Associations of Prenatal Exposure to Per- and Polyfluoroalkyl Substances with the Neonatal Birth Size and Hormones in the Growth Hormone/Insulin-Like Growth Factor Axis.

Toxicological data suggest a significant developmental toxicity of per- and polyfluoroalkyl substances (PFASs); however, evidence in humans remains inconclusive. Furthermore, the effects of prenatal exposure to PFASs on hormones in the growth hormone (GH)/insulin-like growth factor (IGF) axis of newborns remain largely unclear. We aimed to investigate the associations of prenatal exposure to PFASs with the neonatal birth size, GH, IGF-1, and IGF-binding protein 3 (IGFBP-3). The concentrations of 22 PFASs were measured in the plasma of 224 pregnant women collected within 3 days before delivery (39.3 weeks) in Guangzhou, China, and the anthropometric data were gathered from medical records. Paired cord blood was collected at delivery to determine GH, IGF-1, and IGFBP-3 levels. Multivariable linear regression models revealed the inverse associations of several long-chain PFASs with birth weight and ponderal index as well as the significant associations of perfluorobutanoic acid and perfluorooctanoic acid (PFOA) with IGFBP-3 levels. The Bayesian kernel machine regression confirmed the association of perfluorooctane sulfonate with birth weight and ponderal index and of PFOA with IGFBP-3 and identified an inverse joint effect of exposure to a mixture of multiple PFASs on birth weight. The findings provide the first comprehensive evidence on the individual and joint effects of multiple PFASs on the neonatal birth size and hormones in the GH/IGF axis, which requires further confirmation.

Sodium houttuyfonate: A review of its antimicrobial, anti-inflammatory and cardiovascular protective effects.

There is an almost unlimited interest in searching and developing new drugs, especially when we are in an era that are witnessing more and more emerging pathogens. Natural products from traditional medicines represent a large library for searching lead compounds with novel bioactivities. Sodium houttuyfonate is such one bioactive compound derived from Houttuynia cordata Thunb which has been employed in traditional medicine for treating infectious and inflammatory diseases. Sodium houttuyfonate has demonstrated multiple kinds of pharmacological effects, including antifungal, antibacterial, anti-inflammatory, and cardiovascular protective activities, which are discussed here to provide insights into our understanding of the pharmacological effects of SH and the underlying mechanisms.

A Low Concentration of Tacrolimus/Semifluorinated Alkane (SFA) Eyedrop Suppresses Intraocular Inflammation in Experimental Models of Uveitis.

PURPOSE: Corticosteroids remain the mainstay therapy for uveitis, a major cause of blindness in the working age population. However, a substantial number of patients cannot benefit from the therapy due to steroids resistance or intolerance. Tacrolimus has been used to treat refractory uveitis through systemic administration. The aim of this study was to evaluate the therapeutic potential of 0.03% tacrolimus eyedrop in mouse models of uveitis. METHODS: 0.03% tacrolimus in perfluorobutylpentane (F4H5) (0.03% Tacrolimus/SFA) was formulated using a previously published protocol. Tacrolimus suspended in PBS (0.03% Tacrolimus/PBS) was used as a control. In addition, 0.1% dexamethasone (0.1% DXM) was used as a standard therapy control. Endotoxin-induced uveitis (EIU) and experimental autoimmune uveoretinitis (EAU) were induced in adult C57BL/6 mice using protocols described previously. Mice were treated with eyedrops three times/day immediately after EIU induction for 48 h or from day 14 to day 25 post-immunization (for EAU). Clinical and histological examinations were conducted at the end of the experiment. Pharmacokinetics study was conducted in mice with and without EIU. At different times after eyedrop treatment, ocular tissues were collected for tacrolimus measurement. RESULTS: The 0.03% Tacrolimus/SFA eyedrop treatment reduced the clinical scores and histological scores of intraocular inflammation in both EIU and EAU to the levels similar to 0.1% DXM eyedrop treatment. The 0.03% Tacrolimus/PBS did not show any suppressive effect in EIU and EAU. Pharmacokinetic studies showed that 15 min after topical administration of 0.03% Tacrolimus/SFA, low levels of tacrolimus were detected in the retina (48 ng/g tissue) and vitreous (2.5 ng/ml) in normal mouse eyes, and the levels were significantly higher in EIU eyes (102 ng/g tissue in the retina and 24 ng/ml in the vitreous). Tacrolimus remained detectable in intraocular tissues of EIU eyes 6 h after topical administration (68 ng/g retinal tissue, 10 ng/ml vitreous). Only background levels of tacrolimus were detected in the retina (2-8 ng/g tissue) after 0.03% Tacrolimus/PBS eyedrop administration. CONCLUSION: 0.03% Tacrolimus/SFA eyedrop can penetrate ocular barrier and reach intraocular tissue at therapeutic levels in mouse eyes, particularly under inflammatory conditions. 0.03% Tacrolimus/SFA eyedrop may have therapeutic potentials for inflammatory eye diseases including uveitis.

Pharmacological characterization of memoquin, a multi-target compound for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by progressive loss of cognitive function, dementia and altered behavior. Over 30 million people worldwide suffer from AD and available therapies are still palliative rather than curative. Recently, Memoquin (MQ), a quinone-bearing polyamine compound, has emerged as a promising anti-AD lead candidate, mainly thanks to its multi-target profile. MQ acts as an acetylcholinesterase and ß-secretase-1 inhibitor, and also possesses anti-amyloid and anti-oxidant properties. Despite this potential interest, in vivo behavioral studies with MQ have been limited. Here, we report on in vivo studies with MQ (acute and sub-chronic treatments; 7-15 mg/kg per os) carried out using two different mouse models: i) scopolamine- and ii) beta-amyloid peptide- (Aß-) induced amnesia. Several aspects related to memory were examined using the T-maze, the Morris water maze, the novel object recognition, and the passive avoidance tasks. At the dose of 15 mg/kg, MQ was able to rescue all tested aspects of cognitive impairment including spatial, episodic, aversive, short and long-term memory in both scopolamine- and Aß-induced amnesia models. Furthermore, when tested in primary cortical neurons, MQ was able to fully prevent the Aß-induced neurotoxicity mediated by oxidative stress. The results support the effectiveness of MQ as a cognitive enhancer, and highlight the value of a multi-target strategy to address the complex nature of cognitive dysfunction in AD.

A phase I dose-escalating study of ES-285, a marine sphingolipid-derived compound, with repeat dose administration in patients with advanced solid tumors.

BACKGROUND: ES-285 (Spisulosine) is a novel marine compound with antitumor activity in preclinical studies. A phase I study was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), establish a safety profile, and to evaluate pharmacokinetics and efficacy of the drug. PATIENTS AND METHODS: Thirty patients from two centers were treated with a three-hour ES-285 intravenous infusion for five consecutive days, every 3 weeks. Eleven dose levels were explored. RESULTS: No dose-limiting toxicity (DLT) occurred from 2 to 81 mg/m²/day. Three patients had DLT, one each at dose levels 160, 120 and 100 mg/m²/day; all had grade 4 transaminase increases, one of whom (160 mg/m²/day) had concomitant grade 4 hepatitis and grade 3 bilirubin elevation. The MTD of this regimen was not reached due to early termination of the ES-285 phase I program, but was considered to be 80 to 100 mg/m²/day. Other toxicities included mild to moderate asthenia, nausea, vomiting, anemia, lymphopenia, and injection site reaction. Pharmacokinetic analyses showed dose proportionality on Days 1 and 5, a wide distribution and a long half-life. Seven patients (five with colorectal cancer) had stable disease (1.2-4.1 months), lasting for more than 3 months in three patients. CONCLUSIONS: Liver enzyme elevations were dose limiting for ES-285 in this administration schedule. Low antitumor activity was observed.

Occupational asthma caused by inhalation of surfactant composed of amines.

OBJECTIVE: Occupational asthma (OA) is highly prevalent in industrialized countries and nearly 400 causal agents of this condition have been described to date. This study aims to describe the case of a patient who developed OA secondary to exposure to a surfactant agent comprised of alkylamine ethoxylate and a mixture of alkyleneoxy and ethylenediamine. METHODS: We present the case of a male worker in the meat industry suffering from OA resulting from exposure to a surfactant agent used to clean the animal carcass before it is quartered. We performed various tests on the individual, including: a chest computed tomography; total serum immunoglobulin E (IgE) and specific IgE tests against common pneumoallergens; pulmonary function studies; a methacholine test; and a specific inhalation challenge to the surfactant agent. RESULTS: The tests confirmed the diagnosis of OA. CONCLUSIONS: We discuss whether the amines present in the surfactant or the agent itself might be the cause of the condition. Because of the extensive use of surfactants in several types of industries, it is reasonable to think that their possible relationship with OA may have relevant health implications.

Phase I safety, pharmacokinetic, and pharmacogenomic trial of ES-285, a novel marine cytotoxic agent, administered to adult patients with advanced solid tumors.

A dose-escalation, phase I study evaluated the safety, pharmacokinetics, pharmacogenomics, and efficacy of ES-285, a novel agent isolated from a marine mollusc, in adult cancer patients. Patients received a 24-hour i.v. infusion of ES-285 once every 3 weeks until disease progression or unacceptable toxicity. The starting dose was 4 mg/m(2). Dose escalation in cohorts of at least three patients proceeded according to the worst toxicity observed in the previous cohort. Twenty-eight patients were treated with 72 courses of ES-285 across eight dose levels. No dose-limiting toxicities were seen between 4 and 128 mg/m(2). Two of four patients treated at 256 mg/m(2) had dose-limiting reversible grade 3 transaminitis; one patient at 256 mg/m(2) also had transient grade 3 central neurotoxicity. One of three patients subsequently treated at 200 mg/m(2) died following drug-related central neurotoxicity. Other toxicities included phlebitis, nausea, fatigue, and fever. Pharmacokinetic studies indicated dose proportionality with high volume of distribution (median V(ss) at 256 mg/m(2) was 2,389 liters; range, 1,615-4,051 liters) and long elimination half life (median t(1/2) at 256 mg/m(2) was 28 h; range, 21-32 h). The three patients with dose-limiting toxicity had the highest drug exposure. Pharmacogenomic studies of paired surrogate tissue samples identified changes in gene expression following treatment that correlated with increasing dose. Disease stabilization for 6 to 18 weeks was recorded in nine patients. Using this schedule, 128 mg/m(2) was considered safe and feasible. At this dose, pharmacologically relevant concentrations of the drug were safely achieved with pharmacogenomic studies indicating changes in the expression of genes of potential mechanistic relevance.

Safety, efficacy and anti-inflammatory activity of rho iso-alpha-acids from hops.

A defined mixture of rho iso-alpha-acids (RIAA), a modified hop extract, was evaluated for anti-inflammatory efficacy and safety. RIAA inhibited LPS-stimulated PGE(2) formation with >200-fold selectivity of COX-2 (IC(50)=1.3 microg/ml) over COX-1 (IC(50)>289 microg/ml). This occurred only when RIAA was added prior to, but not post, LPS stimulation. Consistent with this observation, RIAA produced no physiologically relevant, direct inhibition of COX-1 or COX-2 peroxidase activity. This suggests that RIAA inhibits inducible but not constitutive COX-2. In support, we found RIAA showed minimal PGE(2) inhibition (IC(50)=21mug/ml) relative to celecoxib (IC(50)=0.024 microg/ml), aspirin (IC(50)=0.52 microg/ml) or ibuprofen (IC(50)=0.57 microg/ml) in the AGS gastric mucosal model, where COX-1 and -2 are expressed constitutively. Taken together these results predict RIAA may have lower potential for gastrointestinal and cardiovascular toxicity observed with COX enzyme inhibitors. Following confirmation of bioavailable RIAA administered orally, gastrointestinal safety was assessed using the fecal calprotectin biomarker in a 14-day human clinical study; RIAA (900 mg/day) produced no change compared to naproxen (1000 mg/day), which increased fecal calprotectin 200%. Cardiovascular safety was addressed by PGI-M measurements where RIAA (1000 mg) did not reduce PGI-M or affect the urinary PGI-M/TXB(2) ratio. Drug interaction potential was evaluated against six major CYPs; of relevance, RIAA inhibited CYP2C9. Toxicity was assessed in a 21-day oral, mouse subchronic toxicity study where no dose dependent histopathological effects were noted. Clinically, RIAA (1000 mg/day) produced a 54% reduction in WOMAC Global scores in a 6-week, open-label trial of human subjects exhibiting knee osteoarthritis.

Treatment of mild to moderate seborrhoeic dermatitis with MAS064D (Sebclair), a novel topical medical device: results of a pilot, randomized, double-blind, controlled trial.

AIM: MAS064D (Sebclair) is a novel steroid-free cream containing multiple active ingredients. Objective of this pilot study was to evaluate the efficacy and safety of MAS064D in the treatment of mild to moderate SD of the face. METHODS: Patients (n = 60) with SD were randomized to receive MAS064D (n = 40) or a matching vehicle (n = 20). The primary study endpoint was investigators' global assessment (IGA) score at day 28, compared with baseline. Secondary endpoints included: IGA score at day 14; investigators' assessment of erythema and scaling; patients' assessment of burning/stinging, pruritus and global response to MAS064D; resort to rescue medication; quality of life. RESULTS: Use of MAS064D for 4 weeks was associated with a higher percentage of success in the MAS064D group than in the vehicle group (approximately 68% vs 11%, P < 0.0001). The effects of MAS064D were significantly better than those of vehicle for investigator-assessed erythema and scaling, and patients' assessed pruritus and global response to MAS064D (P 0.01). No patient in the MAS064D group required rescue medication, compared with two patients in the vehicle group. Four patients (two each in the MAS064D and vehicle groups) reported a total of six non-serious adverse events. CONCLUSIONS: MAS064D appears to be an effective and well tolerated cream for the treatment of mild to moderate SD of the face. Further clinical evaluation of MAS064D in SD is warranted.

Miscellaneous hydrocarbon solvents.

The solvents discussed in this article are common solvents not categorized as halogenated, aromatic, or botanical. The solvents discussed are categorized into two groups: hydrocarbon mixtures and single agents. The hydrocarbon mixtures discussed are Stoddard solvent, naphtha, and kerosene. The remaining solvents described are n-hexane, methyl n-butyl ketone, dimethylformamide, dimethyl sulfoxide, and butyl mercaptans. Effects common to this group of agents and their unique effects are characterized. Treatment of exposures and toxic effects of these solvents is described, and physiochemical properties and occupational exposure levels are listed.

Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model.

The use of many halogenated alkanes such as carbon tetrachloride (CCl4), chloroform (CHCl3) or iodoform (CHI3), has been banned or severely restricted because of their distinct toxicity. Yet CCl4 continues to provide an important service today as a model substance to elucidate the mechanisms of action of hepatotoxic effects such as fatty degeneration, fibrosis, hepatocellular death, and carcinogenicity. In a matter of dose,exposure time, presence of potentiating agents, or age of the affected organism, regeneration can take place and lead to full recovery from liver damage. CCl4 is activated by cytochrome (CYP)2E1, CYP2B1 or CYP2B2, and possibly CYP3A, to form the trichloromethyl radical, CCl3*. This radical can bind to cellular molecules (nucleic acid, protein, lipid), impairing crucial cellular processes such as lipid metabolism, with the potential outcome of fatty degeneration (steatosis). Adduct formation between CCl3* and DNA is thought to function as initiator of hepatic cancer. This radical can also react with oxygen to form the trichloromethylperoxy radical CCl3OO*, a highly reactive species. CCl3OO* initiates the chain reaction of lipid peroxidation, which attacks and destroys polyunsaturated fatty acids, in particular those associated with phospholipids. This affects the permeabilities of mitochondrial, endoplasmic reticulum, and plasma membranes, resulting in the loss of cellular calcium sequestration and homeostasis, which can contribute heavily to subsequent cell damage. Among the degradation products of fatty acids are reactive aldehydes, especially 4-hydroxynonenal, which bind easily to functional groups of proteins and inhibit important enzyme activities. CCl4 intoxication also leads to hypomethylation of cellular components; in the case of RNA the outcome is thought to be inhibition of protein synthesis, in the case of phospholipids it plays a role in the inhibition of lipoprotein secretion. None of these processes per se is considered the ultimate cause of CCl4-induced cell death; it is by cooperation that they achieve a fatal outcome, provided the toxicant acts in a high single dose, or over longer periods of time at low doses. At the molecular level CCl4 activates tumor necrosis factor (TNF)alpha, nitric oxide (NO), and transforming growth factors (TGF)-alpha and -beta in the cell, processes that appear to direct the cell primarily toward (self-)destruction or fibrosis. TNFalpha pushes toward apoptosis, whereas the TGFs appear to direct toward fibrosis. Interleukin (IL)-6, although induced by TNFalpha, has a clearly antiapoptotic effect, and IL-10 also counteracts TNFalpha action. Thus, both interleukins have the potential to initiate recovery of the CCl4-damaged hepatocyte. Several of the above-mentioned toxication processes can be specifically interrupted with the use of antioxidants and mitogens, respectively, by restoring cellular methylation, or by preserving calcium sequestration. Chemicals that induce cytochromes that metabolize CCl4, or delay tissue regeneration when co-administered with CCl4 will potentiate its toxicity thoroughly, while appropriate CYP450 inhibitors will alleviate much of the toxicity. Oxygen partial pressure can also direct the course of CCl4 hepatotoxicity. Pressures between 5 and 35 mmHg favor lipid peroxidation, whereas absence of oxygen, as well as a partial pressure above 100 mmHg, both prevent lipid peroxidation entirely. Consequently, the location of CCl4-induced damage mirrors the oxygen gradient across the liver lobule. Mixed halogenated methanes and ethanes, found as so-called disinfection byproducts at low concentration in drinking water, elicit symptoms of toxicity very similar to carbon tetrachloride, including carcinogenicity.

[An unusual case of self-harm with petroleum distillate]. / Ein ungewöhnlicher Fall von Selbstbeschädigung mit Waschbenzin.

After surgical treatment of an inguinal hernia, a 26-year-old male was discharged from hospital with a well healing surgical wound. Four weeks later he was admitted again with a major localized painful swelling of the soft tissues, whereas the clinical examination revealed no further local or systemic signs of inflammation. The immediate operation disclosed no abscess formation, but a large colliquation necrosis of the subcutaneous tissue with an outstanding petroleum-like odour. On toxicological examination of the necrotic tissue, a respective petroleum distillate was found. The patient was confronted with the suspicion of having injected the petroleum preparation himself to prolong the wound healing and finally admitted the self-mutilating behaviour. The pathophysiology, clinical history and morphological findings are discussed in comparison with case reports of chemically induced self-mutilation.

Skin necrosis and venous thrombosis from subcutaneous injection of charcoal lighter fluid (naptha).

A 33-year-old white man injected approximately 4 cc of charcoal lighter fluid (99.4% naptha/0.6% inert ingredients) subcutaneously into his left antecubital fossa. The injection resulted in the toxic necrosis of his volar forearm skin extending proximally to mid-humerus and distally to the metacarpophalangeal joints of the left hand dorsally over a 6-day period. The patient ultimately required extensive surgical debridement, secondary operative closure, and approximately 150 cm2 of split-thickness skin grafting. This case demonstrates the potential for widespread, delayed toxic necrosis of the skin resulting from subcutaneous injection of naptha. This patient's case appears to represent the most severe and widespread case of toxic necrosis of the skin resulting from the subcutaneous injection of hydrocarbons reported in the literature. This case also demonstrates extensive toxic thrombophlebitis not reported in prior cases involving subcutaneous injection of hydrocarbons.

Effect of soy-derived isoflavonoids on the induced growth of MCF-7 cells by estrogenic environmental chemicals.

Isoflavonoids are natural plant compounds and possess antitumorigenic properties. Many environmental chemicals have been found to be estrogenic and can enhance tumor growth in estrogen receptor-positive cells. In the present study, the effects of genistein, daidzein, biochanin A, formononetin, and equol on the proliferation of estrogen receptor-positive MCF-7 cells induced by synthetic chemicals 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2,2-trichloroethane (o,p'-DDT), 4-nonylphenol (4-NP), and 5-octylphenol (5-OP) found in the environment were investigated. Genistein, biochanin A, equol, and to some extent daidzein, but not formononetin, at < 10 microM can enhance the growth of MCF-7 cells in the absence of environmental chemicals. Formononetin was toxic to MCF-7 cells at the tested concentrations. The environmental chemicals 4-NP, 5-OP, and o,p'-DDT and the natural estrogen 17 beta-estradiol at 5, 5, and 10 microM and 5 nM, respectively, induced proliferation of MCF-7 cells. In the presence of isoflavonoids (> 25 microM), the environmental chemical-induced cell proliferation was inhibited. Individually, genistein (IC50 = 25-33 microM) was the most potent inhibitor against the induced proliferation of MCF-7 cells of the isoflavonoids needed for a 50% suppression of growth induced by 4-NP, 5-OP, and o,p'-DDT. A mixture of isoflavonoids was the most potent inhibitor against the induced proliferation. Estrogen receptor-dependent and -independent pathways could be involved in the inhibitory actions of isoflavonids. Because it is impossible to have a chemical-free environment, the in vitro data presented here are of practical importance to develop evolving dietary strategies and tactics against the adverse health effects of environmental chemicals.

A questionnaire study of road pavers' and roofers' work-related skin symptoms and bitumen exposure.

BACKGROUND: Skin contact with the components in asphalt and bitumen can lead to irritant and allergic contact dermatitis, but few data are available in the dermatologic literature on the skin symptoms caused by work with bitumen. In addition, working methods have changed markedly during recent decades. METHODS: A questionnaire was delivered to 50 roofers and 101 road pavers. The questionnaire dealt with skin symptoms, symptoms caused by solvent products, the use of personal protection, smoking, eating habits, work conditions, changing and cleaning of overalls, etc. RESULTS: Forty-eight per cent of the road pavers and 58% of the roofers responded to the questionnaire. Relatively high percentages of work-induced skin irritation were reported by both the roofers (44%) and the road pavers (31%); 22% of the road pavers had dermatitis often or sometimes compared with 15% of the roofers. The hands, arms, face, and lower extremities were the most common sites affected. In addition to bitumen products, the road pavers considered amine adhesion-improving agents for paving and naphtha and solvents used in machine repairs, to be the main causes of their skin symptoms. The skin problems of the roofers were caused by man-made mineral fibers, cutback bitumen, and hot bitumen burns. CONCLUSIONS: Roofers endure greater exposure to chemicals than road pavers. Certain components, e.g. polycyclic aromatic hydrocarbons in bitumen, can be absorbed through the skin. Skin exposure should be lowered by keeping the tools, working clothes, shoes, and gloves clean. Overalls and gloves are recommended to be changed at least once a week. Water laundering is not sufficient in dissolving bitumen from overalls and underwear. Cleaning the skin with solvents or naphtha is not recommended, as they are skin irritants.

Mechanism of acute lung injury caused by inhalation of fabric protector and the effect of surfactant replacement.

OBJECTIVE: To evaluate the role of surfactant in the mechanism and treatment of acute lung injury caused by inhalation of fabric protector. DESIGN: Prospective, randomized study. SETTING: University laboratory. INTERVENTIONS: In vitro experiment: a porcine surfactant suspension (10 mg.ml-1) was exposed to a fabric protector aerosolized with an ultrasonic nebulizer for 1 min. Minimum surface tension (gamma min) was sequentially measured using pulsating bubble equipment. Animal experiment: 14 adult rats were anesthetized with pentobarbital and mechanically ventilated with pure oxygen. Then, all rats inhaled fabric protector aerosolized with the nebulizer for five breaths. Three hours after inhalation, the rats were randomly assigned to two groups: a surfactant group (n = 7), in which surfactant (100 mg.kg-1) was replaced, and a control group (n = 7), in which no substance was given. MEASUREMENTS AND RESULTS: In vitro experiment: exposure to fabric protector aerosol increased the mean gamma min of the surfactant from 1.7 to 19.2 mN.m-1 (n = 5, p < 0.05). Animal experiment; the mean partial pressure of oxygen in arterial blood (PaO2) in all rats decreased from 62.8 to 17.1 kPa at 3 h after inhalation. The PaO2 in the surfactant group increased to 49.8 +/- 11.1 (SD) kPa at 30 min after surfactant replacement (p < 0.05), while the PaO2 in the control group remained below 20 kPa. CONCLUSIONS: Impairment of surfactant is a factor involved in the development of acute lung injury caused by inhalation of fabric protector. Surfactant replacement may be therapeutic for such injuries.