viroxime and Common-Cold

The picornaviruses are a diverse group of viral pathogens that together comprise the most common causes of infection of humans in the developed world. Within the picornavirus family are three well-known groups of human pathogens--the rhinoviruses, the enteroviruses (including polioviruses, coxsackieviruses and echoviruses) and the hepatoviruses (including hepatitis A virus). This article will focus on the rhinoviruses and enteroviruses, agents for which substantial effort has been expended, and recent successes reported, toward the development of safe and effective antiviral therapy.

Topics: 3C Viral Proteases; Animals; Antiviral Agents; Benzimidazoles; Capsid; Cell Line; Common Cold; Cysteine Endopeptidases; Drug Resistance, Microbial; Enterovirus; Enterovirus Infections; Humans; Immunoglobulins, Intravenous; Interferons; Molecular Structure; Oximes; Picornaviridae Infections; Rhinovirus; Sulfonamides; Viral Proteins

Most colds are caused by rhinovirus infection, perhaps facilitated by chilling or stress. Virus infection begins in the nasopharynx and causes spotty destruction of the nasal ciliated epithelium. Transmission occurs chiefly via droplets of various sizes transported through the air, but some types of virus persist in moist secretions on handled objects and may retain their infectiousness. Living in crowded, poorly-ventilated quarters facilitates transmission. Not many virus particles survive in saliva and it is difficult to infect via the lips or mouth. Kissing does not efficiently spread cold infection. Prophylactic treatment with interferon does not protect against cold infection. Aspirin and acetaminophen reduced serum antibody response and increased nasal symptoms in a controlled Australian study. The combination of intranasal interferon and ipratropium with oral naproxen gave promising results in experimental rhinovirus inoculation. Basically, there has been little or no progress towards effective cold treatment in the past century.

Topics: Antiviral Agents; Benzimidazoles; Common Cold; Humans; Interferon-alpha; Nasopharynx; Oximes; Rhinovirus; Saliva; Sulfonamides

Topics: Benzimidazoles; Chalcone; Chalcones; Common Cold; Flavonoids; Humans; Interferon Type I; Oximes; Rhinovirus; Sulfonamides

The therapeutic effect of intranasally administered enviroxime was tested against naturally occurring common colds. The double-blind evaluation was carried out in Tecumseh, Mich., during a period when rhinoviruses are usually the principal pathogen. Rhinovirus transmission followed the typical pattern during this period of study. Although there were trends indicating greater therapeutic effectiveness for enviroxime when certain nasal symptoms were considered, there were no consistent statistically significant differences between treated and untreated groups. Results were unchanged when illnesses in different periods or associated with rhinovirus isolation were examined. It was concluded that no therapeutic effect of enviroxime was demonstrated.

Topics: Adolescent; Adult; Antiviral Agents; Benzimidazoles; Child; Clinical Trials as Topic; Common Cold; Double-Blind Method; Female; Humans; Male; Middle Aged; Oximes; Rhinovirus; Sulfonamides; Time Factors

The therapeutic effect of intranasal 2-amino-1-(isopropylsulphonyl)-6-benzimidazole phenyl ketone oxime (enviroxime) against human rhinovirus type 9 was evaluated in a double-blind, placebo-controlled volunteer trial. Enviroxime given 6 times a day was well tolerated, producing a reduction in clinical evidence of infection which coincided with the start of medication (44 h after virus challenge). Although there was a statistically significant reduction in clinical score in the enviroxime group on day 5 after virus challenge, reductions in total clinical score accumulated during the trial and reductions in the quantity of nasal secretions were not significant. A separate analysis was performed on data from volunteers who did not have symptoms when medication began (and who might have been expected to benefit more from enviroxime therapy). No apparent enhancement of the effects of enviroxime could be demonstrated in this group.

Topics: Adult; Aged; Antiviral Agents; Benzimidazoles; Common Cold; Double-Blind Method; Drug Evaluation; Female; Humans; Male; Middle Aged; Oximes; Sulfonamides; Time Factors

Intranasal administration of enviroxime by aerosol spray was associated with drug levels in nasal secretions that 1 h later averaged 750-fold higher than those inhibitory for rhinoviruses in vitro (0.2 microgram/ml). However, administration of intranasal enviroxime (one spray per nostril, five times per day) to susceptible volunteers, beginning 1 day before and continuing for 4 days after virus exposure, did not significantly reduce infection or illness due to experimentally induced rhinovirus type 39 infection. The combined results of two separate trials yielded an infection rate of 100% for 21 placebo-treated and 89% for 19 enviroxime-treated subjects. Approximately one-half of the volunteers in each group had seroconversion to the challenge virus. Overall, 52% of the placebo-treated and 53% of the enviroxime-treated subjects developed colds. No significant differences in symptom scores, nasal mucus weights, or numbers of nasal tissues used were observed between the two groups. Two-thirds of the enviroxime-treated volunteers noted intranasal irritation immediately after sprays, as compared with only one-third of the placebo-treated subjects.

Topics: Administration, Oral; Adult; Aerosols; Antiviral Agents; Benzimidazoles; Common Cold; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Oximes; Rhinovirus; Sulfonamides; Time Factors

Enviroxime, an inhibitor of rhinovirus replication, was studied in a double-blind, placebo-controlled trial with 99 volunteers. The efficacy of a nasal-spray formulation of enviroxime was tested as pretreatment or as postchallenge treatment for rhinovirus type 4 infection. In the regimens used, drug administration neither prevented infection nor reduced the frequency of specific colds. The mean concentration of enviroxime in nasal washes (12 h after a dose) differentiated two groups of responders. Those in whom the drug concentration exceeded 100 ng/ml had some benefits, although these were statistically insignificant.

Topics: Administration, Intranasal; Adult; Aerosols; Antibodies, Viral; Antiviral Agents; Benzimidazoles; Common Cold; Double-Blind Method; Female; Humans; Male; Oximes; Rhinovirus; Sulfonamides

Topics: Administration, Intranasal; Administration, Oral; Adolescent; Adult; Antiviral Agents; Benzimidazoles; Cerebrospinal Fluid Rhinorrhea; Clinical Trials as Topic; Common Cold; Double-Blind Method; Female; Humans; Male; Middle Aged; Oximes; Rhinovirus; Sulfonamides

Human rhinovirus (HRV) is the predominant cause of the common cold, but more importantly, infection may have serious repercussions in asthmatics and chronic obstructive pulmonary disorder (COPD) patients. A cell-based antiviral screen against HRV was performed with a subset of our proprietary compound collection, and an aminothiazole series with pan-HRV species and enteroviral activity was identified. The series was found to act at the level of replication in the HRV infectious cycle. In vitro selection and sequencing of aminothiazole series-resistant HRV variants revealed a single-nucleotide mutation leading to the amino acid change I42V in the essential HRV 3A protein. This same mutation has been previously implicated in resistance to enviroxime, a former clinical-stage antipicornavirus agent. Enviroxime-like compounds have recently been shown to target the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIβ). A good correlation between PI4KIIIβ activity and HRV antiviral potency was found when analyzing the data over 80 compounds of the aminothiazole series, covering a 750-fold potency range. The mechanism of action through PI4KIIIβ inhibition was further demonstrated by small interfering RNA (siRNA) knockdown of PI4KB, which reduced HRV replication and also increased the potency of the PI4KIIIβ inhibitors. Inhibitors from two different structural classes with promising pharmacokinetic profiles and with very good selectivity for PI4KIIIβ were used to dissociate compound-related toxicity from target-related toxicity. Mortality was seen in all dosing groups of mice treated with either compound, therefore suggesting that short-term inhibition of PI4KIIIβ is deleterious.

Topics: 1-Phosphatidylinositol 4-Kinase; Animals; Antiviral Agents; Benzimidazoles; Cell Line, Tumor; Cephalosporins; Common Cold; Female; HeLa Cells; Humans; Mice; Oximes; Polymorphism, Single Nucleotide; Rhinovirus; RNA Interference; RNA, Small Interfering; Sulfonamides; Thiazoles; Virus Replication

Enviroxime inhibits the replication of all rhinoviruses tested in vitro at very low concentrations (10-100 ng/ml), but evaluations in humans have not consistently shown efficacy. Lack of an appropriate method for administering this water-insoluble drug may have contributed to the latter result. The present report describes the characteristics and utilization of small particle aerosols to continuously deliver enviroxime-containing liposomes (LE) throughout the respiratory tract. The enviroxime content of liposomes and biological fluids of exposed individuals was quantified by high performance liquid chromatography using C18 resin, a mobile phase of 60:40 acetonitrile:water, and monitoring at 215 nm. Small particle aerosols of LE generated by Puritan-Bennett nebulizers had mass median diameters ranging from 2.4 to 3.1 microns. The concentration of enviroxime in aerosol particles was proportional to the reservoir concentration; during the first hour of operation, the mean concentration was 20 micrograms of enviroxime/l of aerosol. Liposome particles in the reservoir, although initially heterogeneous in size (less than 0.1 to greater than 1 micron), were processed by passage through the nebulizer to smaller, more homogeneous particles; the majority were less than 0.2 micron. In a preliminary study to evaluate short term tolerance and toxicity, five volunteers were exposed to small particle aerosol of LE for 1 h. At 1 h post-treatment, large amounts of enviroxime were still present in the nasal wash as determined both by HPLC and biological assay. Enviroxime was not detected in any urine sample and was detected in only 1 of 5 serum samples. No side effects were noted. This data suggest that liposome aerosols offer a method for the delivery of hydrophobic compounds for the treatment of respiratory diseases.

Topics: Adult; Aerosols; Antiviral Agents; Benzimidazoles; Common Cold; Drug Carriers; Drug Evaluation; Drug Tolerance; Humans; Liposomes; Male; Oximes; Particle Size; Sulfonamides

Marked synergy between the antirhinoviral effect of rHuIFN alpha and enviroxime has been observed in vitro but an attempt to demonstrate it in volunteers was unsuccessful. The sub-optimal intranasal dose of rHuIFN alpha (0.18 Mu four times daily for 4 1/4 days) used prophylactically in the trial did reduce the severity of colds induced by RV9 and 14, but the difference did not reach statistical significance and was not enhanced by the administration of enviroxime (0.28 mg six times daily for six days). The main reason for failure is thought to be the rapid removal of enviroxime from the nose when given intranasally.

Topics: Adolescent; Adult; Benzimidazoles; Common Cold; Drug Synergism; Drug Therapy, Combination; Female; Humans; Interferon Type I; Male; Middle Aged; Oximes; Sulfonamides