Review of toxicity and trends in the use of tiagabine as reported to US poison centers from 2000 to 2012.

BACKGROUND: Tiagabine is a novel antiepileptic that acts by increasing synaptic and extracellular gamma-aminobutyric acid concentrations. Information concerning overdose of tiagabine is limited. After introduction, an increasing number of off-label uses suggested that tiagabine use would increase. However in 2005 and 2008, warnings from the Food and Drug Administration (FDA) were issued on the risk of seizures in non-epileptic and increased suicide ideation. We evaluated the temporal trends associated with these two warnings as well as clinical outcomes from tiagabine overdose. METHOD: A retrospective review of all single substance tiagabine exposures in National Poison Data System (NPDS) from 2000 to 2012. RESULTS: A total of 2147 patients had ingested tiagabine, with a mean of 165 year(-1). This was disproportionally distributed, with a steep rise leading up to 2004 (max 559 year(-1)) and then a significant decline (p < 0.05) between 2005 and 2006. The number of cases reported to NPDS mirrored the sales of tiagabine. Clinical effects were predominantly neurological, with the most commonly reported effects being drowsiness (27%), agitation (19%), confusion (12%), seizures (11%), and tachycardia (10%). In all, 758 patients (35%) showed a major or moderate medical outcome, with no deaths reported. A disproportionate share of the major outcomes was in the suicide attempt group (73%). The majority of patients (75%) were treated in a health-care facility (HCF). CONCLUSIONS: The HCF usage is likely due to high rate of symptomatic patients (59%) and the large proportion of suicide attempt cases. The frequency of tiagabine cases in NPDS mirrored pharmaceutical sales, with steep declines temporally related to the 2005 FDA warning.

Massive lindane overdose with toxicokinetics analysis.

BACKGROUND: Lindane is a possible carcinogen with known teratogenicity and immunologic and neurotoxic properties. Despite reports of seizures, coma, and death associated with its use as well as banning of its environmental use by the Environmental Protection Agency (EPA), the US Food and Drug Administration (FDA) still allows treatment with lindane as a second-line scabicide and pediculicide. We present a case of a massive suicidal ingestion of lindane in which the patient survived the ingestion, though he did expire shortly thereafter from an unrelated cause pre-discharge. METHODS: Pharmacokinetic analysis of serum lindane concentrations was performed with Phoenix® WinNONLIN®. The estimated distribution half-life for lindane was 10.3 h, and the terminal half-life was 162.9 h, much longer than the previously reported terminal half-life of 25-36 h. Because of this long half-life, repeated lindane exposures may lead to accumulation of lindane in the tissues. RESULT: After overdose, toxicity may be delayed and full recovery may be prolonged.

Identification and determination of salicylic acid and salicyluric acid in urine of people not taking salicylate drugs.

BACKGROUND: Salicylic acid (SA) is present in the serum of people who have not taken salicylate drugs. Now we have examined the urine of these subjects and found that it contains SA and salicyluric acid (SU). We have established the identities of these phenolic acids and determined their concentrations. METHODS AND RESULTS: The acidic hydrophobic compounds of urine were separated using high-performance liquid chromatography (HPLC) and were detected and quantified electrochemically. Two approaches were used to establish the identity of SA and SU. First, the retention times (Rt) of the substances extracted and those of SA and SU were compared under two sets of chromatographic conditions; the Rt of the compounds suspected to be SA and SU and those of the authentic substances were very similar under both sets of conditions. Second, the unknown substances, isolated by HPLC, were treated with acetyl chloride in methanol and compared with the methyl esters of SA and SU by using gas chromatography-mass spectrometry; the unknown compounds after esterification had very similar mass spectra and gas chromatographic R, to those of methyl salicylate and methyl salicylurate. The median (n = 10) urinary concentration of SA was 0.56 micromol/L (range 0.07-0.89 micromol/L) and that of SU was 3.20 micromol/L (range 1.32-6.54 micromol/L). SA and its major urinary metabolite, SU, were found in the urine of all of the 10 people examined.

Programmed-life plastics from polyolefins: a new look at sustainability.

The term "sustainable" is often assumed to be synonymous with "renewable". However, polymers made from renewable natural resources are not necessarily eco-efficient. Cellulose-based polymers utilize more nonrenewable fossil fuels and are more polluting during manufacture than petro-based polymers. Sustainable polymers also have to be industrially acceptable, and although ultimate biodegradability in the natural environment is important, polymer-based products are required to biodegrade in a controlled way. Service life may be a year or more before the commencement of environmental degradation occurs. Many natural polymers such as rubber, lignin, and humus, like the synthetic polyolefins, biodegrade by an oxidative mechanism (oxo-biodegradation), and consequently much of nature's biological waste cannot satisfy the rapid mineralization criteria currently advocated by standards committees for synthetic polymers. Although biometric tests are more convenient to use than full composting tests, they are meaningless when applied to hydrocarbon polymers, whether natural or synthetic, since oxo-biodegradation is a slower process than hydro-biodegradation at ambient temperatures. Biodegradation standards currently proposed are unrealistic and will need to be modified on the basis of recent scientific evidence.

Salicylic acid in the serum of subjects not taking aspirin. Comparison of salicylic acid concentrations in the serum of vegetarians, non-vegetarians, and patients taking low dose aspirin.

AIMS: To determine serum salicylic acid concentrations in non-vegetarians and vegetarians not taking salicylate drugs, and to compare these concentrations with those found in patients taking aspirin, 75 mg daily. METHODS: Serum samples were obtained from vegetarians (n = 37) and non-vegetarians (n = 39) not taking salicylate drugs. Non-vegetarians and vegetarians were recruited from the community and from a Buddhist monastery, respectively, in Dumfries and Galloway, Scotland. Patients (n = 14) taking aspirin (75 mg daily) were recruited from the Dumfries diabetic clinic. Serum salicylic acid concentrations were determined using a high performance liquid chromatography method with electrochemical detection. RESULTS: Salicylic acid was detected in every serum sample analysed. Higher serum concentrations of salicylic acid were found in vegetarians than non-vegetarians: median concentrations of 0.11 (range, 0.04-2.47) micromol/litre and 0.07 (range, 0.02-0.20) micromol/litre, respectively; the median of the difference was 0.05 micromol/litre (95% confidence interval for difference, 0.03 to 0.08; p < 0.0001). The median serum concentration of salicylic acid in patients taking aspirin (75 mg daily) was 10.03 (range, 0.23-25.40) micromol/litre, which was significantly higher than that found in non-vegetarians and vegetarians. There was overlap in serum salicylic acid concentrations between the vegetarians and patients taking aspirin. CONCLUSIONS: Salicylic acid, a non-steroidal anti-inflammatory drug, is present in fruits and vegetables and is found in higher concentrations in vegetarians than non-vegetarians. This suggests that a diet rich in fruits and vegetables contributes to the presence of salicylic acid in vivo. There is overlap between the serum concentrations of salicylic acid in vegetarians and patients taking aspirin, 75 mg daily. These findings may explain, in part, the health promoting effects of dietary fruits and vegetables.

Salicylic acid in soups prepared from organically and non-organically grown vegetables.

BACKGROUND: Salicylic acid is a chemical signal in plants infected by pathogens and it is responsible for the anti-inflammatory action of aspirin. Patients who take aspirin have a reduced risk of developing atherosclerosis and colorectal cancer, both of these pathologies having an inflammatory component. Dietary salicylic acid may help to prevent these conditions. We wondered if foods made from organically-reared plants might have a higher content of salicylic acid than those made from non-organic plants, since the latter are more likely to be protected from infection by the application of pesticides. OBJECTIVE: To determine if organic vegetable soups have a higher salicylic acid content than non-organic vegetable soups. METHODS: The contents of salicylic acid in organic and non-organic vegetable soups purchased from supermarkets were determined. Salicylic acid was identified by varying the chromatographic conditions and comparing the retention times of the unknown substance in the extracts with salicylic acid; by treating extracts of the soups with salicylate hydroxylase; and by using GCMS. Salicylic acid was determined by using HPLC with electrochemical detection. RESULTS: Salicylic acid was present in all of the organic and most of the non-organic vegetable soups. The median contents of salicylic acid in the organic and non-organic vegetable soups were 117 (range, 8-1040) ng x g(-1) and 20 (range, 0-248) ng x g(-1) respectively. The organic soups had a significantly higher content of salicylic acid (p=0.0032 Mann Whitney U test), with a median difference of 59 ng g(-1) (95 % confidence interval, 18-117ng x g(-1)). CONCLUSIONS: Organic vegetable soups contained more salicylic acid than non-organic ones, suggesting that the vegetables and plants used to prepare them contained greater amounts of the phenolic acid than the corresponding non-organic ingredients. Consumption of organic foods may result in a greater intake of salicylic acid.

The identification of salicylates as normal constituents of serum: a link between diet and health?

AIM: To examine sera for the presence of salicylic acid and 2,3- and 2,5-dihydroxybenzoic acids (2,3- and 2,5-DHBA), in individuals not taking salicylate drugs. METHODS: Extracts of acidified serum samples were analysed by high performance liquid chromatography with electro-chemical detection. The chromatographic conditions were altered, and the retention times of the unknown compounds compared against authentic salicylic acid, 2,3-DHBA, and 2,5-DHBA. Serum samples (some spiked with salicylic acid) were incubated with salicylate hydroxylase and analyses undertaken. An extract of acidified serum was derivatised using N-methyl-N-trimethylsilyltrifluoroacetamide and the salicylic acid derivative identified by gas chromatography-mass spectrometry. RESULTS: Salicylic acid, 2,3-DHBA, and 2,5-DHBA were identified as being normal constituents of serum. CONCLUSIONS: Salicylic acid, 2,3-DHBA, and 2,5-DHBA possess anti-inflammatory properties. The finding that these compounds are present as normal constituents of serum, possibly arising from diet, raises important questions as to their role in the promotion of health.

Clinical and biochemical determinants of plasma lipid peroxide levels in type 2 diabetes.

The enhanced risk and increased severity of atheroma in diabetes is well recognized but, as yet, incompletely explained. A cross-sectional study of vascular disease risk factors in a group of type 2 diabetic patients from South West Scotland has revealed an association between glycaemic control, assessed by HbAl level and plasma lipid peroxides measured by a specific high-performance liquid chromatography method. Duration of diabetes appeared to be a subsidiary contributor to lipid peroxidation. We suggest this evidence supports the importance of glycaemic control in modulating glyco-oxidative mechanisms probably crucial to production of diabetic complications. Atherosclerosis prevention in diabetes may hinge on exemplary simultaneous control of both hyperglycaemia and hyperlipidaemia.

The Nithsdale Schizophrenia Surveys. XIV: Plasma lipid peroxide and serum vitamin E levels in patients with and without tardive dyskinesia, and in normal subjects.

BACKGROUND: Tardive dyskinesia (TD) may be mediated through free radical damage to neurons. Plasma lipid peroxide levels are a measure of radical damage to fats. Vitamin E is a free radical scavenger. METHOD: One hundred and twenty-eight schizophrenic patients were examined for TD using the Abnormal Involuntary Movements Scale. Blood samples were taken to measure plasma lipid peroxide, serum vitamin E and cholesterol, and vitamin E:cholesterol ratios. Twenty-four patients were also examined in October 1993, January 1994, and April 1994. Biochemical results were compared in 81 patients and 79 normal subjects. RESULTS: Patients with and without TD did not differ in median plasma lipid peroxide and serum vitamin E levels, or vitamin E:cholesterol ratios. Correlations between seasonal change scores in TD and biochemical measurements were low. Lipid peroxide levels were higher and vitamin E:cholesterol ratios lower in patients than in normal subjects. Vitamin E levels were lowest in in-patients and in those living in supported accommodation. CONCLUSIONS: The results do not support the hypothesis that TD is mediated through free radical damage to neurons, but suggest increased free radical activity in schizophrenia.

Veterans' psychiatric benefits: enter courts and attorneys.

In 1988, the Veterans Judicial Review Act (VJRA) was signed into law, ending more than a century of Congressional measures that kept veterans' benefits claims completely out of the appellate court system. Before this new law, any decision made by the Department of Veterans' Affairs (VA) about a veteran's claim was final, and there was no recourse for independent judgment of an appeal. The legislation modified the existing Board of Veterans Appeals (BVA) to enhance its independence from the Veterans' Administration and established a new Court of Veterans Appeals (CVA) with jurisdiction to review BVA decisions. Veterans' benefits proceedings have not only been insulated from the courts, they also have been undesirable to private attorneys, because since 1864 Congress has prohibited attorneys from charging more than $10 to advocate a VA disability claim. The new law allows attorneys to represent veterans before the CVA and receive appropriate remuneration. In 1991, the number of veterans was estimated at 26,897,000, and VA disability compensation programs spent $9.6 billion. Currently, there are about 2,179,000 veterans receiving service-connected monetary compensation; approximately 13.5 percent (293,200) have a primary psychiatric disability. The CVA is a specialized Article I court that has seven justices and sits in Washington, D.C. In its formative years, the Court has reached decisions that have had an impact on the veterans' psychiatric benefits examination process. Now more than ever, non-VA psychiatrists may be asked to offer probative opinions in veterans' benefits proceedings. The authors review VA psychiatric disability procedures and, using case examples, discuss both precedent decisions involving VA psychiatric claimants and the evolving standards of judicial review.

The Nithsdale schizophrenia surveys. IX: Akathisia, parkinsonism, tardive dyskinesia and plasma neuroleptic levels.

Of all known schizophrenics living in Nithsdale, south-west Scotland, 146 (88%) were examined for the presence of the three principal movement disorders secondary to antipsychotic medication, namely akathisia, tardive dyskinesia and Parkinsonism. Of these, 18% had akathisia, 5% pseudoakathisia, 29% tardive dyskinesia, 8% persistent tardive dyskinesia, and 27% Parkinsonism. No movement disorder was seen in 445, 36% had one and 20% had more than one movement disorder. Plasma neuroleptic levels at the time of clinical assessment were measured by the radioreceptor technique. Correlations between dose and plasma level were low; the ratio of mean plasma concentration to mean dose was greatest with fluphenazine decanoate and lowest for sulpiride. The concentration:dose ratio was higher in the elderly. There was no relationship between neuroleptic levels and akathisia, Parkinsonism or tardive dyskinesia. Additional psychotropic medication influenced neuroleptic levels. In 9% of patients receiving oral antipsychotic medication, no drug was detected in plasma.

Cranioplasty using gentamicin-loaded acrylic cement: a test of neurotoxicity.

Cranioplasty represents a formidable challenge for neuro-surgeons, with a significant morbidity from both early and late wound infections. Polymethylmethacrylate (PMMA) is one of the most widely used materials in this setting. Despite the advantages of this material, such as ease of handling and inert biochemical properties, it is still a foreign body that is prone to infection. We present an animal model using a gentamicin-impregnated PMMA patch to assess the neurotoxicity as well as the efficacy of using this as an alternative material to lessen the infectious morbidity in this clinical setting. In part two of our experiment, we used a PMMA patch of similar weight and surface area in a physiological saline solution to determine the rate of gentamicin elution from the patch. The results obtained appear promising with no evidence of neurotoxicity and warrant further study to assess the clinical efficacy of PMMA in this setting.

Pharmacokinetics of haloperidol and fluphenazine decanoates in chronic schizophrenia.

In a double-blind comparison of haloperidol decanoate and fluphenazine decanoate given 4-weekly for 60 weeks as maintenance therapy in 38 chronic schizophrenic in-patients, plasma haloperidol, fluphenazine and prolactin levels were measured at regular intervals by radioimmunoassay. After the first injection, the mean plasma haloperidol level was highest at week 1 and fell gradually towards week 4. Mean pre-dose haloperidol levels changed little after week 8. Results suggested an absorption half-life of 4 weeks, although, in three cases steady state was only achieved after 11 monthly injections. Steady state levels of both haloperidol and fluphenazine correlated highly with dose. In two sub-groups observed at steady state, both drugs produced a biphasic pattern of plasma drug concentration between injections, a rapid rise on day 1 followed by stable elevated levels and a gradual return to pre-injection concentration by the end of week 4. In the fluphenazine sub-group there was a second peak on day 7 and a steeper decline, so that the mean area-under-curve in week 4 was 64% of that in week 1. Drug injections at steady state induced an increase in prolactin secretion in all of the fluphenazine sub-group and in half of those receiving haloperidol. Plasma prolactin changes resembled those for drug concentrations, but differences in times of peaks on day 1 resulted in weak correlations. Fluphenazine appeared more potent than haloperidol in provoking prolactin secretion.

The Scottish first episode schizophrenia study. VII. Two-year follow-up. Scottish Schizophrenia Research Group.

Of 49 schizophrenic patients followed up 2 years after their first admission to hospital, 37% were well, 47% had been readmitted to hospital at some time over the 2 years, and 38% showed schizophrenic symptoms at follow-up. A poor outcome at 2 years was associated with male sex, poor outcome after the first 5 weeks of the first admission, negative schizophrenic symptoms on first admission, and a diagnosis of definite or probable schizophrenia using the Feighner criteria. Only 23% were in employment. A small double-blind discontinuation study of maintenance antipsychotic medication during the second year found more relapses in those switched to placebo medication. Repeat psychometric assessment at 2 years confirmed modest improvements found at 12 months; that is, there was no evidence of intellectual decline. Relatives showed no more psychosocial distress than that found in a normal community sample; what distress there was correlated with patients' schizophrenic symptoms.

Plasma levels of fluphenazine decanoate. Effects of site of injection, massage and muscle activity.

Depot neuroleptics are now commonly used for maintenance therapy of schizophrenia. Their physicochemical composition makes them ideal for such use because they are long-acting and show stable blood levels for prolonged periods. Their absorption from the site of injection may, however, be affected by local muscle factors. This paper describes three such factors in relation to fluphenazine decanoate: varying the site of injection; massage of the injection site; and effects of muscular exercise. Our results suggest that fluphenazine pharmacokinetics are not significantly affected by any of these factors.

Plasma levels of fluphenazine and prolactin in psychiatric patients.

A total of 100 patients receiving fluphenazine (FPZ) decanoate for at least 12 months (96 schizophrenics and 4 other diagnoses) were investigated for plasma levels of FPZ and prolactin on the day of injection (day 0) and 7 days later (day 7). The plasma FPZ level significantly correlated with the weekly dose of FPZ. The plasma FPZ level per weekly FPZ dose multiplied by 100 (the FPZ ratio) showed a 20-fold variation. The FPZ ratio was significantly higher in the day- and in-patients (hospital-patients) than in out-patients. The plasma prolactin level significantly correlated with the plasma FPZ level but the prolactin to FPZ ratio negatively correlated with the plasma FPZ level. The prolactin to FPZ ratio was lower in the hospital patients than in the out-patients. This may suggest either that the high prolactin to FPZ ratio is an indicator of the therapeutic efficacy of FPZ or that there are at least two biologically distinct subgroups, one with a sharp prolactin response to FPZ, therefore with good prognosis, and another with the reverse direction.

Gastric, duodenal, and pancreatic somatostatin-like immunoreactivity during hypovolemic shock.

Because hypovolemic shock is known to cause gastric ulcers in animals and human beings, we investigated the tissue levels of somatostatin-like immunoreactivity (SLI) in the gastric corpus and antrum, duodenum, and pancreas during hypovolemic shock in rats. We studied male Wistar rats (N = 10 each) 15 min, 2 hr, and 12 hr after hypovolemic shock and compared results to a control group (N = 15). Two rats in both 2-hr and 12-hr groups showed gastric ulcers: three corporal and one antral. One animal developed multiple ulcers. In the gastric corpus and antrum and in the duodenum, tissue SLI showed significant decrease 15 min and 2 hr after shock. Gastric SLI remained low, whereas duodenal SLI recovered and rose above control level at 12 hr. Pancreatic SLI showed no significant changes during hypovolemic shock. Gastric tissue SLI levels that were significantly lower after shock than those of normal controls may have contributed to the peptic ulcer disease induced by hypovolemic shock in this experimental model.