The chemical class of quinazoline compounds provides a core structure for the design of anticytomegaloviral kinase inhibitors.

HCMV is a member of the family Herpesviridae and represents a worldwide distributed pathogen with seropositivity rates in the adult population ranging between 40% and 90%. Notably, HCMV infection is a serious, sometimes life-threatening medical problem for newborns and immunosuppressed individuals, including transplant recipients and patients under antitumoral chemotherapy. Current standard therapy with valganciclovir has the disadvantage of inducing drug-resistant virus mutants and toxicity-related side effects. Our analysis stresses the earlier finding that kinase inhibitors of the quinazoline class exert an antiviral response by targeting the viral protein kinase pUL97 without inducing resistance. Therefore, quinazolines have been used as a core structure to gain insight in the mode of inhibitor-kinase interaction. Here, we demonstrate that (i) the novel quinazolines Vi7392 and Vi7453 are highly active against HCMV laboratory and clinically relevant strains including maribavir- and ganciclovir-resistant variants, (ii) antiviral activity is not cell-type specific and was also detected in a placental explant tissue model using a genetically intact HCMV strain (iii) the viral kinase pUL97 represents a target of the anticytomegaloviral activity of these compounds, (iv) induction of pUL97-conferring drug resistance was not detectable under single-step selection, thus differed from the induction of ganciclovir resistance, and (v) pUL97 drug docking simulations enabled detailed insights into specific drug-target binding properties providing a promising basis for the design of optimized kinase inhibitors. These novel findings may open new prospects for the future medical use of quinazoline drug candidates and the use of drug-target dynamic simulations for rational design of antivirals.

[Cauda equina syndrome in lumbar disc herniation].

During the past 5 years 10 patients suffering from cauda equina syndrome as a result of prolapsed disc were treated surgically. Although considerable time had elapsed between the onset of symptoms and the operation, most of the patients improved, at least partially. The syndrome is a rare complication of a common condition of the lower spine. Awareness of its possibility and identification of the early clinical picture are essential. An accurate history and detailed physical examination are the most important factors in early diagnosis. In 5 women and 4 men, who ranged in age from 28-60 and averaged 41 years, the disks involved were L5-S1 in 6, L4-L5 in 2 and L1-T12 in 1 case. Persistent disability was found in most of the patients, including 4 with bladder and 4 with sexual dysfunction. In 7 there was residual sensory loss and in 5 some degree of motor weakness. Earlier surgical treatment seems to be the most effective method for improving the results of treatment.