Diazabicyclononanones,a potent class of kappa opioid analgesics

The 1,5-dimethyl 3,7-diaza-3,7-dimethyl-9-oxo-2,4-di-2-pyridine-bicyclo[3.3.1]nonane-1,5-dicarboxylate, HZ2, has a high and selective affinity for the kappa opioid receptor and an antinociceptive activity comparable to morphine. In addition, it is characterized by a long duration of action and a high oral bioavailability. QSAR studies within series of kappa agonists revealed a chair-boat conformation of a double protonated HZ2 characterized by an almost parallel orientation of the C9 carbonyl group and the N7-H group and at least one aromatic ring to be the pharmacophoric arrangement. Structural variations showed that the pyridine rings in 2 and 4 position can be replaced with p-methoxy-, m-hydroxy- and m-fluoro-substituted phenyl rings. However, all other substituents have to be kept the same for a high affinity to the kappa receptor.     

Secondary thrombocytosis

To estimate the incidence and causes of secondary thrombocytosis in children, a 12 month study of all patients attending a children's hospital and discovered to have a platelet count over two times the upper normal limit (> 800 x 10(9)/l) was undertaken. Data so obtained were analysed both separately and together with those from two previous studies to gain as broad a perspective as possible. Of 7916 children who had platelet counts during the study period, 36 (0.5%) produced a value > 800 x 10(9)/l; there were 19 boys and 17 girls. There was a preponderance of young infants (median age 13 months). Twenty seven of the 36 had some sort of associated infection, bacterial in 18 and viral in nine. The other nine were either recovering from anti-neoplastic chemotherapy (n = 6), were post-operative (n = 2), or simply iron deficient (n = 1). Combining these patients with those described in previous studies allowed a review of 139 unselected children with very high platelet counts. Fifty three (38%) had infections, 29 (20%) had traumatic or surgical tissue damage, 16 (11%) had malignant disease undergoing chemotherapy or surgery, and 13 (9%) had connective tissue or autoimmune disorders. Secondary thrombocytosis is not rare and is most frequently seen in very young infants after infection. It can arise in a wide variety of other circumstances including rebound from myelosuppression, iron lack, or as part of an acute phase response. It is clinically unimportant in terms of morbidity and requires no treatment other than that for the primary condition.     

Congenital thiopurine methyltransferase deficiency and 6-mercaptopurine toxicity during treatment for acute lymphoblastic leukaemia

Two children with acute lymphoblastic leukaemia (ALL) taking daily 6-mercaptopurine as part of a national UK therapeutic trial repeatedly developed profound myelosuppression on 25% of the standard protocol dose. Both were found to have undetectable intracellular activity of thiopurine methyltransferase (TPMT), an enzyme controlling one of the major alternative catabolic pathways of 6-mercaptopurine, and both produced higher concentrations of cytotoxic drug metabolites at 10-25% of the protocol dose than other patients taking 100%. It is supposed that these patients represent the 0.33% of the normal population constitutionally lacking TPMT. It is important to recognise such individuals both to avoid fatal bone marrow failure through inadvertent overdosage, and to be reassured that an adequate drug effect can be achieved at around 10% of the standard dose.     

Vascular effects of gestagens--biochemistry versus epidemiology

The available epidemiologic data indicate that the sequential addition of progestogens enhances the protective effect of estrogens on the cardiovascular risk. A considerable decrease in LDL-cholesterol is also observed during use of progestogens with androgenic properties. The estrogen-dependent reduction of LDL oxidation is not impaired by progestogens. While estrogens inhibit the endothelial synthesis of adhesion molecules, the activation of monocytes and platelets and the proliferation and migration of smooth muscle cells, the effect of progestogens is rarely investigated. A vasoconstrictory effect of progestogens which may attenuate the estrogen-induced dilation of arteries, was not observed in all clinical investigations. It is presumably based on a reduction of estrogen-stimulated release of nitric oxide by progestogens. In most animal experiments, a progestogen-induced enhancement of contractility of arteries was measured, too. A relaxing effect of progesterone was found in in vitro-experiments, while the results on endothelium-independent effects of synthetic progestogens were contradictory. The sex steroids influence the structure of the vessel wall, whereby the elasticity of arteries is enhanced by estrogens and reduced by progestogens. Oral contraceptives may increase the distensibility of veins which correlates with the hormonal potency of the progestogen. During hormone replacement therapy, venous distensibility is also increased which is mainly due to the action of the estrogen. In vitro experiments with veins revealed a dilatory effect of progestogens. With regard to possible unfavourable effects of progestogens on the vessel wall it is recommended to use the additional progestogen at the minimal effective dose necessary for prevention of endometrial hyperplasia.     

Multiple myeloma: evaluation by CT

Although patients who have multiple myeloma usually have straightforward clinical symptoms and corroborative radiographs, in some instances, these patients will present atypically, with symptoms suggesting active disease but radiographs that are normal or nonspecific. We reviewed the records of 32 patients who had documented multiple myeloma and had undergone CT examinations, assessing the value of those examinations. Although CT is not indicated in all patients who have multiple myeloma, it is especially useful in patients who have bone pain and normal or nonspecific radiographs. CT provided confirmatory information in all cases in which lesions were seen on radiographs. CT also frequently demonstrated a greater extent of disease than could be appreciated on the radiographs.     

Presynaptic monoaminergic vesicles in Parkinson's disease and normal aging

We present development and human application of a method for determining the regional cerebral density of the type 2 vesicular monoamine transporter (VMAT2) using positron emission tomography (PET) and [¹¹C]dihydrotetrabenazine (DTBZ). Previous animal studies indicate striatal VMAT2 density is linearly related to the integrity of substantia nigra dopamine neurons and is not subject to drug-or lesion-compensatory regulation. In the present studies, kinetic compartmental modeling was employed to estimate blood-brain [¹¹C]DTBZ transport (K₁,) and VMAT2 binding site density (tissue-to-plasma DTBZ distribution volume, DV)from the cerebral and plasma DTBZ time courses her intravenous tracer injection. In controls, we found reductions of putamen DTBZ DV with advancing age, corresponding to losses of 0.77% per year in specific VMAT2 binding. Parkinson's disease (PD) patients had reduction in specific DTBZ DV in the putamen (?61%) and in the caudate nucleus (?43%). There was no overlap of lowest specific putamen DTBZ DV between individual elderly controls and PD patients. The present results indicate the suitability of [¹¹C]DTBZ PET for objective quantification of nigrostriatal integrity, including evaluation of PD progression and its possible therapeutic modification.