Plasma concentrations of diclazuril following oral administration of diclazuril and diclazuril sodium salt to cattle.

Diclazuril is a triazine-based antiprotozoal agent widely used in veterinary practice that may have clinical application in the treatment of bovine protozoal diseases. The present study reports on the bioavailability, pharmacokinetics, and metabolism of diclazuril and diclazuril sodium salt in cattle following administration of diclazuril suspended in water and by direct application of diclazuril sodium salt to the oral mucosa. Compared with diclazuril itself, the sodium salt formulation of diclazuril applied to the oral mucosa was rapidly and reliably absorbed. Plasma concentrations of diclazuril peaked at around 8 h after oral-mucosal administration of diclazuril sodium salt. On the contrary, application of diclazuril itself orally resulted in delayed and variable absorption. The mean bioavailability of diclazuril as pure powder was 42.5% relative to diclazuril sodium salt indicating approximately 2.5-fold increase in bioavailability of diclazuril as a sodium salt relative to diclazuril as a pure compound in cattle. The present study also reports finding of a previously unreported diclazuril metabolite at high concentrations in plasma especially after oral administration of diclazuril. Further studies, including synthesis and characterization of the novel described metabolite, are required to accurately determine aspects of the metabolism of diclazuril in cattle.

Unscheduled Procedural Sedation: A Multidisciplinary Consensus Practice Guideline.

The American College of Emergency Physicians (ACEP) organized a multidisciplinary effort to create a clinical practice guideline specific to unscheduled, time-sensitive procedural sedation, which differs in important ways from scheduled, elective procedural sedation. The purpose of this guideline is to serve as a resource for practitioners who perform unscheduled procedural sedation regardless of location or patient age. This document outlines the underlying background and rationale, and issues relating to staffing, practice, and quality improvement.

Aminorex identified in horse urine following consumption of Barbarea vulgaris; a preliminary report.

BACKGROUND: Aminorex, (RS)-5- Phenyl-4,5-dihydro-1,3-oxazol-2-amine, is an amphetamine-like anorectic and in the United States a Drug Enforcement Administration [DEA] Schedule 1 controlled substance. Aminorex in horse urine is usually present as a metabolite of Levamisole, an equine anthelmintic and immune stimulant. Recently, Aminorex identifications have been reported in horse urine with no history or evidence of Levamisole administration. Analysis of the urine samples suggested a botanical source, directing attention to the Brassicaceae plant family, with their contained GlucoBarbarin and Barbarin as possible sources of Aminorex. Since horsepersons face up to a 1 year suspension and a $10,000.00 fine for an Aminorex identification, the existence of natural sources of Aminorex precursors in equine feedstuffs is of importance to both individual horsepersons and the industry worldwide. RESULTS: Testing the hypothesis that Brassicaceae plants could give rise to Aminorex identifications in equine urine we botanically identified and harvested flowering Kentucky Barbarea vulgaris, ("Yellow Rocket") in May 2018 in Kentucky and administered the plant orally to two horses. Analysis of post-administration urine samples yielded Aminorex, showing that consumption of Kentucky Barbarea vulgaris can give rise to Aminorex identifications in equine urine. CONCLUSIONS: Aminorex has been identified in post administration urine samples from horses fed freshly harvested flowering Kentucky Barbarea vulgaris, colloquially "Yellow Rocket". These identifications are consistent with occasional low concentration identifications of Aminorex in equine samples submitted for drug testing. The source of these Aminorex identifications is believed to be the chemically related Barbarin, found as its precursor GlucoBarbarin in Kentucky Barbarea vulgaris and related Brassicaceae plants worldwide.

Staying Awake and Aware: The Importance of Sleep in Psychiatric Nursing Practice.

Given that approximately 70 million Americans suffer from sleep-wake disorders and their under-recognized role in practice, psychiatric nurses may see, or may be already seeing, patients with undiagnosed sleep disorders. Assessment of sleep-wake disorders can and should be a part of psychiatric nursing education and practice. Many practicing clinicians lack formal training regarding sleep-wake issues and treatment. Even as sleep disturbances are common concerns among psychiatric populations, sleep-wake issues may go unrecognized. The article presents a stylized progression of care to enable clinicians to identify, address, and treat underlying sleep-wake disorders in psychiatric settings. The article recommends instituting screening procedures for sleep-wake issues and follow-up assessments, particularly overnight pulse oximetry and polysomnograms. Just as clinicians already screen for physical conditions that would affect psychiatric care, practitioners can evaluate patients for potential sleep-wake disorders as part of their existing practice and intake procedures. Further, the piece details implications for psychopharmacology as well as evidence from clinical practice. Psychiatric nurses should stay awake to the importance of sleep medicine and aware of how sleep-wake disorders can affect psychiatric populations.

Therapeutics for Equine Protozoal Myeloencephalitis.

Equine protozoal myeloencephalitis is an infectious disease of the central nervous system caused by Sarcocystis neurona or Neospora hughesi. Affected horses routinely present with progressive and asymmetrical neurologic deficits. The diagnosis relies on the presence of neurologic signs, ruling out other neurologic disorders, and the detection of intrathecally derived antibodies to either S neurona and/or N hughesi. Recommended treatment is use of an FDA-approved anticoccidial drug formulation. Medical and supportive treatment is provided based on the severity of neurologic deficits and complications. This article focuses on recent data related to diagnosis, pharmacologic treatment, and prevention.

Clinical Psychopharmacology Update: What's in a Name? Confusion Prompts Change for Vortioxetine's Brand Name.

Similar names between two unrelated drugs have led the FDA to issue warnings about and now approve a name change for vortioxetine, which was branded as Brintellix® until recently. While the trade name had been screened prior to the product's launch, the FDA received numerous reports of prescribing and dispensing errors, specifically with regard to the anti-coagulant drug Brilinta® (ticagrelor). Starting 1 June 2016, vortioxetine will be marketed under the name Trintellix™ in an effort to reduce confusion. Clinicians are advised that while the name and National Drug Code number with this product will change, it will retain the same formulation, indication, and dosage information. To the extent possible, clinicians can and should take actions to identify and reduce potential medication errors in prescriptions, especially when using electronic records and e-prescription systems.

A cluster of trace-concentration methamphetamine identifications in racehorses associated with a methamphetamine-contaminated horse trailer: A report and analysis.

Three low concentration methamphetamine "positive" tests were linked to use of a methamphetamine-contaminated trailer to transport the affected horses. This incident establishes methamphetamine as a human-use substance that can inadvertently enter the environment of racing horses, resulting in urinary methamphetamine "positives;" an interim regulatory cut-off of 15 ng/mL for methamphetamine in post-race urine is proposed.

Identifications de concentrations de méthamphétamine à l'état de traces chez des chevaux de course associées à une remorque contaminée : rapport et analyse. Trois tests «positifs¼ de faibles concentrations de méthamphétamine ont été associés à l'utilisation d'une remorque contaminée par les méthamphétamines qui était utilisée pour transporter les chevaux affectés. Cet incident établit la méthamphétamine comme une substance à utilisation humaine qui peut pénétrer par inadvertance dans le milieu des chevaux de course, entainant ainsi des tests d'urine «positifs¼; un niveau intérimaire réglementaire de 15 ng/mL pour les méthamphétamines est proposé pour les tests d'urine après la course.(Traduit par Isabelle Vallières).

Clinical Psychopharmacology Update: Additional Safety Concerns for Using Varenicline (Chantix) for Smoking Cessation Treatment.

Smoking cessation remains a positive therapeutic goal and should be encouraged for the millions of individuals who continue to smoke and struggle to quit. While psychiatric nurses should encourage patients to start or continue smoking cessation therapies, they must be aware of the additional safety concerns relating to the use of varenicline (Chantix). Research published subsequent to the last clinical update in this journal (Tobin, 2007 ) has prompted additional warnings from the Food and Drug Administration concerning varenicline for smoking cessation therapy. In particular, clinicians need to be aware of increased concerns about varenicline's association with neuropsychiatric side effects, seizures, and alcohol interactions.

Synthesis and characterization of d5 -barbarin for use in barbarin-related research.

Based on structural similarities and equine administration experiments, Barbarin, 5-phenyl-2-oxazolidinethione from Brassicaceae plants, is a possible source of equine urinary identifications of aminorex, (R,S)-5-phenyl-4,5-dihydro-1,3-oxazol-2-amine, an amphetamine-related US Drug Enforcement Administration (DEA) controlled substance considered illegal in sport horses. We now report the synthesis and certification of d5 -barbarin to facilitate research on the relationship between plant barbarin and such aminorex identifications. D5 -barbarin synthesis commenced with production of d5 -2-oxo-2-phenylacetaldehyde oxime (d5 -oxime) from d5 -acetophenone via butylnitrite in an ethoxide/ethanol solution. This d5 -oxime was then reduced with lithium aluminum hydride (LiAlH4 ) to produce the corresponding d5 -2-amino-1-phenylethan-1-ol (d5 -phenylethanolamine). Final ring closure of the d5 -phenylethanolamine was performed by the addition of carbon disulfide (CS2 ) with pyridine. The reaction product was purified by recrystallization and presented as a stable white crystalline powder. Proton NMR spectroscopy revealed a triplet at 5.88 ppm for one proton, a double doublet at 3.71 ppm for one proton, and double doublet at 4.11 ppm for one proton, confirming d5 -barbarin as the product. Further characterization by high resolution mass spectrometry supports the successful synthesis of d5 -barbarin. Purity of the recrystallized product was ascertained by High Performance Liquid Chromatography (HPLC) to be greater than 98%. Together, we have developed the synthesis and full characterization of d5 -barbarin for use as an internal standard in barbarin-related and equine forensic research.

Atovaquone ameliorate gastrointestinal toxoplasmosis complications in a pregnancy model.

BACKGROUND: Toxoplasma is an important source of foodborne hospitalization with no safe and effective therapy against chronic or congenital Toxopalsmosis. Atovaquone is a drug of choice but not approved for use in congenital Toxoplasmosis. We hypothesized atovaquone to be safe and effective against feto-maternal Toxoplasmosis. MATERIAL/METHODS: Programmed pregnant mice were i.p. infected with 50-2400 Tachyzoites from Type II strain (clone PTG). Dams were treated daily with atovaquone or sham and monitored for pain, and complications. RESULTS: Dams developed pain related abdominal hypersensitivity (allodynia) to mechanical stimuli in a Tachyzoites dose dependent manner. Infected dams were anemic and exhibited ascities and severe hepatitis (score 3.6±0.01 on scale 0--normal to 4--severe) with influx of inflammatory and plasma cells, multinucleated dysplastic hepatocytes and necrosis. In addition, dams expressed mild to severe pancreatitis with mononuclear cell invasion, loss of islets and necrosis. This was consistent with splenomegaly (X3 Fold), and massive infiltration of epithelioid cells and loss of germinal structure. Colon became significantly shortened in length (p<0.01) with semi-normal content. Pathological manifestation included, shortening of crypts with numerous microabscess formations, infiltration of lymphocytes, and macrophages. The severe clinical complications led to abortion (50%), early birth (25%) or still birth (25%) consistent with the high dose of Tachyzoites inoculation. Atovaquone treatment partially but significantly protected the dams from the severity of hepatitis, splenomegaly, colitis, myocarditis, and pain related responses as well as fetal demise. CONCLUSIONS: This is a valuable model for therapeutic evaluation of feto-maternal Toxoplasmosis and gastrointestinal complications. Atovaquone protects dams and their fetuses against some infectious/inflammatory aspects of the disease.

Sporadic worldwide "clusters" of feed driven Zilpaterol identifications in racing horses: a review and analysis.

Zilpaterol is a ß2-adrenergic agonist medication approved in certain countries as a cattle feed additive to improve carcass quality. Trace amounts of Zilpaterol can transfer to horse feed, yielding equine urinary "identifications" of Zilpaterol. These "identifications" occur because Zilpaterol is highly bioavailable in horses, resistant to biotransformation and excreted as unchanged Zilpaterol in urine, where it has a 5 day or so terminal half-life.In horses, urinary steady-state concentrations are reached 25 days (5 half-lives) after exposure to contaminated feed. Zilpaterol readily presents in horse urine, yielding clusters of feed related Zilpaterol identifications in racehorses. The first cluster, April 2013, involved 48 racehorses in California; the second cluster, July 2013, involved 15 to 80 racehorses in Hong Kong. The third cluster, March 2019, involved 24 racehorses in Mauritius; this cluster traced to South African feedstuffs, triggering an alert concerning possible Zilpaterol feed contamination in South African racing. The fourth cluster, September/October 2020 involved 18 or so identifications in French racing, reported by the French Laboratories des Courses Hippiques, (LCH), and in July 2021, a fifth cluster of 10 Zilpaterol identifications in South Africa.The regulatory approach to these identifications has been to alert horsemen and feed companies and penalties against horsemen are generally not implemented. Additionally, given their minimal exposure to Zilpaterol, there is little likelihood of Zilpaterol effects on racing performance or adverse health effects for exposed horses.The driving factor in these events is that Zilpaterol is dissolved in molasses for incorporation into cattle feed. Inadvertent incorporation of Zilpaterol containing molasses into horse feed was the source of the California and Hong Kong Zilpaterol identifications. A second factor in the 2019 Mauritius and 2020 French identifications was the sensitivity of testing for Zilpaterol in Mauritius and France, with the French laboratory reportedly testing at a "more sensitive level for Zilpaterol". As of January 1st, 2021, the new FEI Atypical Finding (ATF) policy specifies Zilpaterol as a substance to be treated as an Atypical Finding (ATF), allowing consideration of inadvertent feed contamination in the regulatory evaluation of Zilpaterol identifications.

Gabapentin, a human therapeutic medication and an environmental substance transferring at trace levels to horses: a case report.

Gabapentin, 1-(Aminomethyl)cyclohexaneacetic acid, MW 171.240, is a frequently prescribed high dose human medication that is also used recreationally. Gabapentin is orally absorbed; the dose can be 3,000 mg/day and it is excreted essentially unchanged in urine. Gabapentin is stable in the environment and routinely detected in urban wastewater. Gabapentin randomly transfers from humans to racing horses and is at times detected at pharmacologically ineffective / trace level concentrations in equine plasma and urine. In Ohio racing between January 2019 and July 2020,18 Gabapentin identifications, all less than 2 ng/ml in plasma, were reported. These identifications were ongoing because the horsemen involved were unable to pin down and therefore avoid the source of these identifications. Given that 44 ng/ml or less is an Irrelevant Plasma Concentration (IPC) of Gabapentin in horses, we proposed a 5 ng/ml plasma interim Screening Limit of Detection for Gabapentin identifications in Ohio racing, and an essentially similar 8 ng/ml plasma Screening Limit of Detection was suggested by a scientific advisor to the Ohio Horse Racing Commission. As such, an analytical Screening Limit of 8 ng /ml in plasma is an appropriate and pharmacologically conservative analytical "cut-off" or Screening Limit of Detection (SLOD) for Gabapentin in equine competitive events to avoid the calling of "positive" identifications on random unavoidable trace level identifications of this widely prescribed human therapeutic medication in equine forensic samples.

Alteration of micromilled carbonate δ18O during Kiel Device analysis.

Isotopic analysis of carbonate material has been greatly facilitated by the development of autosampling devices such as the Kiel III Carbonate Device, allowing rapid automated analysis of small sample sizes. This analysis is facilitated by holding samples and acid at temperatures around 70 °C prior to reaction. In most situations this has no measurable effect on sample powders on practical timeframes, but, when analyzing exceptionally fine-grained material produced by micromilling, the δ(18)O of both aragonite and calcite is altered by -0.1 ‰/day. Laboratories that use this technique should thoroughly test and correct for this phenomenon and avoid storing pre-weighed materials within the Kiel Device or similar drying oven prior to analysis.

Solvatomorphism in (E)-2-(2,6-dichloro-4-hydroxybenzylidene)hydrazinecarboximidamide.

The structures of orthorhombic (E)-4-(2-{[amino(iminio)methyl]amino}vinyl)-3,5-dichlorophenolate dihydrate, C(8)H(8)Cl(2)N(4)O·2H(2)O, (I), triclinic (E)-4-(2-{[amino(iminio)methyl]amino}vinyl)-3,5-dichlorophenolate methanol disolvate, C(8)H(8)Cl(2)N(4)O·2CH(4)O, (II), and orthorhombic (E)-amino[(2,6-dichloro-4-hydroxystyryl)amino]methaniminium acetate, C(8)H(9)Cl(2)N(4)O(+)·C(2)H(3)O(2)(-), (III), all crystallize with one formula unit in the asymmetric unit, with the molecule in an E configuration and the phenol H atom transferred to the guanidine N atom. Although the molecules of the title compounds form extended chains via hydrogen bonding in all three forms, owing to the presence of different solvent molecules, those chains are connected differently in the individual forms. In (II), the molecules are all coplanar, while in (I) and (III), adjacent molecules are tilted relative to one another to varying degrees. Also, because of the variation in hydrogen-bond-formation ability of the solvents, the hydrogen-bonding arrangements vary in the three forms.

ESI-Mass spectrometric and HPLC elucidation of a new ergot alkaloid from perennial ryegrass hay silage associated with bovine reproductive problems.

This case report involves four dairies in the Willamette Valley, Oregon, which experienced reproductive problems associated with the presence of a large, previously unidentified, peak eluting at 5 min in a standard ergovaline high-performance liquid chromatography assay of perennial ryegrass silage fed to those animals. Mycotoxin analysis of the silage was negative, as was serological screening of the herds for infectious bovine rhinotracheitis, bovine diarrhea virus and Leptospirosis, including culturing of urine for Leptospira hardjo hardjobovis. Prolactin concentrations were low in most cattle, consistent with ingestion of ergot alkaloids. We believe that this peak represents a novel ergot alkaloid-related compound due to its extractability with Ergosil, its detectability due to fluorescence, and its chromatographic retention between ergovaline (mw = 533) and ergotamine (mw = 581). Its molecular weight was calculated as 570 owing to the predominance of a m/z 593.5 ion in the full scan ESI(+)MS and its deduced tendency to complex with Na(+) (as m/z 593) or K(+) (as m/z 609) ions. We offer rationales for elucidation of the structure of this compound, with the closest starting point comprising an m.w. of 566-a fructofuranosyl-(2-1)-O-beta-D-fructofuranoside derivative of 6,7-secoergoline from Claviceps fusiformis. This m.w. requires modifications, such as reduction of two double bonds in the secoergoline component to give the target 570 m.w. Despite the lack of a definitive structure, the analysis herein provides a starting point for eventual elucidation of this apparently new ergot alkaloid, and to guide and encourage further investigation as to its association with endophyte toxicosis in livestock.

Polymorphism in 2-(4-hydroxy-2,6-dimethylanilino)-5,6-dihydro-4H-1,3-thiazin-3-ium chloride.

Details of the structures of two conformational polymorphs of the title compound, C(12)H(17)N(2)OS(+)·Cl(-), are reported. In form (I) (space group P-1), the two N-H groups of the cation are in a trans conformation, while in form (II) (space group P2(1)/c), they are in a cis arrangement. This results in different packing and hydrogen-bond arrangements in the two forms, both of which have extended chains lying along the a direction. In form (I), these chains are composed of centrosymmetric R(4)(2)(18) (N-H...Cl and O-H...Cl) hydrogen-bonded rings and R(2)(2)(18) (N-H...O) hydrogen-bonded rings. In form (II), the chains are formed by centrosymmetric R(4)(2)(18) (N-H...Cl and O-H...Cl) hydrogen-bonded rings and by R(4)(2)(12) (N-H...Cl) hydrogen-bonded rings.

Synthesis and characterization of barbarin, a possible source of unexplained aminorex identifications in forensic science.

Aminorex is a US DEA Schedule 1 controlled substance occasionally detected in racing horses. A number of aminorex identifications in sport horses were thought to have been caused by exposure to plant sources of aminorex. Glucobarbarin, found in plants of the Brassicaceae family, has been suggested as a potential proximate chemical source by being metabolized in the plant or the horse to aminorex. In Brassicaceae, glucobarbarin is hydrolyzed by myrosinase to yield barbarin, which serves as an insect repellant and/or attractant and is structurally related to aminorex. The synthesis, purification, and characterization of barbarin is now reported for use as a reference standard in aminorex related research concerning equine urinary identifications of aminorex and also for possible use in equine administration experiments. Synthesis of barbarin was performed via ring closure between phenylethanolamine and carbon disulfide in tetrahydrofuran with the catalyst pyridine under reflux. The reaction yielded a white crystalline substance that was purified and chemically characterized as barbarin for use as a Certified Reference Standard or for studies related to equine aminorex identification.

Intravenous tramadol: effects, nociceptive properties, and pharmacokinetics in horses.

OBJECTIVE: To determine the optimal dose, serum concentrations and analgesic effects of intravenous (IV) tramadol in the horse. STUDY DESIGN: Two-phase blinded, randomized, prospective crossover trial. ANIMALS: Seven horses (median age 22.5 years and mean weight 565 kg). METHODS: Horses were treated every 20 minutes with incremental doses of tramadol HCl (0.1-1.6 mg kg(-1)) or with saline. Heart rate, respiratory rate, step frequency, head height, and sweating, trembling, borborygmus and head nodding scores were recorded before and up to 6 hours after treatment. In a second study, hoof withdrawal and skin twitch reflex latencies (HWRL and STRL) to a thermal stimulus were determined 5 and 30 minutes, and 1, 2, 4 and 6 hours after bolus IV tramadol (2.0 mg kg(-1)) or vehicle. Blood samples were taken to determine pharmacokinetics. RESULTS: Compared to saline, tramadol caused no change in heart rate, step frequency or sweating score. Respiratory rate, head height, and head nodding and trembling scores were transiently but significantly increased and borborygmus score was decreased by high doses of tramadol. Following cumulative IV administration of 3.1 mg kg(-1) and bolus IV administration of 2 mg kg(-1), the elimination half-life of tramadol was 1.91 +/- 0.33 and 2.1 +/- 0.9 hours, respectively. Baseline HWRL and STRL were 4.16 +/- 1.0 and 3.06 +/- 0.99 seconds, respectively, and were not significantly prolonged by tramadol. CONCLUSION AND CLINICAL RELEVANCE: IV tramadol at cumulative doses of up to 3.1 mg kg(-1) produced minimal transient side effects but 2.0 mg kg(-1) did not provide analgesia, as determined by response to a thermal nociceptive stimulus.

Predictors of ROSC in witnessed aeromedical cardiac arrests.

INTRODUCTION: Aeromedical agencies are used routinely to transport critically ill patients to specialty centers. The characteristics of patients suffering a cardiac arrest during transport by aeromedical flight personnel are not well-documented. We completed a retrospective analysis of aeromedical patient care records in order to describe the pre-arrest characteristics and the return of spontaneous circulation (ROSC) in this subset of patients. MATERIALS AND METHODS: A retrospective chart reviews of patients suffering from cardiac arrest while being treated by a single aeromedical transport service between 1998 and 2000. Crew configurations were paramedic/nurse or paramedic/physician. Data were directly abstracted by the authors and descriptive data of patient demographics, vital signs and medical history were obtained. Data were separated into medical and traumatic arrests and analyzed by chi2- and t-test. Logistic regression analyses were performed to determine predictors of ROSC. RESULTS: During the 24-month interval, 12,140 patient transports occurred. Of these, 134 cardiac arrests occurred (1.1%) and are reviewed. Of these, 57 were medical arrests and 76 were traumatic arrests. Nine medical arrests and 37 traumatic arrests were excluded as the patient was in cardiac arrest before crew arrival. In the medical arrest cohort, the presence of a peripheral i.v. before crew arrival and initial rhythm of arrest were associated with ROSC at destination (p=0.05). In the traumatic arrest cohort, patients with lower diastolic blood pressures had a trend toward lower rates of ROSC (p=0.06). CONCLUSION: Cardiac arrest during aeromedical transport is infrequent. Patients with poor i.v. access are less likely to experience ROSC should they experience a cardiac arrest. Patients with traumatic injury and diastolic hypotension may be less likely to survive cardiac arrest during transport.

Unintentional Pediatric Ingestion of Cannabis-Addressing a Growing Public Health Risk.

This Viewpoint discusses the growing unintentional ingestion of cannabis and copycat products by children and urges clinicians, legitimate cannabis companies, large consumer brands, state attorneys general, and national legislators to provide solutions and education to adult users.