Administration of ziprasidone for 10 days increases cocaine toxicity in mice.

Long-term treatment with antipsychotic medications alters the regional density of several of the neurotransmitter receptors that mediate cocaine toxicity. However, the effect of either up- or down-regulation of the neurotransmitter receptors on cocaine toxicity is unknown. In this study, we determined if subacute administration of the atypical antipsychotic ziprasidone altered the toxic effects of cocaine in mice. Ziprasidone (4 mg/kg) or placebo was administered to the first two groups of CF-1 mice for 10 days and, then on day 10, an estimated LD50 dose of cocaine (102 mg/kg) was given to these mice. In a third group, in order to produce a ziprasidone withdrawal state, we administered ziprasidone for 10 days, followed by no treatment for 2 days before cocaine administration. There was no significant difference among the three groups in overall survival: 63% in the treatment group, 60% in the withdrawal group, and 80% in the placebo group. Survival time was significantly shorter for the withdrawal group than for the control group. Our study may have been limited by lower than expected serum ziprasidone concentrations and lower than expected lethality from cocaine. However, our findings suggest that administration of an atypical antipsychotic for 10 days may increase the toxic effects of cocaine.

The effect of acetaminophen (four grams a day for three consecutive days) on hepatic tests in alcoholic patients--a multicenter randomized study.

BACKGROUND: Hepatic failure has been associated with reported therapeutic use of acetaminophen by alcoholic patients. The highest risk period for alcoholic patients is immediately after discontinuation of alcohol intake. This period exhibits the largest increase in CYP2E1 induction and lowest glutathione levels. Our hypothesis was that common liver tests would be unaffected by administration of the maximum recommended daily dosage of acetaminophen for 3 consecutive days to newly-abstinent alcoholic subjects. METHODS: Adult alcoholic subjects entering two alcohol detoxification centers were enrolled in a prospective double-blind, randomized, placebo-controlled trial. Subjects were randomized to acetaminophen, 4 g/day, or placebo for 3 consecutive days. The study had 95% probability of detecting a 15 IU/L difference in serum ALT. RESULTS: A total of 443 subjects were enrolled: 308 (258 completed) received acetaminophen and 135 subjects (114 completed) received placebo. Study groups did not differ in demographics, alcohol consumption, nutritional status or baseline laboratory assessments. The peak mean ALT activity was 57 +/- 45 IU/L and 55 +/- 48 IU/L in the acetaminophen and placebo groups, respectively. Subgroup analyses for subjects presenting with an elevated ALT, subjects fulfilling a diagnosis of alcoholic hepatitis and subjects attaining a peak ALT greater than 200 IU/L showed no statistical difference between the acetaminophen and control groups. The one participant developing an increased international normalized ratio was in the placebo group. CONCLUSION: Alcoholic patients treated with the maximum recommended daily dose of acetaminophen for 3 consecutive days did not develop increases in serum transaminase or other measures of liver injury. Treatment of pain or fever for 3 days with acetaminophen appears safe in newly-abstinent alcoholic patients, such as those presenting for acute medical care.

A randomized trial to determine the change in alanine aminotransferase during 10 days of paracetamol (acetaminophen) administration in subjects who consume moderate amounts of alcohol.

BACKGROUND: Previous studies have suggested that therapeutic doses of paracetamol (acetaminophen) are safe in alcoholic patients when administered for up to 3 days. However, 14 days of therapeutic doses of paracetamol has been associated with an increase in serum transaminases. AIM: To determine the effect of 10 days of the maximal therapeutic dose of paracetamol on serum alanine aminotransferase (ALT) activity in subjects who consume 1 to 3 alcoholic beverages per day. METHODS: This was a randomized, double blind, placebo-controlled trial. Subjects took 4 g of paracetamol (or placebo) daily for 10 days. Serum aspartate aminotransferase (AST), ALT, bilirubin and INR were measured at baseline, day 4 and day 11. Symptoms potentially related to liver injury were also recorded. RESULTS: Paracetamol and placebo groups had no change from baseline values at day 4, but the paracetamol group had an increase in mean ALT at day 11 of 8.7 IU/L. No subject developed symptoms of liver injury or met predefined criteria for hepatotoxicity or liver failure. CONCLUSION: Therapeutic dosing of paracetamol administered for 10 days appears to elevate serum ALT in moderate drinkers, but does not produce clinically evident liver injury.

The 2.0 A crystal structure of Scapharca tetrameric hemoglobin: cooperative dimers within an allosteric tetramer.

The crystal structure of the allosteric tetrameric hemoglobin from Scapharca inaequivalvis (HbII) has been determined in the carbonmonoxy liganded state using a combination of anomalous scattering and molecular replacement. The molecular model has been refined at 2.0 A resolution to a conventional R-factor of 0.173 and a free R-factor of 0.244. The tetramer is formed from two identical heterodimers. Each heterodimer is assembled with intersubunit contacts involving the E and F helices and heme groups in a manner that is very similar to that of the cooperative Scapharca homodimeric hemoglobin. In addition, the ordered water structure observed in these dimeric interfaces is quite similar. These structural similarities strongly suggest that the dimers within the Scapharca tetramer are cooperative. Subunits assemble into a tetramer in a distinctly non-tetrahedral arrangement, with the pseudo 2-fold axes of the heterodimer oriented at an angle of 74.5 degrees relative to the molecular 2-fold. This arrangement requires that two subunit types have distinct locations and contacts, despite the very similar tertiary structures. HbII polymerizes to higher-order assemblages in a ligand, proton and anion dependent fashion. The lattice contacts in the HbII-CO crystal suggest possible modes for this association.

WITHDRAWN: Effect of Vibram FiveFingers Minimalist Shoes on the Abductor Hallucis Muscle.

Ahead of Print article withdrawn by publisher.

An orthogonal C-H borylation--cross-coupling strategy for the preparation of tetrasubstituted "A2B2"-chrysene derivatives with tuneable photophysical properties.

The regioselective, orthogonal functionalisation of 4,10-dichlorochrysene enables the synthesis of a variety of 2,8,4,10-"A2B2"-tetrasubstituted chrysenes. Such compounds exhibit broadened UV-vis absorption spectra, decreased band gap and higher HOMO levels compared to the parent chrysene.

Antivenom therapy in the Americas.

Envenomations are an important cause of injury in the Americas. While supportive care alone may result in an acceptable outcome, antivenom offers a specific therapy that can significantly reduce the injury and symptoms of the envenomation. Antivenoms are hyperimmune sera collected from animals immunised with venom. The antibodies contained in the serum bind and inactive venom components. This leads to cessation or reversal of the toxic effects of the venom. The serum is often processed to increase the level of antibodies directed against venom components and decrease the amount of inactive proteins that may cause allergic reactions. The processing may include precipitation of inactive proteins, chromatographic methods and cleavage of the immunoglobulins to form antibody fragments known as Fab or F(ab)2. In the Americas, antivenoms are produced to treat crotalid and Micrurus snake envenomations. Latrodectus and Loxosceles spider envenomations and Centruroides and Tityus scorpion envenomations. The indications, method of administration and incidence of adverse reactions differ greatly for each antivenom. The adverse effects encountered when using antivenoms are primarily allergic in nature. Anaphylaxis, which may be life threatening, is a major concern. Preparations to treat anaphylaxis must be made before initiating antivenom therapy. Serum sickness is also common with many of the antivenom preparations.

Tricyclic antidepressants directly depress human myocardial mechanical function independent of effects on the conduction system.

OBJECTIVES: To measure the effect of tricyclic antidepressant drugs (TCAs) on human myocardial contractility. METHODS: Human atrial tissue was obtained during cardiac bypass surgery. The tissue was harvested, suspended in a Tyrode buffer at 37 degrees C, and perfused with a 95%/5% oxygen-carbon dioxide mixture. Developed force was continuously measured using a force transducer and recorded by computer. After an equilibration period, escalating doses of amitriptyline or desipramine were added to the bath. All strips were exposed to the following five concentrations of each drug: 0 (control) 0.4, 4, 40, and 400 microM. The results for each experiment were expressed as the difference between the developed force measured prior to the addition of each concentration of drug and the developed force measured after a 30-minute exposure to the drug. RESULTS: Desipramine decreased the developed force by 27%, 49%, and 74% at concentrations of 0.4, 40, and 400 microM, respectively. Amitriptyline decreased the developed force by 38% at the 40-microM concentration and by 89% at the 400-microM concentration. Untreated strips retained 94% of baseline developed force at 150 minutes. CONCLUSIONS: Tricyclic antidepressants depress human myocardial function in a dose-dependent fashion independent of the effects on the cardiac conduction system. While previous work has demonstrated the effect of therapies for the reversal of impaired cardiac conduction following TCA poisoning, to the best of the authors' knowledge, no reports have documented the effects of therapy on direct myocardial depression. Additional therapies targeted at reversing the direct cardiodepressive effects of TCA may improve outcome following TCA poisoning.

Attenuation of verapamil-induced myocardial toxicity in an ex-vivo rat model using a verapamil-specific ovine immunoglobin.

OBJECTIVE: To determine whether an ovine verapamil-specific immunoglobin G (V-IgG) attenuates verapamil toxicity in an ex-vivo rat left ventricular papillary muscle model. METHODS: The authors dissected left ventricular papillary muscle strips from male Sprague-Dawley rats (350-410 g) and suspended them in an oxygen-perfused Tyrode buffer bath at 37.5 degrees C. Muscle strips equilibrated for 90 minutes under electrical stimulation of 1 Hz. Resting and developed tension (mg) were monitored continuously. A concentration-response trial was performed with verapamil concentrations ranging from 31 to 1,020 nM; 510 nM produced consistent reduction in developed tension. A trial of V-IgG was then conducted by administering the following treatments to papillary muscle strips in a randomized manner: V-IgG + 510 nM verapamil, nonspecific ovine IgG (N-IgG) + 510 nM verapamil (protein control), and 510 nM verapamil alone. Immunoglobin G was administered in equimolar concentrations to verapamil. Attenuation was expressed as inhibition of the verapamil-induced reduction of developed tension. RESULTS: The V-IgG comparative trial indicated the V-IgG + verapamil treatment had a mean reduction in developed tension of 14.1% (SD +/- 12.2) compared with 36.2% (SD +/- 14.9) for N-IgG + verapamil and 34.9% (SD +/- 8.1) for verapamil alone (p < 0.05). There was no difference between the two control groups. CONCLUSION: Verapamil-specific IgG attenuated verapamil-induced reduction of developed tension in an ex-vivo rat model.

Inhibition of cisplatin toxicity without decreasing antitumor efficacy. Use of a dithiocarbamate.

OBJECTIVE: To demonstrate whether a dithiocarbamate derivative, N-methyl-D-glucaminedithiocarbamate, could prevent anorexia and weight loss and enhance survival without decreasing the antitumor efficacy of high-dose cisplatin therapy. DESIGN: One hundred forty-two mice were randomized into groups receiving cisplatin, 5 mg/kg per day, 7.5 mg/kg per day, or 10 mg/kg per day for three days with or without N-methyl-D-glucaminedithiocarbamate, 1000 mg/kg per day. Weight loss and morbidity were examined between groups. Antitumor efficacy of cisplatin combined with N-methyl-D-glucaminedithiocarbamate was examined using a subcutaneous melanoma model. SETTING: Institutional laboratory. MAIN OUTCOME MEASURES: N-methyl-D-glucaminedithiocarbamate intervention would decrease morbidity, weight loss, and increase survival without decreasing the antitumor efficacy of cisplatin. RESULTS: Weight loss and morbidity were significantly reduced when N-methyl-D-glucaminedithiocarbamate was coadministered with cisplatin (P < .05) at all doses of cisplatin. The antitumor efficacy of high-dose cisplatin therapy (7.5 mg/kg per day and 10 mg/kg per day) was not significantly decreased (P > .05) at all doses of cisplatin. CONCLUSION: As N-methyl-D-glucaminedithiocarbamate seems to limit morbidity and mortality of high-dose cisplatin administration without decreasing its antitumor efficacy, this drug deserves further investigation in the treatment of cancer.

Prevention of cisplatin-induced toxicity by selected dithiocarbamates.

Cisplatin (CDDP) is a widely used antineoplastic agent, the administration of which is associated with dose-related toxicities. Currently, ototoxicity is the dose-limiting toxicity of cisplatin and difficult to prevent. The purpose of this study was to determine the ability of two substituted dithiocarbamates, diethyldithiocarbamate (DDTC) and N-methyl-D-glucaminedithiocarbamate (NMGDTC) to abrogate cisplatin-induced toxicity in young female Hartley albino guinea pigs. The animals were divided into saline controls, CDDP only, NMGDTC only, and CDDP-DDTC or CDDP-NMGDTC combinations with DDTC or NMGDTC given 30 minutes before or 30 minutes after CDDP. Auditory brainstem responses (ABR) were recorded periodically in sound-attenuated rooms to assess hearing thresholds. Representative cochleas were harvested at autopsy, processed, and examined by scanning electron microscopy (SEM). The NMGDTC produced marked reduction of CDDP-induced ototoxicity and weight loss. No significant ABR shift was found regardless of the order of CDDP and NMGDTC administration, but the derivative was more effective in preventing anorexia and weight loss when given prior to CDDP. Specifically, groups of guinea pigs given NMGDTC prior to CDDP showed the only weight gain among the treatment groups. Diethyldithiocarbamate, the other dithiocarbamate evaluated in this study, did not provide protection from cisplatin ototoxicity regardless of the order of administration. A CDDP-induced weight loss was reduced when DDTC was administered prior to CDDP. In summary, NMGDTC given prior to CDDP offers remarkable protection against cisplatin-induced ototoxicity and weight loss. It may help eliminate dose-limiting cisplatin-induced toxicity and allow the use of cisplatin at higher doses in cancer chemotherapy.

A method for reporting self-harm according to level of injury and location on the body.

Self-mutilation occurs on a continuum from superficial to severe, yet previous studies have not differentiated these acts. This study, conducted over 4 years with emotionally disturbed adolescents, presents a method for reporting four levels of severity of self-mutilation. A group of 32 subjects inflicted 128 self-mutilations. Each wound was rated for level of injury and was mapped according to the location of the wound on the body. This method for reporting self-mutilation was seen as an efficient and reliable procedure for describing the full continuum of self-inflicted injuries. The term self-harm was seen as a more accurate and useful description of these behaviors.

Rupture of ectopic pregnancy after medical therapy with methotrexate: a case series.

Medical treatment of ectopic pregnancy with methotrexate has become the standard of care in many areas of the U.S. Rupture of ectopic pregnancy after medical treatment presents a diagnostic challenge to the Emergency Physician. We review a series of 11 patients with ectopic pregnancy treated with methotrexate who then required surgical treatment for rupture.

Sexual behavior, drugs, and relationship patterns on a college campus over thirteen years.

Three samples of college students at a small New England liberal arts college received questionnaires regarding their sexual philosophies, behavior, relationship with most recent partner, self-perceived attractiveness, relationship with parents, use of drugs and alcohol, attitudes toward marriage and abortion, and other subjects. The college was sampled in 1974, 1979, and 1986. Sexual behavior increased dramatically from 1974 to 1979 and then decreased in 1986 to approximately where it was in 1974. The reason for this change, and findings regarding the relationships between sexual behavior and many of the variables cited above are discussed.

PIP: 3 samples of college students at a small New England liberal arts college received questionnaires regarding their sexual philosophies, behavior, relationship with most recent partner, self-perceived attractiveness, relationship with parents, use of drugs and alcohol, attitudes toward marriage and abortion, and other subjects. The college was sampled in 1974, 1979, and 1986. Sexual behavior increased dramatically from 1974 to 1979 and then decreased in 1986 to approximately where it was in 1974. The authors speculate that the spread of herpes contributed to this trend reversal. The 1980s also brought more common knowledge of chlamydia trachomatis, nonspecific urethritis, and AIDS. There is some evidence that the double standard for sexual behavior is not present for the most recent sample, though men are still more apt to desire sex without concern for a strongly bonded relationship. Still, in 1986, they showed some evidence of movement toward having sex within a more committed relationship as compared to men in 1974. It is conjectured that the data reflect an increase in individualism and a weakening of the influence of religion and parental relationship on sexual behavior.

Reducing wandering by persons with dementia using differential reinforcement.

Wandering behavior of 4 geriatric patients with dementia residing in a long-term care facility was assessed using direct behavioral observations. The consequences identified during the observations as maintaining wandering for each patient were then applied for the absence of wandering using differential reinforcement of other behavior (DRO). The effectiveness of the DRO procedure was evaluated using an ABAB design. Results indicated significant reductions in wandering during treatment.

Psychometric evaluation of the Menstrual Joy Questionnaire.

Analysis of 10 terms in the Menstrual Joy Questionnaire of Delaney, Lupton, and Toth indicated that the 34 undergraduate students did not agree on the definitions of scale items. The authors discuss the use of this questionnaire as a stimulus in experimental research and as a measure of positive perimenstrual experience.

Access thrombosis, hospitalization, and hematocrit level in hemodialysis patients.

Are occurrences of vascular access thrombosis and hospitalization higher in hemodialysis patients with hematocrits (Hcts) > 36% compared to those < 36%? This 12-month retrospective study included 30 male hemodialysis patients who received erythropoietin (rHuEPO) for at least 6 months. Sixty percent (n = 18) had arteriovenous fistulas and 40% (n = 12) had polytetrafluoroethylene grafts. The mean age was 59.6 years. Twenty patients during 216 patient months had a mean Hct < 36% with five thromboses (2.3%). Ten patients during 118 patient months had a mean Hct > 36% with four thromboses (3.4%). There was no statistically significant difference between the thrombosis rates in the two groups. There were four hospitalizations in 118 patient months in the > 36% group (3.4%). There were 33 hospitalizations in 216 patient months in the < 36% group (15.3%). This is 4.5 times higher than the > 36% group. Our data suggest that Hcts > 36% are not associated with increased thrombosis and are associated with lower hospitalization rates.

A single-arm clinical trial of a 48-hour intravenous N-acetylcysteine protocol for treatment of acetaminophen poisoning.

INTRODUCTION: Acetylcysteine prevents hepatic injury when administered soon after acetaminophen overdose. The most commonly used treatment protocols are a 72-hour oral and a 21-hour intravenous (IV) protocol. Between 1984 and 1994, 409 patients were enrolled in a study to describe the outcomes of patients who were treated using a 48-hour IV protocol. In 1991, an interim analysis reported the first 223 patients. The objective of this manuscript is to report the rates of hepatotoxicity and adverse events occurring during a 48-hour IV acetylcysteine protocol in the entire 409 patient cohort. METHODS: This was a multicenter, single-arm, open-label clinical trial enrolling patients who presented with a toxic serum acetaminophen concentration within 24 h of acute acetaminophen ingestion. Patients were treated with 140 mg/kg loading dose followed by 70 mg/kg every 4 h for 12 doses. Serum aminotransferase activities were measured every 8 h during the protocol, and adverse events were recorded. The primary outcome was the percentage of subjects who developed hepatotoxicity defined as a peak serum aminotransferase greater than 1000 IU/L. RESULTS: Four hundred and nine patients were enrolled, and 309 met inclusion for the outcome analysis. The overall percentage of patients developing hepatotoxicity was 18.1%, and 3.4% of patients treated within 10 h developed hepatotoxicity. One acetaminophen-related death occurred in a patient treated at 22 h. Adverse events occurred in 28.9% of enrolled subjects; the most common adverse events were nausea, vomiting, and flushing, and no events were rated as serious by the investigator. CONCLUSIONS: Acetaminophen-overdosed patients treated with IV acetylcysteine administered as 140 mg/kg loading dose followed by 70 mg/kg every 4 h for 12 doses had a low rate of hepatotoxicity and few adverse events. This protocol delivers a higher dose of acetylcysteine which may be useful in selected cases involving very large overdoses.

Single-agent duloxetine ingestions.

Duloxetine is a serotonin and norepinephrine reuptake inhibitor, which is mainly used to treat depression. This retrospective study describes the demographic and clinical effects of duloxetine ingestions reported to the National Poison Data System (NPDS). NPDS data were searched for duloxetine exposures between 2004 and 2010. A total of 11,373 patients were included and exposures were divided into three groups of ages ≤6 years old, 7-12 years and >12 years. Neurological clinical effects occurred in 6.1% of the patients aged ≤6 years, 13.0% of the patients aged 7-12 years and 24.6% of the patients aged >12 years. Cardiovascular effects occurred in 1.4% of the patients aged ≤6 years old, 2.5% of the patients aged 7-12 years and 11.6% of the patients aged >12 years. Gastrointestinal effects occurred in 4.1% of the patients aged ≤6 years old, 16.6% of the patients aged 7-12 years and 13.8% of the patients aged >12 years. Tachycardia, nausea, vomiting, agitation/irritability, dizziness/vertigo and drowsiness were among the most common clinical effects in all three groups. Overall, 61.4% of the patients aged ≤6 years and 77.5% of the patients aged 7-12 years were managed in a non-health care facility, while 55.8% of the patients aged >12 years were referred to or already in a health care facility. We conclude that the majority of ingestions are benign in both pediatrics and adults. Most symptomatic patients have neurologic, gastrointestinal and cardiovascular effects. Most pediatric patients will be able to be managed in a non-health care facility.

The effects of paracetamol (acetaminophen) on hepatic tests in patients who chronically abuse alcohol - a randomized study.

BACKGROUND: Retrospective accounts suggest that therapeutic doses of paracetamol can produce severe hepatic injury in patients with putative high-risk conditions, including alcoholism and infectious hepatitis. Metabolism of paracetamol to its hepatotoxic metabolite is enhanced in patients who abuse alcohol, who also have compromised liver defences from depressed hepatic glutathione. AIM: To determine the effect of paracetamol on serum liver tests of newly abstinent subjects who abuse alcohol, including subjects with hepatitis C infection. METHODS: A randomized, double-blind, placebo-controlled study. Adult alcohol abusers with a current drinking episode longer than 7 days received either placebo or paracetamol 4 g/day for 5 days. RESULTS: Of 142 subjects enrolled, 74 received paracetamol and 68 received placebo. Mean ALT activity during treatment increased from 48 to 62 IU/L in the paracetamol group and from 47 to 49 IU/L in the placebo group. Maximum ALT was 238 and 249 IU/L in the paracetamol and control groups respectively. The INR remained unchanged and serum bilirubin decreased in both groups. Subgroup analyses for subjects with alcoholic hepatitis, hepatitis C virus antibody and other subgroups showed no statistical difference between groups. CONCLUSION: Administration of paracetamol 4 g/day appears safe in newly abstinent patients who abuse alcohol.