Biomedical subjects
Publications and source records attributed to F G Hayden.
A loading dose and short-term administration of oral ribavirin significantly improved symptoms and signs of influenza type A or B infection in 25 patients. The antiviral effect was not significant. No adverse clinical effects or significant laboratory values were observed. Oral treatment of patients with influenza A or B infection might be possible with ribavirin.
Although antihistamines are widely used for symptomatic treatment of seasonal (allergic) rhinitis, the role of histamines in the pathogenesis of infectious rhinitis is not clear. Two antihistamines, orally administered chlorpheniramine maleate (CM) and diphenhydramine hydrochloride (DH) administered by intranasal spray, were used under double-blinded, randomized, placebo-controlled conditions to assess both tolerance and efficacy in volunteers with experimental rhinovirus (RV) colds. In the initial trial, CM (4.0 mg per treatment) was ingested 4 times daily for 4 days beginning 24 h after intranasal inoculation of RV type 29 in susceptible volunteers. In the second trial, DH was sprayed intranasally 4 times daily (2 mg per treatment) for 5 days beginning 24 h after inoculation of RV type 39. Clinical colds occurred in 60% of the CM group (n = 13) and 73% of the placebo (n = 15) in the first study, and in 66% of the DH group (n = 12) compared with 81% in the placebo group (n = 11) in the second. Both CM and DH were well tolerated but had no significant effects on nasal symptoms or nasal mucus production. The findings provide additional evidence against an important role for histamine in the pathogenesis of nasal symptomatology in rhinovirus colds.
The role of parasympathetic/cholinergic mechanisms in the syndrome of the common cold is not clear. Under double-blind, randomized, placebo-controlled conditions, we intranasally administered the anticholinergic atropine methonitrate (AM) to assess its tolerance in uninfected adults and therapeutic efficacy in volunteers with experimental rhinovirus (RV) colds. Healthy adults given sprays of AM intranasally 250 or 500 micrograms 4 times a day for 5 days developed nasal dryness and systemic side effects more often than did placebo (P) recipients. In 2 separate challenge studies, treatments were begun with AM 125 micrograms 3 times a day (AM = 8, P = 7) or AM 250 micrograms 4 times a day (AM = 9, P = 7) for 5 days, 24 h after intranasal inoculation of RV type 39. The low AM dose was well tolerated but had no effect on nasal mucus weights or nasal symptom scores in persons with RV colds. The higher dose of AM was associated with subjective drying and a reduction in nasal mucus production. These findings suggest that cholinergic mechanisms have a role in the pathogenesis of RV colds but that more work is necessary to determine if anticholinergic compounds will be of practical value in their treatment.
Explore the source record for details and available documents.
Respiratory viruses continue to be major causes of morbidity and mortality. Currently available chemotherapy is limited to oral amantadine for uncomplicated influenza A and aerosolized ribavirin for respiratory syncytial virus (RSV) infections. Amantadine is also efficacious for chemoprophylaxis of influenza A virus infections. Rimantadine has similar clinical efficacy and is better tolerated than amantadine. Aerosolized ribavirin may be useful in the treatment of serious respiratory illness caused by viruses other than RSV. Intranasal application of interferon is effective in interrupting the spread of rhinovirus colds in families, but chronic use is limited by nasal toxicity. Several newer agents and approaches for chemoprophylaxis and therapy are at different stages of clinical investigation. Combinations of antiviral agents may offer the best therapeutic advantage but have not been adequately tested in man. As additional drugs become available and uses expand for the currently available agents, rapid viral diagnosis will assume an increasingly important role in their optimal use.
Amantadine and rimantadine are oral antiviral drugs useful in the prophylaxis and treatment of influenza A virus infections. This article reviews the pharmacology, antiviral activity and mechanism of action, pharmacokinetics, toxicities, efficacy, and clinical applications of these agents. When administered in equivalent dosages (200 mg per day), rimantadine has prophylactic efficacy comparable to amantadine but lower potential for causing adverse effects. Despite structural similarities, these drugs differ significantly in their pharmacokinetics, and these differences may account for rimantadine's more favorable toxicity profile. Both drugs provide therapeutic benefit if administered early in uncomplicated influenza, and studies are currently in progress to determine the effectiveness of oral rimantadine in preventing or treating the serious complications of influenza A virus infections.
We conducted a randomized, placebo-controlled, double-blind study to determine whether intranasal alpha 2-interferon could prevent respiratory illnesses in healthy contacts of ill family members. Beginning within 48 hours of the onset of illness in a family member, contacts self-administered interferon (5 X 10(6) IU) or placebo spray once daily for seven days. Respiratory illness developed during the eight-day period, starting with the second day of spraying, in 52 of 222 persons in the placebo group as compared with 32 of 226 in the interferon group (P = 0.02; efficacy, 39 percent). Among persons exposed to laboratory-documented rhinovirus colds, illness developed in 2 of 27 interferon recipients as compared with 12 of 34 placebo recipients (P = 0.02; efficacy, 79 percent). During the two-week period during and after spraying, rhinovirus colds developed in 1.3 percent of those spraying with interferon and in 15.1 percent of those spraying with placebo (P = 0.003; efficacy, 88 percent). Blood-tinged mucus or nasal mucosal bleeding or both were detected in 7.7 percent of placebo and 13.6 percent of interferon users (P = 0.04), but no evidence of cumulative nasal toxicity was found. We conclude that postexposure prophylaxis with intranasal interferon may in some cases provide an effective strategy for controlling the spread of natural colds, especially those caused by rhinoviruses.
Explore the source record for details and available documents.
In a randomized, double-blind trial involving patients with uncomplicated influenza A H3N2 subtype virus infection, rimantadine treatment (200 mg/day for 5 days) was associated with significant reductions in nasal secretion viral titers (days 2 through 4), maximal temperature (days 2 and 3), time until defervescence (mean, 37 h shorter), and systemic symptoms compared with placebo treatment.
In late 1983, five patients living near Charlottesville, Virginia, were treated for an unusual syndrome of fever, headache, altered mentation, multifocal neurologic signs, and cerebrospinal fluid pleocytosis. Clinical signs of brainstem disease developed in four patients. All five had had recent exposure to forests or wood and contact with flea-infested dogs. Two patients died; one survivor has had recurrent seizures. Brain biopsy samples in two patients and autopsy findings in another showed cerebral vasculitis and perivasculitis involving mostly venules and capillaries. In the autopsy, the severest vascular lesions involved the brainstem and thalami, where they were accompanied by acute fibrinoid necrosis, but discrete vascular lesions of lesser intensity were randomly distributed in the white matter and cortex. Serologic studies on paired specimens in four patients showed significant cross-reacting antibody responses to rickettsial (typhus-group) antigens in the indirect hemagglutination, latex agglutination, and IgM microimmunofluorescence tests, but no agent was visualized or isolated. The cause of this serious inflammatory disorder is unknown.
The prophylactic activity of intranasal human interferon-alpha 2 (HuIFN-alpha 2) was determined in a randomized, double-blind, placebo-controlled study. Healthy, working adults self-administered sprays of HuIFN-alpha 2(1.25 X 10(6) IU; n = 142) or placebo (n = 145) twice daily. Drug administration was stopped after 12 days because of the frequent occurrence of nasal irritation manifested by blood-tinged nasal mucus (44% HuIFN-alpha 2 versus 15% placebo, P less than 0.001) and associated nasal mucosal abnormalities. Over 80% of volunteers had participated in a similar field trial conducted 7 months earlier; no evidence of cumulative toxicity was detected. HuIFN-alpha 2 administration did not decrease the occurrence of illnesses associated with rhinorrhea, cough, or feverishness as compared to placebo, but the number of laboratory-documented respiratory viral infections was small (6 HuIFN-alpha 3 placebo). Intranasal HuIFN-alpha 2 1.25 X 10(6) IU twice daily was associated with significant local intolerance.
Table III summarizes clinical applications of antiviral agents in respiratory viral infections. (table: see text) For influenza A virus infections, both oral amantadine and rimantadine are effective when used for seasonal prophylaxis and for prophylaxis in institutional populations. Both of these drugs, as well as aerosolized ribavirin, have antiviral and therapeutic effects in uncomplicated influenza. It remains to be determined whether any of these modalities or possibly their combined use [44] will be useful in treating severe influenza hospitalized patients or whether they can prevent the development of complications in high risk patients. Unfortunately, there is no parenteral formulation of amantadine or rimantadine for use in critically ill patients. Aerosolized ribavirin has also been shown to have modest therapeutic effects in influenza B virus infection. However, a major need exists for an antiviral which is active against influenza B virus and which can be used on an outpatient basis. Controlled clinical trials have shown that aerosolized ribavirin therapy improves arterial oxygenation and modifies the severity of respiratory syncytial virus bronchiolitis and pneumonia [3,5]. Its role in treating life-threatening disease or in modifying the long-term sequelae of RSV infections are unknown at the present time. Again, a specific antiviral agent is needed for outpatient use in preventing or treating RSV infections. Finally, after over a decade of work since the original observation that intranasal interferon could prevent experimental rhinovirus infection [11], recent studies have established that intranasal rIFN-a2 is effective in the postexposure prophylaxis of rhinovirus colds in families [42]. This strategy needs to be studied with regard to the prevention of infection and its complications in high risk patients and it remains to be determined whether intranasal interferon will have therapeutic activity in established colds.
The single-dose pharmacokinetics of amantadine hydrochloride and rimantadine hydrochloride were compared in a randomized, two-period, crossover study involving six young (less than or equal to 35 years) and six elderly (less than or equal to 60 years) adults. Subjects ingested single 200-mg oral doses after an overnight fast, and serial plasma (0 to 96 h), nasal mucus (0 to 8 h), and urine (0 to 24 h) samples were collected for assay of drug concentration by electron capture gas chromatography. For both groups combined, rimantadine differed significantly from amantadine in peak plasma concentration (mean +/- standard deviation, 0.25 +/- 0.06 versus 0.65 +/- 0.22 micrograms/ml), plasma elimination half-life (36.5 +/- 15 versus 16.7 +/- 7.7 h), and percentage of administered dose excreted unchanged in urine (0.6 +/- 0.8 versus 45.7 +/- 15.7%). No significant age-related differences were noted for rimantadine. Urinary excretion (0 to 24 h) of rimantadine and its hydroxylated metabolites averaged 19% of the administered dose. The maximum nasal mucus drug concentration was similar for both drugs (0.42 +/- 0.25 versus 0.45 +/- 0.32 micrograms/g), and the ratio of maximum nasal mucus to plasma concentration was over twofold higher after rimantadine than after amantadine. These findings may in part explain the clinical effectiveness of rimantadine in influenza A virus infections at dosages that have lower toxicity than those of amantadine.
The comparative susceptibilities for rhinovirus isolation were determined for strain MRC-5 human embryonic lung fibroblast and human fetal tonsil cells. Samples from nasopharyngeal and throat swab clinical specimens were inoculated onto duplicate monolayers of each cell type. Of 105 rhinovirus-positive specimens, 78 (74%) were positive in MRC-5 cells, and 102 (97%) were positive in fetal tonsil cells (P less than 0.001). For 75 specimens positive in both, the mean time to cytopathic effect development with standard deviation was 1 +/- 2 days shorter in fetal tonsil cells (P less than 0.01). The use of a second virus culture increased rhinovirus isolations by 10% compared with a single culture.
Nosocomial transmission of herpes simplex virus (HSV) has been described in intensive care units. A cluster of three patients with HSV wound infections within a 6-week period prompted temporary closure of a burn unit and suggested nosocomial cross infection. However, restriction endonuclease "fingerprint" analysis of the HSV isolates showed them to be genetically and therefore epidemiologically unrelated. This report describes these cases and the use of intravenous acyclovir in the treatment of HSV burn wound infections.
Annual immunization against influenza is recommended for numerous individuals, but the antibody response to sequential vaccination has not been well characterized. Levels of hemagglutination-inhibition antibody were measured in adults given either two or three doses of trivalent influenza vaccine at six-month intervals. A significant rise in the number of individuals with antibody titers of greater than or equal to 40 was seen for all three antigens only after initial vaccination. Repeated vaccination was necessary to maintain adequate antibody levels only to the A/Brazil (H1N1) antigen; it did not significantly affect the proportions of individuals with protective levels of antibody to either the A/Bangkok (H3N2) or the B/Singapore 222/79 antigens. These findings do not support the current recommendation for annual immunization when the vaccine formulation has not changed.
Eighty-five immunocompromised patients were entered into a randomized, controlled, crossover study of mucocutaneous herpes simplex virus (HSV) infections. Thirty-nine patients (group A) received vidarabine for seven days followed by placebo for an additional seven days. Forty-six patients (group B) received the reverse regimens. Therapy did not significantly accelerate healing for the total population as assessed by loss of virus from lesions, cessation of lesion formation, and time to crusting. Group A patients demonstrated accelerated loss of pain from lesions (P = 0.0099) and defervescence (P = 0.03). Patients in group A who had HSV type 1 (HSV-1) infections or who were over 40 years of age did clear virus from lesions more rapidly (P = 0.04 and P = 0.03, respectively). No toxicity or significant adverse effects could be attributed to vidarabine administration. Benefit from vidarabine therapy is limited to immunocompromised patients over 40 years of age with HSV-1 infections.
The therapeutic efficacy of recombinant interferon-alpha 2 (HuIFN-alpha 2) in experimental infection with rhinovirus type 39 was assessed in two randomized, double-blind, placebo-controlled studies. Adult volunteers (serum neutralizing antibody titer, less than or equal to 1:2) were given 9 X 10(6) international units of HuIFN-alpha 2 three times a day for five days by intranasal spray (study 1) or drops (study 2) beginning 28 hr after rhinovirus inoculation. HuIFN-alpha 2 did not prevent rhinovirus infection or colds in either study. Treatment by nasal drops and to a lesser extent by spray was associated with significant reductions in duration and quantity of viral shedding. Treatment by drops was associated with significant but modest effects on nasal symptom scores and trends toward reduced quantities of production of nasal mucus. Despite lower nasal wash concentrations of interferon, HuIFN-alpha 2 drops appeared to have greater antiviral activity and therapeutic efficacy than did HuIFN-alpha 2 spray. These findings suggest that HuIFN-alpha 2 may not be therapeutically useful in treating naturally occurring rhinoviral colds.