Dual Effects of Alpha-Hydroxy Acids on the Skin.

AHAs are organic acids with one hydroxyl group attached to the alpha position of the acid. AHAs including glycolic acid, lactic acid, malic acid, tartaric acid, and citric acid are often used extensively in cosmetic formulations. AHAs have been used as superficial peeling agents as well as to ameliorate the appearance of keratoses and acne in dermatology. However, caution should be exercised in relation to certain adverse reactions among patients using products with AHAs, including swelling, burning, and pruritus. Whether AHAs enhance or decrease photo damage of the skin remains unclear, compelling us to ask the question, is AHA a friend or a foe of the skin? The aim of this manuscript is to review the various biological effects and mechanisms of AHAs on human keratinocytes and in an animal model. We conclude that whether AHA is a friend or foe of human skin depends on its concentration. These mechanisms of AHAs are currently well understood, aiding the development of novel approaches for the prevention of UV-induced skin damage.

Pretreatment with xenon protected immature rabbit heart from ischaemia/reperfusion injury by opening of the mitoKATP channel.

BACKGROUND: The noble gas anaesthetic, xenon has previously been shown to protect the adult myocardium from ischaemia/reperfusion (I/R) injury, however its effect on immature myocardium is unclear. The aim of this study was to investigate the effect of xenon on the isolated immature heart. METHODS: Isolated, immature (2-3weeks old) New Zealand rabbit hearts were perfused with Krebs-Henseleit buffer via Langendorff-mode. After 20min of baseline equilibration, hearts were pretreated with 75% xenon, 75% xenon+100µM diazoxide, or 75% xenon+100µM 5-hydroxydecanoate, and then subjected to 1h of global ischaemia and 3h of reperfusion. RESULTS: Pretreatment with 75% xenon significantly improved cardiac function (P<0.01 vs. the I/R group, respectively), limited myocardial infarct size (20.83±2.16%, P<0.01 vs. 35.82±2.14% of the I/R group), reduced cardiac enzyme release (CK-MB, 1.00±0.19IU/L, P<0.01 vs. 0.44±0.14IU/L of the I/R group; LDH, 6.15±1.06IU/L P<0.01 vs. 3.49±0.37IU/L of the I/R group) and decreased apoptosis (6.17±0.56%, P<0.01 vs. 11.31±0.93% of the I/R group). In addition, the mitochondrial structure changes caused by I/R injury were largely prevented by 75% xenon pretreatment (1.37±0.16, P<0.01 vs. 2.32±0.13 of the I/R group). The mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channel opener diazoxide did not influence the effect of xenon, but the specific mitoKATP channel blocker 5-hydroxydecanoate completely abolished this effect. CONCLUSIONS: Our study demonstrated that pretreatment with 75% xenon protected immature heart from I/R injury, and this protection was probably mediated by preservation of myocardial mitochondria and opening of mitoKATP channel.

Muramic acid, endotoxin, 3-hydroxy fatty acids, and ergosterol content explain monocyte and epithelial cell inflammatory responses to agricultural dusts.

In agricultural and other environments, inhalation of airborne microorganisms is linked to respiratory disease development. Bacterial endotoxins, peptidoglycans, and fungi are potential causative agents, but relative microbial characterization and inflammatory comparisons amongst agricultural dusts are not well described. The aim of this study was to determine the distribution of microbial endotoxin, 3-hydroxy fatty acids (3-OHFA), muramic acid, and ergosterol and evaluate inflammatory responses in human monocytes and bronchial epithelial cells with various dust samples. Settled surface dust was obtained from five environments: swine facility, dairy barn, grain elevator, domestic home (no pets), and domestic home with dog. Endotoxin concentration was determined by recombinant factor C (rFC). 3-OHFA, muramic acid, and ergosterol were measured using gas chromatography-mass spectrometry. Dust-induced inflammatory cytokine secretion in human monocytes and bronchial epithelial cells was evaluated. Endotoxin-independent dust-induced inflammatory responses were evaluated. Endotoxin and 3-OHFA levels were highest in agricultural dusts. Muramic acid, endotoxin, 3-OHFA, and ergosterol were detected in dusts samples. Muramic acid was highest in animal farming dusts. Ergosterol was most significant in grain elevator dust. Agricultural dusts induced monocyte tumor necrosis factor (TNF) alpha, interleukin (IL)-6, IL-8, and epithelial cell IL-6 and IL-8 secretion. Monocyte and epithelial IL-6 and IL-8 secretion was not dependent on endotoxin. House dust(s) induced monocyte TNFalpha, IL-6, and IL-8 secretion. Swine facility dust generally produced elevated responses compared to other dusts. Agricultural dusts are complex with significant microbial component contribution. Large animal farming dust(s)-induced inflammation is not entirely dependent on endotoxin. Addition of muramic acid to endotoxin in large animal farming environment monitoring is warranted.

Clinical tolerance and efficacy of capryloyl salicylic acid peel compared to a glycolic acid peel in subjects with fine lines/wrinkles and hyperpigmented skin.

BACKGROUND: Several chemical agents are currently used to perform superficial peels of the face to reduce facial hyperpigmentation and fine lines/wrinkles. Some of the most commonly used agents are alpha hydroxyl acids, such as glycolic acid (GA), or beta hydroxy acid, such as salicylic acid. AIM: This study aims to compare the efficacy of GA to that of a novel derivative of salicylic acid, capryloyl salicylic acid (LHA). SUBJECTS/METHODS: In a split-face study, 50 female volunteers between the ages of 35 and 60 years with mild to moderate facial hyperpigmentation and fine lines/wrinkles were randomized and LHA or GA peel was applied to one side of the face. Increasing peel concentrations were applied (5-10% LHA or 20-50% GA) based on the tolerance level of the subjects and clinical observations of an expert dermatologist for 12 weeks at biweekly intervals. RESULTS: Of the 44 volunteers who completed the study, at 12 weeks 41% of LHA-treated and 30% of GA-treated subjects demonstrated significant reduction of fine lines/wrinkles compared to baseline. Forty-six percent of LHA-treated subjects and 34% of GA-treated subjects showed significant reduction of hyperpigmentation compared to baseline. LHA treatment was better than GA peels, although there were no statistically significant differences between the two groups. CONCLUSIONS: Five percent to 10% of LHA peel is generally safe and as effective as 20-50% GA peel in reducing facial hyperpigmentation and fine lines/wrinkles.

Alpha-hydroxy acids: unapproved uses or indications.

Alpha-hydroxy acids have been used for rejuvenation since ancient times, and now there are several on the market. Depending on the concentration, some have been shown to be effective as peeling agents and for rejuvenation. Glycolic acid and lactic acid are the alpha-hydroxy acids most frequently used in cosmetics, although there are many others used in combination. Some of the most striking advances in dermatology have followed the off-label use of drugs, which is widespread and unavoidable, but a well founded scientific approach to an individual patient's pathology must be emphasized as the number of products, regimens, and adjuncts increases exponentially in the cosmetic field. In this article the authors review some unapproved uses of alpha-hydroxy acids. More published data on the scientific value of these off-label indications that proves whether they are effective or not is needed.

Selective mitochondrial KATP channel activation by nicorandil and 3-pyridyl pinacidil results in antiarrhythmic effect in an anesthetized rabbit model of myocardial ischemia/reperfusion.

The roles of cardiomyocyte sarcolemmal ATP-sensitive K+ (KATP) and mitochondrial KATP channels in cardioprotection and antiarrhythmic activity induced by KATP channel openers remain obscure. However, it has been suggested that the mitochondrial KATP channels are involved as a subcellular mediator in cardioprotection afforded by ischemic preconditioning. In the present study, we investigated the effects of the administration of non-hypotensive doses of ATP-sensitive K+ channel (KATP) openers (nicorandil and 3-pyridyl pinacidil), a specific mitochondrial KATP channel blocker (5-hydroxydecanoate) and a specific sarcolemmal KATP channel blocker (HMR 1883; 1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3- methylthiourea) prior to and during coronary occlusion, as well as prior to and during post-ischemic reperfusion, on survival rate, ischemia-induced and reperfusion-induced arrhythmias and myocardial infarct size in anesthetized albino rabbits. The thorax was opened in the left 4th intercostal space and after pericardiotomy the heart was exposed. In Group I (n = 80), occlusion of the left main coronary artery and hence, myocardial ischemia-induced arrhythmias were achieved by tightening a previously placed loose silk ligature for 30 min. In Group II (n = 186), arrhythmias were induced by reperfusion following a 20 min ligation of the left main coronary artery. In both Group I and Group II, early intravenous infusion of nicorandil (100 micrograms/kg bolus + 10 micrograms/kg/min), 3-pyridyl pinacidil (3.0 micrograms/kg bolus + 1.0 microgram/kg/min), HMR 1883 (3 mg/kg)/nicorandil and HMR 1883 (3 mg/kg)/3-pyridyl pinacidil, just prior to and during ischemia, increased survival rate (75%, 67%, 86% and 75% vs. 60% in the control subgroup in Group I; 67%, 75%, 75% and 67% vs. 43% in the control subgroup in Group II), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. However, late intravenous administration of nicorandil or 3-pyridyl pinacidil at the onset of and during reperfusion did not increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects of both nicorandil and 3-pyridyl pinacidil were abolished by pretreating the rabbits with 5-hydroxydecanoate (5 mg/kg, i.v. bolus), a selective mitochondrial KATP channel blocker, but not by pretreatment with HMR 1883 (3 mg/kg). In the present study, higher levels of malondialdehyde (MDA) and lower levels of reduced glutathione (GSH) and superoxide dismutase (SOD) in the necrotic zone of myocardium in all sixteen subgroups in Group II suggest little anti-free radical property of nicorandil and 3-pyridyl pinacidil. Therefore, we may conclude that intervention by intravenous administration of nicorandil and 3-pyridyl pinacidil (through the selective activation of mitochondrial KATP channels), increases survival rate and exhibits antiarrhythmic and cardioprotective effects during coronary occlusion and reperfusion in anesthetized rabbits, when administered prior to and during coronary occlusion. The mitochondrial KATP channel may be considered to be a potentially important site of cardioprotection and antiarrhythmic activity.

Topical glycolic acid enhances photodamage by ultraviolet light.

BACKGROUND: Alpha-hydroxy acids (AHAs) are widely used as ingredients in cosmetics. Several studies suggest that AHAs can increase the sensitivity of skin to ultraviolet (UV) light. PURPOSE: This study was performed in order to determine whether short-term dermal treatment with glycolic acid, a representative AHA, can enhance the damaging effects of UV light. The duration of the effect of AHAs on the sensitivity of skin to UV light was also examined. METHODS: The backs of 29 Caucasian subjects were treated, once daily, 6 days per week with either 10% glycolic acid (pH 3.5) or placebo in a randomized double-blinded study. At the end of 4 weeks, sites within each treated area were exposed to 1.5 MED of UV light, determined on previously untreated skin. Specimens were obtained for enumeration of sunburn cells (SBCs) in the first group of subjects (n = 16), whereas cyclobutyl pyrimidine dimers (CPDs) in DNA were determined in the second group (n = 13). The minimal erythema dose (MED) in each site was also determined in the first group of subjects. Sunburn cells and MEDs were re-evaluated in the first group 1 week after discontinuing AHA applications. RESULTS: Glycolic acid caused enhanced sensitivity to UV light measured as increased SBC induction and lowered MEDs. Cyclobutyl pyrimidine dimers were elevated but not to a statistically significant level. No differences in SBCs or MEDs were evident after a week of discontinued treatments. CONCLUSION: Short-term application of 10% glycolic acid sensitizes the skin to the damaging effects of UV light. This photosensitivity is reversed within a week of terminating treatments.

Erosion of dentine and enamel in vitro by dietary acids: the effect of temperature, acid character, concentration and exposure time.

Sales of soft drinks has been increasing by 56% over the last 10 years and are estimated to keep rising at about 2-3% a year. Further, the reported incidence of tooth erosion has been increasingly documented. Whilst these factors could well be linked, many individuals with erosive diets are not presenting with erosion. This would suggest the effects of many variables, hence the aim of these investigations. Methodologies included preparing enamel and dentine samples from unerupted human third molars. Groups of five specimens were placed in citric acid over a temperature range of 5-60 degrees C for 10-min exposures; placed in citric, lactic, malic or phosphoric acid (0.05, 0.1, 0.5, and 1% (w/v)) for 10-min exposures; and placed in the same three organic hydroxy acids at 0.3% (w/v) or phosphoric acid at 0.1% (w/v) for 3 x 10-min exposures. Tissue loss was determined by profilometry. Results showed that increasing temperature, concentration and exposure time increased the erosion of dentine and enamel. This study has shown that under highly controlled conditions, erosion of dentine and enamel by dietary acids can be greatly influenced in vitro by temperature, concentration, type of acid and exposure time. These factors could be employed in order to reduce the erosivity of soft acidic drinks.

Pharmacokinetics, safety and tolerability of the orally administered receptor antagonist of cysteinyl-leukotrienes BAY x 7195 in single-dose escalation studies.

BAY x 7195 is a novel receptor antagonist of cysteinyl-leukotrienes currently under development for the treatment of asthma. It is effective in antagonizing the leukotriene-D4 induced bronchoconstriction in healthy volunteers following oral administration. The pharmacokinetics, safety and tolerability of the drug were investigated in six partially placebo-controlled studies in healthy volunteers with single oral administration of a 50, 100, 250, 500 and 1000 mg dose as a tablet. The drug was well tolerated. The only remarkable adverse event was diarrhea in one volunteer receiving the highest dose of 1000 mg. There were no additional clinically relevant changes in any safety parameter including laboratory values. Concentrations of BAY x 7195 were determined in plasma and urine by high performance liquid chromatography with fluorescence detection and plasma-concentrations were further evaluated by compartmental and non-compartmental methods. The concentration vs time profiles of the drug were biphasic with a dominant t1/2 of 0.5-2 h and a terminal t1/2 of 5-10 h. Pharmacokinetics were linear in the investigated range of doses. In spite of substantial inter-subject variability intra-individual variability in AUC and Cmax was reasonable. In general, the concentration vs time profiles could be described with a 2-compartment body model. However, in some cases the occurrence of second and third concentration maxima necessitated the use of a multiple segment absorption model to accomplish a good fit to the data. Enterohepatic recirculation following glucuronidation of the drug is the likely reason for the multiple peaks. Urinary excretion of BAY x 7195 and its glucuronide metabolite was negligible the amount excreted into urine from 0 to 48 h being < 0.1% of the dose. The low renal clearance of BAY x 7195 (< or = 0.07 ml/min) is suggestive of significant reabsorption in the renal tubuli taking into account that the expected renal clearance for a drug with 99.5% protein binding is about 0.6 ml/min.

Tissue response and in vivo degradation of selected polyhydroxyacids: polylactides (PLA), poly(3-hydroxybutyrate) (PHB), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHB/VA).

The tissue response and in vivo molecular stability of injection-molded polyhydroxyacids--polylactides (PLA), poly(3-hydroxybutyrate) (PHB), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHB/VA, 5-22% VA content)--were studied. Polymers were implanted subcutaneously in mice and extirpated at 1, 3, and 6 months in order to study tissue response and polymer degradation. All polymers were well tolerated by the tissue. No acute inflammation, abscess formation, or tissue necrosis was observed in tissues adjacent to the implanted materials. Furthermore, no tissue reactivity or cellular mobilization was evident remote from the implant site. Mononuclear macrophages, proliferating fibroblasts, and mature vascularized fibrous capsules were typical of the tissue response. Degradation of the polymers was accompanied by an increase in collagen deposition. For the polylactide series, the inflammatory response after 1 month of implantation was less for materials containing the D-unit in the polymer chain, whereas in the case of the polyhydroxybutyrate/valerates, the number of inflammatory cells increased with increasing content of the valerate unit in the polymer chain. Between 1-3 months, there was slightly more tissue response to the PHB and PHB/VA polymers than to PLA. This response is attributed to the presence of leachable impurities and a low molecular weight soluble component in the polyhydroxybutyrate/valerates. At 6 months, the extent of tissue reaction was similar for both types of polymers. All polylactides degraded significantly (56-99%) by 6 months. For a poly(L-lactide) series, degradation rate in vivo decreased with increasing initial molecular weight of the injection-molded polymer. Several samples showed pronounced bimodal molecular weight distributions (MWD), which may be due to differences in degradation rate, resulting from variability in distribution of crystalline and amorphous regions within the samples. This may also be the result of two different mechanisms, i.e., nonenzymatic and enzymatic, which are involved in the degradation process, the latter being more extensive at the later stage of partially hydrolyzed polymer. The PHB and PHB/VA polymers degraded less (15-43%) than the polylactides following 6 months of implantation. Generally, the polymer with higher valerate content (19%, 22%) degraded most. The decrease in molecular weight was accompanied by a narrowing of the MWD for PHB and copolymers; there was no evidence of a bimodal MWD, possibly indicating that the critical molecular weight that would permit enzyme/polymer interaction had not been reached. Weight loss during implantation ranged from 0-50% for the polylactides, whereas for the PHB polymers weight loss ranged from 0-1.6%.

Effects of 3-hydroxy-3-methylglutaric acid on plasma and low-density lipoprotein cholesterol levels in familial hypercholesterolemia.

Different doses of 3-hydroxy-3-methyl-glutaric acid (HMG) on plasma lipids were studied in a double-blind trial in 36 patients with familial hypercholesterolemia (type IIa or hyper-beta-lipoproteinemia). The patients were randomly assigned to five groups, and each group received one of the following treatments: placebo, or HMG 750 mg, 1500 mg, 2250 mg, or 3000 mg per day. As compared to placebo, the mean plasma cholesterol levels during the eight-week treatment period were 11 and 13 per cent lower in the 2250-mg and 3000-mg HMG-treated groups (P less than 0.034 and less than 0.021, respectively). At the same dosage levels LDL cholesterol was decreased by 8 per cent. HMG had no significant effect on plasma triglycerides as compared to placebo. Discontinuation of the medication did not result in a rebound of plasma cholesterol. There were no clinical or biologic adverse effects due to the administration of HMG, and all patients maintained excellent compliance to the medication. Because of its lack of toxicity, HMG may be useful as an adjunct to diet in the treatment of familial hypercholesterolemia.