Gamma knife stereotactic radiosurgery for thalamic & brainstem cavernous angiomas.

OBJECTIVE: To determine the safety and efficacy of Gamma Knife stereotactic radiosurgery (GKS) in the treatment of patients with symptomatic cavernous angiomas (CA) of the brainstem or thalamus, by comparing overall outcome to the natural history of the disease. METHODS: Over 10 years a series of 16 consecutively presenting patients (M = 9, F = 7) with thalamic or brainstem CA were treated with GKS to a single lesion, specifically excluding the haemosiderin ring from the target. Within the year prior to treatment eight patients had suffered one symptomatic haemorrhage and eight had suffered more than one symptomatic haemorrhage. Mean age at treatment was 38.9 (15-55) years. Mean prescription dose 13.31 Gray (11.0 Gy-16.0 Gy). Patients were followed up radiologically and, more importantly, clinically for a mean period of 43.8 (11-101) months, median 36 months. RESULTS: One patient suffered recurrent haemorrhage at 23 months post-GKS, but has not re-bled in the following 61 months. One patient died of thalamic haemorrhage from the treated lesion at 90 months. One patient was lost to follow up. There have been no other clinical episodes or radiological findings to suggest post-GKS haemorrhage in the remaining 13 patients, and no other complications were observed in the treated population. The annual haemorrhage rate within the first two years post GKS was 3.72% and the annual haemorrhage rate 2 years post GKS was 3.59% per annum. CONCLUSION: With the dose regimens described, GKS is safe and effective in the treatment of thalamic and brainstem CA, as assessed by significant reduction in observed rate of re-haemorrhage over that expected from the known natural history of those CAs which have already demonstrated a tendency to haemorrhage in highly eloquent areas.

Comparison of radiosurgery planning modalities for acoustic neuroma with regard to conformity and mean target dose.

PURPOSE: To evaluate dose conformity and mean target dose in light of previous comparative studies and state-of-the-art radiosurgery delivery modalities. MATERIALS AND METHODS: Seven patients with acoustic neuromas deemed clinically suitable for linear accelerator or Gamma Knife radiosurgery were planned such that the minimum doses for any plan were equal. Gamma Knife plans were prepared in three ways: by altering the prescription of previously published data, by hand and with the assistance of an automatic planning algorithm (wizard). The linear accelerator plans were prepared utilizing a micro-multileaf collimator in both static and dynamic modes. The dose volume histogram analyses lead to a measure of conformity and the mean and minimum target dose for each plan. Statistical significance was calculated as each planning modality was compared with every other. RESULTS: All Gamma Knife plans demonstrated a statistically significantly better conformity when compared with fixed field linear accelerator techniques. When compared to linear accelerator techniques the wizard-assisted Gamma Knife plans demonstrated significantly better conformity. The mean target dose for all the Gamma Knife plans was significantly higher than that of the linear accelerator plans (19.2 Gy vs. 13.4 Gy). CONCLUSIONS: Conformity of the prescription isodose to the target shape is of major importance in radiosurgery. The modalities compared represent commercially available and widely accepted systems. Gamma Knife plans derived using the 'wizard' option and finalized by hand yield the best conformity.

Syringe tip accuracy for application of Victor Horsley's bone wax.

An inexpensive way of improving the handling properties of white bone wax is described.

SB-243213; a selective 5-HT2C receptor inverse agonist with improved anxiolytic profile: lack of tolerance and withdrawal anxiety.

SB-243213 (5-methyl-1-[[-2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline hydrochloride) is a new, selective 5-hydroxytryptamine (5-HT)2C receptor inverse agonist. SB-243213 has high affinity for the human 5-HT2C receptor (pK(i) 9.37) and greater than a 100-fold selectivity over a wide range of neurotransmitter receptors, enzymes and ion channels. In in vitro functional studies, SB-243213 acted as an inverse agonist at the human 5-HT2C receptor with a pK(b) of 9.8. In in vivo studies, SB-243213 was a potent inhibitor of central 5-HT2C receptor-mediated function in rats, blocking meta-chlorophenylpiperazine-induced hypolocomotion with an ID50 of 1.1 mg/kg p.o. and a long duration of action (>8 h). In rats, SB-243213 exhibited anxiolytic-like activity in both the social interaction and Geller-Seifter conflict tests. Importantly, unlike diazepam, chronic administration of SB-243213 did not result in the development of either tolerance to the anxiolytic-like effects or withdrawal anxiogenesis. Furthermore, in rodents, SB-243213 did not affect seizure threshold, did not increase body weight or induce catalepsy, but attenuated the haloperidol-induced catalepsy. SB-243213 did not affect amphetamine-, MK-801- or phencyclidine-induced hyperactivity. In conclusion, SB-243213 may possess an improved anxiolytic profile compared to benzodiazepines. SB-243213 also modulates dopaminergic transmission, lacks pro-psychotic properties and may have utility in the treatment of schizophrenia and motor disorders.

Head protection in England before the first World War.

Man has sought to protect himself from physical injury resulting either from the vicissitudes of an arbitrary natural environment or from the calculated activity of his fellow creatures since at least the beginning of recorded time. The earliest substantial British evidence of this activity dates from shortly after the Roman invasion of 55 BC. The head has always been seen by both assailant and defender as a region of particular vulnerability, where an incapacitating blow might most effectively be landed. We present an overview of the evolution and development of English military head protection through the ages, with particular reference to the advances made in metallurgical technology at Greenwich through the course of the 16th century. Much of this represents original research by the authors (particularly ARW), published here for the first time. We include the first metallographic data on armor excavated from the Wisby grave-pits (1361), the first scientific analysis of the textile composition of medieval helmet linings from the Wallace Collection, and the first metallurgical study of the Windsor Castle suit, the personal armor of King Henry VIII, perhaps England's most famous monarch. We combine this with our own experimental data, also previously unpublished, relating to the attack energy available from ancient weaponry (whose technology determines the design of defenses, then as now) in an attempt to assess the effectiveness of helmets. Finally, we set this in the context of contemporary medical technology. The latter is found to be woefully inadequate when presented with serious head injuries. Nevertheless, mortality from battlefield injury has been reduced from ancient times to the present day, despite advances in weapons technology.

1-[2-[(Heteroaryloxy)heteroaryl]carbamoyl]indolines: novel and selective 5-HT2C receptor inverse agonists with potential as antidepressant/anxiolytic agents.

Bisaryl ethers have been identified with excellent 5-HT2C affinity and selectivity over both 5-HT2A and 5-HT2B receptors. Compounds such as 11, 27 and 38 have potent oral activity in a centrally mediated pharmacodynamic model of 5-HT2C function and their potential as novel non-sedating anxiolytic and antidepressants is under investigation.

1-[2-[(Heteroarylmethoxy)aryl]carbamoyl]indolines are selective and orally active 5-HT2C receptor inverse agonists.

Bisarylmethoxyethers have been identified with nanomolar 5-HT2C affinity and selectivity over both 5-HT2A and 5-HT2B receptors. Compounds such as 1, 2, 8, 12, 14 and 18 have potent oral activity in a centrally mediated pharmacodynamic model of 5-HT2C function and their therapeutic potential is currently under further investigation.

5-ht6 receptors as emerging targets for drug discovery.

5-ht6 receptors are the latest serotonin receptors to be identified by molecular cloning. Their high affinity for a wide range of drugs used in psychiatry, coupled with their intriguing distribution in the brain, has stimulated significant interest. Antisense oligonucleotides, antipeptide antibodies, selective radioligands, knockout mice, and selective antagonists of the 5-ht6 receptor have recently become available. Surprisingly, 5-ht6 receptors appear to regulate cholinergic neurotransmission in the brain, rather than the expected interaction as modulators of dopaminergic transmission. This interaction predicts a possible role for 5-ht6 receptor antagonists in the treatment of learning and memory disorders. Furthermore, polymorphisms in the sequence of the 5-ht6 receptor gene may provide a genetic tool to further our understanding of the differential responses of patients to antipsychotic medications.

Biarylcarbamoylindolines are novel and selective 5-HT(2C) receptor inverse agonists: identification of 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]- 5-pyridyl]carbamoyl]-6-trifluoromethylindoline (SB-243213) as a potential antidepressant/anxiolytic agent.

The evolution, synthesis, and biological activity of a novel series of 5-HT(2C) receptor inverse agonists are reported. Biarylcarbamoylindolines have been identified with excellent 5-HT(2C) affinity and selectivity over 5-HT(2A) receptors. In addition, (pyridyloxypyridyl)carbamoylindolines have been discovered with additional selectivity over the closely related 5-HT(2B) receptor. Compounds from this series are inverse agonists at the human cloned 5-HT(2C) receptor, completely abolishing basal activity in a functional assay. The new series have reduced P450 inhibitory liability compared to a previously described series of 1-(3-pyridylcarbamoyl)indolines (Bromidge et al. J. Med. Chem. 1998, 41, 1598) from which they evolved. Compounds from this series showed excellent oral activity in a rat mCPP hypolocomotion model and in animal models of anxiety. On the basis of their favorable biological profile, 32 (SB-228357) and 40 (SB-243213) have been selected for further evaluation to determine their therapeutic potential for the treatment of CNS disorders such as depression and anxiety.

Immunohistochemical localisation of the 5-HT2C receptor protein in the rat CNS.

5-HT2C receptor mRNA has a widespread distribution in the human and rat CNS but the absence of a specific high affinity ligand has made autoradiographic localisation of the receptor difficult. By raising polyclonal antibodies against the rat 5-HT2C receptor protein this study reports the immunohistochemical distribution of this receptor in the rat CNS. A sephadex purified 5-HT2C antiserum visualised a single immunopositive band (54 kDa) in Western blots of membranes prepared from several rat brain regions and caused intense membrane immunofluorescence in HEK 293 cells transfected with h5-HT2C cDNA, which were both attenuated by incubation with the antigenic peptide sequence (200-300 microM). 5-HT2C-like immunoreactivity was located on neurones throughout the CNS. The most abundant 5-HT2C-like immunoreactive cell bodies were in the anterior olfactory nucleus, medial and intercalated amygdaloid nuclei, hippocampus layers CA1 to CA3, laterodorsal and lateral geniculate thalamic nuclei, caudate-putamen and several areas of the cortex (including piriform and frontal), consistent with this receptor being located postsynaptic to serotonergic neurones. Immunopositive neurones were also found in the dorsal raphé, suggesting that 5-HT2C receptors may be on some serotonergic neurones. The overall distribution of 5-HT2C-like immunoreactivity complements previous findings with conventional radioligands and agrees well with reported levels of 5-HT2C receptor mRNA.

Attenuation of haloperidol-induced catalepsy by a 5-HT2C receptor antagonist.

Atypical neuroleptics produce fewer extrapyramidal side-effects (EPS) than typical neuroleptics. The pharmacological profile of atypical neuroleptics is that they have equivalent or higher antagonist affinity for 5-HT2 than for dopamine D2 receptors. Our aim was to identify which 5-HT2 receptor contributed to the atypical profile. Catalepsy was defined as rats remaining immobile over a horizontal metal bar for at least 30 s, 90 min after dosing. Radioligand binding assays were carried out with homogenates of human recombinant 5-HT2A, 5-HT2B and 5-HT2C receptors expressed in Human Embryo Kidney (HEK293) cells. Haloperidol (1.13 mg kg(-1) i.p.) induced catalepsy in all experiments. The selective 5-HT2C/2B receptor antagonist, SB-228357 (0.32-10 mg kg(-1) p.o.) significantly reversed haloperidol-induced catalepsy whereas the 5-HT2A and 5-HT2B receptor antagonists, MDL-100907 (0.003-0.1 mg kg(-1) p.o.) and SB-215505 (0.1-3.2 mg kg(-1) p.o.) respectively did not reverse haloperidol-induced catalepsy. The data suggest a role for 5-HT2C receptors in the anticataleptic action of SB-228357.

Model studies on a synthetically facile series of N-substituted phenyl-N'-pyridin-3-yl ureas leading to 1-(3-pyridylcarbamoyl) indolines that are potent and selective 5-HT(2C/2B) receptor antagonists.

A model series of 5-HT2C antagonists have been prepared by rapid parallel synthesis. These N-substituted phenyl-N'-pyridin-3-yl ureas were found to have a range of 5-HT2C receptor affinities and selectivities over the closely related 5-HT2A receptor. Extrapolation of simple SAR, derived from this set of compounds, to the more active but synthetically more complex 1-(3-pyridylcarbamoyl)indoline series allowed us to target optimal substitution patterns and identify potent and selective 5-HT(2C/2B) antagonists.

Stereotactic intracavitary therapy of recurrent cystic craniopharyngioma by instillation of 90yttrium.

Six consecutively presenting patients with craniopharyngiomas, (F:M = 4.2; mean age: 35.2 years, range 17-58) histologically proven by one or more previous operations, and with recurrence of a wholly or predominantly cystic nature, were treated by 90yttrium (90Y) radioisotope instillation into the cyst. Five patients had undergone external beam radiotherapy and the remaining patient had concomitant stereotactic radiosurgery to a co-existing solid component. Seven cysts in six patients have been treated. Five cysts, previously requiring repeated aspiration at intervals of 2-20 weeks have required no further surgical intervention following 90Y treatment (FU mean 3.5 years, range 1.2-7), although two of these required a second 90Y treatment. No patient developed a visual field defect or evidence of hypothalamic dysfunction. One patient died within a month of treatment from complications related to a solid recurrence. One patient developed a large solid/cystic recurrence at 4 months and died shortly thereafter from an unrelated cause. We summarize results from other series that have demonstrated the efficacy of this technique, usually as primary therapy, but this is the first series to demonstrate its usefulness as salvage therapy. The prospect of survival with good quality of life can be offered to patients with multiply recurrent disease who have exhausted all conventional means of treatment. In our experience intracavitary 90Y is a safe and highly effective means of controlling cystic recurrence in refractory craniopharyngioma. Some patients require more than one treatment.

Novel and selective 5-HT2C/2B receptor antagonists as potential anxiolytic agents: synthesis, quantitative structure-activity relationships, and molecular modeling of substituted 1-(3-pyridylcarbamoyl)indolines.

The synthesis, biological activity, and molecular modeling of a novel series of substituted 1-(3-pyridylcarbamoyl)indolines are reported. These compounds are isosteres of the previously published indole urea 1 (SB-206553) and illustrate the use of aromatic disubstitution as a replacement for fused five-membered rings in the context of 5-HT2C/2B receptor antagonists. By targeting a region of space previously identified as sterically allowed at the 5-HT2C receptor but disallowed at the 5-HT2A receptor, we have identified a number of compounds which are the most potent and selective 5-HT2C/2B receptor antagonists yet reported. 46 (SB-221284) was selected on the basis of its overall biological profile for further evaluation as a novel, potential nonsedating anxiolytic agent. A CoMFA analysis of these compounds produced a model with good predictive value and in addition good qualitative agreement with both our 5-HT2C receptor model and our proposed binding mode for this class of ligands within that model.

SB-205384: a GABA(A) receptor modulator with novel mechanism of action that shows subunit selectivity.

1. SB-205384, and its (+) enantiomer (+)-SB-205384 were tested for their modulatory effects on human GABA(A) receptor subunit combinations expressed in Xenopus oocytes by electrophysiological methods. 2. The slowing of the decay rate induced by SB-205384 on native GABA-activated currents in rat neurones was also seen on GABA(A) currents in oocytes expressing human GABA(A) subunits. This temporal effect was observed for the alpha3beta2gamma2 subunit combination with little effect in subunit combinations containing either alpha1 or alpha2. 3. Potentiation of the peak amplitude of the GABA-activated currents by SB-205384 or (+)-SB-205384 was less specific for a particular subunit combination, although the greatest effect at 10 microM drug was seen on the alpha3beta2gamma2 subunit combination. 4. In contrast, zolpidem, a benzodiazepine site modulator, did not significantly slow decay rates of GABA(A) currents in oocytes expressing the alpha3beta2gamma2 subunit combination. Zolpidem, as expected, did selectively potentiate GABA-activated currents on oocytes expressing the gamma2 subunit compared to those containing the gamma1. 5. The results show that the novel kinetic modulatory profile of SB-205384 is selective for the alpha3beta2gamma2 subunit combination. This suggests that the compound is binding to a novel regulatory site on the subunit complex.

Profile of SB-204269, a mechanistically novel anticonvulsant drug, in rat models of focal and generalized epileptic seizures.

1. Earlier optimization of structure-activity relationships in a novel series of 4-(benzoylamino)-benzopyrans, led to the discovery of SB-204269 (trans-(+)-6-acetyl-4S-(4-fluorobenzoylamino)-3,4-dihydro-2, 2-dimethyl-2H-benzo[b]pyran-3R-ol, hemihydrate), a potent orally-active anticonvulsant in the mouse maximal electroshock seizure threshold (MEST) test. 2. Studies have now been undertaken to determine the effects of SB-204269 in a range of seizure models and tests of neurological deficits in rats. In addition, the compound has been evaluated in a series of in vitro mechanistic assays. 3. SB-204269 proved to be an orally-effective anticonvulsant agent, at doses (0.1-30 mg Kg-1) devoid of overt behavioural depressant properties, in models of both electrically (MEST and maximal electroshock (MEST)) and chemically (i.v. pentylenetetrazol (PTZ) infusion)-evoked tonic extension seizures. However, the compound did not inhibit PTZ-induced myoclonic seizures at doses up to 30 mg kg-1, p.o. 4. SB-204269 also selectively reduced focal electrographic seizure activity in an in vitro elevated K+ rat hippocampal slice model at concentrations (0.1-10 microM) that had no effect on normal synaptic activity and neuronal excitability. 5. In all of these seizure models, SB-204269 was equivalent or better than the clinically established antiepileptic drugs carbamazepine and lamotrigine, in terms of anticonvulsant potency and efficacy. 6. Unlike SB-204269, the corresponding trans 3S,4R enantiomer, SB-204268, did not produce marked anticonvulsant effects, an observation in accord with previous findings for other related pairs of trans enantiomers in the benzopyran series. 7. In the rat accelerating rotarod test, a sensitive paradigm for the detection of neurological deficits such as sedation and motor incoordination, SB-204269 was inactive even at doses as high as 200 mg kg-1, p.o. This was reflected in the excellent therapeutic index (minimum significantly effective dose in the rotarod test/ED50 in the MES test) for SB-204269 of > 31, as compared to equivalent values of only 7 and 13 for carbamazepine and lamotrigine, respectively. 8. At concentrations (> or = 10 microM) well above those required to produce anticonvulsant activity in vivo (i.e. 0.1 microM in brain), SB-204269 did not interact with many of the well known mechanistic targets for established antiepileptic drugs (e.g. Na+ channels or GABAergic neurotransmission). Subsequent studies have shown that the anticonvulsant properties of SB-204269 are likely to be mediated by a novel stereospecific binding site present in the CNS. 9. The overall efficacy profile in rodent seizure models, together with a minimal liability for inducing neurological impairment and an apparently unique mechanism of action, highlight the therapeutic potential of SB-204269 for the treatment of refractory partial and generalized tonic-clonic seizures.

SB 242084, a selective and brain penetrant 5-HT2C receptor antagonist.

SB 242084 has a high affinity (pKi 9.0) for the cloned human 5-HT2C receptor and 100- and 158-fold selectivity over the closely related cloned human 5-HT2B and 5-HT2A subtypes respectively. SB 242084 had over 100-fold selectivity over a range of other 5-HT, dopamine and adrenergic receptors. In studies of 5-HT-stimulated phosphatidylinositol hydrolysis using SH-SY5Y cells stably expressing the cloned human 5-HT2C receptor, SB 242084 acted as an antagonist with a pKb of 9.3, which closely resembled its corresponding receptor binding affinity. SB 242084 potently inhibited m-chlorophenylpiperazine (mCPP, 7 mgkg i.p. 20 min pre-test)-induced hypolocomotion in rats, a model of in vivo central 5-HT2C receptor function, with an ID50 of 0.11 mg/kg i.p., and 2.0 mg/kg p.o. SB 242084 (0.1-1 mg/kg i.p.) exhibited an anxiolytic-like profile in the rat social interaction test, increasing time spent in social interaction, but having no effect on locomotion. SB 242084 (0.1-1 mg/kg i.p.) also markedly increased punished responding in a rat Geller-Seifter conflict test of anxiety, but had no consistent effect on unpunished responding. A large acute dose of SB 242084 (30 mg/kg p.o.) had no effect on seizure susceptibility in the rat maximal electroshock seizure threshold test. Also, while SB 242084 (2 and 6 mg/kg p.o. 1 hr pre-test) antagonized the hypophagic response to mCPP, neither acute nor subchronic administration of the drug, for 5 days at 2 or 6 mg/kg p.o. twice daily, affected food intake or weight gain. The results suggest that SB 242084 is the first reported selective potent and brain penetrant 5-HT2C receptor antagonist and has anxiolytic-like activity, but does not possess either proconvulsant or hyperphagic properties which are characteristic of mutant mice lacking the 5-HT2C receptor.

Activation of 5-HT2B receptors in the medial amygdala causes anxiolysis in the social interaction test in the rat.

In a recent study, we reported the presence of neurones expressing 5-HT2B receptor protein in the medial amygdaloid nucleus of the adult rat brain. In the present study, bilateral micro-injection of the 5-HT2B receptor agonist 1-[5-(2-thienylmethoxy)-1H-3-indolyl]propan-2-amine hydrochloride (BW 723C86, 0.09 and 0.93 nmol, 5 min pretest) into the medial amygdaloid nuclei increased the total interaction time of a pair of male rats in the social interaction test, to a comparable extent to chlordiazepoxide (5 mg/kg p.o., 1 hr pretest) without altering locomotor activity; indicative of anxiolytic activity. The increase in social interaction was prevented by pretreatment with the 5-HT2C/2B receptor antagonist N-(1-methyl-5-indoyl)-N'-(3-pyridyl) urea hydrochloride (SB 200646A, at 2 but not 1 mg/kg p.o., 1 hr pretest), which did not alter behaviour when given alone. Intra-amygdala BW 723C86 (0.09, 0.31 and 0.93 nmol, 5 min pretest) did not significantly alter the number of punished responses made when the same rats were examined seven days later in a Vogel punished drinking test, although chlordiazepoxide (5 mg/kg p.o., 1 hr pretest) produced the expected anxiolytic profile. The results are consistent with the proposal that activation of 5-HT2B receptors in the medial amygdala induces anxiolysis in the social interaction model but has little effect on behaviour in a punished conflict model of anxiety. These data suggest that serotonergic neurotransmission in this nucleus may selectively affect specific kinds of anxiety generated by different animal models.