Discovery and hit-to-lead evaluation of piperazine amides as selective, state-dependent NaV1.7 inhibitors.

NaV1.7 is a particularly compelling target for the treatment of pain. Herein, we report the discovery and evaluation of a series of piperazine amides that exhibit state-dependent inhibition of NaV1.7. After demonstrating significant pharmacodynamic activity with early lead compound 14 in a NaV1.7-dependent behavioural mouse model, we systematically established SAR trends throughout each sector of the scaffold. The information gleaned from this modular analysis was then applied additively to quickly access analogues that encompass an optimal balance of properties, including NaV1.7 potency, selectivity over NaV1.5, aqueous solubility, and microsomal stability.

Postpartum hemolytic uremic syndrome associated with antiphospholipid antibodies. A case report and review of the literature.

Postpartum hemolytic uremic syndrome (HUS) is described in a woman with a history of spontaneous abortions and both circulating lupus anticoagulant and anticardiolipin antibody (ACA). After termination of her pregnancy because of severe preeclampsia, ACA blood levels increased simultaneously with the onset of a microangiopathic process associated with severe hypertension and renal failure. Plasma exchange resulted in a rapid decline in ACA levels and immediate improvement in her clinical condition. This case strongly suggests an important causal relationship between ACA and postpartum HUS. The possible mechanisms of ACA-related postpartum HUS and the potential role of plasmapheresis in its treatment are reviewed and discussed.

Specificity of induction of cancer protective enzymes by analogues of tert-butyl-4-hydroxyanisole (BHA).

Protection by 2(3)-tert-butyl-4-hydroxyanisole (BHA) and related phenols against chemical carcinogens, mutagens and other toxins has been attributed to the elevation of tissue levels of non-oxygenative detoxification enzymes. To analyze the mechanisms and specificity of these enzyme inductions, we synthesized a series of mono- and dialkyl ethers of tert-butylhydroquinone (R1O-[(CH3)3C-C6H3]-OR2) and its dimer. The abilities of these compounds to elevate the cytosolic specific activities of glutathione S-transferases (measured with 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene) and of NAD(P)H: quinone reductase in liver, upper small intestine and forestomach of female CD-1 mice were evaluated. The animals were fed five daily doses of 50 mumoles of each monomer (or 25 mumoles of each dimer). The structures of the monomers examined were: R1 = H and R2 = CH3 (I), R2 = C2H5 (VI), R2 = (CH2)2CH3 (VIII), R2 = CH(CH3)2 (X); R1 = CH3 and R2 = C2H5 (VII), R2 = (CH2)2CH3 (IX), R2 = CH(CH3)2(XI); R2 = CH3 and R1 = C2H5(III), R1 = (CH2)2CH3(IV) and R1 = CH(CH3)2 (V). In addition, the monomethyl (XIII), monoethyl (XIV) and mono-n-propyl (XV) ethers of BHA dimer (XII; 2,2'-dihydroxy-3,3'-di-tert-butyl-5,5'-dimethoxybiphenyl) were also prepared. Under the conditions tested, all compounds were ineffective as enzyme inducers in the forestomach but produced coordinate induction of enzymes (generally 2- to 6-fold) in the cytosols of liver and mucosa of proximal small intestine. Increases in bulk of R1 and R2 beyond methyl groups tended to decrease the inductive potency of both monomers and dimers. The lack of strict structural specificity suggests that the induction depends on metabolic conversion of the analogues to common types of metabolites.

Will hemoperfusion be useful for cancer chemotherapeutic drug removal?

One of the major problems in clinical cancer chemotherapy is the inability to safely administer full therapeutic doses of specific drugs in the face of dysfunction of an organ system controlling that drug's metabolism and excretion. Should efficient drug removal from blood be possible following full therapeutic doses and after tumor exposure, then theoretically, even in the presence of organ dysfunction, anticancer drug toxicity may be reduced or avoided. Preliminary experiments in our laboratory have shown that adriamycin may be efficiently removed by activated charcoal from aqueous and protein solutions and blood in vivo, and that daunorubicin is removed in vitro to the same extent. However, although methotrexate is removed efficiently in vitro and extracted 50% in vivo by charcoal hemoperfusion, its overall pharmacokinetics do not appear to be altered in comparison with the alteration in pharmacokinetics of adriamycin achieved with charcoal hemoperfusion. Computer modeling has suggested that efficient adriamycin removal is achievable, and that clinical studies are warranted. For methotrexate removal, however, previous clinical studies and our own data suggest that charcoal hemoperfusion has little utility unless a highly specific sorbent for methotrexate removal can be developed.

iron-overload-associated myopathy in patients on maintenance haemodialysis: a histocompatibility-linked disorder.

Unexplained proximal muscle weakness developed in 10 patients on chronic maintenance haemodialysis. Proximal muscle biopsy in 7 patients disclosed iron deposition in muscle fibres and/or macrophages. All 10 patients had severe iron overload (serum-ferritin level > 1000 ng/ml). Since HLA-A3, B7, and B14 antigens are associated with idiopathic haemochromatosis and, therefore, are linked with alleles regulating iron metabolism, HLA type was reviewed in 61 haemodialysis patients, including the 10 myopathic patients. Serum-ferritin levels showed a significant correlation (p<0.001) with the presence of the HLA-antigens. Close relatives of these patients with HLA-antigen-associated iron-overload myopathy did not have raised serum-ferritin levels. Patients on maintenance haemodialysis who have inherited the "haemochromatosis alleles" thus have an increased risk of iron overload and muscle iron deposition.