Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-03
2002-11-26
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S844000, C514S934000, C514S824000
Reexamination Certificate
active
06486166
ABSTRACT:
BACKGROUND OF THE INVENTION
The entire text of the above-referenced disclosure is specifically incorporated by reference herein without disclaimer.
The present invention relates generally to the fields of prophylaxis and treatment for viral infections. More particularly, it concerns the use of cyclin dependent kinase inhibitors for blocking replication of any DNA virus dependent on Cdk activity for proliferation, an example being herpesvirus and, more particularly, cytomegalovirus. Marek's disease represents a chicken-CMV, equine abortion virus represents a horse variety and cattle have several specific CMV's, to name but a few species-specific CMV's.
Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that infects greater than 80% of the human population. HCMV is capable of establishing a life-long infection following primary infection. Reactivation of HCMV often results during pregnancy, perfusion, and in immunocompromised states (Huang and Kowalik, 1993). HCMV rarely causes symptomatic disease in healthy immunocompetent individuals. However, HCMV can result in severe clinical manifestations in congenitally infected newborns and in immunocompromised individuals, such as those undergoing organ transplantation or those infected with HIV (Alford et al., 1990; Schooley, 1990; Rubin, 1990). Most animal species may be infected with species-specific cytomegalovirus.
HCMV is the most common cause of human congenital viral infections, occurring in approximately 1% of all new born infants (Weller, 1971; Alford et al., 1981). Congenital infections (e.g., those acquired during pregnancy) primarily result from reactivation of a latent infection in the mother and subsequent transmission to the fetus. The majority of HCMV infections are asymptomatic or subclinical. However, about 10% of infants infected in utero display clinical manifestations, approximately 5% display typical cytomegalic inclusion disease (CID), with the other 5% presenting atypical manifestations (Pass et al., 1980). Characteristic manifestations of CID include hepatomegaly, splenomegaly, microcephaly, jaundice, and petechiae (Weller and Hanshaw, 1964). The prognosis for congenital CID is bleak with the mortality rate reaching 30%. The surviving infants may suffer from severe mental and motor abnormalities (Alford et al., 1990).
Perinatal infections are acquired during or shortly after birth. It is estimated that 1 to 15% of infants born in the United States become infected with HCMV by 6 months of age (Alford et al., 1990). The majority of these, infections occur via ingestion of infected breast milk and contact with genital secretions during birth. Approximately 40-60% of infants breast-fed by sero-positive mothers and 25-50% of infants exposed to HCMV in the birth canal become infected (Stagno et al., 1980; Dworsky et al., 1983; Reynolds et al., 1973). The vast majority of these perinatal infections remain asymptomatic. However, there is evidence that perinatal HCMV infection may be associated with interstitial pneurmonitis and result in chronic lung disease (Brasfield et al, 1987).
HCMV's ability to latently infect cells and become reactivated under immunosuppressed conditions pose a severe problem for AIDS patients (Chou, 1990; Drew et al., 1981; Quinn et al., 1987). Essentially 100% of HIV positive homosexual men present serological evidence of either recently acquired or reactivated HCMV infection (Collier et al,. 1987). According to Schooley (1990), HCMV can play at least four possible roles in the pathogenesis of AIDS. These include: 1) direct HCMV-induced morbidity associated with clinical symptoms, 2) increased immunosuppression induced by HIV, 3) enhanced HIV replication by trans-activation at the cellular level, and 4) destruction of the gastrointestinal mucosa, and predisposition to other infections.
HCMV infection is the primary cause of death in over 35% of AIDS patients (Gehrz, 1991). HCMV infection affects numerous organ systems including the central nervous system (CNS), pulmonary system, and gastrointestinal (GI) tract (Smith and. Brunnessel, 1994). HCMV infection of the CNS has been observed in more than 20% of AIDS patients at autopsy. Individuals with CNS infections present with clinically recognized neurological symptoms including encephalitis, polyradiculomyelitis, and neuropathy (Navia et al., 1986; Hawley et al., 1983; Said et al., 1991). It is estimated that ~20% of AIDS patients will develop a gastrointestinal disease caused by HCMV (Dieterich et al., 1993). HCMV infection can result in lesions involving the oral mucosa, esophagus, intestine, and rectum (Kanas et al., 1987). The pain associated with these lesions of the GI tract can obstruct the intake of food and thus contribute to the already poor nutritional status of the patient (Villor et al., 1984).
HCMV also affects the immunological state of AIDS patients. HCMV induces numerous immunological abnormalities that can inhibit the patients ability to fight HIV and other infections. These abnormalities include; changes in the relative distribution of CD4 and CD8 T-lymphocytes (Drew et al., 1985; Detels et al., 1984), a decrease in release of and responsiveness to mitogens, (Kapasi and Rice, 1988; Sing and Garnett, 1984) altered HLA-DR expression, and altered antigen presentation (Fiala et al., 1993).
Interestingly, HCMV may also enhance HIV replication at a molecular level. Previous studies have demonstrated that HCMV and HIV can co-infect numerous cell types (Rice et al., 1984; Nelson et al., 1988). This coinfection of HCMV and HIV can result in the enhancement of HIV replication via the trans-activation of the long terminal repeat (LTR) sequences by HCMV regulatory elements (Schooley, 1990). Although the complete mechanism is far from clear, the net result is enhanced expression of the LTR and increased HIV replication.
A second group of individuals with increased risk of HCMV infection are organ transplant recipients. HCMV is the single most important infectious agent affecting organ recipients. At least two-thirds of these patients develop a HCMV-infection 1-4 months after transplantation (Rubin, 1990). According to Rubin (1990) there are three patterns of HCMV infection following organ transplantation; primary infection, reactivated infection, and superinfection. Primary infection has the greatest clinical impact and occurs when an individual who is sero-negative for HCMV becomes infected by a sero-positive donor organ or transfused blood. In reactivated infection the HCMV sero-positive recipient undergoes reactivation of endogenous latent virus. Virtually all organ recipients who are scro-positive for HCMV will show some evidence of HCMV reactivation (Rubin and Tolkoff-Rubin, 1984; Fiala et al., 1975). Finally, superinfection occurs when a sero-positive recipient receives an allograft from a sero-positive donor that is infected with a different HCMV strain.
HCMV-infection itself can result in a wide variety of conditions ranging from fevers to pneumonia and hepatitis (Rubin, 1990). Secondly, HCMV infection can produce an immunosuppressed state that exceeds that observed from the immunosuppressive drugs alone. This enhanced immunosuppression can result in increased opportunistic infections due to
Pneumocystis carinii
, fungi, and
Listeria monocytogenes
(Rubin, 1990). Finally, HCMV can directly contribute to the rejection of the allograft. These complications demonstrate the need to better understand the HCMV life cycle. Understanding the molecular mechanisms of HCMV replication should aid in the development of novel anti-virals to help control the spread and replication of HCMV.
The structure of the HCMV virion shares characteristics consistent with other DNA viruses, particularly the herpesviruses. The HCMV virion consists of four basic elements: 1) an electron-opaque core, 2) an icosahedral capsid surrounding the core, 3) a tegument surrounding the capsid, and 4) an envelope (Roizmnan and Sears, 1991).
HCMV gene expression is regulated by a complex interaction of both viral and cellular proteins (Huang an
Albrecht Thomas
Bresnahan Wade
Meijer Laurent
Thompson Aubrey E.
Board of Regents The University of Texas
Fulbright & Jaworski
Webman Edward J.
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