Calcium kinetics during bed rest with artificial gravity and exercise countermeasures.

UNLABELLED: We assessed the potential for countermeasures to lessen the loss of bone calcium during bed rest. Subjects ingested less calcium during bed rest, and with artificial gravity, they also absorbed less calcium. With exercise, they excreted less calcium. To retain bone during bed rest, calcium intake needs to be maintained. INTRODUCTION: This study aims to assess the potential for artificial gravity (AG) and exercise (EX) to mitigate loss of bone calcium during space flight. METHODS: We performed two studies: (1) a 21-day bed rest (BR) study with subjects receiving 1 h/day AG (n = 8) or no AG (n = 7) and (2) a 28-day BR study with 1 h/day resistance EX (n = 10) or no EX (n = 3). In both studies, stable isotopes of Ca were administered orally and intravenously, at baseline and after 10 days of BR, and blood, urine, and feces were sampled for up to 14 days post dosing. Tracers were measured using thermal ionization mass spectrometry. Data were analyzed by compartmental modeling. RESULTS: Less Ca was absorbed during BR, resulting in lower Ca balance in BR+AG (-6.04 ± 3.38 mmol/day, P = 0.023). However, Ca balance did not change with BR+EX, even though absorbed Ca decreased and urinary Ca excretion increased, because endogenous excretion decreased, and there was a trend for increased bone deposition (P = 0.06). Urinary N-telopeptide excretion increased in controls during BR, but not in the EX group. Markers of bone formation were not different between treatment groups for either study. Ca intake decreased during BR (by 5.4 mmol/day in the AG study and 2.8 mmol/day in the EX study), resulting in lower absorbed Ca. CONCLUSIONS: During BR (or space flight), Ca intake needs to be maintained or even increased with countermeasures such as exercise, to enable maintenance of bone Ca.

Neuroleptic malignant syndrome: mechanisms, interactions, and causality.

This review focuses on new data from recent publications concerning how compounding interactions between different thermoregulatory pathways influence the development of hyperthermia and/or neuroleptic malignant syndrome (NMS), and the fundamental issue of the presumed causal role of antipsychotic drugs. The formal criteria for substantiating cause-effect relationships in medical science, established by Hill, are applied to NMS and, for comparison, also to malignant hyperthermia and serotonin toxicity. The risk of morbidities related to hyperthermia is reviewed from human and experimental data: temperatures in excess of 39.5°C cause physiological and cellular dysfunction and high mortality. The most temperature-sensitive elements of neural cells are mitochondrial and plasma membranes, in which irreversible changes occur around 40°C. Temperatures of up to 39°C are "normal" in mammals, so, the term hyperthermia should be reserved for temperatures of 39.5°C or greater. The implicitly accepted presumption that NMS is a hypermetabolic and hyperthermic syndrome is questionable and does not explain the extensive morbidity in the majority of cases, where the temperature is less than 39°C. The thermoregulatory effects of dopamine and acetylcholine are outlined, especially because they are probably the main pathways by which neuroleptic drugs might affect thermoregulation. It is notable that even potent antagonism of these mechanisms rarely causes temperature elevation and that multiple mechanisms, including the acute phase response, stress-induced hyperthermia, drugs effects, etc., involving compounding interactions, are required to precipitate hyperthermia. The application of the Hill criteria clearly supports causality for drugs inducing both MH and ST but do not support causality for NMS.

Triptans, serotonin agonists, and serotonin syndrome (serotonin toxicity): a review.

The US Food and Drug Administration (FDA) have suggested that fatal serotonin syndrome (SS) is possible with selective serotonin reuptake inhibitors (SSRIs) and triptans: this warning affects millions of patients as these drugs are frequently given simultaneously. SS is a complex topic about which there is much misinformation. The misconception that 5-HT1A receptors can cause serious SS is still widely perpetuated, despite quality evidence that it is activation of the 5-HT2A receptor that is required for serious SS. This review considers SS involving serotonin agonists: ergotamine, lysergic acid diethylamide, bromocriptine, and buspirone, as well as triptans, and reviews the experimental foundation underpinning the latest understanding of SS. It is concluded that there is neither significant clinical evidence, nor theoretical reason, to entertain speculation about serious SS from triptans and SSRIs. The misunderstandings about SS exhibited by the FDA, and shared by the UK Medicines and Healthcare products Regulatory Agency (in relation to methylene blue), are an important issue with wide ramifications.

Effects of 21 days of bed rest, with or without artificial gravity, on nutritional status of humans.

Spaceflight and bed rest models of microgravity have profound effects on physiological systems, including the cardiovascular, musculoskeletal, and immune systems. These effects can be exacerbated by suboptimal nutrient status, and therefore it is critical to monitor nutritional status when evaluating countermeasures to mitigate negative effects of spaceflight. As part of a larger study to investigate the usefulness of artificial gravity as a countermeasure for musculoskeletal and cardiovascular deficits during bed rest, we tested the hypothesis that artificial gravity would have an effect on some aspects of nutritional status. Dietary intake was recorded daily before, during, and after 21 days of bed rest with artificial gravity (n = 8) or bed rest alone (n = 7). We examined body composition, hematology, general blood chemistry, markers of oxidative damage, and blood levels of selected vitamins and minerals before, during, and after the bed rest period. Several indicators of vitamin status changed in response to diet changes: serum alpha- and gamma-tocopherol and urinary 4-pyridoxic acid decreased (P < 0.001) and plasma beta-carotene increased (P < 0.001) in both groups during bed rest compared with before bed rest. A decrease in hematocrit (P < 0.001) after bed rest was accompanied by a decrease in transferrin (P < 0.001), but transferrin receptors were not changed. These data provide evidence that artificial gravity itself does not negatively affect nutritional status during bed rest. Likewise, artificial gravity has no protective effect on nutritional status during bed rest.

Tricyclic antidepressant pharmacology and therapeutic drug interactions updated.

New data on the pharmacology of tricyclic antidepressants (TCAs), their affinities for human cloned CNS receptors and their cytochrome P450 enzyme inhibition profiles, allow improved deductions concerning their effects and interactions and indicate which of the TCAs are the most useful. The relative toxicity of TCAs continues to be more precisely defined, as do TCA interactions with selective serotonin reuptake inhibitors (SSRIs). TCA interactions with monoamine oxidase inhibitors (MAOIs) have been, historically, an uncertain and difficult question, but are now well understood, although this is not reflected in the literature. The data indicate that nortriptyline and desipramine have the most pharmacologically desirable characteristics as noradrenaline reuptake inhibitors (NRIs), and as drugs with few interactions that are also safe when coadministered with either MAOIs or SSRIs. Clomipramine is the only available antidepressant drug that has good evidence of clinically relevant serotonin and noradrenaline reuptake inhibition (SNRI). These data assist drug selection for monotherapy and combination therapy and predict reliably how and why pharmacodynamic and pharmacokinetic interactions occur. In comparison, two newer drugs proposed to have SNRI properties, duloxetine and venlafaxine, may have insufficient NRI potency to be effective SNRIs. Combinations such as sertraline and nortriptyline may therefore offer advantages over drugs like venlafaxine that have fixed ratios of SRI/NRI effects that are not ideal. However, no TCA/SSRI combination is sufficiently safe to be universally applicable without expert knowledge. Standard texts (e.g. the British National Formulary) and treatment guidelines would benefit by taking account of these new data and understandings.

Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction.

BACKGROUND AND PURPOSE: Monoamine oxidase inhibitors (MAOI) are known to cause serotonin toxicity (ST) when administered with selective serotonin reuptake inhibitors (SSRI). Methylene blue (methylthionium chloride, MB), a redox dye in clinical use, has been reported to precipitate ST in patients using SSRI. MB was assessed for MAO inhibition and so for its potential to precipitate ST. EXPERIMENTAL APPROACH: Inhibition of purified human MAO was quantified using kinetic assays and visible spectral changes to study the interactions of MB with MAO A. KEY RESULTS: MB was a potent (tight binding) inhibitor for MAO A. It also inhibited MAO B but at much higher concentration. Interactions of MB with the active site of MAO A were confirmed by its action both as an oxidising substrate and as a one-electron reductant. CONCLUSIONS AND IMPLICATIONS: MB is a potent reversible inhibitor of MAO A with implications for gut uptake of amines when administered orally. At concentrations reported in the literature after intravenous administration, MAO B would be partially inhibited but MAO A would be completely inhibited. This inhibition of MAO A would be expected to lead to perturbations of 5-hydroxytryptamine metabolism and hence account for ST occurring when administered to patients on SSRI treatment.

Serotonin toxicity associated with the use of linezolid: a review of postmarketing data.

BACKGROUND: Linezolid is the first oxazolidinone antimicrobial marketed in the United States. It exhibits monoamine oxidase (MAO) type A and MAO type B inhibitory effects. The concomitant administration of nonselective MAO inhibitors or MAO-A inhibitors with drugs that increase serotonin concentrations is associated with serotonin toxicity. METHODS: We requested from the US Food and Drug Administration all postmarketing adverse event reports regarding linezolid that included serotonin toxicity or any report describing cognitive or behavioral symptoms and autonomic and neuromuscular excitability. We assessed the case summaries obtained from the Adverse Event Reporting System database for serotonin toxicity. A case of serotonin toxicity was defined as having the following: (1) linezolid as the primary suspect drug; (2) concurrent administration of > or =1 secondary suspect drug known to increase serotonin concentrations in the central nervous system; and (3) serotonin toxicity, as defined by the modified Hunter Serotonin Toxicity Criteria or by the reporter. RESULTS: Twenty-nine cases were classified as serotonin toxicity. Patients' ages ranged from 17-83 years, and the ratio of females to males was 1:1. The most common class of drugs received concurrently with linezolid was selective serotonin reuptake inhibitors (26 of 43 patients). Thirteen patients required an intervention to prevent permanent impairment or required hospitalization for the adverse event. CONCLUSION: The use of linezolid with medications that increase concentrations of serotonin in the central nervous system may result in serotonin toxicity. Prescribers must weigh risks and benefits of this combination. Patients and prescribers should be cognizant of signs and symptoms of serotonin toxicity and should initiate appropriate measures if such symptoms develop.

A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action.

Data now exist from which an accurate definition for serotonin toxicity (ST), or serotonin syndrome, has been developed; this has also lead to precise, validated decision rules for diagnosis. The spectrum concept formulates ST as a continuum of serotonergic effects, mediated by the degree of elevation of intrasynaptic serotonin. This progresses from side effects through to toxicity; the concept emphasizes that it is a form of poisoning, not an idiosyncratic reaction. Observations of the degree of ST precipitated by overdoses of different classes of drugs can elucidate mechanisms and potency of drug actions. There is now sufficient pharmacological data on some drugs to enable a prediction of which ones will be at risk of precipitating ST, either by themselves or in combinations with other drugs. This indicates that some antidepressant drugs, presently thought to have serotonergic effects in animals, do not exhibit such effects in humans. Mirtazapine is unable to precipitate serotonin toxicity in overdose or to cause serotonin toxicity when mixed with monoamine oxidase inhibitors, and moclobemide is unable to precipitate serotonin toxicity in overdose. Tricyclic antidepressants (other than clomipramine and imipramine) do not precipitate serotonin toxicity and might not elevate serotonin or have a dual action, as has been assumed.

Alpha-methyldopa in schizophrenia.

The dopamine hypothesis of schizophrenia suggests that there is a functional excess of dopaminergic activity within the brain of schizophrenics. Alpha-methyldopa interferes with dopaminergic transmission in the central nervous system. We report a case of a schizophrenic in whom, after an overdose of alpha-methyldopa, there was a dramatic and apparently complete resolution of psychotic symptomatology, followed after a few weeks by a sudden return of psychosis.

Human platelet phenolsulphotransferase: separate control of the two forms and activity range in depressive illness.

Human phenolsulphotransferase exists in two forms, one specific for dopamine and tyramine, termed "M" and one for phenol, termed "P". In this study we have shown that these two forms are under separate control by correlating their activities in different individuals using different substrates. There was a highly significant correlation between the activities with dopamine, p-tyramine and 4-hydroxy-3-methoxyphenylglycol, but no significant correlation between the activities with any of these three substrates and that with phenol. Neither age nor sex had any effect on platelet phenolsulphotransferase "M" or "P" activities. Nor was there any significant correlation between platelet monoamine oxidase activity and phenolsulphotransferase "M" or "P" activities. Human platelet phenolsulphotransferase "M" was found to be unstable at temperatures above 35 degree C and it lost substantial activity when stored deep frozen in isotonic saline. However it was stable for up to four months when stored in isotonic sucrose or 10 mmol/l phosphate buffer (pH 7.4). Phenolsulphotransferase "M" amd "P" activities were measured in platelets from depressed patients of a diagnostic type characterized by low output of tyramine-O-sulphate after oral tyramine loading but their enzyme activities were not different from those in two control groups.

Serotonin syndrome: history and risk.

This review focuses on the history of investigations into the behavioural reaction resulting from excess stimulation of post-synaptic 5-hydroxytryptamine receptors and the relative risk of this occurring with different combinations of drugs. Other aspects, particularly treatment with 5-hydroxytryptamine receptor antagonists, are reviewed in a recent separate paper [44]. The first human case was in 1955 and animal work had defined the characteristic features by 1958, and established they were lessened by chlorpromazine. Substantial evidence of a 'dose-effect' relationship existed by 1984. The relative risk with different drug combinations is assessed from available evidence and argued to be strongly associated with the degree of elevation of 5-hydroxytryptamine, which is greatest following combinations of irreversible inhibitors of monoamine oxidase A and B with potent serotonin reuptake inhibitors. The various serotonergic drugs that may be implicated in serotonin syndrome are tabulated and discussed in relation to the relative risk. It is suggested that the proposed 'diagnostic criteria' for serotonin syndrome are inappropriate since there is a continuous spectrum from side effects to toxicity. The term 'serotonin syndrome' may encourage the presumption that it is an idiosyncratic response, as neuroleptic malignant syndrome is usually considered to be. The terms 'toxic serotomimetic reaction' or 'toxic serotonin syndrome' may be preferable alternatives. The differences between serotonin syndrome and neuroleptic malignant syndrome are highlighted with examples from difficult or questionable cases in the recent literature. It is proposed that more systematic national collection of toxicity data is essential in order to quantify the relative risk of serotonin syndrome with various combinations of serotonergic drugs.

The serotonin syndrome and its treatment.

Serotonin syndrome is caused by drug induced excess of intrasynaptic 5-hydroxytryptamine. The clinical manifestations are mediated by the action of 5-hydroxytryptamine on various subtypes of serotonin receptors. There is no effective drug treatment established. The history of the treatment of serotonin syndrome with 5-hydroxytryptamine blocking drugs is reviewed. A literature search was undertaken using both Medline and a manual search of the older literature. Reports of cases treated with the 5-HT2 blockers cyproheptadine and chlorpromazine were identified and analysed. There is some evidence suggesting the efficacy of chlorpromazine and cyproheptadine in the treatment of serotonin syndrome. The evidence for cyproheptadine is less substantial, perhaps because the dose of cyproheptadine necessary to ensure blockade of brain 5-HT2 receptors is 20-30 mg, which is higher than that used in the cases reported to date (4-16 mg).

Physiological and hormonal responses of lambs repeatedly implanted with zeranol and provided two levels of feed intake.

Forty crossbred wethers (average weight 30 kg) were implanted with zeranol (12 mg) at 30-d intervals and fed at two levels of intake in a 2 x 2 factorial arrangement of treatments to determine performance, carcass and bone characteristics, blood metabolites, and hormones. Restricted lambs were fed to gain one-half the BW gained by lambs with ad libitum feed access. Lambs with ad libitum and restricted access to feed were slaughtered after 98 and 154 d, respectively. Zeranol increased ADG (P = .047; 20%), gain to feed (P = .023; 17%), metacarpal length (P = .004; 6%) and weight (P = .013; 13%), and tended to increase carcass crude protein gain (P = .106; 63%) while reducing kidney pelvic fat (P = .001; 33%) and dressing percentage (P = .038; 3%). Restricted feed intake increased the percentage of carcass ash and metacarpal length and weight by 27% (P = .048), 5% (P = .006), and 10% (P = .045), respectively, while reducing quality grade scores (P = .022; 5%), gain to feed (P = .001; 49%), longissimus muscle area (P = .001; 28%), the percentage of kidney pelvic fat (P = .033; 13%), and daily fat gain (P = .001; 54%). Zeranol increased pituitary weight (P = .001; 166%), plasma glucose (P = .036; 13%), mean serum growth hormone (GH; P = .011; 52%), baseline GH (P = .048; 34%), GH pulse amplitude (P = .003; 59%), and IGF-I (P = .001; 53%) concentrations. The results indicate that continuous administration of zeranol from 60 d of age to slaughter increases GH release, which directs nutrient utilization such that a carcass with more desirable lean and fat deposition patterns is obtained when nutrient availability is adequate.