Glomus tumors of the head-neck-region

Glomus tumors of the head and neck are rare tumors of adulthood which arise from paraganglia or glomus cells within the carotid glomus, vagus nerve, middle ear or jugular foramen. The diagnosis of these mostly benign lesions is predominantly done with CT and MRI. DSA can provide important additional information. Besides surgical resection, one therapy option is radiological intervention with tumor embolisation. Because of the typical radiological imaging and the "salt and pepper appearance" in MRI, glomus tumors can be differentiated from other lesions in the head and neck. This review gives a survey of the classification, diagnosis and therapy of paragangliomas with images to demonstrate characteristic features.     

Trends in accessibility to medicines for children in New Zealand: 1998-2002

BACKGROUND: Reported rates of unlicensed and off-label use of medicines in children raise concerns regarding overall access of children to medicines OBJECTIVE: To assess changes in availability of proprietary formulations suitable for infants and young children; licensing of medicines; and subsidization of medicines for children in New Zealand. METHODS: Review of the New Ethicals Catalogue, New Ethicals Compendium, product data sheets and the New Zealand Pharmaceutical Schedule covering the years 1998-2002 inclusive. RESULTS: There was a decrease in the total number of medicines licensed in New Zealand from 2014 to 1840; but there was an increase in the number and percentage of suitable formulations that were licensed for paediatric use from 616[31%] to 642[35%]. The number of suitable paediatric formulations that were subsidized decreased from 281[13.9%] to 260[14.1%]. The number of orally available chemical entities with suitable formulations, licensed and subsidized for paediatric use declined from 101[5.0%] to 94[5.1%], but all of these chemical entities that were withdrawn had therapeutic alternatives that were licensed and subsidized. Only 36% of new medicines that had licensing for children were licensed for the 0-23 month age group. CONCLUSION: There have been modest improvements in licensing of medicines for children in New Zealand from 1998 to 2002.     

Compliance with poisons center referral advice and implications for toxicovigilance

BACKGROUND: When Poisons Information, or Poisons Control Centers (PCC) give directive advice in response to general public calls it is usually assumed that the advice will be followed, but it is difficult to measure the actual compliance of callers to a PCC. Epidemiological data regarding the incidence of poisoning incidents (Toxicovigilance) often utilizes reports of calls to a PCC. METHODS: Retrospective review of advice given to all callers to the New Zealand National Poisons Centre (NZNPC) from a defined area for the calendar year 2001. Callers to the NZNPC telephone hotlines who were advised to attend or not to attend the hospital Emergency Department (ED) were subsequently matched with actual ED visits. RESULTS: The compliance rate for those advised to attend the ED was 76.1%, whereas those advised not to attend had a compliance rate of 98.7%. The overall compliance rate was 94.1%. Of the patients presenting to the ED with a potential poisoning, only 10.2% were referred by the PCC. The callers referred by PCC and direct ED visitors appeared to differ in some respects. CONCLUSIONS: Compliance with PCC telephone advice is similar to the compliance rates in many other health interventions. Comparisons between populations calling a PCC and those self-presenting to an ED show that PCC data may not reflect the true burden of poisoning to health care systems.     

Vascular malformations in newborn infants, infants and children

Vascular malformations are the cause of nearly all non-traumatic intracranial hemorrhage in children beyond the neonatal stage. Therefore, any child presenting with spontaneous intracranial hemorrhage should be evaluated for child abuse and for vascular malformations. Intracerebral malformations of the cerebral vasculature include vein of Galen malformations, arteriovenous malformation (AVM), cavernomas, dural arteriovenous fistulas, venous anomalies (DVA), and capillary teleangiectasies. Although a few familial vascular malformation have been reported, the majority are sporadic. Clinical symptoms, diagnostic and therapeutic options are discussed.     

Inhibition by arachidonic acid and other fatty acids of dopamine uptake at the human dopamine transporter

It is known that arachidonic acid, in addition to promoting release of dopamine, can inhibit its transport. The present study provides preliminary information on structure-activity relationships for uptake inhibition by rotating disk voltammetry in human embryonic kidney-293 cells expressing the human dopamine transporter. Except for anandamide, all other fatty acids studied at a pretreatment concentration of 80 microM caused significant reductions in Vmax but not Km. Increasing saturation of the hydrocarbon tails (partial saturation: oleic acid, linoleic acid; full saturation: arachidic acid, stearic acid, stearic acid ethyl ester) removed inhibitory activity incrementally, suggesting a role for cis-unsaturation (folding/bending of hydrocarbon tails). The relative lack of effect of 5,8,11,14-eicosatetraynoic acid also supports the idea that less linear structures are less inhibitory on dopamine uptake. Esterification of the free carboxylic group (arachidonic acid ethyl ester) prevented most of the inhibitory activity, arguing against mere membrane lipid disruption. Finally, the endogenous cannabinoid anandamide greatly reduced uptake Vmax accompanied by a small decrease in Km, a potentially important effect on dopaminergic neurotransmission.     

Dopamine transporter as target for drug development of cocaine dependence medications

Because much evidence implicates the dopamine transporter in the reinforcing effects of cocaine, development of potential medications for cocaine dependence has included the dopamine transporter as a target. The present overview covers progress in the drug development area regarding several classes of dopamine uptake inhibitors, with an emphasis on structure-activity relationships that enhance potency and selectivity at transporters for dopamine compared with those for serotonin or norepinephrine. The following categories of compounds are covered: tropane, benztropine, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR), methylphenidate, mazindol, and phencyclidine analogs. Activity at transporters as well as on behavior is highlighted.     

Inhibition of VEGF-dependent multistage carcinogenesis by soluble EphA receptors

Elevated expression of Eph receptors has long been correlated with the growth of solid tumors. However, the functional role of this family of receptor tyrosine kinases in carcinogenesis and tumor angiogenesis has not been well characterized. Here we report that soluble EphA receptors inhibit tumor angiogenesis and tumor progression in vivo in the RIP-Tag transgenic model of vascular endothelial growth factor (VEGF)-dependent multistage pancreatic islet cell carcinoma. Soluble EphA receptors delivered either by a transgene or an osmotic minipump inhibited the formation of angiogenic islet, a premalignant lesion, and reduced tumor volume of solid islet cell carcinoma. EphA2-Fc or EphA3-Fc treatment resulted in decreased tumor volume but increased tumor and endothelial cell apoptosis in vivo. In addition, soluble EphA receptors inhibited VEGF and betaTC tumor cell-conditioned medium-induced endothelial cell migration in vitro and VEGF-induced cornea angiogenesis in vivo. A dominant negative EphA2 mutant inhibited--whereas a gain-of-function EphA2 mutant enhanced--tumor cell-induced endothelial cell migration, suggesting that EphA2 receptor activation is required for tumor cell-endothelial cell interaction. These data provide functional evidence for EphA class receptor regulation of VEGF-dependent tumor angiogenesis, suggesting that the EphA signaling pathway may represent an attractive novel target for antiangiogenic therapy in cancer.     

Population Pharmacokinetic Modeling of Steady State Carbamazepine Clearance in Children, Adolescents, and Adults

Carbamazepine (CBZ) clearance decreases from childhood to adulthood and the factors determining this change could include age, size, autoinduction, or maturational changes. This study aims to describe the population pharmacokinetics of CBZ in children and young adults and test the hypothesis that CBZ clearance correlates with weight, surface area, and age. CBZ therapeutic drug monitoring data (sparse data) were collected from child and adult epileptics, and rich data were obtained from a bioequivalence study of CBZ in young adults. Population pharmacokinetic analysis was performed using NONMEM V. Forward stepwise, multiple regression was performed on the covariates. Bootstrap validation was performed. A total of 946 observations from 91 subjects, ages 0.7–37 years, were collected and analyzed. A one-compartment, first-order absorption and elimination model, with exponential interindividual error and additive residual error models was developed. The population model was: Clearance (Lhr ^–1)=((2.24 · Surface area (m ²))+(0.047 · Dose (mg · kg ^–1)); Volume of distribution (L)=0.37 · weight (kg); Absorption rate constant=0.013 (hr ^–1). CBZ clearance increased with surface area and dose.     

Structure-activity relationship studies of 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine derivatives and their N-analogues: evaluation of O-and N-analogues and their binding to monoamine transporters

In our effort to develop a pharmacotherapy for the treatment of cocaine addiction, we embarked on synthesizing novel molecules targeting the dopamine transporter (DAT) molecule in the brain as DAT has been implicated strongly in the reinforcing effect of cocaine. Our previously developed DAT-selective piperidine analogue, 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine, was the basis for our current structure-activity relationship (SAR) studies exploring the significance of the contribution of the benzhydryl O- and N-atoms in these molecules in interacting with the DAT. Thus, we replaced the benzhydryl O-atom with an N-atom, altered the location of the benzhydryl N-atom to an adjacent position, and in one other occasion converted the benzhydryl O-ether linkage into an oxime-type derivative. Furthermore, we also evaluated the important contribution of the piperidine N-atom to binding by altering its pK(a) value chemically. Novel analogues were tested for potency in inhibiting [3H]WIN 35,428, [3H]citalopram, and [3H]nisoxetine binding at the DAT, serotonin transporter (SERT), and norepinepherine transporter (NET). [3H]DA was used to measure DA reuptake inhibition. The results indicated that the benzhydryl O- and N-atoms are exchangeable for the most part. On the other hand, an enhanced interaction with the SERT was observed when the benzhydryl N-atom moved to an adjacent position (21a; DAT (IC(50)) = 19.7, SERT (IC(50)) = 137 nM, NET (IC(50)) = 1111 nM). In either cases, further alkylation of the N-atom reduced the activity for the transporter. The presence of a powerful electron-withdrawing cyano group in compound 5d expectedly produced the most potent and selective ligand for the DAT (DAT (IC(50)) = 3.7 nM, DAT/SERT = 615). Selected compounds were further analyzed in the dopamine reuptake inhibition assay. Preliminary behavioral assessment of some of the selected compounds in mice indicated that these compounds are much less stimulating when compared with cocaine at comparable doses. In drug-discrimination studies these selected compounds incompletely generalized from the cocaine stimulus in mice trained to discriminate 10 mg/kg cocaine from vehicle.