Range of Neurological Signs in Cynomolgus Monkeys After Intrathecal Bolus Administration of Antisense Oligonucleotides.

Intrathecal (IT) dosing (ie, injection into the subarachnoidal space at the lumbar region) is a common route of administration in cynomolgus monkey preclinical safety studies conducted for antisense oligonucleotides (ASO) that target central nervous system diseases. Herein we report on neurological signs that have been observed in 28 IT studies conducted in 1,016 cynomolgus monkeys. Neurological signs were classified into 5 groups: (1) A nonadverse transient absence of lower spinal reflexes. This observation occurred at low incidence in nontreated animals and in those that were injected artificial cerebrospinal fluid. The incidence increased in animals that were injected an ASO. Reflexes were present again at 24 hours or 48 hours after dosing. The incidence appeared to increase with dose. (2) Test-article-related adverse muscle tremor or muscle spasticity occurring during the injection procedure or immediately thereafter. In one-third of animals this finding responded to treatment with diazepam, in two-third it required euthanasia. (3) Neurological findings occurring between 30 minutes and 4 hours after dosing were characterized by any combination of ataxia, paresis, nystagmus, urinary incontinence, or muscle tremor. Those conditions either spontaneously resolved or they slowly worsened, eventually resulting in a poor general condition. (4) Neurological findings due to spinal cord injury were characterized by rapidly progressing paralysis of hind limbs. Magnetic resonance imaging revealed a focal hyperintense lesion, indicative of spinal cord necrosis. (5) Test-article-related adverse hind limb paresis or paralysis that occurred between 2 and 18 days after dosing. Those findings were rare and resulted in a poor general condition requiring euthanasia.

Tuberculosis drug safety and pharmacovigilance in health system of Kosova: A cross-sectional analysis.

BACKGROUND: Tuberculosis (TB) remains a significant worldwide social and life-threatening epidemiological problem. Because this disease requires multiple drug treatment and prolonged therapy for several months, followed by a high probability of adverse effects (AEs), we assessed AE monitoring for anti-TB drugs in the Health Care System of Kosova. METHODS: This survey was a cross-sectional analysis performed at the primary, secondary and tertiary health care levels in Kosova. We included 930 registered tuberculosis patients within three levels of this health system in our study. Furthermore, we interviewed 62 physicians and 71 nurses at TB health facilities. Data were collected from official TB registers and personal contact with patients for 12 months. RESULTS: The representative age group was 19 to 29 years (30.49%), followed by a group of patients aged >60 years (23.23%). Among 930 patients treated with TB drugs, the total incidence of adverse AEs was 29.03%. Female TB patients had a higher rate of AEs than did male patients (33.56% vs 28.84%, respectively). The highest incidence of registered AEs was recorded in the gastrointestinal system (270, 80.83%), followed by the central nervous system (CNS, 7.50%) and was lower in other organ systems. The reporting of anti-TB drug effects by medical staff (TB medical doctor and TB medical nurse) at different levels of TB medical settings occurred among 62.90% of medical doctors and 81.69% of nurses. Only 53.23% of medical doctors and 46.48% of nurses completed pharmacovigilance training. CONCLUSION: The pharmacovigilance approach in Health System of Kosova is not comprehensible and not systematic. The relatively low incidence of AEs among TB patients is due under reporting of these by medical staff. The knowledge, attitudes, and adherence of medical staff reveal low awareness for pharmacovigilance activities, and this concern should be addressed to reinforce this important issue for the safe treatment of TB patients.

Evaluating amino acids as protectants against ß-N-methylamino-l-alanine-induced developmental neurotoxicity in a rat model.

With accumulating evidence that supports the role of ß-N-methylamino-l-alanine (BMAA) in neurodegeneration, it is necessary to elucidate the mechanisms and modes of BMAA toxicity so as to facilitate the search for potential preventative/therapeutic strategies. Daily supplementation with l-serine was suggested as a possible therapy to treat BMAA-induced neurotoxicity, based on the hypothesized mechanism of BMAA misincorporation into proteins for l-serine. As an alternative to misincorporation, it was hypothesized that BMAA toxicity may, in part, be due to its high affinity for associating with hydroxyl group-containing amino acids, and that a dietary excess of the hydroxyl-containing l-serine might offer protection by binding to BMAA and reducing its toxicity. Additionally, l-serine can also reduce the uptake of BMAA into human cells by competitive uptake at ASCT2, and l-phenylalanine, by competitive uptake at LAT1, and l-alanine, by competitive uptake at SNAT2, can also reduce BMAA uptake into human cells. The aim of this study was therefore to determine the protective value of l-serine, l-phenylalanine and l-alanine in reducing the effects of neonatal exposure to BMAA in a Sprague Dawley rat model. Pre-treatment with l-phenylalanine reduced the observed behavioral abnormalities and neuropathologies by 60-70% in most cases. l-serine was also effective in reducing some of the behavioral abnormalities and neuropathologies, most markedly spinal cord neuronal loss. However, the protective effect of l-serine was obfuscated by neuropathies that were observed in l-serine-treated control male rats. l-alanine had no effect in protecting against BMAA-induced neurotoxicity, suggesting that competitive amino acid uptake plays a minor role in protecting against BMAA-induced neurotoxicity.

Hyperbaric medicine simulation education curriculum: CNS toxicity during Treatment Table 6 and intubated ICU patient with mucous plugging.

INTRODUCTION/BACKGROUND: The incidence of complications and number of critically ill patients in hyperbaric medicine is relatively low [1]. This poses a challenge to those tasked with educating trainees as well as maintaining the skills of staff. Hyperbaric medicine fellows may not be exposed to critical patient scenarios or complications of hyperbaric medicine during a one-year fellowship. Additional staff may be unfamiliar with these situations as well. The purpose of hyperbaric simulation curriculum is to train health care providers for rare situations. To our knowledge, this hyperbaric simulation curriculum is the first published use of simulation education in the specialty of undersea and hyperbaric medicine. MATERIALS AND METHODS: Two simulation cases have been developed that involve a patient with oxygen toxicity during hyperbaric treatment as well as an ICU patient with mucous plugging. RESULTS: Medical training simulations are an effective method of teaching content and training multiple roles in Undersea and Hyperbaric Medicine. SUMMARY/CONCLUSIONS: A hyperbaric simulation curriculum is an achievable educational initiative that is able to train multiple team members simultaneously in situations that they may not encounter on a regular basis. We believe that this could be easily exported to otherinstitutions for further education.

Calculated risk of pulmonary and central nervous system oxygen toxicity: a toxicity index derived from the power equation.

BACKGROUND: The risk of oxygen toxicity has become a prominent issue due to the increasingly widespread administration of hyperbaric oxygen (HBO) therapy, as well as the expansion of diving techniques to include oxygen-enriched gas mixtures and technical diving. However, current methods used to calculate the cumulative risk of oxygen toxicity during an HBO exposure i.e., the unit pulmonary toxic dose concept, and the safe boundaries for central nervous system oxygen toxicity (CNS-OT), are based on a simple linear relationship with an inspired partial pressure of oxygen (PO2) and are not supported by recent data. METHODS: The power equation: Toxicity Index = t2 × PO2c, where t represents time and c represents the power term, was derived from the chemical reactions producing reactive oxygen species or reactive nitrogen species. RESULTS: The toxicity index was shown to have a good predictive capability using PO2 with a power c of 6.8 for CNS-OT and 4.57 for pulmonary oxygen toxicity. The pulmonary oxygen toxicity index (PO2 in atmospheres absolute, time in h) should not exceed 250. The CNS-OT index (PO2 in atmospheres absolute, time in min) should not exceed 26,108 for a 1% risk. CONCLUSION: The limited use of this toxicity index in the diving community, after more than a decade since its publication in the literature, establishes the need for a handy, user-friendly implementation of the power equation.

Iron and manganese-related CNS toxicity: mechanisms, diagnosis and treatment.

INTRODUCTION: Iron (Fe) and manganese (Mn) are essential nutrients for humans. They act as cofactors for a variety of enzymes. In the central nervous system (CNS), these two metals are involved in diverse neurological activities. Dyshomeostasis may interfere with the critical enzymatic activities, hence altering the neurophysiological status and resulting in neurological diseases. Areas covered: In this review, the authors cover the molecular mechanisms of Fe/Mn-induced toxicity and neurological diseases, as well as the diagnosis and potential treatment. Given that both Fe and Mn are abundant in the earth crust, nutritional deficiency is rare. In this review the authors focus on the neurological disorders associated with Mn and Fe overload. Expert commentary: Oxidative stress and mitochondrial dysfunction are the primary molecular mechanism that mediates Fe/Mn-induced neurotoxicity. Although increased Fe or Mn concentrations have been found in brain of patients, it remains controversial whether the elevated metal amounts are the primary cause or secondary consequence of neurological diseases. Currently, treatments are far from satisfactory, although chelation therapy can significantly decrease brain Fe and Mn levels. Studies to determine the primary cause and establish the molecular mechanism of toxicity may help to adapt more comprehensive and satisfactory treatments in the future.

The transition from day-to-night activity is a risk factor for the development of CNS oxygen toxicity in the diurnal fat sand rat (Psammomys obesus).

Performance and safety are impaired in employees engaged in shift work. Combat divers who use closed-circuit oxygen diving apparatus undergo part of their training during the night hours. The greatest risk involved in diving with such apparatus is the development of central nervous system oxygen toxicity (CNS-OT). We investigated whether the switch from day-to-night activity may be a risk factor for the development of CNS-OT using a diurnal animal model, the fat sand rat (Psammomys obesus). Animals were kept on a 12:12 light-dark schedule (6 a.m. to 6 p.m. at 500 lx). The study included two groups: (1) Control group: animals were kept awake and active during the day, between 09:00 and 15:00. (2) Experimental group: animals were kept awake and active during the night, between 21:00 and 03:00, when they were exposed to dim light in order to simulate the conditions prevalent during combat diver training. This continued for a period of 3 weeks, 5 days a week. On completion of this phase, 6-sulphatoxymelatonin (6-SMT) levels in urine were determined over a period of 24 h. Animals were then exposed to hyperbaric oxygen (HBO). To investigate the effect of acute melatonin administration, melatonin (50 mg/kg) or its vehicle was administered to the animals in both groups 20 min prior to HBO exposure. After the exposure, the activity of superoxide dismutase, catalase and glutathione peroxidase was measured, as were the levels of neuronal nitric oxide synthase (nNOS) and overall nitrotyrosylation in the cortex and hippocampus. Latency to CNS-OT was significantly reduced after the transition from day-to-night activity. This was associated with alterations in the level of melatonin metabolites secreted in the urine. Acute melatonin administration had no effect on latency to CNS-OT in either of the groups. Nevertheless, the activity of superoxide dismutase and catalase, as well as nitrotyrosine and nNOS levels, were altered in the hippocampus following melatonin administration. On the basis of these results, we suggest that a switch from diurnal to nocturnal activity may represent an additional risk factor for the development of CNS-OT. Utilizing a diurnal animal model may contribute to our understanding of the heightened risk of developing CNS-OT when diving with closed-circuit oxygen apparatus at night.

Drug discrimination: A versatile tool for characterization of CNS safety pharmacology and potential for drug abuse.

Drug discrimination studies for assessment of psychoactive properties of drugs in safety pharmacology and drug abuse and drug dependence potential evaluation have traditionally been focused on testing novel compounds against standard drugs for which drug abuse has been documented, e.g. opioids, CNS stimulants, cannabinoids etc. (e.g. Swedberg & Giarola, 2015), and results are interpreted such that the extent to which the test drug causes discriminative effects similar to those of the standard training drug, the test drug would be further characterized as a potential drug of abuse. Regulatory guidance for preclinical assessment of abuse liability by the European Medicines Agency (EMA, 2006), the U.S. Food and Drug Administration (FDA, 2010), the International Conference of Harmonization (ICH, 2009), and the Japanese Ministry of Health Education and Welfare (MHLW, 1994) detail that compounds with central nervous system (CNS) activity, whether by design or not, need abuse and dependence liability assessment. Therefore, drugs with peripheral targets and a potential to enter the CNS, as parent or metabolite, are also within scope (see Swedberg, 2013, for a recent review and strategy). Compounds with novel mechanisms of action present a special challenge due to unknown abuse potential, and should be carefully assessed against defined risk criteria. Apart from compounds sharing mechanisms of action with known drugs of abuse, compounds intended for indications currently treated with drugs with potential for abuse and or dependence are also within scope, regardless of mechanism of action. Examples of such compounds are analgesics, anxiolytics, cognition enhancers, appetite control drugs, sleep control drugs and drugs for psychiatric indications. Recent results (Swedberg et al., 2014; Swedberg & Raboisson, 2014; Swedberg, 2015) on the metabotropic glutamate receptor type 5 (mGluR5) antagonists demonstrate that compounds causing hallucinatory effects in humans did not exhibit clear discriminative effects when tested against classical drugs of abuse in drug discrimination studies, and were not self-administered by rats. However, these compounds did cause salient discriminative effects of their own in animals trained to discriminate them from no drug. Therefore, from a safety pharmacology perspective, novel compounds that do not cause discriminative effects similar to classical drugs of abuse, may still cause psychoactive effects in humans and carry the potential to maintain drug abuse, suggesting that proactive investigation of drug abuse potential is warranted (Swedberg, 2013). These and other findings will be discussed, and the application of drug discrimination procedures beyond the typical standard application of testing novel compounds against known and well characterized reference drugs will be addressed.

CNS safety pharmacology: A focus on cognitive functions.

INTRODUCTION: The guidelines from different agencies do not include studies on cognitive functions as part of safety pharmacology. This is unfortunate as it seems important to verify that drugs entering into the central nervous system (CNS) are devoid of detrimental effects on cognition. Our aim is to show examples on how an evaluation of unwanted effects of drugs on cognitive functions may be included in preclinical studies. Rather than a review of the scientific context, the present text is an appeal for a wider consideration of cognition as a safety pharmacology endpoint. METHODS: The following procedures provide an index of the ability of substances to induce cognitive deficits in rodents. In the passive avoidance (PA) test, rats receiving an electric shock show on a later occasion an avoidance of the shock-associated environment. In the social recognition (SR) test, rats recognize familiar congeners. In the Morris water maze (MWM) test, rats placed into a tank containing water learn to find an invisible escape platform using extra-maze visual cues. In the delayed alternation (DA) test, rats placed in a Skinner box learn to alternate their pressing behavior between two levers in order to obtain food rewards. In the operant reversal (OR) test, rats adapt their behavior following a change of the reinforcement rule. RESULTS: Standard reference agents were used to confirm that the different assays were able to detect pharmacologically induced cognitive impairments. Diazepam decreased associative memory performances in the PA test. MK-801-induced memory deficits in SR. Haloperidol increased escape latencies in the MWM test. Scopolamine decreased the number of correct responses in the DA test, and nicotine decreased the number of correct responses in the OR test. The relationship between the doses administered and the effects observed was also evaluated. DISCUSSION: Cognitive assays may provide utility in determining potential undesirable effects or discharging perceived risks with novel CNS drugs under development.

Long Chain Omega-3 Polyunsaturated Fatty Acid Supplementation Alleviates Doxorubicin-Induced Depressive-Like Behaviors and Neurotoxicity in Rats: Involvement of Oxidative Stress and Neuroinflammation.

Doxorubicin (DOX) is a chemotherapeutic agent widely used in human malignancies. Its long-term use can cause neurobiological side-effects associated with depression. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), the essential fatty acids found in fish oil, possess neuroprotecitve and antidepressant activities. Thus, the aim of this study was to explore the potential protective effects of ω-3 PUFAs against DOX-induced behavioral changes and neurotoxicity. ω-3 PUFAs were given daily by gavage (1.5 g/kg) over three weeks starting seven days before DOX administration (2.5 mg/kg). Open-field test (OFT) and forced swimming test (FST) were conducted to assess exploratory activity and despair behavior, respectively. Our data showed that ω-3 PUFAs supplementation significantly mitigated the behavioral changes induced by DOX. ω-3 PUFAs pretreatment also alleviated the DOX-induced neural apoptosis. Meanwhile, ω-3 PUFAs treatment ameliorated DOX-induced oxidative stress in the prefrontal cortex and hippocampus. Additionally, gene expression of pro-inflammatory cytokines, including IL-1ß, IL-6, and TNF-α, and the protein levels of NF-κB and iNOS were significantly increased in brain tissues of DOX-treated group, whereas ω-3 PUFAs supplementation significantly attenuated DOX-induced neuroinflammation. In conclusion, ω-3 PUFAs can effectively protect against DOX-induced depressive-like behaviors, and the mechanisms underlying the neuroprotective effect are potentially associated with its anti-oxidant, anti-inflammatory, and anti-apoptotic properties.

The emerging role of in vitro electrophysiological methods in CNS safety pharmacology.

Adverse CNS effects account for a sizeable proportion of all drug attrition cases. These adverse CNS effects are mediated predominately by off-target drug activity on neuronal ion-channels, receptors, transporters and enzymes - altering neuronal function and network communication. In response to these concerns, there is growing support within the pharmaceutical industry for the requirement to perform more comprehensive CNS safety testing prior to first-in-human trials. Accordingly, CNS safety pharmacology commonly integrates several in vitro assay methods for screening neuronal targets in order to properly assess therapeutic safety. One essential assay method is the in vitro electrophysiological technique - the 'gold standard' ion channel assay. The in vitro electrophysiological method is a useful technique, amenable to a variety of different tissues and cell configurations, capable of assessing minute changes in ion channel activity from the level of a single receptor to a complex neuronal network. Recent advances in automated technology have further expanded the usefulness of in vitro electrophysiological methods into the realm of high-throughput, addressing the bottleneck imposed by the manual conduct of the technique. However, despite a large range of applications, manual and automated in vitro electrophysiological techniques have had a slow penetrance into the field of safety pharmacology. Nevertheless, developments in throughput capabilities and in vivo applicability have led to a renewed interest in in vitro electrophysiological techniques that, when complimented by more traditional safety pharmacology methods, often increase the preclinical predictability of potential CNS liabilities.

Oxygen toxicity.

Oxygen is one of the most widely available and used therapeutic agents in the world. However, it is all too easy forget that oxygen is a prescribable drug with specific biochemical and physiologic actions, a distinct range of effective doses and well-defined adverse effects at high doses. The human body is affected in different ways depending on the type of exposure. Short exposures to high partial pressures at greater than atmospheric pressure lead to central nervous system toxicity, most commonly seen in divers or in hyperbaric oxygen therapy. Pulmonary and ocular toxicity results from longer exposure to elevated oxygen levels at normal atmospheric pressure.

Does long term supplementation of vitamin E cause detrimental effects on the central nervous system? Morphological and histological study in experimental male Wistar rats.

AIM: Aging is attributed to neuronal loss associated with increased oxidative stress. Vitamin E, and in particular, tocotrienol are potent antioxidants, which have been shown to be neuroprotective. The main aim of the present study was to observe the effect of long term intake of vitamin E in the form of tocotrienol rich fraction (TRF) and refined, bleached, deodorized palm olein (RBDPO) on the brain of experimental rats. MATERIALS AND METHODS: Thirty male Wistar rats aged 3 months were either supplemented with TRF (dose of 200 mg/kg body weight), RBDPO (dose of 1 ml/kg body weight) or distilled water, continuously for 8 months. The animals were then examined in vivo for clinical magnetic resonance imaging (MRI) studies before being sacrificed. The brain was extracted, measured and studied for histological changes. RESULTS: The magnetic resonance imaging (MRI) scan of the lateral ventricle, cortical thickness of cingulate gyrus and hippocampus size did not show any significant changes in all three groups. The brain weight, length and width as well as histological sections of the brain showed no significant changes between the groups. CONCLUSION: It is thereby concluded that chronic consumption of vitamin E was not detrimental to the central nervous system.

[Central nervous system complications in patients undergoing cytotoxic chemotherapy and targeted therapies]. / Complications neurologiques centrales des chimiothérapies cytotoxiques et des thérapies ciblées.

Anti-cancer treatments (cytotoxic chemotherapies, targeted therapies and hormonotherapies) are known to induce early and delayed neurological toxicities. Acute encephalopathies and posterior reversible encephalopathies are better known and described, physiopathological hypotheses are emerging. It is difficult to discriminate what drug is causing the symptoms in patients treated with multiple cytotoxic drugs. Methotrexate and ifosfamide are responsible for acute encephalopathies. L-asparaginase and methotrexate or targeted therapies may induce cerebrovascular complications. As life expectancy increases and more complex regimen including innovative targeted therapies are developed, new toxicity profiles can be expected. To be able to provide an early diagnosis, prevention, and treatment (when existing) of these pathologies remains a tremendous challenge that would allow a good quality of life with social and professional life after their cancer is cured.

Concurrent ivermectin and Solanum spp. toxicosis in a herd of horses.

BACKGROUND: Representatives from a herd of horses with acute onset of neurologic signs after administration of ivermectin presented for evaluation and treatment. OBJECTIVES: Describe clinical signs of horses intoxicated by ingestion of Solanum sp. and administered ivermectin. ANIMALS: Six of 11 affected unrelated horses presented for evaluation and treatment. The remaining 5 affected horses were treated at the farm. Four additional horses, housed separately, were unaffected. METHODS: Case series is presented. Serum ivermectin concentrations were evaluated in the 6 hospitalized horses. The remnants of the tubes of ivermectin paste were analyzed for ivermectin concentration. The hay fed to the affected horses was analyzed for the presence of toxic plants. RESULTS: Serum ivermectin concentrations were higher than expected, given the dosage of ivermectin administered. The ivermectin concentration remaining in the administration tubes did not exceed specifications. The hay was heavily contaminated by 2 Solanum species. All horses returned to normal neurologic function with supportive care. CONCLUSIONS AND CLINICAL IMPORTANCE: Horses might exhibit signs of ivermectin toxicity after appropriate dosing of the drug if they concurrently consume toxic plants of the Solanum family.

Nervous system disruption and concomitant behavioral abnormality in early hatched pufferfish larvae exposed to heavy oil.

BACKGROUND AND OBJECTIVE: Spills of heavy oil (HO) over the oceans have been proven to have an adverse effect on marine life. It has been hypothesized that exposure of early larvae of sinking eggs to HO leads largely to normal morphology, whereas abnormal organization of the developing neural scaffold is likely to be found. HO-induced disruption of the nervous system, which controls animal behavior, may in turn cause abnormalities in the swimming behavior of hatched larvae. To clarify the toxicological effects of HO, we performed exposure experiments and morphological and behavioral analyses in pufferfish (Takifugu rubripes) larvae. EXPERIMENTAL PROCEDURE: Fertilized eggs of pufferfish were exposed to 50 mg/L of HO for 8 days and transferred to fresh seawater before hatching. The hatched larvae were observed for their swimming behavior, morphological appearance, and construction of muscles and nervous system. RESULTS AND DISCUSSION: In HO-exposed larvae, we did not detect any anomaly of body morphology. However, they showed an abnormal swimming pattern and disorganized midbrain, a higher center controlling movement. Our results suggest that HO-exposed fishes suffer developmental disorder of the brain that triggers an abnormal swimming behavior and that HO may be selectively toxic to the brain and cause physical disability throughout the life span of these fishes.

Is peri-articular multimodal drug infiltration in knee arthroplasty safe when used in conjunction with autologous retransfusion drains?

INTRODUCTION: Adequate peri-operative analgesia following total knee arthroplasty (TKA) promotes earlier rehabilitation but remains problematic because of the drug side-effects. Peri-articular multimodal drug infiltration (PMDI) has been developed as an alternative strategy to avoid such complications. Autologous retransfusion drains reduce the need for peri-operative allogenic blood transfusions and the consequent risk. There is a theoretical risk of local anaesthesia toxicity when these systems are used concurrently. We performed a review of current practice to quantify this risk. PATIENTS AND METHODS: A series of 10 patients undergoing TKA by the senior author (CAB) had drain fluid analysed for the concentration of ropivacaine. At the same time, the patients completed a questionnaire to establish the presence of ropivacaine-induced side-effects. RESULTS: The ropivacaine level in the retransfusion blood was less than 10 mg in all patients. This concentration was a factor of 6 below the published safe level. Three patients had minor neurological disturbances which recovered spontaneously and quickly. There were no cases of significant cardiovascular compromise. CONCLUSIONS: The theoretical risk of local anaesthesia toxicity when these systems are used together is negligible and we conclude that peri-articular multimodal drug infiltration is safe in conjunction with the use of autotransfusion drains.

Low-level hydrogen sulfide and central nervous system dysfunction.

Forty-nine adults living in Lovington, Tatum, and Artesia, the sour gas/oil sector of Southeastern New Mexico, were tested for neurobehavioral impairment. Contributing hydrogen sulfide were (1) an anaerobic sewage plant; (2) two oil refineries; (3) natural gas/oil wells and (4) a cheese-manufacturing plant and its waste lagoons. Comparisons were to unexposed Wickenburg, Arizona, adults. Neurobehavioral functions were measured in 26 Lovington adults including 23 people from Tatum and Artesia, New Mexico, and 42 unexposed Arizona people. Participants completed questionnaires including chemical exposures, symptom frequencies and the Profile of Mood States. Measurements included balance, reaction time, color discrimination, blink reflex, visual fields, grip strength, hearing, vibration, problem solving, verbal recall, long-term memory, peg placement, trail making and fingertip number writing errors (FTNWE). Average numbers of abnormalities and test scores were adjusted for age, gender, educational level, height and weight, expressed as percent predicted (% pred) and compared by analysis of variance (ANOVA). Ages and educational attainment of the three groups were not statistically significantly different (ssd). Mean values of Lovington residents were ssd from the unexposed Arizona people for simple and choice reaction times, balance with eyes open and closed, visual field score, hearing and grip strength. Culture Fair, digit symbol substitution, vocabulary, verbal recall, peg placement, trail making A and B, FTNWE, information, picture completion and similarities were also ssd. The Lovington adults who averaged 11.8 abnormalities were ssd from, Tatum-Artesia adults who had 3.6 and from unexposed subjects with 2.0. Multiple source community hydrogen sulfide exposures impaired neurobehavioral functions.

Prediction of adverse drug reactions using decision tree modeling.

Drug safety is of great importance to public health. The detrimental effects of drugs not only limit their application but also cause suffering in individual patients and evoke distrust of pharmacotherapy. For the purpose of identifying drugs that could be suspected of causing adverse reactions, we present a structure-activity relationship analysis of adverse drug reactions (ADRs) in the central nervous system (CNS), liver, and kidney, and also of allergic reactions, for a broad variety of drugs (n = 507) from the Swiss drug registry. Using decision tree induction, a machine learning method, we determined the chemical, physical, and structural properties of compounds that predispose them to causing ADRs. The models had high predictive accuracies (78.9-90.2%) for allergic, renal, CNS, and hepatic ADRs. We show the feasibility of predicting complex end-organ effects using simple models that involve no expensive computations and that can be used (i) in the selection of the compound during the drug discovery stage, (ii) to understand how drugs interact with the target organ systems, and (iii) for generating alerts in postmarketing drug surveillance and pharmacovigilance.