DMSO Background Literature
J. Shupack, M. Stiller, L Davis, C Kenny, L. Jondreau
Section of Dermatopharmacology Department of Dermatology New York University Medical Center
New York, N.Y.
Received: February 21, 1991
The recent in vivo appearance of acyclovir-resistant strains of herpes simplex virus stresses the need for new therapeutic agents to combat this common virus. Topical interferon preparations may help fill this void. In the present study dimethyl sulfoxide was combined with -interferon in an ointment base to increase percutaneous penetration. In this double-blind, placebo-controlled trial, patients with recurrent genital herpes simplex using the topical -interferon preparation had a more rapid cessation of viral shedding when compared to the placebo group (66% culture negative on day 1 vs. 25% of placebo patients; p<0.02). In the 90-day post-treatment period, interferon-treated patients had fewer recurrences than their placebo-treated counterparts (1.18 vs. 2.25). This reduction while not statistically significant was encouraging, (P<0.10).
Recently, the incidence of genital herpes simplex infections in the United States has risen dramatically.1 There are an estimated 260,000-500,000 cases per year, and genital herpes simplex virus (HSV) infections are a source of significant physical and psychological morbidity.2 Clinical studies in patients with recurrent genital herpes simplex have demonstrated a decrease in frequency and shortened duration of episodes, as well as a more rapid healing of lesions in those receiving oral acyclovir versus placebo. Oral acyclovir has been shown to safely decrease the frequency of episodes when taken daily for periods up to 3 years.3-10 Straus et al.11 recently reported that chronic suppressive oral acyclovir failed to reduce the rate of asymptomatic viral shedding. It is potentially significant that these investigators cultured acyclovir-resistant strains of HSV from asymptomatic, nonimmunocompromised hosts with increased frequency.Interferon, a glycoprotein with antiviral and antineoplastic activity, was first shown to be beneficial in preventing reactivation of herpes labialis in patients undergoing microneurological decompression of the trigeminal nerve. -Interferon administered intramuscularly prior to operation significantly reduced viral shedding and new lesion formation in these patients.12We recently reported that topical -interferon (at a concentration of 106 IU/g in a nonoxynol-9 gel base) was more effective than placebo in a double-blind, placebo-controlled clinical trial in patients with recurrent genital HSV. (Nonoxynol-9 is a widely used, safe surfactant which aids in the uniform dispersion of interferon in the vehicle.13 The duration of viral shedding and the time until the end of all subjective symptoms including pain, burning and itching were significantly reduced in patients receiving the interferon preparation.14 Friedman-Kein et al.15 using a similar topical -interferon preparation reported favorable results. In their placebo-controlled study there was a decrease in viral shedding, time to scabbing and formation of new lesions in the group of patients who received the -interferon. Several clinical trials by Israeli investigators have evaluated topical human fibroblast ()-interferon in the treatment of recurrent genital and facial HSV infections. These investigators reported not only a decrease in the duration of episodes and severity of symptoms but also a decrease in the subsequent recurrence rate.16-18 Topical acyclovir in an aquaeous propylene glycol cream base has shown significant efficacy in the treatment of recurrent genital HSV infections in controlled clinical trials.19-22 On the other hand, 5% acyclovir in a polyethylene glycol ointment base, the topical preparation which is commercially available in the United States, has failed to show significant clinical efficacy in double-blind studies.23-26 Furthermore, topical acyclovir use has failed to alter the frequency of recurrences or the amount of time between recurrences.27-28In the present study -interferon was combined with dimethyl sulfoxide (DMSO). DMSO, a dipolar aprotic solvent, has been shown in clinical studies to be effective in enhancing the penetration of topical medications.29-31We report the results of a study comparing the efficacy and safety of a topical -interferon ointment which also contained DMSO in the treatment of recurrent genital herpes.
The study population consisted of 40 immunocompetent men and women, aged 18 years or older, who had had at least two episodes of recurrent genital herpes simplex within the past 6 months. Diagnosis was confirmed by viral culture or by a dermatologist's clinical evaluation. All patients agreed to discontinue the use of topical and systemic medications intended for treatment of herpes simplex or which might alter symptoms such as pruritus or pain, e.g. antihistamines and analgesics, 30 days prior to enrollment and for the duration of the study. A phisical examination and medical history were obtained on all subjects prior to enrollment. This clinical trial was approved by the Institutional Board of Research Associates of New York University Medical Center prior to its initiation, and an informed consent was obtained from all participants in accordance with Food and Drug Administration guidelines. This clinical trial was double-blinded with a placebo control. The patients were given identically labeled tubes of either 105 IU/g -interferon in hydrophilic ointment with 5% DMSO or hydrophilic ointment with 5% DMSO, which served as a placebo control. The decision to use a lower concentration of interferon than was used in our earlier clinical trial 14 was based on consideration of the more penetrating DMSO-containing vehicle in the present study. Human leukocyte interferon was prepared by Vira-Tech Inc. The ointment base contained water, petrolatum, mineral oil, mineral wax, wool alcohol, 2-bromo-2-nitropropane-1,3-diol, benzyl alcohol, carboxymethyl cellulose and 5% DMSO.The patients were interviewed at a time when they were not having a herpetic outbreak and instructed to begin applying the ointment four times a day at the onset of the first prodromal symptoms of their next attack. All patients were then examined at our institution within 24 h of the onset of that episode of herpes simplex (day 1) and again on days 3, 5, and 7. Outbreaks were treated until resolution or up to a maximum of 7 days. Subsequent recurrences were not treated. Additionally, all participants were required to make a follow-up visit to NYU Medical Center 60-90 days after the day 5 visit. Additionally, during the 6-month period after cessation of therapy, the study subjects were expected to keep a diary recording the number of herpetic episodes they had and the duration of those recurrences. This information was obtained from the study subjects in a 6-month post-treatment phone interview conducted by one of the study coordinators. During all visits herpetic lesions were morphologically staged (as papules, vesicles, crusts, or healed), lesion counts and measurements taken, and patients were asked to rate their subjective symptoms (which included pain, pruritus, burning, and stinging). Patient serum was collected on day 3 to determine serum electrolytes, liver function tests, hematologic profiles as well as DMSO levels. DMSO serum levels were measured by gas chromatography at the National Medical Services Laboratory, Willow Grove, Pa., USA. Specimens for virus isolation were taken on days 1, 3, and 5 by the methods used by Friedman-Klein et al.15Statistics were prepared by 2 analysis and Student's t test where applicable.
Of the 40 patients who initially enrolled in this patient-initiated clinical trial and received tubes of medication, 20 completed therapy of one HSV recurrence (12 medicated, 8 placebo). Of these 20, 19 individuals continued participation in the study through the 60- to 90-day posttreatment follow-up visit.The patients in the interferon-treated group demonstrated decreased viral shedding and more rapid healing than those in the placebo group. 66% of the interferon-treated patients were culture negative after 24 h of treatment (day 1), whereas only 25% of the patients in the placebo group were culture negative at that time (p<0.02). By day 5, 91% of the interferon group was culture negative compared to 85% of the placebo group (p > 0.66; fig. 1). On day 5, 25% of the patients in the placebo group had active lesions, while no patients in the interferon group had active lesions (p > 0.02).
Patients presenting with a negative viral isolation text.
After completion of therapy, the patients in the placebo group had twice as many recurrences over the ensuing 6 months as did their counterparts who had received interferon ointment. Furthermore, the recurrences in the placebo-treated group took 2.3 days longer to heal than recurrences in the interferon group (p>0.10; table 1). At the end of the study, the patients were asked whether or not they believed that their treatment had been useful. Eleven of the 12 patients (92%) in the interferon group rated their treatment as 'useful.' Only 1 of 8 patients (12%) in the placebo group regarded treatment as 'useful' (p<0.003). The physician's global evaluation corresponded rather closely with that of the patients. Investigators rated therapy as worthwhile in 11/12 (92%) of individuals in the interferon group versus 2/8 (25%) in the placebo group (p<0.01).
Average number of recurrences (after treatment)
These results further support our belief that topical interferon preparations mav have a role in the treatment of recurrent HSV infections.13-18 Topical interferon could be used in place of systemic acyclovir in patients who dislike taking oral medications. Additionally, a topical agent, such as the one evaluated in this study or our earlier clinical trial,12 could be used as an adjunct along with systemic acyclovir to minimize the emergence of acyclovir-resistance strains of HSV.8,32-43One area of concern is the high dropout rate in this clinical trial. Only 20/40 study subjects completed therapy of one recurrent episode. This 50% dropout rate is not unusually high for a patients-initiated study for recurrent herpes. In 1983, Fiddian et al.19 reported that 62% of the 137 patients enrolled in their acyclovir cream study for recurrent genital HSV completed that clinical trial. In a larger multicenter study evaluating acyclovir ointment in recurrent genital herpes, 56% of the 547 entering patients completed therapy.23 In another multicenter clinical trial testing topical acyclovir in recurrent oral HSV, Spruance et al.44 reported that only 20% of the 352 enrollees finished the study. Subsequently, our 50% dropout rate does not seem alarmingly high for a patient-initiated study of this type.Based upon published studies evaluating a variety of topical interferon preparations in recurrent facial and Genital HSV infections, it is not possible to select an optimal preparation. The topical -interferon cream tested by Israeli investigators16-18 and the topical -interferon preparations evaluated by us and Friedman-Kien et al.14.15 were all similarly impressive in reducing the duration of viral shedding and of subjective symptoms. In the present clinical trial and in the study by Glezerman et al.,6 there was an impressive decrease in the recurrence rate and in the seventy of subsequent recurrences after the study terminated and use of topical interferon was discontinued. This can be just as easily attributed to the small study population in both clinical trials (40 patients in the present study and 25 in the report of Glezerman et al.) as to any long-term, positive residual pharmacologic effect from interferon.As described under Materials and Methods, the preparation tested contained DMSO. This was added to enhance the penetration of interferon.19-21 Although we cannot unequivocally exclude the possibility that DMSO enhances the antiviral activity of interferon, we can confidently assert that DMSO absorption was not significant and that there was no systemic toxicity (as shown by DMSO drug levels, blood chemistries, hematologic profiles, and physical examination).In summary, we feel that topical -interferon is a potentially safe and useful therapy for recurrent herpes genitalis. It might be utilized adjunctively along with oral acyclovir or as monotherapy, either during recurrences or by asymptomatic carriers between episodes to diminish the emergence of resistant strains of HSV.
Pharmacology and Treatment, Dermatology 1992;184:40-44
This clinical trial was supported by a grant from Virapen Corporation.
Jerome Shupack, MD
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