L-694,247: a potent 5-HT1D receptor agonist.

1. The 5-hydroxytryptamine (5-HT) receptor binding selectivity profile of a novel, potent 5-HT1D receptor agonist, L-694,247 (2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl ]- 1H-indole-3-yl]ethylamine) was assessed and compared with that of the 5-HT1-like receptor agonist, sumatriptan. 2. L-694,247 had an affinity (pIC50) of 10.03 at the 5-HT1D binding site and 9.08 at the 5-HT1B binding site (sumatriptan: pIC50 values 8.22 and 5.94 respectively). L-694,247 retained good selectivity with respect to the 5-HT1A binding site (pIC50 = 8.64), the 5-HT1C binding site (6.42), the 5-HT2 binding site (6.50) and the 5-HT1E binding site (5.66). The pIC50 values for sumatriptan at these radioligand binding sites were 6.14, 5.0, < 5.0 and 5.64 respectively. Both L-694,247 and sumatriptan were essentially inactive at the 5-HT3 recognition site. 3. L-694,247, like sumatriptan, displayed a similar efficacy to 5-HT in inhibiting forskolin-stimulated adenylyl cyclase in guinea-pig substantia nigra although L-694,247 (pEC50 = 9.1) was more potent than sumatriptan (6.2) in this 5-HT1D receptor mediated functional response. L-694,247 (pEC50 = 9.4) was also more potent than sumatriptan (6.5) in a second 5-HT1D receptor mediated functional response, the inhibition of K(+)-evoked [3H]-5-HT release from guinea-pig frontal cortex slices.(ABSTRACT TRUNCATED AT 250 WORDS)     

Health-related quality of life and pressure ulceration assessment in patients treated in the community

Little is known of the impact of pressure ulceration on adult patients' health-related quality of life. The purpose of this study was to determine the impact pressure ulceration has on pressure ulcer patients cared for in the community. A case control study design was used by drawing a random sample from patients receiving community nursing care, stratified by the presence of pressure ulceration. In all, 75 patients with pressure ulcers were compared with 100 controls without ulcers using the four-point ulcer grading scale described by United Kingdom consensus guidelines. Patients were interviewed using the Short Form-36 (SF-36) questionnaire and activities of daily living assessed using the modified Barthel scale. Patients with pressure ulcers had significantly poorer physical function (mean difference (d) = 37.6, 95% CI 28.6-46.6, p < 0.001) and social functioning (d = 33.9, 95 % CI 24.0-43.9, p < 0.001) than published age- and sex-matched normative data from the United Kingdom. The difference between cases and controls was much smaller in these domains, with neither approaching statistical significance. After adjustment for age and gender, scores for bodily pain were poorer in patients with no ulceration (d = -10.5, 95% CI - 20.6 to - 0.4, p = 0.042) indicating greater pain in these patients compared with the cases with ulceration. Activities of daily living determined by the modified Barthel scale showed reduced self-care (d = -7.6, 95% CI -12.5 to - 2.7, p = 0.010) and mobility (d = -9.2, 95% CI -14.6 to - 3.8, p = 0.001) in patients with pressure ulceration. The overall ability to perform these activities was also significantly poorer in this group (d = -16.3, 95% CI -27.3 to -5.3, p = 0.004). While patients with pressure ulceration experience some deficits in their health-related quality of life compared with a normal population, these differences are similar to those experienced by other patients receiving community nursing care.     

Three novel PROC gene lesions causing protein C deficiency

Hallam PJ, Mannucci P, Tripodi A, Bevan D, Laursen B, Tengborn L, Wacey A, Cooper DN. Three novel PROC gene lesions causing protein C deficiency. Clin Genet 1998: 54: 231–233. 0 Munksgaard, 1998
Missense mutations. three of them novel (Am210→Val, Asn248→ Ile, Ah355→Val), were found in the protein c ( PROC ) genes of 7 patients with inherited protein C deficiency associated with venous thrombosis. Comparison with the phenotypic effects of mutations in the analogous residues of factor IX causing hdernophilia B and the use of molecular modelling has provided explanations as to how these lesions might alter either the structure, function or secretion of the protein C molecules encoded.     

Characterization of the binding of [3H]-SB-204269, a radiolabelled form of the new anticonvulsant SB-204269, to a novel binding site in rat brain membranes

1. SB-204269 (trans-(+)-6-acetyl-4S-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-benzol[b]pyran-3R-ol, hemihydrate) shows potent anticonvulsant activity in a range of animal seizure models, with a lack of neurological or cardiovascular side-effects. The profile of the compound suggests that it may have a novel mechanism of action. This study describes the characteristics of a binding site for [³H]-SB-204269 in rat forebrain membranes.
2. Specific [³H]-SB-204269 binding was saturable and analysis indicated binding to a homogenoeous population of non-interacting binding sites with a dissociation constant (K_D) of 32±1 nM and a maximum binding capacity (B_max) of 253±18 fmol mg⁻¹ protein. Kinetic studies indicated monophasic association and dissociation. Binding was similar in HEPES or Tris-HCl buffers and was unaffected by Na⁺, K⁺, Ca²⁺ or Mg²⁺ ions. Specific binding was widely distributed in brain, but was minimal in a range of peripheral tissues.
3. Specific [³H]-SB-204269 binding was highly stereoselective, with a 1000 fold difference between the affinities of SB-204269 and its enantiomer SB-204268 for the binding site. The affinities of analogues of SB-204269 for binding can be related to their activities in the mouse maximal electroshock seizure threshold (MEST) test of anticonvulsant action.
4. None of the standard anticonvulsant drugs, phenobarbitone, phenytoin, sodium valproate, carbamazepine, diazepam and ethosuximide, or the newer anticonvulsants, lamotrigine, vigabatrin, gabapentin and levetiracetam, showed any affinity for the [³H]-SB-204269 binding site. A wide range of drugs active at amino acid receptors, Na⁺ or K⁺ channels or various other receptors did not demonstrate any affinity for the binding site.
5. These studies indicate that SB-204269 possesses a specific CNS binding site which may mediate its anticonvulsant activity. This binding site does not appear to be directly related to the sites of action of other known anticonvulsant agents, but may have an important role in regulating neuronal excitability.