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.

Fatal methylene blue associated serotonin toxicity.

This is the first report of a fatal outcome from serotonin toxicity, precipitated by an interaction between methylene blue and venlafaxine. Methylene blue-associated serotonin toxicity has been described before but usually as mild toxicity. Its presentation after general anaesthesia may be atypical and therefore more difficult to diagnose. However, the syndrome is completely preventable if serotonin re-uptake inhibiting agents are stopped beforehand.

CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity.

Methylene blue has only recently been noted to cause severe central nervous system toxicity. Methylene blue is used for various conditions, including, intravenously, in methemoglobinemia, vasoplegia and as an aid to parathyroidectomy (at doses of 1-7.5 mg kg(-1)). This review of the current evidence concludes that 13 of 14 of the reported cases of CNS toxicity were serotonin toxicity that met the Hunter Serotonin Toxicity Criteria. That has important preventative and treatment implications. Serotonin toxicity is precipitated by the monoamine oxidase inhibitor (MAOI) property of methylene blue interacting with serotonin reuptake inhibitors. Serotonin toxicity is reviewed, using the lessons inherent in the methylene blue story and experience, to illustrate how the mechanisms and potency of serotonergic drugs interact to determine severity. Recent human data showed that an intravenous dose of only 0.75 mg kg(-1) of methylene blue produced a peak plasma concentration of 500 ng ml(-1) (1.6 µM), indicating that the concentration in the central nervous system reaches a level that inhibits monoamine oxidase A. That is consonant with the actual occurrence of severe serotonin toxicity in humans at the dose of only 1 mg kg(-1). It seems that all proposed uses of methylene blue entail levels that block monoamine oxidase, so cessation of serotonin reuptake inhibitors should be very carefully considered before using methylene blue.

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.

Risk of severe serotonin toxicity following co-administration of methylene blue and serotonin reuptake inhibitors: an update on a case report of post-operative delirium.

In a previous case report, published in this journal, we described a postoperative delirium in a patient during recovery from parathyroidectomy. We noted that the delirium resembled serotonin toxicity and that the patient had been taking paroxetine until 2 days before surgery. We offered several tentative explanations for this event, including an adverse interaction between paroxetine and other agent(s) used in the course of the anaesthesia. Recent developments in characterisation of serotonin toxicity have prompted us to re-examine the clinical details surrounding this life-threatening event. It is now known to be important that the patient was given methylene blue, pre-operatively, to enable visualisation of the parathyroid glands. Methylene blue has been found to be a potent inhibitor of monoamine oxidase (MAO), and several cases of serotonin toxicity have been reported recently following its administration. All these cases are consistent with the well-known risk of serotonin toxicity when drugs that augment serotonergic transmission are given in combination with an MAO inhibitor. Methylene blue is used in a variety of surgical settings as well as for treatment of various types of hypotensive shock and methemoglobinaemia. It is also being studied for treatment of Alzheimer's disease and malaria. In this paper, we outline the pharmacology of methylene blue and the aetiology of serotonin toxicity to help prevent further unintentional co-administration of drugs that risk precipitating this life-threatening drug interaction.

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.