Steven J. Sperber

Effects of Naproxen on Experimental Rhinovirus Colds: A Randomized, Double-Blind, Controlled Trial

OBJECTIVE To determine whether naproxen, a propionic acid inhibitor of cyclooxygenase, alters the course of experimental rhinovirus colds. DESIGN A randomized, double-blind, controlled trial. SETTING Rhinovirus challenge model in volunteers cloistered in individual hotel rooms. VOLUNTEERS Eighty-seven healthy young adults with serum neutralizing antibody titers of less than or equal to 1:2 to the challenge virus; 79 were evaluable. INTERVENTION Thirty-nine participants received naproxen (loading dose, 400 mg or 500 mg followed by 200 mg or 500 mg three times daily for 5 days). Forty participants received placebo. Treatment was started 6 hours after viral challenge. MEASUREMENTS Daily measurement of viral titers, symptoms, nasal mucus production, and nasal tissue use; incidence of infection and illness; and measurement of homotypic serum neutralizing antibody responses. RESULTS Viral titers and serum homotypic antibody responses were similar in the naproxen and placebo groups. Significant reductions in headache, malaise, myalgia, and cough occurred in the naproxen group. A 29% reduction was noted in the total (5-day) symptom score in the naproxen group (95% CI, 16% to 42%). CONCLUSION Naproxen treatment did not alter virus shedding or serum neutralizing antibody responses in participants with experimental rhinovirus colds, but it had a beneficial effect on the symptoms of headache, malaise, myalgia, and cough. Prostaglandins may be among the inflammatory mediators that play a role in the pathogenesis of rhinovirus colds.

Echinacea purpurea for Prevention of Experimental Rhinovirus Colds

Abstract A randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the ability of Echinacea purpurea to prevent infection with rhinovirus type 39 (RV-39). Forty-eight previously healthy adults received echinacea or placebo, 2.5 mL 3 times per day, for 7 days before and 7 days after intranasal inoculation with RV-39. Symptoms were assessed to evaluate clinical illness. Viral culture and serologic studies were performed to evaluate the presence of rhinovirus infection. A total of 92% of echinacea recipients and 95% of placebo recipients were infected. Colds developed in 58% of echinacea recipients and 82% of placebo recipients (P = .114, by Fishers exact test). Administration of echinacea before and after exposure to rhinovirus did not decrease the rate of infection; however, because of the small sample size, statistical hypothesis testing had relatively poor power to detect statistically significant differences in the frequency and severity of illness.

Alternating and intermittent regimens of zidovudine and dideoxycytidine in patients with AIDS or AIDS-related complex

Zidovudine is a nucleoside analog that reduces progression of human immunodeficiency virus type 1 (HIV)-associated disease and prolongs survival [1-3]. The use of this drug at high doses in patients with advanced disease has been limited by hematologic toxicity [4-6]. Initial studies of another nucleoside analog, 2,3-dideoxycytidine (ddC), have shown that it is a potent inhibitor of HIV replication; therapy with ddC results in both the rapid suppression of serum p24 antigen levels and increases in CD4 cell counts [7, 8]. The principal dose-limiting toxicity of ddC is sensory peripheral neuropathy, which is related to both dose and duration of therapy [7-10]. Both zidovudine and ddC have been studied at lower doses to construct a tolerable monotherapy regimen [2, 6, 9, 11]. Alternating courses of zidovudine and ddC have been studied in an attempt to reduce dose-limiting toxicity. By limiting the continuous administration of each drug, the use of alternating therapy may allow any short-term toxicity from one drug to resolve during the administration of the other, and cumulative toxicity may be avoided. In addition to a reduction in toxicity, several other benefits of alternating therapy have been suggested. First, such combination therapy may have a synergistic or additive effect on virologic and immunologic markers; preliminary studies in vitro and in vivo suggest that alternating regimens have an enhanced antiretroviral effect [7, 12]. Concurrent zidovudine and ddC therapy has shown similar in vitro and in vivo effects and has recently been approved for use by the Food and Drug Administration [13, 14]. Second, it may be possible to maintain continuous high-dose therapy, thereby maximizing central nervous system concentrations. Third, in limiting the time of exposure to each drug, the sequential use of two agents may reduce or retard the emergence of drug-resistant isolates. We evaluated monthly and weekly alternating schedules of zidovudine and ddC to determine whether a reduction in toxicity or an enhanced antiretroviral effect, or both, could be achieved by this method of administration of the two agents. Intermittent zidovudine and ddC limbs were included to assess the relative contribution of each of the components to the overall effect. Continuous zidovudine, 1200 mg/d, served as the control treatment regimen. Methods Patients The study sample consisted of patients with AIDS-related complex or AIDS. We defined AIDS-related complex as the documented presence of one of the following: weight loss exceeding 15 pounds or 10% of body weight within 120 days before entry; a temperature greater than 38.5 C that persisted for more than 14 consecutive days or was documented on more than 15 days in a 30-day interval; diarrhea (three or more liquid stools per day) for at least 30 days without a definable cause; recurrent oral candidiasis; hairy leukoplakia; or a history of herpes zoster. We defined AIDS according to Centers for Disease Control criteria [15]. All study patients had circulating serum p24 antigen levels of 70 pg/mL or more on two occasions before enrollment. No restriction was placed on entry CD4 cell count. Patients were excluded from the study if they met any of the following criteria: a hemoglobin concentration of less than 95 g/L; transfusion dependence; an absolute granulocyte count less than 1.2 109/L; a platelet count less than 100 109/L; a calculated creatinine clearance rate of 50 mL/min per 1.73 m2 body surface area or less; transaminase levels 5 or more times the upper limit of normal; a Karnofsky performance score of less than 60; pregnancy or lactation; significant malabsorption; cardiac or liver disease; or AIDS-defining conditions requiring systemic maintenance chemotherapy. Patients with evidence of preexisting peripheral neuropathy and those who had had previous ddC treatment were also excluded. We encouraged all patients with less than 200 CD4 cells/mm3 to undergo aerosolized pentamidine prophylaxis (300 mg every month) for Pneumocystis carinii pneumonia. Study Design An unblinded, randomized trial (Protocol 047) was conducted at 12 AIDS Clinical Trials Units. Seven regimens were tested (Figure 1). At the time the study began, the standard zidovudine dose was 200 mg every 4 hours. Figure 1. The seven treatment regimens. Randomization was stratified by center and according to CD4 cell count (> 200 cells/mm3 or 200 cells/mm3). At least 16 patients were assigned to each limb. Patients who did not complete the first 8 weeks of therapy for any reason other than toxicity were replaced. All study patients gave informed consent and institutional review board approval was obtained at each institution. Study medication was to be administered for up to 49 weeks, with an additional follow-up period of 3 weeks. Study patients being treated with an intermittent regimen who had less than a 50% reduction in the serum p24 antigen level at 6 months had the option to change to an alternating regimen. Patients who completed 49 weeks of therapy and showed evidence of a beneficial response (defined as a 50% reduction in p24 antigen level or an improvement in CD4 cell count) had the option to continue therapy past 52 weeks. For the present analyses, only the first 48 weeks of data were used. Patient Evaluation Pretreatment evaluations included a medical history, physical examination, weight measurement, Karnofsky score, complete blood count, hepatic and renal function studies, T-cell subset analysis, and serum p24 antigen determination (Abbott Laboratories, North Chicago, Illinois). Follow-up evaluation was done weekly for the first 8 weeks and every 4 weeks thereafter. Serum specimens for p24 antigen determination were collected weekly for the first 8 weeks and then 3 of every 4 weeks thereafter. An evaluation for peripheral neuropathy was done on enrollment and was repeated as follows: neuropathy symptom questionnaire every 2 weeks, peripheral neurologic examination every 4 weeks, and quantitative sensory testing of vibration every 8 weeks [10]. Signs or symptoms suggestive of opportunistic infection or malignancy were evaluated according to standard AIDS Clinical Trials Group guidelines [15]. Hematologic toxicity for patients being treated with a zidovudine-containing regimen was defined and managed as follows: Transfusion was allowed for symptomatic grade 2 anemia (hemoglobin, 80 to 94 g/L) and for grade 3 (hemoglobin, 65 to 79 g/L) or grade 4 anemia (hemoglobin < 65 g/L). Study drug dosage was reduced or held in cases of grade 3 or 4 anemia if the patient declined transfusion or required more than 4 units of packed red blood cells in 6 weeks; or in cases of grade 3 (granulocyte count, 500 to 750; leukocyte count < 1.5 109/L) or grade 4 (granulocyte count >500, leukocyte count < 1.0 109/L) granulocyte-leukocyte toxicity. Patients were removed from the study if they developed grade 3 or 4 anemia or granulocyte-leukocyte toxicity that either failed to respond to dose adjustment or recurred. Patients treated with intermittent ddC were removed from the study for the following reasons: a first episode of grade 3 anemia if the patient declined transfusion or required more than 4 units of packed red blood cells in 6 weeks; grade 3 granulocyte-leukocyte toxicity that either failed to respond to dose adjustment or recurred; or a first episode of grade 4 anemia or granulocyte-leukocyte toxicity. Dose-limiting peripheral neuropathy was defined by the occurrence of bilateral burning or shooting pains in the lower extremities that were of moderate (grade 2) intensity and persisted for 72 hours or more; a symptom of severe (grade 3) intensity of any duration; or a symptom of moderate intensity of any duration plus either a supporting abnormality in the affected limb on standardized peripheral nerve examination or a supporting abnormality in the affected limb on quantitative sensory testing. Statistical Analysis Data from all enrolled patients were used in the analyses; however, data collected beyond the point at which patients switched from their initially assigned therapy were not included in the analysis. The Fisher exact test and chi-square tests were used to compare subgroups when the data were discrete [16] and Wilcoxon-Mann-Whitney tests were used for continuous data [17]. The Kaplan-Meier method and log-rank tests were used to analyze time-to-event data [18]. All P values were two-sided. The area under the curve (AUC) of absolute CD4 cells/mm3 was calculated, and the resulting total area was divided by time on therapy (T) to derive AUC/T [19]. The baseline CD4 count was subtracted from AUC/T to obtain the average change in CD4 cell count from baseline. A linear regression model was then calculated, with the average change in CD4 cell count as the dependent variable and both the baseline CD4 cell count and the assigned treatment limb as the independent variables. Results Patients One hundred thirty-one patients were enrolled in the study between 24 June 1988 and 17 October 1989 (Table 1). Most patients were male (96%) and white (76%) and had not received zidovudine within 90 days of study entry (96%). Seventy-seven percent had AIDS-related complex and 23% had AIDS. The median CD4 cell count at entry was 142 cells/mm3, and the median serum p24 antigen level was 257 pg/mL. Table 1. Patient Characteristics at Study Entry* The median follow-up for the entire study group was 40 weeks. Fifty-nine patients (45%) completed 48 weeks of therapy (Table 2). Twenty patients were withdrawn from the study because of toxicity related to ddC or zidovudine. Twenty-eight patients were removed because of AIDS-related opportunistic infection, malignancy, or dementia; 13 of these patients were removed from the study before completing 8 weeks of therapy. These 13 patientsalong with 4 patients who voluntarily withdrew from the study, were lost to follow-up, or were removed from the study for protocol violations in the first 8 weekswere

Effectiveness of Clemastine Fumarate for Treatment of Rhinorrhea and Sneezing Associated with the Common Cold

Limited data support the use of first-generation antihistamines for treatment of the common cold. The purpose of this study was to test the effectiveness of clemastine fumarate, a first-generation antihistamine, for treatment of sneezing and rhinorrhea associated with naturally occurring common colds. Four hundred three subjects (202 clemastine fumarate recipients and 201 placebo recipients) who reported new onset (< 24 hours) of cold symptoms that included rhinorrhea or sneezing were studied. At baseline (day 1), the mean symptom-severity scores +/- SEM for the clemastine fumarate and placebo groups were not significantly different. The mean rhinorrhea-severity score +/- SEM was not different on day 2; however, on day 3, the mean rhinorrhea-severity score +/- SEM was 1.02 +/- 0.07 for the clemastine fumarate group and 1.39 +/- 0.07 for the placebo group (P < .001). This treatment effect persisted on day 4. A significant effect on sneezing was noted on days 2-4. Sedation occurred in 14% of the clemastine fumarate-treated subjects and 1.5% of the placebo-treated subjects (P < .0001).

Serologic response and reactogenicity to booster immunization of healthy seropositive adults with live or inactivated varicella vaccine

The immunogenicity and reactogenicity of live and heat-inactivated varicella vaccine were evaluated in 95 healthy seropositive adults (mean age, 32 yrs). Live-attenuated vaccine containing 28,000 pfu, 2800 pfu, or 280 pfu of Oka/Merck strain virus (8.4, 0.84, and 0.08 antigen units, respectively) or heat-inactivated vaccine with comparable antigen content (7.1, 0.71, and 0.07 antigen units) was administered subcutaneously to 15 to 16 adults per group in a randomized, single-blind study. ELISA antibody responses were dose-dependent but independent of whether the vaccine was live or inactivated. Mean titers reached a peak on day 14 and remained elevated through day 42 in recipients of the highest dosages but declined by followup at eleven months. A minority of vaccinees developed a four-fold or greater increase in antibody titer on day 14 (25 to 31 percent in the high-dose groups [greater than or equal to 7.1 antigen units], less than or equal to 7 percent of other groups). The vaccine was generally well tolerated. Localized erythema and swelling occurred at the injection site in 44 to 56 percent of the high- and middle dose recipients [greater than or equal to 0.71 antigen units], compared with 0 to 6 percent of those receiving the lowest dose. Although statistically significant increases in varicella antibody titer were observed after immunization with high doses of live or inactivated vaccine, the duration and clinical significance of this booster effect remains to be determined.

Low-dose oral recombinant interferon-αA in patients with HIV-1 infection : a blinded pilot study

ObjectiveTo evaluate the efficacy of low-dose oral recombinant interferon-α (IFN-αA) on clinical parameters, body weight, CD4+ lymphocyte counts and natural killer cell cytoiytic activity in HIV-infected patients. DesignBlinded crossover trial with controls for the protein and diluent components of the drug preparation. SettingMedical school outpatient referral center. Patients, participantsEight patients with HIV-1 infection and a CD4+ lymphocyte count between 150 and 600 χ 106/1. Concurrent use of zidovudine was permitted. InterventionsPatients received (daily, by mouth) 10 ml of a study solution of 2.5% albumin for 6 weeks, 150 IU IFN-αA for 6 weeks, and normal saline for 6 weeks. Main outcome measuresAfter two baseline visits, clinical assessments, vital signs, body weight, and laboratory tests, including enumeration of number and percentage of CD4+ and CD8+ lymphocytes and natural killer cell cytoiytic activity, were performed every 3 weeks. Complete physical examinations were conducted every 6 weeks. ResultsNo significant clinical or laboratory changes were observed during treatment with IFN-αA. Peak CD4+ lymphocyte counts were achieved at baseline in one patient, during albumin treatment in two patients, during IFN-αA treatment in one patient, and during saline treatment in four patients. All patients remained HIV-seropositive. Treatments were well-tolerated. ConclusionThis blinded pilot study of orally administered IFN-αA (150IU daily for 6 weeks) did not demonstrate clinical benefit in HIV-infected patients.

Ineffectiveness of Recombinant Interferon-βserine Nasal Drops for Prophylaxis of Natural Colds

Abstract Two randomized, double-blind, placebo-controlled trials during early autumn of 1986 and 1987 evaluated the efficacy and tolerance of recombinant interferon-βserine (rIFN-βser) nasal drops for prevention of natural rhinovirus colds. In 1986, 9 × 106 units of rIFN-βser (139 subjects) or placebo (157) were adminstered once daily except Sundays for 4 w. Rhinovirus colds occurred in 2.8% of rIFN-βser recipients and 6.0% of placebo recipients during the treatment period (52% reduction, P = .3). In 1987, 24 × 106 units of rIFN-βser (186) or placebo (197) were given daily for 25 consecutive days. Rhinovirus colds developed in 6.3% of rIFN-βser recipients and 5.3% of placebo recipients. In each study, illness frequency and number of days with subjective colds did not differ between the groups. Recipients of nasal drops of rIFN-βser at either dosage did not differ in tolerance from placebo recipients. The lack of both prophylactic efficacy and nasal toxicity are in contrast to prior observations with nasal sprays of rIFN-α2b.

Recurrent Staphylococcus lugdunensis central nervous system infection associated with a ventricular peritoneal shunt

Abstract A case of recurrent Staphylococcus lugdunensis central nervous system (CNS) infection associated with a ventricular peritoneal (VP) shunt is reported. A total of five S. lugdunensis isolates were isolated from the patient (four from ventricular fluid and one from a VP catheter tip). All five isolates share an indistinguishable pulsed-field gel electrophoresis profile. A full range of conventional biochemical tests and 16S rRNA gene nucleotide sequence analyses were performed to confirm identification of the organism. This is the first report of S. lugdunensis in catheter-related VP fluid infection. The isolate was capable of colonizing the CNS and was difficult to treat.