Bilayer-forming synthetic lipids: drugs or carriers?

Since their introduction as bilayer-forming synthetic compounds in the eighties, dioctadecyldimethylammonium (DODA) and dihexadecylphosphate (DHP) salts have found many uses in strategic, applied areas. In particular, DODA chloride or bromide vesicles interacted with negatively charged prokaryotic or eukaryotic cells, yielding adsorption isotherms of high affinity for the cell surface, causing cell adhesion and flocculation, changing the cell surface charge from negative to positive, and causing loss of cell viability over DODA concentration ranges that depended on the cell type being tested. This work reviews data on DODA effects on cell viability (bacteria, fungus and cultured mammalian cells) to propose DODA salts as effective anti-microbial agents that exhibit differential cytotoxicity in vitro and, therefore, deserve to be investigated as potential drugs. The full utility of these inexpensive synthetic bilayers and bilayer fragments able to act as drugs themselves and, simultaneously, as drug, gene or vaccine carriers remains hitherto unexplored.     

Lung surfactants for neonatal respiratory distress syndrome: animal-derived or synthetic agents?

Exogenous surfactant therapy is widely used in the management of neonatal respiratory distress syndrome. Two types of surfactants are available: synthetic surfactants, and those derived from animal sources ("natural" surfactants). Both of these surfactants have been shown to be effective. In this article, we review the evidence to compare the two types of surfactants in terms of their physical properties, physiologic effects, and clinical outcomes. Natural surfactants have been shown to have advantages over synthetic surfactants in their physical properties and physiologic effects in animals, as well as in humans. A systematic review of 11 randomized clinical trials comparing natural and synthetic surfactants demonstrated that the use of natural surfactant preparations results in greater clinical benefits compared with synthetic surfactants. These benefits include a more rapid improvement in oxygenation and lung compliance after surfactant therapy, a decrease in the risk of mortality (typical relative risk 0.87; typical risk difference -0.02), and a decrease in the risk of pneumothorax (typical relative risk 0.63; typical risk difference -0.04). Although the use of natural surfactants results in a slightly increased risk of intraventricular hemorrhage (typical relative risk 1.09; typical risk difference 0.03), there is no increase in the risk of grade 3 or 4 intraventricular hemorrhage. There are theoretical but unproven risks of natural surfactants, such as transmission of infectious agents, immunogenicity and impurities in composition. The use of natural surfactants is preferred in most situations. In addition, clinicians should determine the costs of different types of surfactants in their individual practice settings and use this information in decision-making.     

A natural sobriety enzyme: a party pill or snake oil?

Promoters of a recently marketed "natural dietary supplement" called ALCOZYME claimed the product could rapidly and dramatically lower the blood ethanol concentration by metabolizing ethanol from the blood. We undertook a demonstration of the product in accordance with labeled instructions to replicate the results described by the manufacturer. We also tested ALCOZYME invitro in a solution of known ethanol concentration to determine whether the product directly degrades ethanol. In human volunteers, ALCOZYME showed no tendency toward mitigating blood ethanol concentrations and had no effect on the clinical signs of alcohol intoxication. ALCOZYME did not metabolize ethanol invitro.     

Garlic-derived natural polysulfanes as hydrogen sulfide donors: Friend or foe?

In vitro and in vivo studies reported the anti-cancer potential of organosulfur compounds (OSCs) as they trigger biological effects leading to cell cycle arrest with accumulation of cells in G2/M, alteration of the microtubular network, modulation of Bcl-2 family protein expression patterns and changes of the redox status. Despite these well-described effects, no OSC derivative is yet undergoing clinical trials even though their chemistry is well understood as OSCs act as hydrogen sulfide (H₂S) donors. H₂S is a biological mediator, synthesized through cysteine degradation and modulates vasodilation, cytoprotection, inflammation and angiogenesis. It is well accepted that H₂S plays a biphasic pharmacological role: the inhibition of endogenous synthesis of H₂S and paradoxically also the use of H₂S donors to increase H₂S concentration, induce both anti-cancer effects leading therefore to controversial discussions. Altogether, the role of H₂S in the anti-cancer action of OSCs remains poorly understood. In this review, we hypothesize that OSCs act through H₂S signaling pathways in cancer cells, and that a clearer understanding of the mechanism of action of H₂S in OSC-mediated anti-cancer activity is required for further application of these compounds in translational medicine.     

Impulsive action and impulsive choice across substance and behavioral addictions: Cause or consequence?

Substance use disorders are prevalent and debilitating. Certain behavioral syndromes (‘behavioral addictions’) characterized by repetitive habits, such as gambling disorder, stealing, shopping, and compulsive internet use, may share clinical, co-morbid, and neurobiological parallels with substance addictions. This review considers overlap between substance and behavioral addictions with a particular focus on impulsive action (inability to inhibit motor responses), and impulsive choice (preference for immediate smaller rewards to the detriment of long-term outcomes). We find that acute consumption of drugs with abuse potential is capable of modulating impulsive choice and action, although magnitude and direction of effect appear contingent on baseline function. Many lines of evidence, including findings from meta-analyses, show an association between chronic drug use and elevated impulsive choice and action. In some instances, elevated impulsive choice and action have been found to predate the development of substance use disorders, perhaps signifying their candidacy as objective vulnerability markers. Research in behavioral addictions is preliminary, and has mostly focused on impulsive action, finding this to be elevated versus controls, similar to that seen in chronic substance use disorders. Only a handful of imaging studies has explored the neural correlates of impulsive action and choice across these disorders. Key areas for future research are highlighted along with potential implications in terms of neurobiological models and treatment. In particular, future work should further explore whether the cognitive deficits identified are state or trait in nature: i.e. are evident before addiction perhaps signaling risk; or are a consequence of repetitive engagement in habitual behavior; and effects of novel agents known to modulate these cognitive abilities on various addictive disorders.     

Is Cerazette the minipill of choice?

Around 5% of women aged 16-49 years in Great Britain use a progestogen-only pill (POP; 'minipill') as contraception. These pills are used as alternatives to combined oral contraceptives (COCs), compared to which they are less reliable at preventing pregnancy: the estimated contraceptive failure rate of POPs is 0.5 pregnancies per 100 woman-years when used consistently and correctly, compared with 0.1 per 100 woman-years for COCs. Cerazette (Organon), a new POP, is being promoted by the company as "the first oestrogen free pill to consistently inhibit ovulation", as having "the efficacy of a combined pill, with the reassurance of an oestrogen free pill" and offering "reliable contraception for women of any reproductive age". Here, we consider whether Cerazette offers advantages over established POPs.     

Oxcarbazepine for epilepsy--a useful new choice?

Oxcarbazepine* (Trileptal-Novartis), an anti-epileptic first marketed in the UK in 2000, is licensed for use both as adjunctive (add-on) therapy and as monotherapy for adults and children aged 6 years or over with partial-onset epileptic seizures, with or without secondary generalisation. The company claims that oxcarbazepine has "comparable efficacy" to carbamazepine with "greater tolerability", and causes "fewer withdrawals due to side effects compared to most established antiepileptic drugs". Here we discuss the place of oxcarbazepine in the treatment of epilepsy.     

To smoke or not to smoke: Does delay discounting affect the proximal choice to smoke?

Background: Delay discounting rate shows robust predictive validity for tobacco use behaviors and is a new therapeutic target in the treatment of tobacco use. Identifying factors that influence relations between delay discounting and the choice to smoke cigarettes is key to the development of effective interventions that target delay discounting to reduce cigarette consumption. Objective: To examine relations between delay discounting, motivational factors, self-efficacy, nicotine dependence level, and the proximal choice to smoke in the context of other commonly rewarding activity choices. Methods: In this cross-sectional design, daily smokers (n?=?480) from Amazon Mechanical Turk completed a questionnaire that assessed delay discounting rate; motivation, intention, and self-efficacy to quit smoking; nicotine dependence level, and the preference for immediately engaging in multiple commonly rewarding activities. We hypothesized that 1) greater motivation to quit would be associated with lower priority given to smoking; 2) the relation between delay discounting and the priority given to smoking would be mediated by motivation, self-efficacy, and nicotine dependence level. Results: Greater motivation to quit was significantly associated with a lower priority given to smoking. The relation between delay discounting and the priority given to smoking was marginally mediated by nicotine dependence level (p > .057). Conclusions: Motivation to quit influences decision-making by impacting the prioritization of choices. Nicotine dependence is likely to mediate the relation between delay discounting and the choice to smoke. Interventions that target delay discounting to reduce cigarette consumption or prevent relapse need to account for motivation to quit and nicotine dependence level.     

Hydrochlorothiazide: is it a wise choice?

INTRODUCTION: Hydrochlorothiazide (HCTZ) has not been shown to reduce mortality or cardiovascular events when given as a single agent. In fact, HCTZ increased cardiovascular death and coronary artery disease (CAD) compared to placebo and usual care in 2 randomized trials, yet it is the most prescribed diuretic in the United States (U.S.). The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure does not recommend one thiazide diuretic over another. However, there are more clinical data for chlorthalidone and indapamide than HCTZ. AREAS COVERED: This review summarizes the differences between HCTZ, chlorthalidone and indapamide for pharmacological profile, surrogate marker data and clinical trial data. EXPERT OPINION: The use of the term 'thiazide diuretic' should be replaced with 'non-thiazide sulfonamide diuretic' for chlorthalidone and indapamide. Furthermore, chlorthalidone and indapamide, rather than HCTZ, should be recommended due to the lack of evidence and potential harm of the latter.     

Oral or intravenous N-acetylcysteine: which is the treatment of choice for acetaminophen (paracetamol) poisoning?

BACKGROUND: The optimal route and duration of administration for N-acetyl-cysteine in the management of acetaminophen (paracetamol) poisoning are controversial. It has been stated on the basis of a selected post-hoc analysis that oral N-acetylcysteine is superior to intravenous N-acetylcysteine in presentations later than 15 hours. AIM OF STUDY: To investigate the efficacy of intravenous or oral N-acetylcysteine. PATIENTS AND METHODS: We analyzed a series of acetaminophen poisonings treated with a protocol including activated charcoal and intravenous N-acetylcysteine. The outcomes assessed included use of N-acetylcysteine, adverse effects of intravenous N-acetylcysteine, and the occurrence of hepatotoxicity (transaminase > 1000 U/L). We incorporated these results in a meta-analysis of previously reported series of acetaminophen poisonings to compare the outcomes from intravenous and oral N-acetylcysteine use. RESULTS: Of 981 patients admitted over 10 years, 4% (40) presented later than 24 hours and 10% (100) had concentrations of acetaminophen that indicated a probable or high risk of hepatotoxicity. The 30 patients who developed hepatotoxicity presented later, took larger amounts, had higher concentrations, and received N-acetylcysteine later than those who did not. No patients received a liver transplant but 2 patients died (one after referral to a transplant unit and one just before). Adverse reactions to intravenous N-acetylcysteine occurred in 6% (12/205) of patients but none prevented completion of the treatment. In the meta-analysis, those with probable or high risk concentrations had similar outcomes with intravenous (pooled n = 341) and oral N-acetylcysteine (pooled n = 1462) administration. Rates of hepatotoxicity for those treated within 10 hours (3 and 6%), late (10-24 hours: 30 and 26%), and overall (0-24 hours: 16 and 19%) were all similar. The proportion of patients classified as presenting later than 10 hours is much greater in the oral N-acetylcysteine studies (64%) than in many of the intravenous N-acetylcysteine studies (38%, 44%, and 63%). CONCLUSIONS: The differences claimed between oral and intravenous N-acetylcysteine regimes are probably artifactual and relate to inappropriate subgroup analysis. A shorter hospital stay, patient and doctor convenience, and the concerns over the reduction in bioavailability of oral N-acetylcysteine by charcoal and vomiting make intravenous N-acetylcysteine preferable for most patients with acetaminophen poisoning.     

Human exposure to synthetic endocrine disrupting chemicals (S-EDCs) is generally negligible as compared to natural compounds with higher or comparable endocrine activity. How to evaluate the risk of the S-EDCs?

ABSTRACT

Theoretically, both synthetic endocrine-disrupting chemicals (S-EDCs) and natural (exogenous and endogenous) endocrine-disrupting chemicals (N-EDCs) can interact with endocrine receptors and disturb hormonal balance. However, compared to endogenous hormones, S-EDCs are only weak partial agonists with receptor affinities several orders of magnitude lower than S-EDCs. Thus, to elicit observable effects, S-EDCs require considerably higher concentrations to attain sufficient receptor occupancy or to displace natural hormones and other endogenous ligands.

Significant exposures to exogenous N-EDCs may result from ingestion of foods such as soy-based diets, green tea, and sweet mustard. While their potencies are lower as compared to natural endogenous hormones, they usually are considerably more potent than S-EDCs.

Effects of exogenous N-EDCs on the endocrine system were observed at high dietary intakes. A causal relation between their mechanism of action and these effects is established and biologically plausible. In contrast, the assumption that the much lower human exposures to S-EDCs may induce observable endocrine effects is not plausible. Hence, it is not surprising that epidemiological studies searching for an association between S-EDC exposure and health effects have failed.

Regarding testing for potential endocrine effects, a scientifically justified screen should use in vitro tests to compare potencies of S-EDCs with those of reference N-EDCs. When the potency of the S-EDC is similar or smaller than that of the N-EDC, further testing in laboratory animals and regulatory consequences are not warranted.     

Effects of synthetic Δ9-tetrahydrocannabinol on binocular depth inversion of natural and artificial objects in man

Binocular depth inversion represents an illusion of visual perception that is sensitive to various behavioural and psychiatric conditions. It is affected by cannabinoids, reflecting associated changes in perception. The present study investigated the differences in binocular depth inversion of different classes of natural and artificial objects and the effect of synthetic Δ⁹-tetrahydrocannabinol (Dronabinol) on these illusionary perceptions. Using this model, the effects of orally administered Dronabinol on binocular depth inversion were investigated in 17 healthy male volunteers. Pictures from natural and artificial objects were presented stereoscopically and the depth perception of the volunteers was scored in an operationalized way. The time-course of the effects of Dronabinol on binocular depth inversion was analyzed with regard to the stimulus classes (natural and synthetic objects). Significant differences in binocular depth inversion of the different groups of stimuli were revealed. Objects with a higher degree of everyday familiarity were generally seen as more illusionary than those with a lower degree of everyday familiarity. A strong impairment of binocular depth inversion due to Dronabinol was found in most classes of objects. Analysis of different stimulus classes provides further information on the underlying perceptual processing of binocular depth inversion. An impairment of top-down processing of visual sensory data by Dronabinol is suggested. The anandamidergic system seems to be involved in areas of visual information processing. Received: 13 March 1998/Final version: 11 September 1998     

Human exposure to synthetic endocrine disrupting chemicals (S-EDCs) is generally negligible as compared to natural compounds with higher or comparable endocrine activity. How to evaluate the risk of the S-EDCs?

Theoretically, both synthetic endocrine disrupting chemicals (S-EDCs) and natural (exogenous and endogenous) endocrine disrupting chemicals (N-EDCs) can interact with endocrine receptors and disturb hormonal balance. However, compared to endogenous hormones, S-EDCs are only weak partial agonists with receptor affinities several orders of magnitude lower. Thus, to elicit observable effects, S-EDCs require considerably higher concentrations to attain sufficient receptor occupancy or to displace natural hormones and other endogenous ligands.Significant exposures to exogenous N-EDCs may result from ingestion of foods such as soy-based diets, green tea and sweet mustard. While their potencies are lower as compared to natural endogenous hormones, they usually are considerably more potent than S-EDCs.Effects of exogenous N-EDCs on the endocrine system were observed at high dietary intakes. A causal relation between their mechanism of action and these effects is established and biologically plausible. In contrast, the assumption that the much lower human exposures to S-EDCs may induce observable endocrine effects is not plausible. Hence, it is not surprising that epidemiological studies searching for an association between S-EDC exposure and health effects have failed.Regarding testing for potential endocrine effects, a scientifically justified screen should use in vitro tests to compare potencies of S-EDCs with those of reference N-EDCs. When the potency of the S-EDC is similar or smaller than that of the N-EDC, further testing in laboratory animals and regulatory consequences are not warranted.     

Human exposure to synthetic endocrine disrupting chemicals (S-EDCs) is generally negligible as compared to natural compounds with higher or comparable endocrine activity. How to evaluate the risk of the S-EDCs?

Theoretically, both synthetic endocrine disrupting chemicals (S-EDCs) and natural (exogenous and endogenous) endocrine disrupting chemicals (N-EDCs) can interact with endocrine receptors and disturb hormonal balance. However, compared to endogenous hormones, S-EDCs are only weak partial agonists with receptor affinities several orders of magnitude lower. Thus, to elicit observable effects, S-EDCs require considerably higher concentrations to attain sufficient receptor occupancy or to displace natural hormones and other endogenous ligands.Significant exposures to exogenous N-EDCs may result from ingestion of foods such as soy-based diets, green tea and sweet mustard. While their potencies are lower as compared to natural endogenous hormones, they usually are considerably more potent.Effects of exogenous N-EDCs on the endocrine system were observed at high dietary intakes. A causal relation between their mechanism of action and these effects is established and biologically plausible. In contrast, the assumption that the much lower human exposures to S-EDCs may induce observable endocrine effects is not plausible. Hence, it is not surprising that epidemiological studies searching for an association between S-EDC exposure and health effects have failed.Regarding testing for potential endocrine effects, a scientifically justified screen should use in vitro tests to compare potencies of S-EDCs with those of reference N-EDCs. When the potency of the S-EDC is similar or smaller than that of the N-EDC, further testing in laboratory animals and regulatory consequences are not warranted.