Biomedical subjects
Publications and source records attributed to S L Spruance.
To determine the effectiveness of an antiviral to prevent herpes labialis during a brief, high-risk circumstance, 147 persons with a history of sun-induced recurrences were treated prophylactically with oral acyclovir or matching placebo and were observed during their ski holidays. Five (7%) of 75 acyclovir-treated subjects developed lesions compared with 19 (26%) of 72 persons in the placebo group.
Animal and human models of ultraviolet radiation-induced herpes simplex virus disease provide opportunities to study the mechanism of virus latency and reactivation. These models can also be used to study the efficacy of antiviral agents. Prophylactic oral acyclovir altered the development of ultraviolet radiation-induced herpes labialis under both natural and experimental conditions.
Recurrent herpes simplex labialis has proved to be a difficult disease to treat. Despite 25 years of clinical research with established antiviral substances, only small benefits from experimental therapies have been demonstrated. Progress has been slow, in part, because of the time-consuming nature of large, patient-initiated clinical trials. The dorsal cutaneous guinea pig model is a rapid and efficient means to identify topical antiviral formulations with clinical promise. The cumulative results of our studies with 19 different test treatments show that 8 were equal in efficacy to 5% acyclovir ointment, one was worse and ten were better. Two of the treatments found to be better than 5% acyclovir ointment have been studied clinically, with limited but encouraging results. Differences between the guinea pig model and the human illness mandate caution in predicting the degree of clinical efficacy from experimental outcomes. An effective and conservative use of the model is to optimize the topical formulation of a single antiviral substance.
Recombinant human interferon-alpha A (rIFN-alpha A) was evaluated for therapeutic efficacy against an experimental dorsal cutaneous herpes simplex virus type 1 (HSV-1) infection of guinea pigs. Human IFN has activity in this species. Animals were treated either systemically (i.m.) or topically with different formulations of rIFN-alpha A. Therapy was initiated 24 h before (-24 h), 30 min after (+0.5 h), or 24 h following (+24 h) virus inoculation, and treatment was continued for 3-5 days. Efficacy was evaluated on day 4 following infection. Treatment with rIFN-alpha A given systemically beginning at -24 h was effective, reducing lesion number, total lesion area, and lesion virus titer by 64%, 85%, and 98% respectively (p less than 0.001). Efficacy diminished with delay in initiation of i.m. therapy. Topical rIFN-alpha A formulations were generally ineffective, showing only a marginal effect with therapy initiated -24 h or +0.5 h and no effect when treatment was delayed to +24 h. In summary, rIFN-alpha A is effective against cutaneous HSV-1 infection in this model if therapy is initiated prophylactically and if drug delivery is assured by systemic injection. Topical application of rIFN-alpha A showed little therapeutic effect. The large molecular weight of IFN likely retards its percutaneous delivery.
A rapid, in vivo measurement of the penetration of antiviral compounds into the skin would improve our ability to predict the therapeutic efficacy of topical treatments for herpes simplex virus (HSV) infection. We have studied the concentration of iododeoxyuridine (IDU) in the stratum corneum of guinea pig skin by tape stripping at different time points after single and multiple topical doses of the drug. These results were correlated with the efficacy of topical IDU against an experimental cutaneous HSV infection. Ten adhesive tape strippings were performed on depilated guinea pig dorsum in vivo at serial intervals after a single topical dose of [3H]IDU. Iododeoxyuridine levels in the stratum corneum peaked at 1-3 h (67-70 mg/g of tissue) and then gradually declined over the next 3-24 h. We hypothesized that the peak IDU stratum corneum concentration would correlate with therapeutic efficacy. Accordingly, we determined the quantity of IDU in guinea pig stratum corneum 2 h after a topical application of seven different concentrations of IDU in dimethylsulfoxide (DMSO) and examined the in vivo efficacy of these formulations in an experimental dorsal cutaneous HSV-1 infection in guinea pigs. The results showed an excellent correlation between the quantity of IDU in the stratum corneum and reduction in lesion severity (r = 0.95-0.97). Fifteen percent IDU in DMSO provided the highest therapeutic efficacy (90-94%). We also studied the relationship between the clinical efficacy of different dosing frequencies and the amount of IDU in the stratum corneum. Serial IDU stratum corneum concentrations were measured over 24 h following 1, 2, 3, or 4 applications per day of 1, 3, and 15% IDU in DMSO treatments and parallel efficacy studies of the different regimens were conducted in the animal model. Within each dosing frequency, the cumulative amount of drug in the stratum corneum correlated with the strength of the test formulation and with efficacy in the animal model. For each of the three formulations, increasing the number of daily doses from one up to three led to progressive increases in cumulative stratum corneum IDU levels and clinical efficacy. An increase in the number of daily applications to four had little effect on drug efficacy and was associated with a plateau in stratum corneum IDU levels. Stratum corneum IDU concentrations were rapid and easy to determine and correlated well with clinical events.(ABSTRACT TRUNCATED AT 400 WORDS)
A 35-year-old patient who underwent renal transplant developed persistent fever, hypoxemia, and diffuse interstitial pulmonary infiltrates one month after allograft implantation. An open lung biopsy specimen demonstrated simultaneous infection with cytomegalovirus and herpes simplex virus type 1. This initially was unsuspected on routine histology, but was confirmed by the demonstration of both viruses with immunofluorescence, as well as the timely recovery in culture of both. The clinical and pathologic implications of an accurate diagnosis of such a simultaneous infection are discussed.
To determine the value of serum arabinitol concentrations in clinical practice, we identified all patients at the University of Utah Medical Center for whom a serum arabinitol determination had been requested by the attending physician or housestaff to assist in the management of candidiasis. The patient population was divided into three categories on the basis of clinical and pathological findings: superficial candidiasis, possible deep, invasive candidiasis, and definite, deep invasive candidiasis. Abnormal renal function was associated with elevated concentrations of serum arabinitol in proportion to the degree of renal dysfunction. Both the serum arabinitol concentration and the arabinitol/creatinine ratio were increased in the combined patient population with candidiasis relative to normal uninfected controls (p = 0.06 and 0.001, respectively). However, neither of these tests reliably distinguished patients with invasive candidiasis from those with only superficial candidal disease.
Topical antiviral treatments for recurrent infection with herpes simplex virus in immunocompetent patients have been generally ineffective. We investigated whether in vitro drug measures could predict in vivo efficacy. Twelve topical antiviral formulations were evaluated in vitro by measuring inhibition of viral plaque formation in cell culture (ID50) and drug penetration through excised guinea pig skin. In vivo efficacy for each treatment was determined in an experimental cutaneous infection with herpes simplex virus type 1 in guinea pigs and expressed as the percent reduction in lesion number, lesion area, and virus titer in the lesions. The in vitro findings were correlated with the results in the animal model. ID50 was a poor predictor of in vivo efficacy, whereas stronger correlations were found between the degree of skin penetration and in vivo activity. The best correlation was noted by using a summary expression of the in vitro results as follows: the ratio of drug penetration through skin at 37 C to ID50 (r = .95, .94, and .92 for lesion number, area, and virus titer, respectively, P less than .0005). Determination of this in vitro index should be included in the preclinical evaluation of new topical antiviral formulations.
Arildone is an aryl diketone which is inhibitory in vitro against herpes simplex virus type 2 at a concentration of 2 micrograms/ml or less. One hundred forty-five patients with recurrent genital herpes were enrolled in a multicenter, randomized, placebo-controlled, double-blind trial to evaluate the efficacy and safety of an 8% arildone cream. Patients initiated therapy a mean of 9.9 h and a maximum of 24 h after the reported onset of lesions and applied medication 6 times daily for 7 days. The duration of viral shedding was shorter among women (P less than 0.05) and the duration of local itching was shorter among men (P less than 0.05) in patients that received arildone than in those that received placebo, but there were no significant differences between treatment groups in duration of pain, time to crusting or healing of lesions, or percentage of patients developing new lesions. Mild local irritation after application of ointment was common and occurred equally in both treatment groups. Despite early application, topical arildone cream was ineffective in the therapy of acute recurrences of genital herpes.
Topical acyclovir (ACV) in polyethylene glycol (PEG) ointment has been disappointing in the treatment of recurrent herpes simplex virus infections in immunocompetent patients. To investigate the possible role of poor drug delivery from this formulation, we studied the penetration of ACV through excised human skin from three vehicles; PEG ointment, modified aqueous cream, and dimethyl sulfoxide. A second antiviral agent, idoxuridine, was studied in the same formulations, and drug delivery through excised guinea pig skin was also assessed for comparison. The delivery of ACV from PEG ointment was very slow for both human and guinea pig skin (drug flux, 0.055 and 0.047 microgram/cm2 per h, respectively). Formulation of ACV in modified aqueous cream and in dimethyl sulfoxide resulted in an 8- and 60-fold increase, respectively, in the flux of ACV through human skin. Idoxuridine behaved similarly to ACV in the three vehicles. The poor clinical results seen with topical use of ACV ointment may be due in part to retarded drug delivery from this formulation.
Topical foscarnet (PFA) and acyclovir (ACV) were compared in the dorsal cutaneous guinea pig model of herpes simplex virus type 1 infection. The relative order of efficacy was PFA cream greater than ACV cream greater than ACV ointment. In vitro studies demonstrated that PFA and ACV formulated in cream vehicles penetrated through guinea pig skin 7- to 10-fold faster than did ACV in ointment.
Single applications of 1-fluoro-2,4-dinitrobenzene (DNFB) or oxazolone to one ear of a mouse resulted in brisk local cell-mediated immunity (CMI) upon antigenic rechallenge of the same ear. However, only a minimal CMI reaction occurred when the other ear was treated with antigen. The relative unresponsiveness of the contralateral ear persisted for periods as long as 14 weeks. The depressed CMI of the contralateral ear was eliminated when cyclophosphamide was given prior to initial antigenic exposure, and therefore, appeared to be mediated by suppressor cells. These observations indicate that regional variations in the intensity of cutaneous CMI can be induced in mice. The significance of these observations is discussed.
The authors performed a retrospective analysis of 87 consecutive immunocompromised patients who underwent open-lung biopsy at the University of Utah Medical Center, Salt Lake City, Utah, from January 1971 to June 1982. A specific histologic diagnosis was obtained in 62 (71%) of the patients, 33 of whom had infections. Pneumocystis carinii was the most common microbial pathogen (16 patients), but no cases have been observed since 1980 when the routine use of prophylactic trimethoprim/sulfa began. The other specific diagnoses included malignancy or drug-induced lung disease. Specific therapy was available for 52 patients, and in 33 cases, a change in therapy was necessary to treat according to the lung biopsy diagnosis. Forty-one patients received an adequate course of therapy and 27 (66%) of these improved clinically, including 16 of 26 patients with infections, 11 of 14 with malignancies, and 1 of 2 with a vasculitis. Among the subgroup of 33 patients for whom a new, specific therapeutic option was available as a result of the biopsy diagnosis 21 (64%) responded to the treatment. Eleven significant operative complications were encountered, but no deaths were attributable to the biopsy. An open-lung biopsy in immunocompromised patients is a relatively safe, accurate diagnostic procedure which frequently facilitates appropriate therapy and clinical improvement.
Arildone, an investigational antiviral agent, was compared to both its vanishing cream and 90% dimethyl sulfoxide (DMSO) solution vehicles to determine cutaneous and systemic tolerance as well as percutaneous absorption. In separate studies, immunosuppressed patients randomly received either arildone in vanishing cream (study 1), arildone in DMSO solution (study 2), or the vehicles without arildone. Test formulations were applied to the same area of one forearm four times daily for seven days. Blood, urine, and fecal samples were collected on days 1, 4, and 7, and patients were observed daily. Arildone was sporadically detected in biologic specimens suggesting limited percutaneous absorption. Unexpectedly, DMSO did not appear to enhance absorption of the drug. No clinical or laboratory evidence of systemic intolerance was observed for any preparation. While cutaneous tolerance was excellent for the vanishing cream preparations, the DMSO preparations were associated with a high (90%) incidence of erythematous reactions.
Approximately 30% of persons with frequent episodes of herpes labialis are deficient in the production of HSV-induced immune-specific interferon (IFN) (Green, 1985). Herpes simplex virus (HSV) strains isolated from persons who make immune-specific IFN and from persons who do not make it were examined for their immunostimulatory capabilities. HSV isolated from the primary oral lesions of two patients deficient in immune-specific IFN production, one person with an intact immune-specific IFN response, HSV types 1 and 2 laboratory strains, and Newcastle disease virus (NDV) were added to cultures of peripheral blood mononuclear cells (PBML) from HSV seropositive donors. All HSV-isolates induced comparable titers of immune-specific IFN. These studies suggest that failure of some patients to develop an immune-specific IFN response is determined by the host, not the virus.
Immune-specific IFN (IFN) is produced by the peripheral blood mononuclear leukocytes (PBML) of greater than 95% of HSV-seropositive humans with infrequent recurrences of herpes labialis [Green, Yeh, and Overall, 1981]. However, herpes virus-induced immune-specific IFN was produced by PBML from only 33 of 48 (68.8%) persons with frequent recurrences (2-12 episodes a year). Two of eight subjects with primary herpes gingivostomatitis also failed to produce immune-specific IFN during either the acute or convalescent phases of their initial HSV infection. These data suggest that some persons have a defective immune-specific IFN response that exists from the time of their primary oro-labial HSV type 1 infection. This defect may predispose to a higher frequency of disease in some individuals.
The potential efficacy of topical therapy with (E)-5-w-bromovinyl)-2'-deoxyuridine (BVDU) for cutaneous herpesvirus infection was evaluated in vitro and in guinea pigs. Drug sensitivity testing against herpes simplex virus type 1 strain E115 revealed an ID50 of 0.008 microgram/ml for BVDU and 0.19 microgram/ml for acyclovir (ACV). In vitro drug diffusion studies showed poor penetration of guinea pig skin by BVDU from the cream compared to BVDU from dimethylsulfoxide (DMSO) (0.04 vs. 1.5 microgram/cm2 per h). 5% BVDU cream, 5% BVDU/DMSO, and 5% ACV in polyethylene glycol (PEG) were then compared in the treatment of experimental dorsal cutaneous HSV-1 infection in guinea pigs. Lesion number, total lesion area and virus titer were reduced by all three formulations compared to control sites treated with the corresponding drug vehicles (P less than or equal to 0.01). BVDU cream effected a greater reduction in lesion number (20+ vs. 13%) and total lesion area (40% vs. 28%) than did ACV/PEG and a significantly greater decrease in virus titer (990% vs. 55%, P less than 0.002). BVDU/DMSO was clinically twice as effective as BVDU cream (P less than or equal to 0.01) and reduced lesion virus titers to a similar degree. The results of these studies show that BVDU is a more potent virus-inhibitory agent than ACV in vitro and is superior to topical ACV in vivo when formulated in a simple aqueous cream. The marked efficacy of BVDU/DMSO in the animal model demonstrates the potential of this antiviral if drug delivery is improved.
Butylated hydroxytoluene (BHT) is a hydrophobic compound with in vitro activity against many enveloped viruses, including herpes simplex virus. The effect of topical therapy with 15% BHT in mineral oil on the course of recurrent herpes simplex labialis was examined in 30 patients in a double-blind, placebo-controlled pilot study in which treatment was initiated by the physician. Sixteen patients received BHT and 14 received the placebo mineral oil vehicle. The time from lesion onset to dry crust formation was slightly shorter among BHT recipients than among placebo recipients (2.0 and 2.4 days; P = 0.01). Duration of the vesicle-ulcer stages was likewise shorter (1.2 and 2.0 days; P = 0.09), and lesion virus excretion appeared to be less in the subjects who received BHT than in the controls, but these differences were not significant. There was no clinical or laboratory evidence of toxicity.