Pediatric prehospital care in urban and rural areas

There are limited data concerning pediatric prehospital care, although pediatric prehospital calls constitute 10% of emergency medical services activity. Data from 10,493 prehospital care reports in 11 counties of California (four emergency medical services systems in rural and urban areas) were collected and analyzed. Comparison of urban and rural data found few significant differences in parameters analyzed. Use of the emergency medical services system by pediatric patients increased with age, but 12.5% of all calls were for children younger than 2 years. Calls for medical problems were most common for patients younger than 5 years of age; trauma was a more common complaint in rural areas (64%, P = .0001). Frequency of vital sign assessment differed by region, as did hospital contact (P less than .0001). Complete assessment of young pediatric patients, with a full set of vital signs and neurologic assessment, was rarely performed. Advanced life support providers were often on the scene, but advanced life support treatments and procedures were infrequently used. This study suggests the need for additional data on which to base emergency medical services system design and some directions for education of prehospital care providers.     

Novel antagonists of the 5-HT3 receptor. Synthesis and structure-activity relationships of (2-alkoxybenzoyl)ureas.

A series of benzoylureas derived from bicycle amines were prepared and evaluated for 5-HT3 antagonist activity on the rat isolated vagus nerve. From among these compounds, those analogues which were ortho substituted by an alkoxy group on the benzoyl function were shown to be potent 5-HT3 antagonists with similar or greater potency than the standard agent ondansetron. NMR and X-ray crystallography studies showed these o-alkoxy compounds to exist as a planar, hydrogen-bonded, tricyclic ring system. In molecular modeling studies on endo-N-[[(8-methyl-8-azabicyclo[3.2.1]octan-3-yl-amino] carbonyl]-2-(cyclopropylmethoxy)benzamide (30) the central hydrogen-bonded ring was able to mimic an aromatic ring present in previously reported 5-HT3 antagonists.     

Acetylator genotype-dependent metabolic activation of carcinogenic N-hydroxyarylamines by S-acetyl coenzyme A-dependent enzymes of inbred hamster tissue cytosols: relationship to arylamine N-acetyltransferase

A genetic polymorphism in S-acetyl coenzyme A (AcCoA)-dependentN-acetyltransferase has been associated with a differentialrisk for certain cancers in humans. In this study, several tissuesfrom the inbred Syrian hamster with a genetically defined AcCoA-dependentN-acetyltransferase polymorphism (homozygous rapid acetylator,Bio. 87.20; homozygous slow acetylator, Bio. 82.73/H; and heterozygousacetylator, Bio. 87.20 x Bio. 82.73/H F₁), were investigatedfor the relationship of arylamine N-acetyltransferase to theAcCoA-dependent metabolic activation of carcinogenic N-hydroxy(N-OH)-arylamines to bind to DNA (O-acetyltransferase). Thelevels of both 2-aminofluorene (AF) N-acetyltransferase andN-OH-AF O-acetyltransferase activity reflected the N-acetylatorgenotype in liver, intestine, kidney and lung cytosols. A significantacetylator gene—dose response for AF N-acetyltransferaseand N-OH-AF O-acetyltransferase activities was observed in liverand lung cytosols. In contrast, acetylator genotype was notconsistently expressed for the AcCoA-dependent N-acetylationof 4-aminobiphenyl (ABP), nor for the AcCoA-dependent metabolicactivation of N-OH ABP and N-OH-3,2'-dimethyl-4-aminobiphenylin these me tissue cytosols. Two peaks of acetyltransferaseactivity were partially purified by ion exchange FPLC chromatographyfrom the hepatic cytosol of both the homozygous rapid and homozygousslow acetylator hamster. In contrast to unfractionated cytosol,the isozyme(s) eluting first clearly demonstrated levels ofAcCoA-dependent arylamine N-acetyltransferase and N-OH-arylamineO-acetyltransferase activities that were consistent with N-acetylatorgenotype (polymorphic) for all substrates tested. In contrast,the slower eluting isozyme(s) in each acetylator cytosol showedlevels of AcCoA-dependent N-and O-acetyltransferase activitiesthat did not vary with N-acetylator genotype (monomorphic).The AcCoA-dependent O-acetyltransferase activity of both themonomorphic and polymorphic peaks was paraoxon resistant. Thesestudies demonstrate acetylator genotype-dependent control ofAcCoA-dependent metabolic activation of N-OH-arylamines(O-acetylation)by polymorphic isozyme(s) similar to that for AcCoA-dependentN-acetylation of arylamines in the hamster. The polymorphicgenetic control of N-OH arylamine O-acetyltransferase may bean important risk factor for arylamine-induced cancer, in thosespecies and tissues expressing appreciable levels of O-acetyltransferaseactivity.     

Oral and maxillofacial surgery in patients with chronic orofacial pain.

PURPOSE: In this investigation, we evaluated a population of patients with chronic orofacial pain who sought treatment at a pain center in an academic institution. These patients were evaluated with respect to 1) the frequency and types of previous oral and maxillofacial surgery procedures, 2) the frequency of previous significant misdiagnoses, and 3) the number of patients who subsequently required surgical treatment as recommended by an interdisciplinary orofacial pain team. The major goal of this investigation was to determine the role of oral and maxillofacial surgery in patients with chronic orofacial pain. Patients and Methods: The study population included patients seen at the Center for Oral, Facial and Head Pain at New York Presbyterian Hospital from January 1999 through April 2001. (120 patients; female-to-male ratio, 3:1; mean age, 49 years; average pain duration, 81 months; average number of previous specialists, 6). The patient population was evaluated by an interdisciplinary orofacial pain team and the following characteristics of this population were profiled: 1) the frequency and types of previous surgical procedures, 2) diagnoses, 3) the frequency of previous misdiagnoses, and 4) treatment recommendations made by the center team. RESULTS: There was a history of previous oral and maxillofacial surgical procedures in 38 of 120 patients (32%). Procedures performed before our evaluation included endodontics (30%), extractions (27%), apicoectomies (12%), temporomandibular joint (TMJ) surgery (6%), neurolysis (5%), orthognathic surgery (3%), and debridement of bone cavities (2%). Surgical intervention clearly exacerbated pain in 21 of 38 patients (55%) who had undergone surgery. Diagnoses included myofascial pain (50%), atypical facial neuralgia (40%), depression (30%), TMJ synovitis (14%), TMJ osteoarthritis (12%), trigeminal neuralgia (10%), and TMJ fibrosis (2%). Treatment recommendations included medications (91%), physical therapy (36%), psychiatric management (30%), trigger injections (15%), oral appliances (13%), biofeedback (13%), acupuncture (8%), surgery (4%), and Botox injections (1%) (Allergan Inc, Irvine, CA). Gross misdiagnosis leading to serious sequelae, with delay of necessary treatment, occurred in 6 of 120 patients (5%). CONCLUSIONS: Misdiagnosis and multiple failed treatments were common in these patients with chronic orofacial pain. These patients often have multiple diagnoses, requiring management by multiple disciplines. Surgery, when indicated, must be based on a specific diagnosis that is amenable to surgical therapy. However, surgical treatment was rarely indicated as a treatment for pain relief in these patients with chronic orofacial pain, and it exacerbated and perpetuated pain symptoms in some of them.     

Kinetic characteristics of ICI D1694: a quinazoline antifolate which inhibits thymidylate synthase.

The thymidylate synthase (TS) inhibitor ICI D1694 (N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N -methylamino]-2 - thenoyl)-S-glutamic acid) is a structural analogue of the substrate N5,N10-methylenetetrahydrofolate (5,10-CH2FH4) and is currently under clinical evaluation as a treatment for cancer. The compound is shown here to be a mixed non-competitive inhibitor of TS from murine leukemia (L1210) cells when 5,10-CH2FH4 is varied. This result suggests formation of an inactive complex between TS, 5,10-CH2FH4 and the inhibitor. Thus, binding to only one of the two active sites on the TS homodimer may be sufficient to prevent catalysis fully. Treatment of L1210 cells with ICI D1694 is known to cause intracellular accumulation of the tetraglutamate derivative which is shown here to have a 60-fold higher affinity for TS. The IC50 for inhibition of L1210 cell growth is below the Ki value of ICI D1694 for L1210 TS but above that of the tetraglutamate. The formation of polyglutamates and concentration of drug inside cells, therefore, seem to be responsible for biological activity.     

Compression plating for child and adolescent femur fractures.

Twenty-five children ranging in age from 6-16 years underwent AO compression plate fixation for treatment of a femur fracture. Generally, the most common reason for plate fixation was to simplify nursing care and rehabilitation of children with an associated severe head injury or polytrauma. Twenty-three fractures healed in 11 weeks on the average, most by periosteal bone formation. Leg length discrepancy was not a clinical problem. Nursing care and polytrauma rehabilitation were simplified in all children. We believe that plate fixation is a reasonable treatment option for femoral fracture care in children aged less than 11 years with severe head injury or associated polytrauma.     

The pharmacology of GR203040, a novel, potent and selective non-peptide tachykinin NK1 receptor antagonist.

1. The in vitro and in vivo pharmacology of GR203040 ((2S, 3S)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-y l)-amine), a novel, highly potent and selective non-peptide tachykinin NK1 receptor antagonist, was investigated in the present study. 2. GR203040 potently inhibited [3H]-substance P binding to human NK1 receptors expressed in Chinese hamster ovary (CHO) and U373 MG astrocytoma cells, and NK1 receptors in ferret and gerbil cortex (pKi values of 10.3, 10.5, 10.1 and 10.1 respectively). GR203040 had lower affinity at rat NK1 receptors (pKi = 8.6) and little affinity for human NK2 receptors (pKi < 5.0) in CHO cells and NK3 receptors in guinea-pig cortex (pKi < 6.0). With the exception of the histamine H1 receptor (pIC50 = 7.5). GR203040 had little affinity (pIC50 < 6.0) at all non-NK1 receptors and ion channels examined. Furthermore, GR203040 produced only weak inhibition of Na+ currents in SH-SY5Y neuroblastoma and superior cervical ganglion cells (pIC50 values < 4.0). GR203040 produced only weak antagonism of Ca(2+)-evoked contractions of rat isolated portal vein (pKn = 4.1). The enantiomer of GR203040, GR205608 (2R, 3R)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-y l)-amine), had 10,000 fold lower affinity at the human NK1 receptor expressed in CHO cells (pKi = 6.3). 3. In gerbil ex vivo binding experiments, GR203040 produced a dose-dependent inhibition of the binding of [3H]-substance P to cerebral cortical membranes (ED50 = 15 micrograms kg-1 s.c. and 0.42 mg kg-1 p.o.). At 10 micrograms kg-1 s.c., the inhibition of [3H]-substance P binding was maintained for > 6 h. In the rat, GR203040 was less potent (ED50 = 15.4 mg kg-1 s.c.) probably reflecting, at least in part, its lower affinity at the rat NK1 receptor. 4. In guinea-pig isolated ileum and dog isolated middle cerebral and basilar arteries, GR203040 produced a rightward displacement of the concentration-effect curves to substance P methyl ester (SPOMe) with suppression of the maximum agonist response (apparent pKB values of 11.9, 11.2 and 11.1 respectively). 5. In anaesthetized rabbits, GR203040 antagonized reductions in carotid arterial vascular resistance evoked by SPOMe, injected via the lingual artery (DR10 (i.e. the dose producing a dose-ratio of 10) = 1.1 micrograms kg-1, i.v.). At a dose 20 fold greater than its DR10 value (i.e. 22 micrograms kg-1, i.v.), significant antagonism was evident more than 2 h after GR203040 administration. 6. In anaesthetized rats, GR203040 (3 and 10 mg kg-1, i.v.) produced a dose-dependent inhibition of plasma protein extravasation in dura mater, conjunctiva, eyelid and lip in response to electrical stimulation of the trigeminal ganglion. 7. It is concluded that GR203040 is one of the most potent and selective NK1 receptor antagonists yet described, and as such, has considerable potential as a pharmacological tool to characterize the physiological and pathological roles of substance P and NK1 receptors. GR203040 may also have potential as a novel therapeutic agent for the treatment of conditions such as migraine, emesis and pain.