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PubMed1976

Computer-based approach to chelation therapy: a theoretical study of some chelating agents for the selective removal of toxic metal ions from plasma.

COMICS is a computer programme for calculating equilibrium concentrations of metal complexes and reactive species in multi-metal-multi-ligand systems. Its usefulness for analysing metal ion equilibria in blood plasma has been improved by including albumin as a ligand. Using this model system the distribution and removal of copper(II) and zinc ions in histidinaemia, lead poisoning and Wilson's disease have been examined. The efficacy of TRIEN in removing excess copper(II) is shown. The use of specific tripeptides such as Gly-Gly-His methyl ester for the selective removal of copper(II) is suggested. A possible chemoprophylaxis of influenza based on complexation of zinc is discussed. Calculations confirm that thiosemicarbazones such as methisazone and 2-acetylpyridine thiosemicarbazone are effective competitors for heavy metal ions under physiological conditions.

Amino Acid Metabolism, Inborn Errors↗
PubMed2003

Potential antiviral therapeutics for smallpox, monkeypox and other orthopoxvirus infections.

We assessed the activities of 24 different antiviral compounds against smallpox (two strains of variola major and one of variola minor), monkeypox, vaccinia and cowpox viruses by a neutral red uptake assay. To establish assay parameters, we examined viral replication and its inhibition at various times postinfection and at several multiplicities of infection. Drugs were selected to target a range of functions involved in viral replication. Eight compounds (cidofovir, cyclic HPMPC (cHPMPC), HPMPA, ribavirin, tiazofurin, carbocyclic 3-deazaadenosine, 3-deazaneplanocin A and DFBA (1-(2,4-difluorobenzyloxy)adenosine perchlorate)-a derivative of adenosine N1-oxide) inhibited the replication of all three variola strains and the other orthopoxviruses at drug concentrations within a pharmacologically achievable range. Two others (methisazone and bis-POM-PMEA) showed a lesser degree of antiviral effect, while the remainder were inactive. To examine possible naturally occurring drug resistance among a large number of variola isolates obtained from different geographical regions and at different times, we examined the sensitivity of 35 different strains of variola as well as other orthopoxviruses to a subset of three of the most active compounds: cidofovir, cHPMPC, and ribavirin. Preliminary data indicate that nearly all isolates appear to have similar drug sensitivities. These findings are currently being verified and expanded.

Animals↗
PubMed2003

A review of compounds exhibiting anti-orthopoxvirus activity in animal models.

Several animal models using mice (most frequently), rabbits, or monkeys have been used to identify compounds active against orthopoxvirus infections. The treatment of vaccinia virus infections has been well studied in models involving infection of scarified skin or eyes, or resulting from intravenous, intraperitoneal, intracerebral, or intranasal virus inoculation. Cowpox virus has been used in intranasal or aerosol infection studies to evaluate the treatment of lethal respiratory infections. Rabbitpox, monkeypox, and variola viruses have been employed to a lesser extent than the other viruses in chemotherapy experiments. A review of the literature over the past 50 years has identified a number of compounds effective in treating one or more of these infections, which include thiosemicarbazones, nucleoside and nucleotide analogs, interferon, interferon inducers, and other unrelated compounds. Substances that appear to have the greatest potential as anti-orthopoxvirus agents are the acyclic nucleotides, (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (cidofovir, HPMPC) and 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine (cyclic HPMPC), and the acyclic nucleoside analog, 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (S2242). Other classes of compounds that have not been sufficiently studied in lethal infection models and deserve further consideration are thiosemicarbazones related to methisazone, and analogs of adenosine-N(1)-oxide and 1-(benzyloxy)adenosine.

Animals↗
PubMed2003

Pathogenesis and potential antiviral therapy of complications of smallpox vaccination.

Vaccination against smallpox may result in a variety of complications, ranging in severity from benign to lethal. Universal vaccination was halted in the US in 1972, so almost half the present population has never been vaccinated. Because side effects occur most often in first-time vaccinees, current plans for rapid large-scale vaccination in the event of bioterrorist attack raise concerns about the occurrence of a large number of adverse events. Most complications result from the excessive replication of vaccinia virus, making them potential targets for antiviral therapy. Effective treatment is especially needed for persons with atopic dermatitis or eczema, who are unusually susceptible to the initiation and spread of vaccinia infection because of defects of innate immunity in the skin, and for individuals with defective cell-mediated immunity, who are unable to eliminate vaccinia infection once it has begun. In the past, many complications were treated with vaccinia immune globulin (VIG) and/or the antiviral drug methisazone, but neither was tested in placebo-controlled trials. New antiviral drugs are now available, but have not yet been evaluated for treating vaccinia infections in humans. Both laboratory research and clinical studies are needed to help prevent serious complications in any major vaccination campaign.

Antiviral Agents↗
PubMed2004

Rethinking smallpox.

The potential consequences of a competently executed smallpox attack have not been adequately considered by policy makers. The possibility of release of an aerosolized and/or bioengineered virus must be anticipated and planned for. The transmission and infectivity of variola virus are examined. Arguments for and against pre-event vaccination are offered. The likely morbidity and mortality that would ensue from implementation of a mass pre-event vaccination program, within reasonable boundaries, are known. The extent of contagion that could result from an aerosolized release of virus is unknown and may have been underestimated. Pre-event vaccination of first responders is urged, and voluntary vaccination programs should be offered to the public. Two defenses against a vaccine-resistant, engineered variola virus are proposed for consideration. Methisazone, an overlooked drug, is reported to be effective for prophylaxis only. The extent of reduction in the incidence of smallpox with use of this agent is uncertain. It is useless for treatment of clinical smallpox. N-100 respirators (face masks) worn by uninfected members of the public may prevent transmission of the virus.

Biological Warfare↗
PubMed1981

Vaccinia necrosum after smallpox vaccination for herpes labialis.

We have described a patient with vaccinia necrosum after smallpox vaccination for persistent herpes labialis. The patient eventually recovered after surgical resection of the lesion and multiple courses of vaccinia immune globulin and methisazone. This report emphasizes the needless risks of vaccinating patients with herpetic infections.

Female↗
PubMed1973

Inhibition of granulocyte-macrophage colony formation in vitro by substituted isatin thiosemicarbazones.

The 1-methylisatin derivative of isatin thiosemicarbazone was previously shown to inhibit granulocyte-macrophage colony growth in vitro by an action at the early stages of colony development. The parent compound isatin thiosemicarbazone and 25 other derivatives were tested, and a wide range of activity was found (50% colony inhibition from 0.07 to > 100 mug per ml of culture). High activity was not associated with any specific substituent although 1-methyl or 1-ethyl isatin groups in association with 4'4' morpholino or 4'4' tetramethylene thiosemicarbazone substitutions were within the most active group. No correlation between the antimarrow and known antiviral activities of these compounds was apparent. Two of the more active compounds were compared with methisazone and were shown to have the same property of selective action on the early stages of granulocyte-macrophage differentiation in culture. It is suggested that this group of compounds might possibly provide some useful antileukemia agents.

Bone Marrow↗
PubMed1989

Rational design of antiviral agents.

Examining the change in the state of the art of antiviral drug discovery, from the discovery nearly 40 years ago of a smallpox drug (methisazone) of unknown mechanism of action to the analysis of an antiviral agent bound to a virus at atomic resolution, gives the reader an appreciation for the magnitude of the advances in the science of antiviral chemotherapy. The clinical success of amantadine, acyclovir, and azidothymidine have proved that antiviral chemotherapy is a reality. The next step will be to apply the new tools of x-ray crystallography and computational chemistry to the antiviral challenges that lie before us.

Animals↗
PubMed2005

Biological activities of isatin and its derivatives.

Isatin is an endogenous compound identified in humans that possesses a wide range of biological activities. Isatin has anxiogenic, sedative, anticonvulsant activities and acts as a potent antagonist on atrial natriuretic peptide receptors in vitro. A series of p-substituted isatin semicarbazones have shown anticonvulsant activity in MES, scPTZ and scSTY tests. Various isatin-N-Mannich bases of isatin-3-thiosemicarbazones have shown antiviral and tuberculostatic activity. Methisazone is an effective compound against variola and vaccinia viruses. The N-dimethyl and morpholino derivative of 5-methyl isatin and trimethoprim exhibited an EC50 of more than 4.3 and 17.7 mg mL(-1), respectively. Isatin (3-o-nitrophenyl) hydrazone has shown activity against Walker carcinoma-256. Various substituted indolinones showed antitubercular activity against M. tuberculosis H37Rv with MIC ranging from 10-20 microg mL(-1). Isatin derivatives of Mannich bases had fibrinolytic, muscle relaxant, antiallergic, immunosuppressant, and antithrombotic activity. Isatin showed cardioinhibitory effect on frog heart, and hypotensive, respiratory depression and antidiuretic effects.

Animals↗
PubMed1975

[Research on substances with antiviral activity. II. Derivatives of N-substituted 2-chloro-3-formylindoles].

Thiosemicarbazones and amidinohydrazones of N-substituted 2-chloroindole-3-aldehydes were synthesized and investigated for antiviral activity against RNA virus (parainfluenza type 3, HA-I/CR-8 stock) and DNA virus (vaccinia virus, HID stock). The thiosemicarbazones of 1-(o,m,p,-chlorobenzoyl)-2-chloroindole-3-aldehydes were more active than methisazone against vaccinia virus.

Amidines↗
PubMed1977

[Research on substances with antiviral activity. VII. Activity and lipophilic of property N-alkyl-2-chloro-3-formylindole thiosemicarbazone].

Thiosemicarbazones of N-alkyl-2-chloroindole-3-carboxaldehydes were synthesized and investigated for antiviral activity against RNA virus (parainfluenza type 3, HA-I/CR-8 stock) and DNA virus (vaccinia virus, HID stock). The effect of lipophilicity on the activity against vaccinia virus was considered. Relative lipophilicities were measured by a reversed phase thin-layer chromatographic technique. The most active compound N-isopropyl-2-chloroindole-3-carboxaldehyde thiosemicarbazone appeared comparable for its activity to methisazone.

Antiviral Agents↗
PubMed1977

Viral chemotherapy.

New antiviral compounds are being tested constantly and may be of considerable value with increasing availability. More than 200 analogues of purines and pyrimidines have been found to inhibit DNA and RNA viruses. Adenine arabinoside is most effective against disseminated herpes simplex virus and disseminated herpes zoster. Idoxuridine is useful in treatment of herpetic keratitis. Interferon still is in the experimental stage, and, because of its short half-life and high cost, it probably will not be released in the near future. Amantadine appears to be useful in prevention of A2 influenza, but its value against swine flu has not been established. Methisazone is effective in prevention of smallpox and in the treatment of complications of vaccinia.

Adult↗
PubMed1981

[Substances with antiviral. XVI. Thiosemicarbazones containing benzofuran and 1H-indene moieties].

A few hydrazones with benzofuran and 1H-indene moieties were synthesized and screened in vitro against vaccinia virus strain IHD, parainfluenza type 3 virus strain HA-1/CR-8, and the MP mutant of herpes simplex virus type 1 [HSV-1 (MP)]. Only the thiosemicarbazones were active. The thiosemicarbazone of 3-chloro-2-formyl-1H-indene inhibited vaccinia virus to a greater extent than methisazone, used as reference standard. Furthermore, this compound was active also against parainfluenza and herpes viruses.

Antiviral Agents↗
PubMed1983

Progressive vaccinia associated with combined variable immunodeficiency.

Progressive vaccinia developed in a previously healthy woman following smallpox vaccination and was successfully treated with vaccinia immune human globulin and methisazone. Immunologic evaluation over the next 4 1/2 years revealed evidence for combined variable immunodeficiency with increased numbers of circulating OKT 8 positive (suppressor-cytotoxic T) cells and the virtual absence of OKT 4 positive (helper-inducer T) cells.

Female↗
PubMed1978

The influence of some thiosemicarbazone derivatives with antiviral activity on immune response in mice.

The aim of the present study was to examine the influence of the thiosemicarbazone-group of compounds with antiviral activity on the humoral and cellular immune response in R III, CBA and Balb/c mice, immunized with sheep erythrocytes or sensitized with oxazolon. The plaque forming cells test, according to Jerne's method and the oxazolon hypersensitivity test were performed. All of the examined compounds, inhibited the humoral immune response, and three of them decreased also the cellular response. The relationship between the antiviral activity and their immuno-suppressive activity has been discussed. Low antiviral activity of compound Hoe 105 could be due to its immunosuppressive action. Moreover, the mechanism of antiviral activity of one of the tested compounds, which displayed strong activity against vaccinia virus, was examined and compared with the activity of methisazone.

Animals↗
PubMedDate not supplied

[New properties of trental as an inhibitor of viral activity with a wide range of activity].

Experimental investigations on the spectrum and degree of the expression of trental antiviral activity were carried out. The investigations were done in cell cultures and laboratory animals using laboratory strains (including drug-resistant ones) of 13 viruses, causative agents of human and animal infections. The drug demonstrated its activity against 8 viruses of 7 families. It was highly active against 5 viruses: herpes simplex virus (including its acyclovir-resistant strain), vaccinia virus (including its methisazone-resistant strain), rotavirus and tick-borne encephalitis virus. As regards other viruses, its activity was less pronounced (hepatitis JA virus) or low (vesicular stomatitis virus, West Nile virus). It was concluded that, being a cardiovascular drug, trental was an effective broad spectrum virus inhibitor.

Animals↗
PubMed1996

Theoretical grounds and experimental confirmation of the antiviral effect of the preparation Ukrain.

The preparation Ukrain was studied in order to confirm its theoretically substantiated properties in comparison with amitozin as its structural and functional analogue, and two other functional analogues, namely methisazone (against herpesvirus and poxvirus) and remantadine (against grippevirus). The experiments were carried out on albino Swiss mice of either sex weighing initially 18-20 g. They were kept at room temperature (20-21 degrees C) on a natural day-night cycle, were housed in groups of ten per cage and had free access to food and water. The Ukrain preparation's activity as concerns grippe virus of A type (England) 42/72 (H3N2) was determined in ovo and in vivo, the treatment beginning 2 h after infection. The control animals, infected by appropriate virus dose, were injected with placebo. For the activities of the remedies investigated, our estimate was based on the median duration of life in the mice of the subexperimental and control groups (duration of experiments 14 days), the degree of intensity of pulmonary tissue changes, and the difference in median HR titres. The totality of Chelidonium majus alkaloids, thiophosphamide (the alkalizing agent), the sum of alkaloids modified by thiotepa, and some other alkaloids as their alkalized derivatives, all showed a statistically reliable inhibiting effect. The most significant biological activity was demonstrated by Ukrain as concerns the models of viral processes, and by the sum of alkaloids and amitozin as concerns the models of associated infections. This coincides with the results of biological assessment of modified products (1, 3, 5) with metabolites, alkaloids in particular, or alkaline substances.

Alkaloids↗
PubMed1977

Inhibition of amino acyl tRNA synthetase activity by copper complexes of two metal binding ligands. N-Methyl isatin beta-thiosemicarbazone and 8-hydroxyquinoline.

Copper complexes of N-methyl isatin beta-thiosemicarbazone, 1-formyl isoquinoline thiosemicarbazone and thiosemicarbazide inhibit amino acyl tRNA synthetase activity. Copper complexes of 8-hydroxyquinoline and 8-mercaptoquinoline also inhibit. The 1 : 1 ligand-metal complex is significantly more active than the 2 : 1 complex. The free ligand alone and copper sulfate alone have little, if any, effect. These complexes have no effect on the ATP-PPi exchange reaction and do not cause deacylation of amino acyl tRNAs. This indicates that the process inhibited by these complexes is the amino acylation reaction. This is the first report that these copper binding ligands can inhibit enzymatic processes which involve nucleic acids but which are not viral, bacterial or mammalian cell polymerases.

Amino Acyl-tRNA Synthetases↗