Cytomegalovirus Ebooks Catalog

The One Minute Herpes Cure

The only treatment that finally eliminates the Real Cause of Herpes! Contents: Step-by-step instructions for this safe, inexpensive and powerful healing method. the root causes and symptoms of herpes. A treatment that is deadly to herpes, but yet nearly tasteless and easy to administer! exactly how to avoid and prevent future outbreaks. how to diminish your herpes outbreak. The one thing you are lacking that could revolutionize your health. Combat the stress level contributing to your herpes. How to kill not only Herpes, but Salmonella, Cholera, E.coli, Streptococcus, Pseudomonas and Staphylococcus without killing beneficial bacteria. Other ailments such as depression, Alcoholism, and Diabetes can be cured with this same miracle treatment you'll be surprised how easy it is! the most amazing health secret anyone could ever possess. Why this groundbreaking therapy has been deliberately kept secret from you . Page 15 how this same treatment made Aids/Hiv patients go into immediate remission! How this remarkable,

The One Minute Herpes Cure Summary

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Herpes simplex virus type

Initial HSV-1 infection usually occurs before age 20 years. Virus becomes latent, primarily in trigeminal and other cranial nerve ganglia, and reactivates under stress or sunlight exposure to produce recurrent herpes labialis. of virus replication, cerebral inflammation and the predilection of HSV-1 to replicate in the medial temporal lobe and orbital surface of the frontal lobes. HSV-1 encephalitis occurs at any time of the year and is characterized by the acute onset of fever, headache, irritability, lethargy, confusion, seizures, aphasia and focal deficits.1 Before acyclovir, the mortality, often due to uncal herniation, was 60-70 . Even with treatment, the mortality approaches 30 , and survivors often have permanent seizure disorders, memory loss, higher cognitive dysfunction, aphasia and focal neurological deficits.2 HSV encephalitis is treated with intravenous acyclovir, 15-30 mg kg three times daily for 10 days. Because cerebral edema is a frequent cause of death, intubation...

Human herpesvirus types 6 7 and

Human herpesvirus type 6 (HHV-6) causes roseola infantum. Acute infection has been associated with febrile seizures in childhood74 as well as with encephalitis.75 In adults, HHV-6 may produce encephalitis76 and myelopathy.77 HHV-6 DNA and antigen have been found in the brains of patients with multiple sclerosis78,79 and progressive multi-focal leukoencephalopathy,80 perhaps reflecting its presence in blood mononuclear cells that have crossed the blood-brain barrier. Encephalitis patients have been treated with ganciclovir81 and foscarnet,82 but controlled studies are lacking. HHV-7 has been implicated in childhood meningitis and may produce the same spectrum of disease as HHV-6.83 HHV-8 has been linked to encephalitis in three patients, two of whom were HIV-positive.84

Herpes zoster virus and neuropathic pain

Herpes zoster virus (HZV) is up to ten times more common in the HIV-positive population, increasing in frequency as CD4 counts fall.41 Those with a CD4 count < 200 x 106 L are most at risk of major ocular or neurological complications. Patients with HIV demonstrate more complicated HZV infections with multidermatomal involvement, recurrent episodes, and systemic disease being more common.42 Pain from HZV infection is more likely in advanced HIV infection.4 The development of postherpetic neuralgia (PHN) is proportional to baseline pain severity and duration of zoster lesions43 III and occurs in a surprising proportion of young patients. In one retrospective study where all patients were less than 43 years of age, 18 percent of those who experienced HZV went on to develop PHN.41 IV Symptoms of herpes simplex and zoster infections also occur as part of the immune reconstitution syndrome. It is estimated to occur in 10-25 percent of patients commencing HAART and represents a recovering...

Epidemiology of herpes zoster

Population-based epidemiologic data suggest an annual incidence of HZ between 1.3 and 4.1 per 1000 population 18-20 . Some longitudinal studies suggest an increase in incidence in the last two decades although the reason for this is not clear 5, 20 . The incidence is much higher in the elderly a recent study suggests an incidence rate of 2.1 per 1000 person-years in those under 50 and 10.1 in those over 80, a fivefold difference 20 . Other large studies show a similar trend 1, 19 . These figures are generally accepted to reflect the natural decline in cell-mediated immunity with advancing age. All reported studies rely on the clinical presentation of HZ. Some studies suggest that 10 of the diagnoses of HZ made in primary care are in fact due to zosteriform herpes simplex. Other common misdiagnoses include common dermatologic diseases such as contact dermatitis, erysipelas and insect bites 5, 21 . By contrast, atypical forms of herpes zoster also exist, such as zoster sine herpete, in...

Acute Herpes Zoster and Postherpetic Neuralgia PHN

Acute herpes zoster (AHZ shingles) presents as pain usually in V1, distribution the ophthalmic division of the trigeminal nerve. The pain is spontaneous and is described as burning, aching or lancinating. There is associated hyperalgesia. Small cutaneous vesicles are seen during AHZ (acute phase) and scarring may be present during post-herpetic neuralgia (PHN). Post-herpetic neuralgia describes the persistence ofpain after a month, when the vesicles have healed.

Engineering Techniques

Alterations of the HSV genome can be achieved in a number of ways. These usually require a two-step process (named marker transfer marker rescue) in which portions of the herpes genome, which have been cloned into a plasmid vector, are first modified in vitro. The plasmid DNA is then cotransfected into cultured cells with infectious viral DNA and recombinant viruses are selected. Several methods have been described to insert DNA sequences into the viral genome. Efficient recombination into specific sites within the viral genome has been achieved in vitro using a recombination system derived from phage PI.79 It is also possible to enhance the frequency of recombination.59 The initial requirement is the insertion ofa reporter gene such as -galactosidase (lacZ) cassette flanked by Pad or PmeI restriction enzyme sites not otherwise found in the viral genome. The second phase is the substitution of the reporter gene with other foreign cDNAs by digestion of the vector DNA with Pad or Pmel...

HSV1 Based Vectors Applications

HSV replication-defective viruses with mutations in essential genes that fail to form progeny virions and DISC viruses with mutations in structural protein genes that form uninfectious progeny virions have been used as vaccines against HSV infections and as vaccine vectors.108'110 It has been shown that an H S V-2 double mutant (dl5-29) does not cause any disease in immunodeficient mice indicating that the virus would be safe even in immunocompromised individuals.111 DISC -H S V-2 has been shown to be an efficient vector for cytokine gene delivery into tumor cells and that the expression of mGM-CSF or hIL-2 enhances the immunogenicity of whole-cell vaccines.112 tk gene was left intact and functional, conferring acyclovir sensitivity to the recombinant virus. When used as a live viral vaccine in a guinea pig model of HSV-1 infection, it was shown to be protective and it was also demonstrated that the immunologic answer depended on the route of administration of the virus.

Abstract

The very deep knowledge acquired on the generics and molecular biology of herpes simplex virus (HSV), major human pathogen whose lifestyle is based on a long-term dual interaction with the infected host characterized by the existence of lytic and latent infections, has allowed the development of potential vectors for several applications in human healthcare. These include delivery and expression of human genes to cells of the nervous system, selective destruction of cancer cells, prophylaxis against infection with HSV or other infectious diseases and targeted infection of specific tissues or organs. Three different classes ofvectors can be derived from HSV-1 replication-competent attenuated vectors, replication-incompetent recombinant vectors and defective helper-dependent vectors known as amplicons. This chapter highlights the current knowledge concerning design, construction and recent applications, as well as the potential and current limitations of the three different classes of...

Methods and Procedures Principle

The mammalian two-hybrid system is a simple and inexpensive, yet powerful technique capable of assaying for protein-protein interactions within a cellular environment. Like the yeast two-hybrid system originally described by Fields and Song,9 this is an in vivo assay based on the functional reconstitution of a transcription activator. Typically, in this system, one protein of interest is expressed as a fusion protein with the yeast Gal4 DNA-binding domain (DBD), and the other protein is expressed as a fusion to the activation domain of the VP16 protein of the herpes simplex virus. The vectors that encode these fusion proteins are then cotransfected along with a luciferase reporter gene into a mammalian cell line. The expression of the luciferase gene within the reporter plasmid is under the control of Gal4-binding elements. If the two fusion proteins interact, this will bring together the Gal DBD and VP16 domains, forming a hybrid transcription activator capable of binding the Gal4...

Not All Protein Drugs And Vaccines Of The Same Name Are Identical

A slight chemical modification in a small molecule can dramatically change biologic activity. For example, the addition of methyl groups at position 1,3, and 7 of the natural substance xanthine produces the widely consumed compound caffeine the addition of methyl groups at position 1 and 3 or 3 and 7 produces the bron-chodilator theophylline or a related compound, theobromine. By the same token, the addition of a hydroxy-methyl group to the anti-herpes simplex drug acyclovir results in ganciclovir, which has anti-cytomegalovirus activity. Acyclovir Acyclovir

Identification of Chemokine Receptors as G Protein Coupled Receptors

The biological usefulness of these genes is also highlighted by the discovery of virally encoded chemokine and receptor homologues. These include chemo-kine homologues expressed by members of the herpesvirus and poxvirus families as well as receptors found in certain herpesviruses. Although a full appreciation of the function of these virally pirated genes is far from clear, these chemokine homologues provide a convenient mechanism for the infectious agent to escape the wrath of the host immune system. As such, they will likely have value in the drug discovery process. Virally encoded chemokine peptides and receptors are discussed further in Chapters 2 and 15.

Differential Diagnosis

Many disease processes present with pain, thus associated pain syndromes should be part of the physician's differential diagnosis (Overcash et al. 2001). Diabetic neuropathy (Tesfaye et al. 1994) is a frequently encountered pain, characterized by burning, muscle cramps, lancinating pain, metatarsalgia, hyperalgesia, allodynia, loss of proprioception, tingling, and numbness in lower extremities. Human immunodeficiency virus (HIV) patients present with pain including neuropathic, somatic, visceral, and headache symptoms. Patients suffering from autoimmune disease will often present with joint pain associated with inflammation, achiness, and stiffness. Post-surgical pain is commonly encountered and is usually somatic or visceral in nature. Infectious processes involving intra-abdominal organs are more likely to present with visceral pain while infectious processes involving the skin (e.g., herpes zoster) will present with somatic or neuropathic pain.

Delivery by Barrier Disruption

Morphological studies in rats, where the induction of neuropathological changes by osmotic opening was examined, provided evidence of uptake of macromolecules by the brain. The extravasation of plasma proteins such as fibrinogen and albumin was shown immuno-histochemically at the light microscopic level. Electron microscopy revealed ultrastructural changes such as swelling of astrocytic processes and severe mitochondrial damage in neurons 73 . There was also evidence of prolonged (24 h) cellular stress or injury in neurons and glia as expressed by the induction of heat shock protein (HSP-70). While the nonspecific opening of the BBB to plasma proteins harbours a risk of eliciting neuropathological changes, osmotic disruption has been tested for its potential as a delivery method for macromolecular drugs such as monoclonal antibodies against various tumour antigens or their Fab fragments. In other studies, uptake after intracarotid administration of nanoparticles (20-nm iron oxide...

Virally Encoded Constitutively Active Chemokine Receptors 243

Viral Strategies to Evade the Host Immune System 243 Chemokines and Chemokine Receptors 243 Viral Homologues of Chemokines and Chemokine Receptors and Viral Chemokine-binding Proteins 246 The Human Cytomegalovirus-encoded Chemokine Receptor Homologue pUS28 248 Characteristics of Human Cytomegalovirus Infection 248

Drug management of dental and oral conditions Dental and orofacial pain p 257

Azithromycin), p. 352 Clindamycin, p. 354 Metronidazole, p. 367 Fusidic acid p. 735 Fungal infections, p. 695 Local treatment, p. 695 Systemic treatment, p. 373 Viral infections Herpetic gingivostomatitis, local treatment, p. 696 Herpetic gingivostomatitis, systemic treatment, p. 392 and p. 696 Herpes labialis, p. 739 Anaesthetics, anxiolytics and hypnotics Anaesthesia, sedation, and resuscitation in dental

Marine Algal Sources As Therapeutics

Marine alga has rich biodiversity potential can serve various requirements as food, natural sources, bioactive compounds for treatment remedies for various types of bacterial diseases like tuberculosis, multidrug-resistant bacteria, viral infections like HIV, Herpes viruses, fungal infections, protozoan infection like malaria and is also helpful against hel-minthis diseases, cancer immunogenic, cardiovascular, neurological, and other diverse mechanisms and functions of these bioactive compounds need to be explored (Bernam et al., 2004 Chang et al., 2003 Fennell et al., 2003 Luescher-matti, 2003 Maskey et al., 2004 Mayer et al., 1999 Venkateshwar Goud et al., 2003 Zhu et al., 2004).

Viruses in neurological disease

Neurotropic virus infection is a frequent cause of morbidity and mortality worldwide. This chapter reviews the most common viruses that infect the nervous system. It begins with the human herpesvirus family, not only because they are a common cause of serious disease involving the central and peripheral nervous systems, but also because some of the herpesviruses respond to antiviral treatment. The second section discusses the neurological complications of HIV, the most common viral cause of neurological disease worldwide. HTLV-1 myelopathy is discussed in the same section. Finally, the last section reviews the neurological complications produced by a wide spectrum of enteroviruses, myxoviruses, arthropod-borne viruses, adenoviruses, arenaviruses, papovaviruses, parvoviruses, filoviruses, rhabdoviruses and para-myxoviruses.

Granulomatous Arteritis

From 2 weeks to 6 months after an attack of tri-geminal distribution zoster, patients may develop contralateral neurological symptoms attributable to granulomatous arteritis. These symptoms include transient ischemic attacks (TIAs), mental status changes or hemiplegia. Ipsilateral central artery occlusion,31 brainstem infarcts32,33 and thalamic infarcts34 have also been reported. These complications occur in persons over the age of 60 without any gender predilection, and mortality is 25 . The CSF contains a mononuclear pleocytosis with less than 100 cells mm3, an increased IgG index and oligo-clonal bands.35 Focal and segmental stenosis of the middle cerebral, internal carotid and anterior cerebral arteries is often evident on angiography. Strokes, more often ischemic36 than hemorrhagic,37 are common in large-vessel territories. Based on the clinical, pathological and virological findings, intravenous acyclovir (10-15 mg kg three times daily for 7-10 days) and a short course of oral...

Smallvessel Encephalitis

This condition is usually seen in immunocompro-mised patients. Initial symptoms include headache, fever, vomiting, mental status changes, focal deficits and seizures. Disease is often subacute or chronic.38 The CSF contains a mononuclear pleocytosis and may also reveal red blood cells, mild protein elevation, and normal to low glucose. PCR may reveal VZV DNA in CSF. MRI reveals mixed ischemic or hemorrhagic infarcts, with deep-seated lesions that involve white more than gray matter. Pathological examination reveals perivenous encephalomalacia with focal hemorrhage and necrosis. Plaque-like demyelinating lesions situated at gray-white junctions are common.39 Brain vessels and parenchyma contain inclusions and viral antigen and DNA. Aggressive treatment with intravenous acyclovir, 30 mg kg three times daily, is recommended. Immunocompromised individuals who survive VZV small-vessel encephalitis may need to be maintained on oral acyclovir or famciclovir to prevent further virus...

Viral and Bacterial Infections

Kaposi's sarcoma associated herpes virus (KSHV). KSHV is a large DNA virus. It associates with Kaposi's sarcoma, which is the most common skin malignancy among acquired immunodefiency syndrome (AIDS) patients. Three R5F2R4C PPMO sequences were found to inhibit two key proteins, RTA and LANA, and control replication of KSHV. RTA is an immediate early gene that is expressed at the start of the lytic replication cycle and LANA is required to maintain latency of KSHV. PPMOs targeting three sequences of KSHV were found to knock down KSHV protein expression. If the cells were not induced to enter the lytic cycle with tetradecanoyl phorbol acetate (TPA), less than 1 of cells were RTA-positive, indicating that less than 1 of the cells had spontaneously entered the lytic cycle. After induction of lytic replication by TPA treatment, 20 of cells treated with control PPMO or not treated with PMO were RTA-positive. If cells were treated with RP1 PPMO, the fraction of cells becoming RTA-positive...

Annotated References

Antunes Bras JM, Epstein AL, Bourgoin S, Hamon M, Cesselin F, Pohl M (1998) Herpes simplex virus 1-mediated transfer of preproenkephalin A in the rat dorsal root ganglia. J Neurosci 70 1299-1303. Kesari S, Randazzo BP, Valyi-Nagi T, Huang QS, Brown SM, Maclean AR, Lee VM, Trojanowski JQ, Fraser NW (1995) Therapy of experimental human brain tumors using a neuro attenuated herpes simplex virus mutant. Lab Invest 73 636-648.

PArrestins In Gpcr Internalization And Trafficking

Several examples illustrate that P-arrestin-dependent GPCR desensitization and sequestration are not inextricably linked. The thrombin receptor protease-activated receptor (PAR)-1 undergoes agonist-dependent phosphorylation and binds to P-arrestin 1. In murine embryo fibroblasts (MEFs) lacking expression of either P-arrestin 1 or 2, PAR-1 receptor desensitization is markedly impaired, which is consistent with the loss of homologous receptor desensitization, but clathrin-dependent receptor endocytosis proceeds normally. Interestingly, a C-terminal phosphorylation site mutant of PAR-1 fails to internalize in either the P-arrestin replete or P-arrestin null background, suggesting that PAR-1 receptors use a phosphorylation-dependent, but P-arrestin-independent, mechanism for endocytosis (51). Similar results have been obtained using the N-formyl peptide receptor (52), and the somatostatin (SST) receptor type 2A (53). The human cytomegalovirus GPCR US28, a homolog of the human chemokine...

Laboratory studies in PACNS

CNS vasculitides, diagnosed as PACNS, are reported to occur in patients with viral and to a lesser extent with bacterial and other infections, both in immunocompromised and immunocompetent patients. The most commonly encountered infections associated with CNS vasculitis are varicela-zoster virus (VZV), HIV, cytomegalovirus (CMV) and, rarely, Mycobacterium tuberculosis, Borrelia burgdorferi and Treponema pallidum. Several fungal and rickettsial infections have also been reported in association with vasculitis of the nervous system.6,7 Hence, serological studies should be carried out to exclude these infections as well as hepatitis B and hepatitis C virus infections, which are known to be associated with systemic vasculitic syndromes.20

Brain biopsy in PACNS

Histological confirmation is the gold standard for the diagnosis of PACNS. As mentioned before, brain biopsy is important not only to confirm the diagnosis, but also for the exclusion of a number of other conditions which may mimic vasculitis. Vasculo-pathy due to hypertension and atherosclerosis, multiple sclerosis or its variants, sarcoidosis, primary brain lymphoma and other lymphoprolifer-ative diseases, primary or metastatic brain tumours, and infectious encephalitis such as neurocysticerco-sis, cytomegalovirus, herpes simplex, fungal infections, progressive multifocal leukoencephalopathy and Creuzfeldt-Jacob disease were some of the diagnoses found in patients referred for a brain biopsy with a suspected clinical diagnosis of PACNS (Table 20.1).8,15,16

Epigenetics Of Tissue Homeostasis

The actual causative virus in KS is a 165 kb herpes virus, HHV8 or KHSV. Kaposi sarcoma consists of a mixture of mesenchymal cell types, which may partially be derived from an undifferentiated precursor cell. It is not quite clear which proteins of the virus are oncogenic. Some suppress apoptosis. Others act as cytokines and still others induce cytokine receptors. In KS, HIV may contribute more directly, beyond immunosuppression. HIV-infected cells release the viral transactivator protein tat, which may promote replication of KHSV and expression of viral proteins in cells harboring that virus. Moreover, HIV tat may induce secretion of the cytokine IL6 in uninfected cells, promoting the proliferation of KHSV-infected and other cells in the tumor.

Effects of Depression and Stress on Acquired Immune Lymphocyte Responses

Compared with chronic severe stress, major depression has been less well characterized in terms of effects on in vivo functional immunity however, the little evidence that is available suggests that depression, like chronic severe stress, may impair T-cell function in ways that are relevant to disease vulnerability. For example, although it is not known whether major depression is associated with an increase in antibody titers to latent viruses, one study reports that patients with major depression have a marked decrease in the ability to generate lymphocytes that respond to the herpes zoster virus (Irwin et al. 1998). Also consistent with impaired T-cell function in depression is the observation that depressed patients, especially those with melancholia, demonstrate impaired DTH (Hickie et al. 1993).

Postherpetic neuralgia

Postherpetic neuralgia (PHN) follows herpes zoster infections, mainly in the elderly. It occurs in the affected area in about 50 percent of patients over 50 years old following healing of the skin lesions, and persists for more than 12 weeks. It presents as a continuous burning or intense paroxysmal pain, and may be associated with tactile allodynia. It can be severe, debilitating, and reduce quality of life. The time-course is variable. It may abate within months, but may also continue for years. Certain human leukocyte antigen (HLA) class I antigens, such as HLA-A33 and -B44, have been shown to be associated with the development of PHN in Japanese patients.39 The results of randomized, controlled trials and meta-analyses suggest that treatment with acyclovir, famciclovir, and valaciclovir reduce the risk of developing PHN.40,41,42 It is now accepted that corticosteroids do not prevent the development of PHN.43 Topically applied capsaicin and lidocaine have both been shown to be...

Mononeuritis multiplex

Mononeuritis mulitplex can present with sensory or motor deficits in the distribution of a single or multiple cranial, spinal, or peripheral nerve. Mononeuritis multiplex may occur early in HIV infection as a result of immune mechanisms or vasculitis. In advanced HIV infection, coinfection with cytomegalovirus (CMV) or HZV can produce a similar picture. Lymphomatous infiltration of cerebrospinal fluid or meninges can also

Regulation of ILlp Transcription mRNA Formation

A variety of classical transcription factors can either enhance or suppress IL-ip gene transcription. Transcription factors which increase IL-lp gene activation include (a) AP-1 (activator protein-1 a heterodimer of c-Jun and c-Fos) created by cross-linking ICAM-1 adhesion molecules and also by IL-ip, cAMP, and PKC (Abe,Tanaka, Saito, Shirakawa, Koyama, Goto, & Eto, 1997 Fenton, 1992 Koyama et al., 1996 Serkkola & Hurme, 1993 Turner, Chantry, Buchan, Barrett, & Feldmann, 1989) (b) a tyrosine-phosphorylated protein induced by both LPS and IL-ip, which is similar to Signal Transducers and Activators of Transcription STAT proteins used by other cytokines (Tsukada, Waterman, Koyama, Webb, & Auron, 1996) (c) a heterodimer of nuclear factor (NF)-IL-6 and cAMP response element binding (CREB) protein induced by LPS (Tsukada, Saito, Waterman, Webb, & Auron, 1994) (d) a heterodimer of NF-IL-6 and a non-CREB protein induced by LPS (Tsukada et al., 1994) (e) NF-IL-6 induced by...

Carbocyclic CNucleosides

Since the discovery of Acyclovir as an anti-herpes drug, important efforts have been made toward the synthesis of analogs of acyclovir and other acyclic nucleo-sides. A comprehensive review made by Chu and Cutler110 summarizes the major At least three representative synthesis of acyclovir have been made, the first by Schaeffer et al.111 involving a condensation reaction of dichloropurine with ether chloride intermediate, and further purine transformation to generate 9-(2-hydroxyethoxymethyl)guanine (acyclovir) (Figure 4.66). which was then condensed with the halogenated purine to yield after hydrolysis and ammonolysis the target acyclovir (Figure 4.67). Robins and Hatfield114 employed a chemoenzymatic approach for preparing acyclovir consisting initially in the use of mercury salts and hexamethyldisilane (HMDS) and in the final step an enzymatic conversion. Thus, the procedure

Immunosuppressive actions of PGE

An immunotolerance for spermatozoa within the female reproductive tract is essential for their survival and the success of internal fertilization, since seminal fluid has a high antigenic potential. Human seminal plasma contains several immunosuppressive factors including prostaglandins. Recent findings 220 demonstrated powerful effects of PGE and 19-hydroxy-PGE on the balance of cytokines released by antigen-presenting cells. The induction of immunotolerance may be explained by stimulating IL-10 and inhibiting IL-12 production. However, defense against sexually transmitted diseases (gonorrhea, herpes, papilloma and HIV) may also be impaired by these mechanisms.

Discovery of Ubiquitin Based Sorting

There is now good evidence for ubiquitination regulating the internalization of the EGF (177-179), MET (180), and CSF-1 (181, 182) receptors, the epithelial sodium channel (ENaC) (171), the aggregated IgG-bound Fc receptor FcRyIIA (183), and the transmembrane Notch ligand Delta (184-186). The a1 subunit of the glycine receptor is modified with one to three ubiquitin molecules at the plasma membrane as a prelude to uptake (187), and ubiquitination of E-cadherin precedes internalization (188). There is also evidence that endocytosis of the pre-T cell receptor in thymocytes is dependent upon ubiquitination (189). In C. elegans, targeted neural overexpression of ubiquitin reduces the surface density of glutamate receptors (190) in a manner that is dependent on clathrin-mediated endocytosis, as mutant unc-11 (AP180) counteracts the effect of the excess ubiquitin. Direct ubiquitination of the glutamate receptor can be demonstrated biochemically (190). Final corroboration of the role of...

Antiviral Activity of Botanical Polysaccharides

A number of botanical polysaccharides have also been recognised for their ability to enhance host antiviral defences. For example, ingestion of soluble P-glucan derived from oats reduced morbidity and mortality after an intranasal Herpes simplex virus type 1 (HSV-1) challenge in mice after strenuous exercise 281 . Likewise, Ohta and co-workers 282 found that intranasal application of acidic polysaccharides isolated from the fungi Cordyceps militaris protected mice from lethal influenza infection. In this model, protection was proposed to involve enhancement of host immune function, and the animals treated with C. militaris polysaccharides demonstrated increased levels of TNF-a and IFN-y 282 , both being cytokines with antiviral properties 283 . For example, Peng and co-workers 284 found that Achyranthes bidentata polysaccharides exhibited anti-HIV-1 activity if they

Prevention Of Hz And

Antiviral drugs, apart from providing good control of acute pain and rash progression, reduce the duration of pain following HZ. Because of study design, it is difficult to say to what extent they may prevent PHN.35,36 I It is certain that PHN occurs and persists in many patients despite appropriate use of antiviral drugs. Interpretation of pain data from the studies suggests that the number of patients with pain at six months may be approximately halved with the prodrugs valaciclovir and famciclovir given t.d.s being more effective than acyclovir given 5 x daily. Brivudin has recently been licensed in some countries for once daily use and appears equivalent to famci-clovir but with the disadvantage of a serious, sometimes fatal, interaction with 5 fluorouracil should the drugs be coadministered. With this exception the antiviral drugs, which have their effect by inhibition of VZV viral DNA replication, are specific and remarkably safe. Evidence-based guidelines suggest that antiviral...

Prodrugs for nasal delivery

A series of 2'-(0-acyl) derivatives of 9-(2-hydroxyethoxymethyl)gua-nine (acyclovir) was synthesized by Shao and coworkers.63,64 The bioconversion kinetics of the prodrugs appeared to depend on both the polar and the steric properties of the acyl substituents. Rat nasal perfusion studies using the in situ perfusion technique showed no measurable loss of acyclovir from the perfusate. Also, the extent of nasal absorption appeared to depend on the lipophilicity of the prodrugs. All the prodrugs showed enhanced absorption. Branching of the acyl side-chain significantly retarded acyclovir prodrug breakdown, suggesting that a branched-chain prodrug with enhanced lipophilicity may exhibit better absorption and lower presystemic degradation than other designs. The L-aspartate beta-ester prodrug of acyclovir was synthesized to target active transport mechanisms.65

Uses of the PCR in research and clinical diagnosis

It is often important clinically to be able to detect incredibly low levels of a particular sequence of DNA in patient samples. An example of this is the detection of HIV, a virus that is not detectable by conventional methods in the circulation but which is detectable by the PCR using specific oligonucleotide primers to the viral DNA. This is now used on a regular basis as a rapid and sensitive method for HIV screening in genitourinary clinics and provides results more rapidly than the conventional method of immunological screening (Markham, 1993). The PCR also has been used to detect the measles virus RNA in brain biopsy specimens from patients with subacute sclerosing panencephalitis (Markham, 1993) and for the detection of herpesvirus DNA in the aqueous humour of uveitis patients, in whom it has been used for confirmation of the clinical diagnosis of viral uveitis (Yamamoto et al., 1996). The PCR has also been employed in the diagnosis of upper respiratory tract infections caused...

Painful Polyneuropathies

Acute herpes zoster, commonly called shingles, is an acute viral infection that primarily affects the posterior spinal root ganglia of spinal nerves or ganglia of the cranial nerves may be similarly affected. The causative agent, varicella zoster, belongs to a DNA group of viruses

Choice of Cell Line and Promoter

The choice of the host cell line has a significant impact on gene expression levels. Although, many promoters are transcriptionally active in a wide range of cell types, a defined cell line often has to be used for the generation of a cellular reporter system because of its specific transduction cascade. On activation, the resulting signal leads to transcriptional activation of only those downstream target reporter genes containing the corresponding transcription factor binding motifs in their promoter regions. Therefore, the specific responsiveness of cell lines must be carefully considered prior to the construction and use of expression vectors.9,10 For example, the widely used cytomegalovirus (CMV) promoter exhibits low transcriptional activity in hepato-cytes.11 Strong constitutive and rather unspecific promoters are the adenovirus major late promoter, the human CMV immediate early promoter, and the SV40 and Rous sarcoma virus promoter. For many cell-based screening assays, a...

Role of IDO in the Defense Against Infectious Pathogens

One of the most simple and ancient host defense against pathogens is the depletion of nutrients, such as iron-chelating proteins. The kynurenine pathway, by depleting Trp, can locally impair the growth of microbes. Soon after the discovery of IDO, it was observed that this enzyme is notably induced in mouse lung after an intraperitoneal administration of bacterial LPS 91 , leading to Trp degradation and increased plasma kynurenine levels 92 . IFN-7 inhibits IDO-dependent growth of group B streptococci 93 , intracellular pathogens (e.g., Chlamydia psittaci, Leishmania donovani, and Toxoplasma gondii) 94, 97 , and viruses (e.g., cytomegalovirus or Herpes Simplex Virus) 95, 96 . This effect is mediated by increased Trp degradation, and inhibition could be reversed by the addition of Trp excess. Infection with Candida albicans produces an IFN-7-dependent IDO induction in DCs and polymorphonuclear neutrophils that inhibits fungi growth, and in this case the antioxidant properties of IDO...

Metal complexes of drugs used as ligands

The anti-viral activity of Pd(II) complexes with the anti-herpic drug pen-ciclovir (pen) of formulae cis- (pen)2PdCl2 and cis- (nucl)2Pd(pen)2 Cl2 (nucl guanosine, inosine, cytidine or penciclovir) were tested. All prepared complexes were markedly active against HIV-1 and HSV-2 (herpes simplex virus) strains but not against the thymidine kinase-deficient HSV-1 strain in E6SM diploid fibroblastic cell cultures.21

Gene therapy the real diseases

The delivery of cytotoxic genes to tumour cells has been used essentially for the treatment of localised tumour deposits that are accessible to gene delivery but are inoperable. The most commonly used strategy involves delivering a gene encoding an enzyme that will activate a prodrug to a toxic metabolite, leading to the death of the cell expressing the gene. An example of such a system currently in clinical trials is the herpes simplex virus thymidine kinase gene (HSVtk) coupled with the anti-herpetic drug, ganciclovir (GCV) (Culver et al., 1992). This system has the added advantage that a local bystander killing effect leads to the killing of (non-transduced) cells neighbouring the cells expressing the HSVtk gene as a result of transfer of toxic metabolites between juxtaposed cells (Bi et al., 1993 Freeman et al., 1993). Hence, in a trial at the National Institutes of Health in the United States, patients with inoperable gliomas receive retroviral vectors encoding HSVtk by...

Delivery systems for gene therapy

Other viral vectors, not yet approved for clinical use, are currently in development, including herpes simplex virus, parvovirus and adeno-associated viruses (Jolly, 1994). As the number of vector systems which are sufficiently well characterised to be safely used in patients increases, so the conflicts between the different requirements of each system should be easier to resolve. It may also soon be possible to synthesise custom-designed delivery vehicles by incorporating the best features of different individual vectors into hybrid constructs that have the specific, combined properties required for the gene therapy protocol of choice (Miller and Vile, 1995).

Vasculitis in the inflammatory neuropathy due to infectious agents

NA of the type observed in PAN, with fibrinoid necrosis and leukocytoclasia, is also observed in HIV neuropathy.67,69 In this setting, however, in contrast with the usual pattern of lesions observed in PAN, mononuclear cells predominate in the inflammatory infiltrate, which is often present in the endoneural space, and affect small endoneural blood vessels. The lesions of nerve fibers observed in this setting often included a higher than usual proportion of demyelinated fibers in a series of patients with necrotizing vasculitis and HIV infection. Additionally, inflammatory myopathy and lesions of muscle arteries are often present. At late stages of the immunosuppression induced by HIV infection, opportunistic infection of nerve blood vessels, especially of endothelial cells of endoneural capillaries by cytomegalovirus, can further damage nerves.

Stress And The Immune System

Examination stress in University students has been the subject of several studies in the United States. Thus, a decrease in natural killer cell number and function has been reported by several groups of investigators (Glaser, Rice, and Speicher 1986 Kiecolt-Glaser and Glaser (1988), effects that were not attributable to poor nutritional status. In addition, academic stress has been associated with significant changes in antibody titers to latent herpes viruses suggesting changes in cellular immunity. In particular, elevated antibody titers to the Epstein Barr virus (the causal agent for infective mononucleosis), herpes simplex virus type 1 (that causes cold sores), and cytomegalovirus (which causes the monucleosis syndrome) were raised prior to examinations but returned to normal levels following the examination (Glaser, Kiecolt-Glaser, and Stout, 1985). There were additional changes in mitogen stimulated lymphocyte replication associated with academic stress. Thus, the incidence of...

Zidovudine Retrovir

The genomes of retroviruses, such as HIV, consist of single-stranded RNA which must be converted to double-stranded DNA in order for viral replication to occur, since only double-stranded DNA can be integrated into the chromosomes of the host cell. The RNA to DNA conversion is carried out by the enzyme reverse transcriptase that is present in each HIV virus along with two copies of the retroviral RNA. AZT is converted to the 5'-triphosphate derivative, which is a potent and specific inhibitor of the enzyme HIV reverse transcriptase. In addition, when AZT-5'-triphosphate is incorporated into DNA, chain termination results.2 (See also acyclovir on page 148).

Expression Using Mammalian Cells

The mammalian cell expression system contains all the necessary regulatory machinery for accurate and efficient processing and secretion of eukaryotic proteins, although there may be species differences. Foreign DNA is introduced into the cells either via virus infection or directly, employing chemical (for instance lipocomplexes or calcium phosphate) and physical (electroporation or microinjection) methods. The transcriptional control elements (enhancers and promoters) are complex and vary between mammalian cell types. However, simian virus 40 (SV40) and human cytomegalovirus (CMV) promoters are active in many cell types and are therefore commonly used. Obtaining stable transfected cell lines can be time consuming and therefore a transient expression system is often used for initial analysis. Typically COS (African green monkey kidney) and CHO (Chinese hamster ovary) cells are used for this purpose. An obvious advantage of mammalian cell expression is the possibility of advanced...

Virion Associated Vif May Have a Crucial Role in Regulating Viral Infectivity

One hypothetical model that invokes an active role of Vif during a preintegration step in virus replication involves the transport of the nucleo-protein or preintegration complex from the plasma membrane to the nucleus. Active transport of nucleocapsids from the cell surface to the nucleus has been reported for other viruses such as herpes simplex virus (Sodeik et al., 1997) or human foamy virus (Saib, 1997). In the case of herpes simplex virus, viral nucleocapsids were found to associate with the minus-end directed microtubule motor dynein for active transport along microtubules to the perinuclear region (Sodeik etal., 1997). Similarly, infection of cells by human foamy virus was found to result in a microtubule-dependent centrosomal accumulation of Gag proteins (Saib et al., 1997). Several lines of evidence suggest that virion-associated Vif could be similarly involved in active nuclear targeting of viral nucleoprotein complexes. First, it is well documented that vif-defective HIV-1...

Prevention of postherpetic neuralgia

And in the over-50s 2.13 (95 CI 1.42-3.19) (some unpublished data were included). Pain reduction in those receiving acyclovir was greater at 3 and 6 months 34 . Jackson included data from five studies and measured the risk of any pain at 6 months. The odds ratio for the incidence was 0.54 (95 CI 0.34-0.81) 33 . In a single multicenter double-blind placebo-controlled trial, famciclovir reduced the duration of postherpetic pain from 119 days (placebo) to 63 days (1500 mg day) or 61 days (2250 mg day) 36 . Comparison studies with valaciclovir and brivudin showed no difference 37, 38 . Although the overall evidence is limited 39 , recommendations from expert panels favor commencement of antiviral in the first 72 hours after the onset of rash, among other things to maximize the speed of resolution of pain 5 . It is clear from existing data that prompt use of antivirals cannot guarantee freedom from chronic pain in severe cases.

Plasmidderived Short Hairpin RNAs

Transcription with RNA polymerase II yields RNAs that contain a cap at the 5'-end and a poly-A tail at the 3'-end. Only a few reports of work employing RNA polymerase II promoters to generate shRNAs have therefore been published to date. Since the cap and poly-A tail are not compatible with the RNAi machinery, this approach requires a setup with an optimized version of the cytomegalovirus promoter, as well as a minimized poly-A cassette to generate functional shRNA molecules.15

The Synthesis Of Nucleoside Analogues

The 9-N-H of guanine 6.67 is rendered acidic by the imino group of the purine ring system. In some respect, it is the nitrogen analogue of a carboxylic acid. A protected guanine treated with triethylamine and the chloromethyl ether 6.68 gives the benzoate of acyclovir 6.69, which is then hydrolysed to acyclovir 6.54.

Psychological Effects Of Immune Activation In Humans

Acute infectious illness, such as influenza, upper respiratory tract infections, gastroenteritis, Epstein-Barr virus, and cytomegalovirus, are associated with a range of depressive symptoms, including fatigue, psychomotor retardation, anorexia, somnolence, lethargy, muscle aches, cognitive disturbances, and depressed mood (Hickie & Lloyd, 1995). The evidence for these alterations is mainly anecdotal and only few studies examined these symptoms systematically. Experimentally-induced viral infections (e.g., common cold, influenza) are associated with decreased psychomotor performance of simple reaction-time tasks and memory impairments (Smith, Thomas, Brockman, Kent, & Nicholson 1993 Smith,Tyrrell, Al-Nakib, Coyle, Donovan, Higgins, & Wiliman, 1987 Smith,Tyrrell, Al-Nakib, Coyle, Donovan, Higgins, & Willman, 1988). In addition, they are often associated with long term psychiatric effects, particularly depression. Experimentally-induced influenza (but not infections with...

GPCR Mediation of Interactions Between Virus and Host

The study of the genomics of the GPCRs involved in infection, inflammation, and disease progression has identified novel classes of receptor genes that may become pharmaceutical targets. The potential for pharmaceutical intervention into viral infection has been established not only for HIV progression but also for the development of Kaposi sarcoma (KS), a common sequel resulting from the Kaposi herpes virus, KSHV. The potential of GPCR pharmacogenomics is suggested by experimental evidence supporting a key role for a particular KSHV gene, a constitutively active G protein-coupled receptor (vGPCR), in the development of KS. Although this receptor, like the cytomegalovirus (CMV)-encoded GPCR (232), originates in a nonhuman genome, it is able to function in human cells and thereby coopt many functions. In particular, it is able to function as a receptor for human ligands affecting immunomodulating cytokines such as interleukin 6. This GPCR may facilitate viral control of the host...

Categories Of Viral Vectors

There are four categories of viral vectors currently undergoing clinical trials in gene therapy protocols. These include the retroviruses, adenoviruses, adeno-associated viruses and herpes-simplex viruses. Each category has its own inherent set of advantages and limitations and the choice of viral vector developed and tested depends on an array of factors. These include the type of target tissue the size of the exogenous DNA the nature of the gene products and the required duration of expression of the gene product. An ideal vector would be target cell specific and capable of delivering the therapeutic gene and regulatory elements of sufficient size for the particular clinical application. It would be capable of regulated gene expression for the appropriate time duration to achieve the desired clinical response. It would also be capable of avoiding the host defence system and would not induce immunogenic or inflammatory responses, or generate replicative competent viruses. As the...

Adenoassociated Virus Vectors

Adeno-associated viruses (AAV) comprise a non-pathogenic parovirus family that are indigenous to humans. They are not autonomous in that they require a helper virus (the adeonoviruses or certain other viruses such as herpes virus) to complete their replicative cycle. The AAV genome consists of a small (4.7 kb) single strand of DNA with an extremely simple prototypical organisation comprising just two genes, designated rep and cap (Figure 43(a)). The rep gene encodes a family of four overlapping proteins involved in replication and integration while the cap gene encodes three proteins involved in encapsidation. These are flanked by inverted terminal repeat (ITR's) which contain palindromic sequences that function in cis during viral replication.

Additional virus vectors

A number of additional viruses have been developed as gene therapy vectors. These include herpes simplex virus, vaccinia virus, and poxvirus vectors. The use of these viruses as gene therapy vectors expands the scope and efficiency of gene delivery to potentially facilitate therapeutic gene transfers to a wider range of clinical conditions. However, common problems associated with the development of these viruses as vectors have been the increased difficulty in generating replication incompetent viruses and safety issues associated with high levels of immunogenicity and cytotoxicity, stemming from the large size and complex replicative cycles of the wild-type genomes (Table 38). Herpes simplex viruses (HSV) have received a lot of attention as potential gene therapy vectors. HSV can establish a latent infection in neurons of the peripheral and central nervous system by existing as an episome with tight control of viral lytic genes. Though it has a natural tropism for the central...

Gene therapy and genetic disorders

Gene therapy has also been applied to correct genetic mechanisms associated with non-mendelian disorders. Neurodegenerative diseases represent an important class of such target disorders for gene therapy. These include Alzheimers, Parkinsons and Huntingtons disease. The targets for their therapy includes the underlying causative genes, neurotrophic factors that affect neuronal function and survival, and secondary metobolic and neurotransmitter functions (38). Vectors derived from the Herpes Simplex viruses have mainly been used in protocols for these diseases because of their natural tropism for post-mitotic neuronal cells. However, retroviral vectors have been used to deliver cytotoxic agents to tumors of the CNS because their

Gene Therapy and Cancer

Suicide gene therapy involves the transduction of a gene whose product converts a non-toxic pro-drug into a toxic substance. The pro-drug is administered systemically and activated in transduced cells. The most widely used suicide gene therapy involves the use of the Herpes Simplex virus thymidine kinase (HSN-tk) gene which converts gancyclovir into cytotoxic gancyclovir triphosphates that function as nucleoside analogues inhibiting DNA synthesis. The first such protocols approved involved retroviral vector-mediated transduction of HSV-i& to brain tumours 40 and the strategy is now being applied to a range of cancer with significant tumor suppression being noted (41). This is, in part, the result of a significant bystander killing effect of non-transduced cells due to diffusion of the toxins. Adenoviruses have been used to transduce liver tumour cells with the Escherischia coli cytosine deaminase (CD) gene which converts 5-fluorcytosine to the chemotherapeutic agent 5-fluorouracil....

Physicochemical Properties Of Drugs Affecting Permeability Across Ocular Barriers

The cornea is composed of five or six layers of columnar epithelium with tight junction proteins. On the other hand, passive diffusion is the primary route for hydrophilic drugs to permeate the cornea. Thus the lipoidal nature of the corneal epithelium presents a major barrier to the entry of hydrophilic drugs like acyclovir, ganciclovir, epinephrine, and pilocarpine. In humans, ocular bioavailability is predicted to be 1-5 for lipophilic molecules (octanol-to-water distribution coefficient greater than 1) and to be less than 0.5 for hydrophilic molecules (octanol-to-water distribution coefficient less than 0.01) (39). Chemical modifications have been carried out to improve the partition coefficient of hydrophilic drugs by acyl ester prodrug design, and the results showed improved

Ginsengasian Panax ginseng Ginsana G115 Korean red ginseng

Promoted to improve vitality and well-being 200 mg PO daily. Ginsana 2 caps PO daily or 1 cap PO bid. Ginsana Sport 1 cap PO daily. Preliminary evidence of efficacy for erectile dysfunction. Efficacy unclear for improving physical or psychomotor performance, diabetes, herpes simplex infections, cognitive or immune function. American College of Obstetrics and Gynecologists and North American Menopause Society recommend against use for postmenopausal hot flashes. Not by prescription. 2- -

Melissa officinalis L

Lemon balm is a delicious lemony-tasting botanical that is widely used for colic, restlessness, teething, and fever in children. It is also used as a mood elevator, antidepressant, and relaxing diaphoretic in adults, among many other uses. In Europe, a balm made from the essential oil-rich leaves is also used topically as an antiviral for the treatment of oral herpes. Although the leaves of lemon balm are not readily subject to adulteration, whole-plant lemon balm may also be traded. This material would include fragments of stem and flowers.

Organic Cation Transporters Oct Octn Slc22A

OCT1-3 are polyspecific transporters capable of transporting various organic cations (Table 7.7), including model compounds such as tetraethylammonium (TEA) and N-methylquinine, as well as other xenobiotics including 1-methyl-4-phenylpyridium (MPP+), acyclovir and ganciclovir, metformin and phenformin, memantine, as well as quinidine (Koepsell et al., 2003 Koepsell and Endou, 2004 You, 2004). Endogenous substrates of the OCTs include the monoamine neurotransmitters acetylcholine, dopamine, serotonin, histamine, choline, and physiological compounds such as creatinine, guanidine, and thiamine (Koepsell et al., 2003 Koepsell and Endou, 2004 You, 2004). Although organic cations are clearly the preferred ligands of the OCTs, several uncharged or anionic compounds are known to be substrates of these transporters (Table 7.7). For example, hOCT2 is partially responsible for the transport of cimetidine, a weak base (Barendt and Wright, 2002), while both hOCT1 and hOCT2 mediate the transport of...

Intraocular Dosage Forms

Ophthalmic products, which are introduced into the interior structures of the eye either during ocular surgery or via an intravitreal injection, are a special class that requires the application of technology from parenteral dosage forms in their design, packaging, and manufacture. The development of cytomegalovirus (CMV) retinitis as a common opportunistic infection in patients with AIDS has resulted in the initial expansion of this class of ocular product to include solid inserts and injections of antiviral agents administered directly to the vitreous cavity. As discussed previously, topical and systemic administration often fail to achieve therapeutic concentrations in the vitreous cavity.

Compound haemorrhoidal preparations with corticosteroids

Corticosteroids are often combined with local anaesthetics and soothing agents in preparations for haemorrhoids. They are suitable for occasional short-term use after exclusion of infections, such as herpes simplex prolonged use can cause atrophy of the anal skin. See section 13.4 for general comments on topical corticos-teroids and section 1.7.1 for comment on local anaesthetics.

Varicellazoster virus

Herpes zoster consists of dermatomal distribution vesicular rash on an erythematous base associated with burning pain and mixed hypesthesia and hyperpathia. Elderly patients may develop a toxic encephalopathy Treatment of zoster pain includes extra-strength acetaminophen and 30-60 mg codeine every 6 h. Phenytoin (300-400 mg daily), carbamazepine (400-1200 mg daily)14 and gabapentin (900 mg daily) are often useful. Oral acyclovir (800 mg five times daily) or famciclovir (500 mg three times daily) reduce the duration of rash but do not prevent post-herpetic neuralgia (PHN).20,21 All patients with ophthalmic distribution zoster should be treated with an antiviral agent. Steroids have not been shown to prevent PHN, but are often given for 3-5 days during acute zoster to reduce rash duration.22,23

Ocular Pharmacodynamics

For fungal and viral infections, there are a very few agents that the ophthalmologist can prescribe. These organisms' resistance and similarity to mammalian tissue make it difficult to find effective and safe therapies. For instance, idoxuridine, a selective metabolic inhibitor, has been shown to be useful against herpes simplex virus infection of the cornea. For the trachoma virus and viruses that cause inclusion conjunctivitis i.e., TRIC (the single largest cause of blindness worldwide) , no specific antiviral agent has demonstrated satisfactory activity, and the secondary bacterial ramifications of this disease are managed by conventional antibiotics, such as tetracycline, chloramphenicol, and erythromycin. The trachoma virus itself seems to be somewhat susceptible to these antibiotics however, up to six weeks of treatment, antibiotics are required three times per day to achieve an 80 cure rate (52,53).

Antiviral Agents for Ophthalmic

Trifluridine (viroptic) Vidarabine (vira-a) Acyclovir (Zovirax) Herpes simplex keratitis and conjunctivitis Herpes simplex keratitis and conjunctivitis Herpes zoster ophthalmicus Herpes simplex iridocyclitis Herpes simplex keratitis Herpes zoster ophthalmicus Herpes simplex keratitis Herpes zoster ophthalmicus Cytomegalovirus retinitis Cytomegalovirus retinitis Cytomegalovirus retinitis Cytomegalovirus retinitis

Dosage Form And Routes Of Administration

A small number of biopharmaceuticals are delivered by nonparenteral means. Recombinant DNase is given by inhalation aerosol to reduce the viscosity of mucus in the lungs of patients with cystic fibrosis. A platelet-derived growth factor in the form of a gel is administered topically for wound healing. Several hormones and peptides are administered in solution by the intranasal route. A solution of an antisense drug used for the treatment of cytomegalovirus retinitis is injected directly into the eye.

Rdnaderived Miscellaneous Products

Antihemophilic factor (factor VIII) (Humate-P, Hemophil M, Koate HP, Monoclate-P) is a glycoprotein found in human plasma and a necessary cofactor in the blood-clotting mechanism. This high-molecular-weight glycoprotein has a complex structure with several components (subcofactors).95 The commercially available concentrates derived from blood collected from volunteer donors by the American Red Cross Blood Services are used primarily for the treatment of patients with hemophilia A. Because the commercially available products are purified concentrates derived from blood pooled from millions of donors, the major precautions in using the products relate to transmission of viruses, such as hepatitis virus, herpesvirus, and HIV. This major problem has been alleviated, mostly because of the development and marketing of rDNA-derived antihemophilic factors.

Idoxuridine Enters The Cell And Is Phosphorylated At

Idoxuridine

In the United States, idoxuridine is approved only for the topical treatment of herpes simplex virus (HSV) keratitis although outside the United States, a solution of idoxuridine in dimethyl sulfoxide is available for the treatment of herpes labialis, genitalis, and zoster. The use of idoxuridine is limited because the drug lacks selectivity low, subtherapeutic concentrations inhibit the growth of uninfected host cells. The effective concentration of idoxuridine is at least 10 times greater than that of acyclovir.

Creating Mouse Models By Gene Targeting

The replacement vector used in gene targeting typically contains 10-15 kb of DNA homologous to the target gene, say Gene X, followed by a neomycin-resistant gene (neor) and a herpes simplex thymidine kinase gene (HSV-tk) adjacent to the target homology (Figure 9.8). The neor gene disrupts the coding sequence of the target gene and acts as a marker conferring resistance to a neomycin-like drug (G418) that is used for selecting cells that contain a copy of the recombinant vector. The pMC1 NEO neor vector is used in these constructs because it maximized the expression efficiency of the DNA integrated into the stem cells. The HSV-tk gene is used to negatively select for nonhomologous events. Nonhomologous events will lead to the insertion of tk and the resultant clone can be selected against with gancyclovir. In the more recent protocol, a nucleoside analog, FIAU (that specifically kills cells with functional HSV-tk genes, but is not toxic to cells with only cellular Tk), replaces...

Prodrugs for ocular delivery

In recent years, the following prodrugs have been tested experimentally and clinically for ocular delivery prodrugs of adrenergic agonists (epinephrine and phenylephrine prodrugs),82 prodrugs of P-adrenergic antagonists (P-blockers) (timolol, nadolol, and tilisolol prodrugs),83 pilocaprine prodrugs (mono- and diesters of pilocapric and bispilocapric acids),84 antiviral prodrugs (acyclovir and idoxuridine esters),85,86 carbonic anhydrase inhibitor prodrugs, and steroids.87 Several examples of ocular prodrugs designed to improve ocular bioavailability are summarized in Table 3.6.

Vidarabine Phsphodiester Bond Inhibition

At one time in the United States, intravenous vidarabine was approved for use against HSV encephalitis, neonatal herpes, and herpes or varicella zoster in immunocompro-mised patients. Acyclovir has supplanted vidarabine as the drug of choice in these cases. Acyclovir Acyclovir, 9- 2-(hydroxyethoxy)methyl -9H-guanine (Zovirax), is the most effective of a series of acyclic nucleosides that possess antiviral activity. In contrast with true nucleosides that have a ribose or a deoxyribose sugar attached to a purine or a pyrimidine base, the group attached to the base in acyclovir is similar to an open chain sugar, albeit lacking in hydroxyl groups. The clinically useful antiviral spectrum of acyclovir is limited to herpesviruses. It is most active (in vitro) against HSV type 1, about two times less against HSV type 2, and 10 times less potent against varicella-zoster virus (VZV). An advantage is that uninfected human cells are unaffected by the drug. The ultimate effect of acyclovir is the...

Dissolution Method for Quality Control of Immediate Release Dosage Forms 3611 Dissolution Media

The most commonly used dissolution apparatus for solid oral dosage forms are the basket method (USP Apparatus I), the paddle method (USP Apparatus II), the reciprocating cylinder (USP Apparatus III) and the flow-through cell system (USP Apparatus IV). The first two apparatus are commonly used for dissolution testing of immediate-release dosage forms. The major advantage of these two devices is that they are simple, robust, and well standardized. The reciprocating cylinder apparatus has also been used for the dissolution testing of immediate-release products of highly soluble drugs, such as metoprolol and ranitidine, and some immediate-release products of poorly soluble drugs, such as acyclovir (Yu et al., 2002). However, this apparatus should be considered only when the basket and paddle method are shown to be unsatisfactory. Due to the potential need for the large volume of medium, the flow-through cell system is not suitable for a dissolution test that is used routinely for the QC...

Antisense Oligonucleotides

Paper Dna Printable Pattern

The only AS ON approved by the FDA to date is the 21-mer phosphorothioate Vitravene (fomivirsen) which targets the immediate early mRNA of the human cytomegalovirus (CMV).5 The ON is injected intravitreally and is used to treat CMV-induced retinitis in immunodeficient patients with acquired immunodeficiency syndrome (AIDS). The complicated mode of administration and the existence of efficient alternative drugs, however, hinder its broad application. Two additional phosphorothioates that have been tested in advanced stages of clinical investigations to treat cancer are Genasense (see Chapter 2) and Affinitak, which target Bcl-2 and PKC-a, respectively. The results of clinical trials with these ONs, however, did not meet the expectations. The primary mode of action of Genasense still remains somewhat ambiguous and may not even be antisense inhibition of the targeted gene.6 But, despite this uncertainty, it might be a general problem for AS therapeutics for cancer...

Colloidal silver suspension for treating skin problems in tropical and decorative fish

Excerpt(s) The presence of skin lesions in tropical and decorative fish is commonplace. Whether caused by scrapes during handling or a skin disease, these ailments must be treated with great care. Otherwise, because of the extreme sensitivity of these fish, they may suffer a life-threatening upset, possibly as a result of an allergic reaction triggered by exposure to certain chemicals, and succumb. While conceivable treatment scenarios include direct injection as well as the administration of a liquid medicine orally or in powdered form in the fish feed, the easiest method, for a large number of fish, is to add therapeutic substance(s) directly to their aquarium tank water. Tests have shown that skin problems in tropical and decorative fish can be treated successfully by adding a highly dilute suspension of colloidal silver to the aquarium water in which such fish are living. Among the species which have been treated are koi, goldfish and a variety of tropical and marine fish, which...

Systemic Viral Infections And

Herpesviruses (Epstein-Barr virus, cytomegalovirus, VZV, HSV, HHV6) 'Stealth virus' (simian cytomegalovirus) in the post-war period. The concept of a persistent systemic viral infection as a cause of CFS was first developed during the 1980s, following the reports of persistent fatiguing illness associated with serologi-cal evidence of EBV infection and the description of a cluster of cases in Incline Village, Nevada.27 It was quickly discovered that EBV serologies did not discriminate outbreak cases from controls, a fact that was borne out in the subsequent studies.28,29 Indeed, data from multiple studies on virus isolation, genomic detection and lymphocyte transformation generally show no difference between cases and the control population.30,31 Apart from EBV, a variety of other causative viruses and infective agents have been proposed as models of persistent infection and fatigue in CFS, including enteroviruses, herpesviruses, retroviruses, animal (simian) cytomegalovirus ('stealth...

Constitutive Activity of GPCRs and Pathophysiology of Disease

Constitutive Activity

Fig. 7.2 Constitutive activity of GPCRs and pathophysiology of disease. Genetic mutations may elicit constitutive receptor activity (left) and thereby cause several diseases. Constitutive GPCR activity may also be relevant for viral diseases (right). Virally encoded GPCRs (e.g., the cytomegalovirus GPCR Fig. 7.2 Constitutive activity of GPCRs and pathophysiology of disease. Genetic mutations may elicit constitutive receptor activity (left) and thereby cause several diseases. Constitutive GPCR activity may also be relevant for viral diseases (right). Virally encoded GPCRs (e.g., the cytomegalovirus GPCR Other examples of constitutively active receptors of potential relevance for disease are virally encoded GPCRs. Such GPCRs have been described in the genomes of human cytomegalovirus (CMV) and in Kaposi sarcoma herpes virus (KSHV) 12 . Human CMV carries four GPCRs, termed US27, US28, UL33, and UL78 (see also Chapter 15) 20 . Cytomegaloviruses are species-specific herpes viruses that may...

Creation And Maintenance Of Cell Lines Stably And Heterologously Expressing nAChR Of Defined Subunit Composition

Initial success in stably and heterologously expressing a7-nAChR18 can be attributed to selection of host cell (see next section) and selection of vector. The pCEP4 (Invitrogen) vector was chosen because it has the cytomegalovirus (CMV) promoter, which gives high constitutive expression of the downstream transgene of interest in human host cell lines. pCEP4 also contains genes coding for the Epstein-Barr virus nuclear antigen (EBNA) and origin of replication (ORI) allowing episomal replication of the vector in human cells. That is, a vector was chosen that would eliminate a requirement for insertion of the transgene into the host genome, where it might become silenced or subject to variable regulation of expression. This helped to ensure high copy number for the transgene and its stable expression under constant selective pressure via coordinate expression of the hygromycin resistance gene, all from the same plasmid.

Gene therapy in the clinic

Experiments on 21 adult patients suffering from head and neck squa-mous cell carcinoma. Gene transfer is achieved by intratumoral injection of the replication-defective type 5 adenovirus vector, Ad5CMV-p53, which contains the normal human p53 tumour-suppressor gene. The E1 region of Ad5CMV-p53 has been replaced with a p53 expression cassette containing the human cytomegalovirus (CMV) promoter. This and other similar trials have recently received approval in the United States. Culver K W, Link C J, Carlstrom T, et al. (1994) Gene therapy for the treatment of malignant brain tumours with in vivo tumour transduction with the herpes simplex thymidine kinase gene ganciclovir system. Hum Gene Ther 5 343-379. Vile R G, Hart I R (1993) Use of tissue-specific expression of the Herpes simplex virus thymidine kinase gene to inhibit growth of established murine melanomas following direct intratumoral injection of DNA. Cancer Res 53 3860-3864.

Other biological activities of fucoidan

Hemmingson et al. (2006) demonstrated the potential antiviral activity of galactofucan sulfates extracted from U. pinnatifida against herpes viruses HSV-1, HSV-2, and HCMV. In recent years, few other antivirus activities of sulfated polysaccharides-containing fucose have been demonstrated (Hayashi et al., 2008 Mandal et al., 2007).

Solvents Not Widely Used for Topical Preparations

Dimethylsulphoxide is a universal solvent but can cause itching erythema and uticaria when applied to skin. However, it has been used medicinally in bladder instillations (at 50 in water) for interstitial cystitis, and is a vehicle for idoxuridine for herpes infections (though is of little value). Together with acetone, DMSO is a class 3 solvent under the FDA guidance, not known as a human health hazard at levels normally expected in pharmaceuticals and which can thus be limited by appropriate GMP practices.

Antiviral Agents 6121 Viral Diseases

A number of diseases of man are of viral origin. These include poliomyelitis, common cold (rhinovirus), influenza, hepatitis A and B (liver disease), herpes simplex (cold sores), rubella and measles, papillomas (warts) and the human immunodeficiency virus (HIV-AIDS). A virus Acyclovir (Zovirax ) 6.54 is a guanosine analogue which lacks part of the deoxyribose. Once it has entered the virus, the viral kinase phos-phorylates acyclovir to give the triphosphate and attaches this to the developing nucleic acid chain. However, further chain elongation cannot take place because the relevant sugar hydroxyl group is missing. This antiviral drug is relatively safe and it is used in the treatment of herpes simplex virus. Acyclovir is found in some 'over-the-counter' medicines for the treatment of 'cold sores'. A pro-drug, valaciclovir 6.55, has a valine unit attached, while a carbocyclic analogue, carbovir 6.56, is also used.

Molecular Biology Of Burkitt Lymphoma

Since EBV is found in so many BL, it is tempting to speculate that this herpes virus may provide a complementary function to that of MYC in the development of this tumor. The relationship has, however, emerged as more roundabout. EBV occurs in > 90 of all adults, but only in a fraction of B-cells. It is capable of immortalizing cells of this type. This ability is therefore used in the laboratory to generate permanent lymphoblastoid lines. The virus exists as an episome, whose maintenance and replication require minimally the expression of the EBNA-1 protein (Figure 10.7). In lymphoblastoid lines and in long-term infected cells in vivo, further genes are expressed which down-regulate apoptosis and help to avoid immune detection. These genes are obvious candidates for synergizing with MYC in BL, but most of them are more weakly expressed in the actual disease than normally. The EBER RNAs of the virus are also good candidates for cooperating with MYC. Conversely, there is evidence that...

Miscellaneous GPCRs

GPCRs are not only encoded by eukaryotic genes but also by viral genes. To date, 18 putative GPCRs have been identified within herpes and pox viruses. Involvement of GPCRs in the pathophysiologic role of viruses has been impressively demonstrated for the Kaposi's sarcoma-associated herpes virus (KSHV) receptor and so-called UL78 gene family found in the cytomegalovirus (Oliveira and Shenk 2001). The KSHV-GPCR, closely related to chemokine and interleukin receptors, was found to agonist-independently activate the Gq n PLC signal transduction pathway (Arvanitakis et al. 1997).

Cytoplasmic Delivery

Schwarze et al. reported on the development of a recombinant fusion protein consisting of the protein transduction domain of HIV-derived TAT and the 120-kDa -galactosidase. The TAT protein was able to deliver the large molecular weight protein to the interior of the cells in vitro. Interestingly, the enzymatic activity of intracellularly delivered -galactosidase peaked about 2 h later than did the intracellular concentration. This likely reflects a slow posttransduction refolding of the protein by intracellular chaperones. Intraperitoneal injection of the fusion protein in mice resulted in delivery of the biologically active fusion protein to all tissues, including the brain 41 . Similarly, the Herpes simplex virus tegument protein VP22 is able to deliver proteins into the cytoplasm of cells 42 . Both approaches may prove useful to enhance the delivery of e.g. enzymes for pro-drug protocols.

Introduction

The importance of the contributions of molecular pharmacology to biomedical research is reflected in the number of Nobel Prizes in medicine awarded over the past 50 years for fundamental discoveries in disease causality and the manner in which drugs affect these processes. Thus, the prize has been given for discoveries relating to mechanisms for the storage, release, and inactivation of humoral transmitters the action of hormones signal transduction in the cardiovascular and nervous systems peptide hormone production regulation of cholesterol metabolism and the establishment of modern mechanistic principles for drug treatment. With respect to the last topic, the Nobel Prize was awarded to Gertrude Elion, George Hichens, and Sir James Black for their discoveries relating to particular drug entities, namely azathioprine, acyclovir, and the H2 receptor blocker cimetidine

Human Cancers

In contrast, two members of the herpes virus family are accepted as co-carcinogens for human cancers. HHV8 (or KHSV) is a crucial agent in the development of Kaposi sarcoma, which most often arises in the context of immunodeficiency caused by the retrovirus HIV ( Box 8.1). Epstein Barr Virus (EBV) is best known for its role as a co-carcinogen in Burkitt lymphoma ( 10.3), but is very likely also involved in further malignancies including nasopharyngeal carcinoma and certain Hodgkin and non-Hodgkin lymphomas. It appears to act mainly by suppressing apoptosis ( 7.2) of lymphoid cells.

Parallel Processing

Microwave-assisted reactions allow rapid product generation in high yield under uniform conditions. Therefore, they should be ideally suited for parallel synthesis applications. The first example of parallel reactions carried out under microwave irradiation conditions involved the nucleophilic substitution of an alkyl iodide with 60 diverse piperidine or piperazine derivatives (Scheme 4.22) 76 . Reactions were carried out in a multimode microwave reactor in individual sealed polypropylene vials using acetonitrile as solvent. Screening of the resulting 2-aminothiazole library in a herpes simplex virus-1 (HSV-1) assay led to three confirmed hits, demonstrating the potential of this method for rapid lead optimization.

Infection

Another approach using Morpholinos to study infectious disease is to knock down host factors required for the invasiveness or growth of the pathogens. Morpholinos have been used to study the requirement for host factors in pathogenesis by Kaposi's sarcoma-associated herpes virus38 and Legionella pneumophila.39

Radiculoneuropathy

Reactivation of HSV-2 along peripheral nerves is accompanied initially by neuralgia, malaise and fever followed by a painful vesicular rash on an erythematous base with pain and numbness along the affected dermatome. Although the first attack may be confused with VZV eruption, recurrent 'zoster' in an otherwise immunocompetent individual is due to HSV-2, not VZV. The 'below the waist' location of most recurrent neuropathy suggests that HSV-2 rather than HSV-1 is the causative agent. Although no trials have been performed to establish treatment protocols, oral acyclovir, 800 mg five times daily, or famciclovir, 500 mg three times daily for 7-10 days, are reasonable choices.

Encephalitis

HSV-2 encephalitis is rare and occurs primarily in newborns and immunocompromised adults, especially HIV-infected individuals with concurrent CMV infection. Neurological features include seizures, altered mental status and focal neurological deficits. Unlike the restriction of HSV-1 encephalitis to the temporal and frontal lobes, HSV-2 encephalitis is usually diffuse.11 Even so, a few cases of HSV-2 encephalitis with primary temporal lobe involvement have been reported in adults.12 Treatment of acute encephalitis is the same as for HSV-1 encephalitis (above). In AIDS patients, long-term treatment with oral acyclovir or famciclovir has been used however, acyclovir-resistant strains of HSV have emerged.13

Viral Vectors

Over the past few years, several viral vectors with low toxicity, high infection rate, and persistent expression have extended the methodology of delivery of genes to mammalian cells. These viruses include DNA viruses, such as adenoviruses and adeno-associated viruses, herpes simplex viruses, and RNA retroviruses. Recently, as a result of advances in genetic manipulation, adenoviruses and adeno-associated viruses have been more widely applied to gene transfer. The advantages of adenoviruses are 1) the ability to carry large sequences of foreign DNA, 2) the ability to infect a broad range of cell types, and 3) an almost 100 expression of the foreign gene in cells.

Conclusion

There is also the possibility that some viral infection is the cause of the acute phase response in major depression and TRD. Pathogenetic role of viral infections (mostly with herpes-type viruses) has long been suggested in the onset or recurrence of affective illness episodes. Several groups of investigators reported that antibody titers to herpes simplex virus (HSV) are increased in unipolar and bipolar depressive psychoses (Lycke et al., 1974 Cappel et al., 1978). The location of the latent herpes viruses in the limbic system suggest their involvement in the pathogenesis of affective recurrences (Stroop, 1986). Zorzenon et al. (1996) found an evidence of active viral multiplication and elevated antibody titers with herpes viruses in 41 of patients with major depression. In our recent study we have found significantly elevated antibody titers against HSV-1 and HSV-2 in 48 major depressed patients during an acute episode. Patients with higher antibody titers had higher...

Myelitis

VZV myelitis develops in both immunocompetent and immunocompromised individuals. Acute para-paresis, bowel and bladder incontinence and a sensory level usually develop 1-2 weeks after zoster.14 MRI reveals T2 hyperintensity with or without spinal cord swelling. In immunocompro-mised patients, myelitis may be protracted, and MRI reveals more extensive longitudinal enhancing lesions. CSF shows a mild mononuclear pleocytosis and slight protein elevation. PCR usually reveals amplifiable VZV DNA.41 Immunocompromised patients should be treated with intravenous acyclovir, 30 mg kg three times daily,42 with or without a short course of steroids. A standard treatment for immunocompetent individuals has not been established.

Epstein Barr virus

More than 90 of adults have antibody to EBV.57 Despite the ubiquity of EBV infection, neurological complications are rare. Of the eight human herpesviruses, EBV, along with VZV, produces the most diverse neurological complications. Any level of the neuraxis may be involved.

Prodrugs

Hydrocortisone 2.44 is used to alleviate inflammation at various sites in the body. The sodium succinate C-21 ester 2.45 provides a water-soluble pro-drug while the 21-palmitate 2.46 is a lipid-soluble pro-drug enabling it to reach different sites of activity. Another example is the antiviral agent acyclovir 2.47, which is transported into a virus before it is phosphorylated to give the active species. The triphosphate of acyclovir would not cross the viral cell wall. Azathioprine 2.48 is a pro-drug for 6-mercaptopurine 2.49, which is used as an immunosuppressant.

Other Viruses

Diagnosis depends upon CSF examination. White blood cell count is frequently elevated (rarely above 100 cells mm3) with a polymorphonuclear predominance for 1-2 days followed by lymphocytic predominance. Glucose is typically normal but can be decreased in one-third of patients with entero-virus (coxsackie and echoviruses), mumps and lymphocytic choriomeningitis virus infection. Gram stain and culture are unrevealing. Virus culture is not usually helpful (exceptional instances are described below), but PCR for viral DNA or RNA along with the detection of antiviral antibody can help in diagnosis. Rising serum antibody titers may also be useful. Treatment is supportive. Intravenous fluids, airway protection, balanced nutrition, careful monitoring of serum electrolytes and alertness for a syndrome of inappropriate antidiuretic hormone (SIADH) in some forms of encephalitis are all important. HSV, VZV and CMV warrant specific antiviral therapy (see herpesvirus section).

Rna As A Target

In recent years, antisense compounds have received quite a bit of publicity. It is relatively easy to identify a short RNA sequence that can be bound by an antisense compound to downregulate protein production with very good specificity. The problems in bringing antisense drugs to market have been associated with the pharmacokinetics of making such compounds orally bioavailable, and capable of being transported into the cell and to the target RNA. At present, only one antisense drug has been approved by the FDA for prescription use fomivirsen (trade name Vitravene, from Isis Pharmaceuticals), for the treatment of cytomegalovirus retinitis.

Basic Science

Addition, they implanted SCS in four patients with acute herpes zoster pain. As PHN often slowly resolves over time, the results of many therapies may appear more successful than is actually the case. To prevent undue emphasis on the results from SCS, the authors employed quarterly SCS inactivation tests to note any spontaneous resolution of pain with the SCS turned off. The results of this study were a median decrease in the visual analog pain scores from 9 to 1 (p< 0.001). Long-term pain relief was noted by 82 percent of patients with PHN, and 8 of 29 were able to cease therapies. In the acute herpes zoster pain group, resolution occurred by 2.5 months on average.

Oxidoethyl1Hazoles

Title epoxides show activity against bacteria and fungi pathogen to humans, and acticity against herpes simplex infection of mice and guinea pigs. They control Erysiphe graminis and Puccinia recondita on wheat, wheat brown rust, Plasmo-para viticola on grape leaves, Botrytis cinerea on paprika, and also display herbici-dal action and plant growth regulation. 3.1017

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