.2%, diazolidinyl urea 0.5-1.4%, imidazolidinyl urea 0.3-1.4%, quaternium-15 0.6-1.9% (for DMDM hydantoin no recent data are available). All releasers score (far) higher prevalences in the USA; the possible explanations for this are discussed. The relevance of positive patch test reactions has been insufficiently investigated. In the USA, approximately 20% of cosmetics and personal care products (stay-on products: 17%, rinse-off products 27%) contain a formaldehyde-releaser. The use of quaternium-15 is decreasing. For Europe, there are no comparable recent data available. In the second part of the article, the patch test relationship of the releasers in cosmetics to formaldehyde contact allergy will be reviewed and it will be assessed whether products preserved with formaldehyde-releasers may contain enough free formaldehyde to pose a threat to individuals who have contact allergy to formaldehyde.

Conjugated bile acid replacement therapy in short bowel syndrome patients with a residual colon.

AIM: To test the efficacy of cholylsarcosine (synthetic conjugated bile acid) and ox bile extracts (mixture of natural conjugated bile acids) on fat absorption, diarrhea, and nutritional state in four short bowel syndrome (SBS) patients with a residual colon not requiring parenteral alimentation. METHODS: The effect of cholylsarcosine (2 g/meal) on steatorrhea and diarrhea was examined in short-term balance studies with a constant fat intake in all four patients. The effect of continuous cholylsarcosine ingestion on nutritional state was assessed by changes in body weight in three patients. In two patients, the effects of cholylsarcosine were compared with those of ox bile extracts. Because of the low incidence rate of SBS this is not a controlled study. RESULTS: In balance studies, cholylsarcosine increased fat absorption from 65.5 to 94.5 g/day (a 44 % increment), an energy gain of 261 kcal/d. Fecal weight increased by 26 %. In two patients natural conjugated bile acids also reduced steatorrhea, but greatly increased diarrhea. As outpatients consuming an unrestricted diet and ingesting cholylsarcosine, three patients gained weight at an average rate of 0.9 kg/week without worsening of diarrheal symptoms. CONCLUSIONS: Cholylsarcosine is efficacious and safe for enhancing fat absorption and nutritional status in short bowel syndrome patients with residual colon. Natural conjugated bile acids improve steatorrhea to a smaller extent and greatly worsen diarrhea.

Final report on the safety assessment of Cocoyl Sarcosine, Lauroyl Sarcosine, Myristoyl Sarcosine, Oleoyl Sarcosine, Stearoyl Sarcosine, Sodium Cocoyl Sarcosinate, Sodium Lauroyl Sarcosinate, Sodium Myristoyl Sarcosinate, Ammonium Cocoyl Sarcosinate, and Ammonium Lauroyl Sarcosinate.

This safety assessment addresses cosmetic ingredients that are N-acyl derivatives of sarcosine and are generally referred to as acyl sarcosines, and those that are salts, known generally as acyl sarcosinates. Previous assessments have addressed the safety of each of the fatty acids that appear in these acyl sarcosines and sarcosinates (Coconut Acid, Oleic Acid, Lauric Acid, and Myristic Acid). In each case the fatty acid was either safe for use or safe as used in cosmetic formulations. Acyl sarcosines are considered modified fatty acids with greater solubility and increased acidity of the carboxylic acid group compared to the parent fatty acid. They are used in a large number of cosmetic formulations as hair-conditioning agents and surfactant-cleansing agents. In soaps, concentrations are reported to be as high as 12.9%. These ingredients have low oral toxicity in rats. Although cytotoxic to Chinese hamster cells in culture, acyl sarcosines and sarcosinates are not mutagenic in those cells, nor in bacterial cells in culture. Carcinogenicity data were not available. These ingredients are nonirritating and nonsensitizing to animal and human skin, although they can enhance the penetration of other ingredients through the skin. For that reason, caution should be exhibited in formulating cosmetic products that contain these ingredients in combination with other ingredients whose safety is based on their lack of absorption or where dermal absorption is a concern (e.g., HC Yellow No. 4, Disperse Yellow 3). Because sarcosine can be nitrosated to form N-nitrososarcosine, a known animal carcinogen, these ingredients should not be used in cosmetic products in which N-nitroso compounds may be formed. With the above caveat, and based on the available data, it was concluded that these acyl sarcosines and sarcosinates are safe as used in rinse-off products. They may be safely used in leave-on products at concentrations up to 5%, the highest concentration tested in clinical irritation and sensitization studies. Oleoyl Sarcosine is used as a corrosion inhibitor in some aerosol products, at extremely low concentrations. In this circumstance, the ingredient is not being used as a cosmetic ingredient and this report is not intended to limit that use. Because of the absence of data on inhalation toxicity, however, it was concluded that the available data were not sufficient to support the safety of acyl sarcosines and sarcosinates as cosmetic ingredients in products where they are likely to be inhaled.

Effectiveness of N,N-dimethylglycine in autism and pervasive developmental disorder.

N,N-dimethylglycine, a dietary supplement, has been reported to be beneficial in children with autism and pervasive developmental disorder. We examined the effectiveness of dimethylglycine in children with autism and pervasive developmental disorder in a double-blind, placebo-controlled study. Thirty-seven children between 3 and 11 years of age with a diagnosis of autism and/or pervasive developmental disorder were gender and age matched and randomly assigned to receive either placebo or dimethylglycine for 4 weeks. All children were assessed before and after treatment on two behavioral measures, the Vineland Maladaptive Behavior Domain and the Aberrant Behavior Checklist. Standardized neurologic examinations before and after treatment on 33 children showed no change. An overall improvement on all behavioral measures was observed for both the placebo and the dimethylglycine groups. However, the improvement among the children who received dimethylglycine was not statistically different from the improvement observed among the children who received the placebo. The children who participated in this study were a heterogeneous group, and their apparent responses to the dimethylglycine varied. Some children appeared to respond positively to the dimethylglycine, and there was a smaller proportion of negative changes in the dimethylglycine group, but the quantitative changes in the dimethylglycine behavioral assessments were not significantly different from what was observed among children who received placebo.