New antiviral agents for dermatologic disease

The authors provide an overview of the topic of stimulant use in psychiatric sports medicine. They address the following areas: 1) the history of stimulant use in sports; 2) recent events related to the use of stimulants in sports, including a new stimulant used at the 1996 Olympic competition in Atlanta, GA; 3) ergogenic or ergolytic (i.e., performance-impairing) potential of several major categories of stimulants, including amphetamines, beta2 agonists, caffeine, and cocaine; 4) review of how the brain reward circuit is affected by stimulants; 5) individual factors that induce athletes to utilize stimulants; and 6) sports organizational factors that induce athletes to use stimulants.     

Hepatotoxicity of antiviral agents

Because most therapeutic agents used for viral infections are relatively new, experience with their adverse effects is still evolving. Hepatic toxicity has not been among the most important concerns with this class of drugs so far. Liver damage has been increasingly noted with accumulating experience, especially with antiretroviral drugs and those used to treat chronic hepatitis (e.g., fialuridine), but it is often difficult to distinguish between effects of therapy and of the underlying disease. It is important for clinicians to be aware of the possibility of hepatotoxicity in such situations, and further reporting of adverse experiences should contribute to more definitive evaluation of the potential influence of antivirals on liver function.     

Protease inhibitors as antiviral agents

Currently, there are a number of approved antiviral agents for use in the treatment of viral infections. However, many instances exist in which the use of a second antiviral agent would be beneficial because it would allow the option of either an alternative or a combination therapeutic approach. Accordingly, virus-encoded proteases have emerged as new targets for antiviral intervention. Molecular studies have indicated that viral proteases play a critical role in the life cycle of many viruses by effecting the cleavage of high-molecular-weight viral polyprotein precursors to yield functional products or by catalyzing the processing of the structural proteins necessary for assembly and morphogenesis of virus particles. This review summarizes some of the important general features of virus-encoded proteases and highlights new advances and/or specific challenges that are associated with the research and development of viral protease inhibitors. Specifically, the viral proteases encoded by the herpesvirus, retrovirus, hepatitis C virus, and human rhinovirus families are discussed.     

HIV integrase: a target for AIDS therapeutics

HIV integrase catalyses the incorporation of virally derived DNA into the human genome. This unique step in the virus life cycle provides a variety of points for intervention and hence is an attractive target for the development of new therapeutics for the treatment of AIDS. In this review we summarize current knowledge of the function of this enzyme and discuss some of the obstacles to the development of appropriate drugs.     

Development of antiviral therapeutic agents from traditional medicines

Traditional medicines contain various metabolites derived from nucleic acid, protein, and lipid metabolism. Some of these specific metabolites may recognize the differences between viral and host metabolism resulting in anti-viral activity; hence traditional medicines may be useful sources for new antiviral agents. Traditional medicines can be cheaply obtained and have been orally administered as hot-water extracts. Therefore, they may be used for the prophylactic and therapeutic treatment of viral infection by drinking them, such as coffee or tea. Here we describe how the antiviral activity of traditional medicines was screened in vitro and how their therapeutic antiviral activities were verified in vivo, to obtain traditional antiviral medicines that can be clinically used. Therefore, we have selected 12 herbal extracts, from more than 250 herbal medicines, that exhibit therapeutic activities against cutaneous herpes simplex virus (HSV) type 1 (HSV-1) infection in mice. Four of the 12 augmented the therapeutic efficacy of acyclovir (ACV) in mice and showed potent anti-HSV activity against infection with ACV-resistant HSV-1 mutants in mice. These herbal extracts selectively inhibited viral DNA synthesis and showed a different mode of anti-HSV-1 action from that of ACV. They were also effective against both recurrent HSV and cytomegalovirus infections, without toxicity. Such prophylactic and therapeutic antiviral activities of the traditional medicines were verified by the purification of major active compounds. We could show new indications of traditional medicines as antiviral agents. Thus, the drinking of the extracts, in a daily tea or coffee, may be used for prophylaxis and therapy of diseases caused by herpes virus infection and improve the quality of life.     

The use of an algorithmic method for small molecule superimpositions in the design of antiviral agents

The new American Association on Mental Retardation (AAMR) definition of mental retardation (Luckasson et al., 1992) represents a radical departure from previous definitions. In the present paper we examined the extent to which the new definition provides decision rules to guide clinicians and researchers in classification efforts. We concluded that the IQ criterion of 75 will increase the proportion of the general population eligible near the cut-off score. Moreover, the 10 adaptive skill areas adopted fail to consider developmental factors and cannot be assessed reliably with current scales. Proposed differentiation by levels of needed supports is also challenged as being imprecise and not amenable to reliable measurement. Implications of this new definition for diagnostic practices and research endeavors were explored.     

Treatment of Herpes simplex virus infections with topical antiviral agents

Clinical studies of topical therapy against Herpes simplex virus (HSV) infections have been reviewed. Idoxuridine (IDU) 15% in dimethyl sulfoxide (DMSO), interferons, and penciclovir result in significant clinical benefit against this virus. IDU reduced pain duration and decreased time to loss of crust in a study of 301 patients. Alpha-interferon has shown synergism with other anti-HSV drugs such as caffeine, trifluorothymidine (TFT), DMSO, and nonoxynol-9. Finally, in a study of over 2,000 patients, application of penciclovir cream, both early and late in the course of HSV infection, decreased the duration of lesions, pain, and viral shedding. Acyclovir (ACV)-resistant strains of HSV are susceptible to (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine (HPMPC), and ascorbic acid shows promising effects against HSV. Using a vehicle that enhances skin penetration of a drug or possibly further exploring combination therapy may result in efficacious treatment of HSV. The possibility of topical vaccination or topical gene therapy may also prove beneficial in the future.     

Assessment and psychotherapy practice implications of new combination antiviral therapies for HIV disease.

New combination antiviral regimens that include protease inhibitors have created heightened levels of optimism about the future of HIV-related health care as well as new challenges with important implications for mental health intervention. Emerging issues in HIV-related mental health treatment are described herein, and strategies for assessment and psychotherapy are outlined, highlighting ways to address newly emerging themes in clinical practice. Clinical evaluation and therapeutic intervention specific to psychological adjustment, antiviral treatment adherence, access to care, HIV risk behavior, and central nervous system functioning are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Synthesis of nucleosides having unusual branched sugars as potential antiviral agents

Enantiomerically pure novel nucleosides having unusual branched sugars were synthesized in a stereospecific manner from a common chiral pool of (S, S)-1,4-bis(benzyloxy)-2,3-epoxybutane and evaluated for antiviral activity.     

Synthesis of imidazo[1,2-a]pyridines as antiviral agents

The synthesis of original imidazo[1,2-a]pyridines bearing a thioether side chain at the 3 position and their antiviral activity are reported. From the synthesized compounds, 4, 15, and 21 were highly active against human cytomegalovirus with a therapeutic index superior to 150. These compounds also showed pronounced activity against varicella-zoster virus. Their structure-activity relationship is discussed.     

New antiviral agents in the treatment of chronic hepatitis B and C

Interferon (IFN) is the drug universally used in the treatment of B and C chronic hepatitis. Due to its low efficacy, 40% in the treatment of chronic hepatitis B and 10-20% in the treatment of chronic hepatitis C, and to its adverse events, in some cases severe, new antiviric molecules are being investigated. Lamivudin, famciclovir and the association of ribavirin and IFN are the more relevant and will be clinically accepted in an immediate future. It is also probable that rigid indications for hepatic transplantation in patients with liver cirrhosis by B virus change in the next years due to the use of these new antiviric drugs before and after transplantation. In this revision we analyze the current situation of these new therapies. However, most information come from pilot studies, and multicentric randomized studies are needed to establish firm conclusions about the role that these new therapies are going to play in the treatment of viral chronic hepatitis.     

HIV peptide conjugated to heat-killed bacteria promotes antiviral responses in immunodeficient mice

Enhancement of immunity in the setting of HIV infection is difficult owing to loss of functional CD4+ T cells. The MHC class II-deficient mouse (II-/-) environment simulates that of the immunocompromised HIV-infected individual, since these mice have low CD4+ T cell numbers, defective CD4-dependent responses, and are susceptible to opportunistic infection. This strain was used to test whether heat-killed Brucella abortus (BA), covalently conjugated to the V3 peptide of HIV-1 (MN), could elicit anti-HIV responses. V3-BA, but not the T-dependent antigen V3-KLH, induced high levels of IL-12, IFN-gamma, and IL-10 mRNA in both wild-type (WT) and II-/- mice within 24 hr of injection. V3-BA-treated, but not V3-KLH-treated, II-/- mice developed serum IgG and IgA anti-V3 antibodies, with IgG2b and IgG3 as the predominant isotype. Viral neutralization studies, using a syncytium inhibition assay, demonstrated that the antibodies generated by V3-BA in II-/- mice were capable of neutralizing HIV. These experiments demonstrate that a heat-inactivated bacterium such as BA, when used as a carrier, can generate a cytokine environment that results in the production of neutralizing antiviral antibodies in an immunodeficient host. Such strategies could be important in the development of immunotherapies and vaccines for HIV-1 patients.     

Carbocyclic adenosine analogues as S-adenosylhomocysteine hydrolase inhibitors and antiviral agents: recent advances

Various carbocyclic analogues of adenosine, including aristeromycin (carbocyclic adenosine), carbocyclic 3-deazaadenosine, neplanocin A, 3-deazaneplanocin A, the 5'-nor derivatives of aristeromycin, carbocylic 3-deazaadenosine, neplanocin A and 3-deazaneplanocin A, and the 2-halo (i.e., 2-fluoro) and 6'-R-alkyl (i.e., 6'-R-methyl) derivatives of neplanocin A have been recognized as potent inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase. This enzyme plays a key role in methylation reactions depending on S-adenosylmethionine (AdoMet) as methyl donor. AdoHcy hydrolase inhibitors have been shown to exert broad-spectrum antiviral activity against pox-, paramyxo-, rhabdo-, filo-, bunya-, arena-, and reoviruses. They also interfere with the replication of human immunodeficiency virus through inhibition of the Tat transactivation process.     

Synthesis of arylidenehydrazono- and glycopyranosylhydrazino-sulfonylbenzylidene-2,4-imidazolidinediones as potential antiviral and antitumoral agents

Low-intensity pulsed ultrasound recently has been shown to accelerate long bone fracture healing, but its effect on bone growth and development is unknown. The longitudinal growth and bone density of the femur and tibia in young rats was measured after application of an ultrasound transducer emitting 1.5-MHz pulsed ultrasound (30 mW/cm2, SATA) for 20 min/day. After 28 days, no length difference was detected (< or = 2%) compared to the sham-treated leg or to unexposed controls. Also, no significant difference in bone mineral density (BMD) of the femur or tibia was found (< or = 6%). In a repeated experiment in which a periosteal trauma stimulus was created in the femoral diaphysis, the ultrasound also had no effect on growth or BMD. This results suggests that physeal bone growth is far less sensitive to this level of ultrasound application than is fracture repair. This may be related to the cascade of cellular events and regulatory factors that are present after a fracture.     

Neurologic manifestations of HIV infection. Using imaging studies and antiviral therapy effectively

Patients with HIV infection are at risk for neurologic complications that can arise through various means. Nervous system disorders sometimes occur as a direct consequence of the HIV infection itself. Or, as immunodeficiency progresses, patients can become susceptible to numerous opportunistic infections and other conditions that have neurologic involvement. Even the antiviral drugs used to treat HIV infection can induce neurologic manifestations. Dr Rachlis discusses several of these manifestations and their management.     

Tubulin as a target for anticancer drugs: agents which interact with the mitotic spindle

Tubulin is the biochemical target for several clinically used anticancer drugs, including paclitaxel and the vinca alkaloids vincristine and vinblastine. This review describes both the natural and synthetic agents which are known to interact with tubulin. Syntheses of the more complex agents are referenced and the potential clinical use of the compounds is discussed. This review describes the biochemistry of tubulin, microtubules, and the mitotic spindle. The agents are discussed in relation to the type of binding site on the protein with which they interact. These are the colchicine, vinca alkaloid, rhizoxin/maytansine, and tubulin sulfhydryl binding sites. Also included are the agents which either bind at other sites or unknown sites on tubulin. The literature is reviewed up to October 1997.