Atomoxetine treatment in children and adolescents with ADHD and comorbid tic disorders.

OBJECTIVE: To test the hypothesis that atomoxetine does not significantly worsen tic severity relative to placebo in children and adolescents with attention deficit/hyperactivity disorder (ADHD) and comorbid tic disorders. METHODS: Study subjects were 7 to 17 years old, met Diagnostic and Statistical Manual of Mental Disorders-IV criteria for ADHD, and had concurrent Tourette syndrome or chronic motor tic disorder. Patients were randomly assigned to double-blind treatment with placebo (n = 72) or atomoxetine (0.5 to 1.5 mg/kg/day, n = 76) for up to 18 weeks. RESULTS: Atomoxetine treatment was associated with greater reduction of tic severity at endpoint relative to placebo, approaching significance on the Yale Global Tic Severity Scale total score (-5.5 +/- 6.9 vs -3.0 +/- 8.7, p = 0.063) and Tic Symptom Self-Report total score (-4.7 +/- 6.5 vs -2.9 +/- 5.2, p = 0.095) and achieving significance on the Clinical Global Impressions (CGI) tic/neurologic severity scale score (-0.7 +/- 1.2 vs -0.1 +/- 1.0, p = 0.002). Atomoxetine patients also showed greater improvement on the ADHD Rating Scale total score (-10.9 +/- 10.9 vs -4.9 +/- 10.3, p < 0.001) and CGI severity of ADHD/psychiatric symptoms scale score (-0.8 +/- 1.1 vs -0.3 +/- 1.0, p = 0.015). Discontinuation rates were not significantly different between treatment groups. Atomoxetine patients had greater increases in heart rate and decreases of body weight, and rates of treatment-emergent decreased appetite and nausea were higher. No other clinically relevant treatment differences were seen in any other vital sign, adverse event, or electrocardiographic or laboratory measures. CONCLUSIONS: Atomoxetine did not exacerbate tic symptoms. Rather, there was some evidence of reduction in tic severity with a significant reduction of attention deficit/hyperactivity disorder symptoms. Atomoxetine treatment appeared safe and well tolerated.

Loracarbef versus clarithromycin in children with acute otitis media with effusion.

Two multicenter, randomized, single-masked, parallel-group studies compared loracarbef and clarithromycin with regard to efficacy, tolerability, and patient acceptance. Three hundred thirty-four children aged 6 months to 3 years with acute otitis media with effusion received loracarbef (15 mg/kg) or clarithromycin (7.5 mg/kg) orally twice daily for 10 days. Patients were assessed for the presence of the diagnostic signs and symptoms of otitis media with effusion by physical examination and pneumatic otoscopy at 48 hours pretreatment, 3 to 5 days after initiation of treatment, 0 to 3 days after the final dose (posttreatment), and 14 to 21 days later (termination). Symptoms were assigned numeric values. Symptomatic response was assessed at the posttherapy and termination visits. Tolerability was determined by assessing adverse events, and a patient acceptance survey was completed by each patient's caregiver. The combined results of these 2 studies showed that the efficacy and tolerability of loracarbef were comparable to those of clarithromycin. Adverse events were reported by 46.4% of loracarbef patients and 41.0% of clarithromycin patients, with no statistically significant difference between groups. In the intent-to-treat analysis, 57.9% of loracarbef patients were cured at the termination of the study, compared with 55.7% of clarithromycin patients. Improvement was seen in 4.1% of loracarbef patients and 2.7% of clarithromycin patients. Results of the patient acceptance survey showed a clear preference for loracarbef over clarithromycin. Difficulties with administration of treatment were reported by 36.3% of clarithromycin caregivers, compared with 7.8% of loracarbef caregivers (P < 0.001). A desire to stop treatment was reported by 23.8% of clarithromycin caregivers, compared with 7.8% of loracarbef caregivers (P < 0.001). Taste and texture issues were most frequently cited as reasons for nonacceptance.

Passive immunization for prevention of rotavirus illness in healthy infants.

Infant formula supplemented with bovine antibody (BCIg) to human rotavirus has been reported to prevent or modify rotavirus infection and illness. The purpose of this field trial was to determine the safety and feasibility of passive immunization with bovine antibody for the prevention of rotavirus infection and illness in healthy infants. Sixty-four infants, 31 of whom received BCIg and 33 placebo, participated in the study. Rotavirus infection was detected in 11 (35%) and 14 (42%) infants in the 2 groups, respectively. Symptomatic rotavirus infection was documented in 1 (3%) of the infants receiving BCIg and in 6 (18%) of the infants who received the placebo (P > 0.05). The number of days with diarrhea/1000 days of observation was significantly less in the BCIg group, 4.2, than in the placebo group, 16.8 (P < 0.01). Similarly the number of days with rotavirus-associated diarrhea/1000 days was less in the BCIg group, 1.0, than in the placebo group, 13 (P < 0.01). This study establishes the feasibility of providing passive immunity for the prevention of rotavirus illness in healthy infants.

Comparison of the opsonic and complement triggering activity of human monoclonal IgG1 and IgM antibody against group B streptococci.

We have compared the opsonic and complement-triggering activity of transfectoma-derived, class-switched human IgG1 and IgM mAb (HumAb) against types Ia, II and III group B streptococci (GBS). These antibodies appear to be directed against the common group B cell wall Ag of these organisms. The HumAb IgM promotes uptake of type Ia and II GBS at concentrations as low as 37 ng/ml and type III GBS at concentrations of 150 ng/ml in the presence of human neonatal complement. In contrast, the IgG1 GBS HumAB showed no detectable opsonic activity in concentrations up to 600 ng/ml. When the concentration of HumAb IgG1 is raised to 2.5 micrograms/ml, significant opsonic activity against GBS is detected and when the concentration is approximately 40 micrograms/ml, the opsonic activity peaked at a slightly higher level than that with the HumAb IgM. Thus, approximately 100- fold higher concentrations of the IgG1 than the IgM HumAb are required for optimal opsonization. The opsonic activity of the IgM and IgG1 HumAb are closely related to their ability to consume complement and deposit C3 on the surface of type Ia, II, and III GBS (r = 0.959). We believe that the marked opsonic and protective activity of the IgM GBS HumAb is due to its enhanced avidity and ability to trigger the complement system. Further studies are indicated to determine the feasibility of employing human IgM antibody preparations in the immunotherapy of neonatal GBS disease.

Monoclonal antibodies in the therapy of experimental neonatal group B streptococcal disease.

Group B streptococcal (GBS) infections continue to be a major cause of morbidity and mortality in human neonates. This has led a number of investigators to explore the role of immunotherapy in the treatment of neonatal GBS disease. In early studies, we showed that intravenous immune globulin (IVIG) offered some protection against less virulent strains of GBS in a neonatal rat model of disease. Against more virulent strains, which produce an excess of sialic acid-containing type-specific antigen, IVIG offered little protection even when given in much higher doses. For this reason, we developed murine monoclonal antibodies (MuMAb) against type III GBS. MuMAb directed against the type III-specific antigen provided excellent protection against virulent (greater than 95%) and less virulent (94-100%) strains of GBS when administered in doses as low as 400 micrograms/kg up to 24 hr after bacterial inoculation. MuMAb IgM antibody was approximately 100-fold more effective than MuMAb IgG2a antibody. Unfortunately, MuMAbs are unlikely to be approved for use in human neonates. For this reason, we have evaluated a human monoclonal antibody (HuMAb) preparation against GBS derived from Epstein-Barr virus-immortalized peripheral blood B lymphocytes. This IgM HuMAb, which appears to be directed against the group B carbohydrate, is extremely active in both opsonic and protective assays against type Ia, II, and III GBS. Optimal immunotherapy of neonatal GBS disease may involve the use of HuMAb preparations, alone or in combination with polyclonal IVIG.

Comparative protective activity of human monoclonal and hyperimmune polyclonal antibody against group B streptococci.

Group B streptococcal (GBS) infections cause significant morbidity and mortality in neonates and compromised hosts, who usually lack opsonic antibody to their infecting strain. Unfortunately, most conventional immunoglobulin preparations possess little GBS antibody. The protective activity of a human monoclonal antibody (HuMAb) and a human hyperimmune intravenous immunoglobulin (HivIg) were evaluated against these organisms and compared with a conventional intravenous immunoglobulin (ivIg). The HuMAb and the HivIg possessed significant protective activity (50%-95%) against extremely virulent strains of types I, II, and III GBS in doses as low as 4-20 mg/kg. In contrast, the conventional ivIg had little protective activity against some of these strains in doses as high as 500 mg/kg. The opsonic activity of the HuMAb and HivIg also usually exceeded that of the conventional ivIg. These studies suggest HivIg or HuMAb with markedly enhanced specific activity may provide optimal immunotherapy for GBS infections.

Minimal antigenicity of intron A in human recipients demonstrated by three analytical methods.

Antibodies to recombinant human interferon alpha 2b (Intron A) were detected in only a small number of 101 Intron A recipients. This group of cancer patients received Intron A for a mean treatment time of 4.3 months and were selected from disease categories in which subjects were expected to be immunocompetent. Three methods for the detection of antibodies were employed: (a) a bioassay measuring the neutralizing activity of the sera for the antiviral action of interferon alpha 2b, (b) a radioimmunological assay measuring the ability of the sera to prevent the detection of interferon alpha 2b by an immunoradiometric assay (IRMA), and (c) an enzyme-linked immunosorbent assay (ELISA) that measures the binding of immunoglobulins to interferon alpha 2b attached to a solid support. Three of the 101 patients developed neutralizing activity during treatment. Two of these exhibited low neutralizing titers of 1:6-1:9 and were unreactive in the IRMA and ELISA, while only one was positive by bioassay, IRMA, and ELISA. An additional seven patients were positive only in the ELISA. Six of these were borderline positive, i.e., the posttreatment:pretreatment ratio was less than or equal to 5. The results of this study confirm that Intron A is minimally antigenic in human subjects.

Alterations in lymphocyte recirculation within ultraviolet light-irradiated mice: efferent blockade of lymphocyte egress from peripheral lymph nodes.

Ultraviolet irradiation (uvR) has been demonstrated to have profound effects on many functions of the immune system. In particular, exposure to this physical agent can alter the tissue distribution and function of a number of immunologically active cell types, even at sites remote from direct uvR exposure. The present investigation demonstrates that uvR exposure of mice induces an efferent blockade of lymphocyte egress from the peripheral lymph nodes which drain the irradiated skin, resulting in marked retention of lymphocytes. In vivo studies of this efferent blockade established that the condition appeared similar in mechanism to that induced by the administration of poly-inosinic:poly-citidylic acid, murine interferon alpha/beta and specific antigen. We were able to establish that a common mechanism in the genesis of an efferent lymphatic blockade may involve prostaglandin biosynthesis. The potential contribution of efferent blockade to the development of systemic suppression of contact hypersensitivity induced by uvR exposure is discussed.

Prevention of experimental coronavirus colds with intranasal alpha-2b interferon.

Fifty-five volunteers treated with either intranasal recombinant interferon (rIFN; 2 X 10(6) IU/day) or placebo for 15 days were exposed to coronavirus by direct intranasal inoculation on the eighth day of treatment. Symptom scores were recorded, and cultures of virus were taken daily for all volunteers for seven days after inoculation. Nineteen (73%) of the 26 placebo recipients met symptom-score criteria for a cold, compared with 12 (41%) of the IFN recipients (P = .02). The mean nasal symptom scores in the placebo and IFN groups were 9.2 and 5.4, respectively (P = .03), and the mean total symptom scores in the two groups were 23.2 and 9.4, respectively (P = .003). The mean number of days with a total symptom score greater than 4 was 1.6 in the placebo recipients and 0.5 in the rIFN recipients (P = .02). Prophylactic intranasal rIFN effectively shortened the duration and reduced the severity of coronavirus cold symptoms.

A radioimmunologic technique to screen for antibodies to alpha-2 interferon.

A radioimmunologic technique has been developed to screen sera of persons receiving human alpha-2 interferon for the presence of specific antibodies to alpha-2 interferon. The method is sensitive and easy to perform. It tests the ability of the sera to neutralize alpha-2 interferon and prevent the interferon from being detected by an immunoradiometric assay. The results obtained using this technique are in good agreement with an anti-viral, cytopathic effect assay. Using the immunological technique, the sera from more than 1000 individuals who had received different doses of alpha-2 interferon by one or more of various routes of administration were tested. Twenty-five sera representing 14 individuals gave a positive or possibly positive reaction in the assay. Three of the 14 individuals were positive prior to receipt of alpha-2 interferon. Another 3 had reverted to negative when tested a few months later. Of the remaining 8, only 4 developed titers greater than 100 neutralizing units/ml. Hence approximately 1% of the alpha-2 interferon recipients may have produced neutralizing antibodies.

Production of alpha and gamma interferons by spleen cells from cytomegalovirus-infected mice.

Antigen-induced lymphocyte proliferation and the production of a murine immune or type II interferon (MuIFN-gamma) by spleen cells in vitro were used to examine the cellular immune response to a cytomegalovirus infection of mice. Lymphocyte blastogenesis was induced by interaction with cytomegalovirus-infected mouse embryo fibroblasts in spleen cells from mice infected at least 6 days previously with cytomegalovirus. The peak of the blastogenic response occurred after 72 hr in culture with antigen. MuIFN was detected in cultures of cytomegalovirus-infected mouse embryo fibroblasts and spleen cells from both normal and infected mice. The MuIFN produced by spleen cells from normal or infected mice early during the course of the infection (days 1 to 2) was predominantly viral or type I interferon (MuIFN-alpha). Peak titers of MuIFN-alpha were present 24 to 48 h after exposure to antigen in vitro and before the peak of the blastogenic response. In contrast, spleen cells from mice infected at least 6 days previously produced both MuIFN-alpha and MuIFN-gamma in culture with the infected mouse fibroblasts. MuIFN-alpha was present early in the culture, before peak blastogenic activity. Peak levels of MuIFN-gamma were detected as lymphocyte blastogenic activity subsided. These results indicate that the cellular immune system of the murine host is capable of responding to cytomegalovirus infection, the afferent limb by antigen recognition and the efferent limb by the production of the lymphokine MuIFN-gamma.

Cytomegalovirus and dual infection in infants.

In four unrelated infants without underlying immunodeficiency, dual infections with cytomegalovirus (CMV) and another microorganism developed. The patients included the following: (1) a 3-month-old girl with congenital CMV and perinatal cutaneous herpes simplex virus; (2) a 5-week-old girl with CMV and Pneumocystis carinii; (3) a 12-week-old girl with CMV and Haemophilus influenzae meningitis; and, (4) a 2 1/2-month-old girl with CMV and Escherichia coli meningitis. In all four cases, the patient's initial symptoms were referable not to CMV, but to the companion infecting organism. The diagnoses of CMV infection were made, respectively, by a high index of clinical suspicion in the first three cases and on the basis of a lucent parenchymal defect on computerized tomographic scan in the fourth patient. These cases provide additional evidence that CMV infection may predispose to secondary infection. We recommend that infants who have signs of infection and evidence of CNS abnormalities have cultures made for CMV. Both human CMV and experimental murine CMV infections have been associated with suppressed cellular and possibly humoral immunity.

Alteration of host defense mechanisms by murine cytomegalovirus infection.

An animal model of a sublethal infection, utilizing murine cytomegalovirus (MCMV), was developed to determine whether immunological factors could contribute to the establishment of a persistent viral infection. Adult female C3H mice inoculated intraperitoneally with 10(5) plaque-forming units of MCMV developed splenomegaly 5 to 12 days after infection. Virus replicated to peak titers (10(3) to 10(6) plaque-forming units per g of tissue) in liver, spleen, lung, kidney, and salivary gland tissue during the acute phase of the infection (3 to 12 days); it then decreased to undetectable levels in all tissues except salivary gland. Serum interferon was detected as early as 12 h after infection, peaked at 36 h (1,093 U/ml), and was undetectable by 4 days after infection. MCMV-infected animals were hyporeactive to interferon induction with New castle disease virus on days 5 to 9 of the infection. Splenic lymphocyte reactivity to phytohemagglutinin and lipopolysaccharide was normal early during the course of the infection, was suppressed during the acute phase of the infection, and had returned to normal by day 18. These data indicate that several parameters of host defense are transiently suppressed during the course of a MCMV infection. The capacity of cytomegaloviruses to alter host resistance may be one factor that contributes to the establishment of a persistent infection.

Suppressed response to interferon inducation in mice infected with encephalomyocarditis virus, Semliki forest virus, influenza A2 virus, Herpesvirus hominis type 2, or murine cytomegalovirus.

Mice infected with encephalomyocarditis virus, Semliki Forest virus, influenza A2 virus, Herpesvirus hominis type 2, or murine cytomegalovirus developed a state of hyporeactivity to interferon induction. In general, the capacity of infected animals to produce interferon in response to inducers became progressively impaired during the course of infection. The severity and time of onset of hyporeactivity, however, were dependent upon the inducer and the nature of the viral infection. During viral infections associated with generalized hyporesponsiveness, a factor that could inhibit interferon production by murine cells in culture was identified in the serum. This serum hyporeactive factor may have mediated the development of hyporeactivity in vivo. Hyporeactivity of the host's interferon response was associated with progression of viral infection and may be partially responsible for the limited effectiveness of interferon inducers in the modification of viral infections, when administered after onset of symptoms.

Effect of cytosine arabinoside and 5-iodo-2'-deoxyuridine on a cytomegalovirus infection in newborn mice.

Murine cytomegalovirus was inhibited by 0.6 to 1.2 mug of cytosine arabinoside per ml and by 0.3 to 0.6 mug of 5-iodo-2'-deoxyuridine in mouse embryo fibroblast cells. Human cytomegalovirus was inhibited by similar concentrations of the two drugs in WI-38 cells. Intraperitoneal inoculation of suckling mice with 10(4.5) plaque-forming units of murine cytomegalovirus provides a model for disseminated human cytomegalovirus infection in human newborn infants and is characterized by a widespread infection involving the liver, spleen, lung, kidney, and brain with a 70 to 90% mortality in 7 to 9 days. Treatment with 12.5 mg of cytosine arabinoside per kg or 25 mg of 5-iodo-2'-deoxyuridine per kg twice daily for 8 days had no effect on final mortality or the pathogenesis of the infection with the exception of reduced viral titers in the spleen of 5-iodo-2'-deoxyuridine-treated animals. These data indicate that neither cytosine arabinoside nor 5-iodo-2'-deoxyuridine are effective in the treatment of murine cytomegalovirus infections in suckling mice and suggest that they may be of limited value in the treatment of severe cytomegalovirus infections in human neonates.