Safety and immunogenicity of RIX4414 live attenuated human rotavirus vaccine in adults, toddlers and previously uninfected infants.

A live attenuated human rotavirus (HRV) vaccine, strain RIX4414, was tested sequentially in adults, previously infected toddlers, and previously uninfected infants. A single dose was given to adults and toddlers and found well tolerated. Next, a dose ranging (three different viral concentrations) safety and immunogenicity study was conducted in rotavirus IgA antibody negative infants (N= 192), who received two doses of RIX4414 vaccine or placebo at 2 and 4 months of age. No side effects were seen after vaccination. Specifically, administration of RIX4414 vaccine was not temporally associated with fever, diarrhea, or increase in liver transaminases. Rotavirus IgA seroconversion ranged from 50 to 88% after one dose and from 73 to 96% after two doses, depending on vaccine titer. After the first dose, on days 7-9 post vaccination, between 38 and 60% of the infants shed the vaccine virus, whereas after the second dose only 0 to 13% of the vaccinees shed the vaccine virus. It is concluded that RIX4414 strain HRV vaccine is virtually non-reactogenic and, at high titer, highly immunogenic in susceptible infants.

Comparative tolerability and immunogenicity of Typherix or Typhim Vi in healthy adults: 0, 12-month and 0, 24-month administration.

BACKGROUND: This study was carried out to compare the immunogenicity and tolerability of Typherix, a recently developed typhoid Vi polysaccharide vaccine, with Typhim Vi, the first available Vi polysaccharide vaccine, in healthy adults. Three different production lots of Typherix were also compared. METHODS: All subjects were randomised to receive an initial dose of Typhim Vi, or one of three production lots of Typherix, and subsequently randomised to receive a second dose of vaccine at 12 or 24 months. Adverse events were recorded by patients for 6 days after vaccination. Anti-Vi antibodies were measured in serum on days 0, 7, 14 and 28, at months 6, 12 and 24, and 1 month after the second dose (month 13 or 25). RESULTS: A total of 400 healthy subjects aged between 18 and 50 years received the first dose of vaccine. Significantly fewer patients in the three Typherix groups than in the Typhim Vi group reported adverse events (17 to 21% vs 44%, respectively). Seropositivity rates were 95.7 to 97.9% among subjects in the three Typherix groups at day 14, and 96.8% in the Typhim Vi group (no significant between-group differences). The only significant difference between the vaccines in seropositivity was observed at day 7 (71.8% for Typherix vs 86.4% for Typhim Vi). Of subjects receiving the second dose of Typherix at 12 and 24 months, 77% and 61% were seropositive before revaccination, compared with 69% and 46% for Typhim Vi (no significant difference). There were no significant differences in seropositivity or adverse events between the two vaccines after administration of the second dose (12 or 24 months). CONCLUSIONS: The initial dose of Typherix was associated with fewer adverse events than Typhim Vi. On the basis of serum Vi titres, the two vaccines demonstrated equivalent immunogenicity, with 0, 12-month and 0, 24-month administration. There were no differences between the three different production lots of Typherix.

Alternative vaccination schedules (0, 1, and 6 months versus 0, 1, and 12 months) for a recombinant OspA Lyme disease vaccine.

We have compared the immunogenicity profile of a recombinant lipoprotein outer-surface protein A (OspA) Lyme disease vaccine administered on schedules of 0, 1, and 6 months (group 1) or 0, 1, and 12 months (group 2) to 800 healthy subjects, aged 15-50 years. One month after the second dosing, geometric mean titers of IgG antibodies to OspA were 1,309 ELISA units (EL.U)/mL in group 1 and 1,404 EL.U/mL in group 2. One month after the third dosing, the titers were 7,205 EL.U/mL and 10,659 EL.U/mL, respectively. Using bioequivalence methodology, we showed that the two vaccination schedules elicit an equivalent immune response 1 month after administration of dose 3: at that point, 91%-93% of all subjects had titers > or =1,400 EL.U/mL, proposed to be protective for one tick season. The vast majority of local and systemic symptoms were mild to moderate and of limited duration. The 0, 1, and 6 months vaccination schedule is a viable alternative to the 0, 1, and 12 months schedule and can provide protection against Lyme disease during one tick season.

Concomitant vaccination against hepatitis A and typhoid fever.

BACKGROUND: The purpose of this study was to evaluate the reactogenicity and immunogenicity of a hepatitis A vaccine (Havrix-1440TM) when administered simultaneously with a Vi polysaccharide typhoid vaccine. METHODS: Two open, randomized studies were conducted using 2 and 4 treatment groups respectively, at the Clinique Notre-Dame de Grâce, Belgium (Study 1) and University Hospital of Hradec Kralové, Czech Republic (Study 2). SUBJECTS: Healthy adults aged 18-50 years were administered either both vaccines concomitantly in separate arms or a single injection of the two vaccines mixed extemporaneously (Study 1), or one injection of each vaccine alone, or the combined vaccine, or both vaccines concomitantly in separate arms (Study 2). The study measured solicited and unsolicited signs and symptoms until 28 days post-vaccination. Anti-hepatitis A and anti-Vi titers were determined in pre- and post-vaccination sera. RESULTS: The vast majority of local and general symptoms were mild to moderate and all resolved without sequelae. No serious adverse events were reported in either study. In study 1, geometric mean antibody titers (GMTs) were similar after extemporaneous syringe mixing of both vaccines (anti-Vi = 1159 EL.U/mL; anti-HAV = 302 EL.U/mL) and after concomitant vaccination (anti-Vi = 1331 EL.U/mL; anti-HAV = 367 EL. U/mL). In study 2, GMTs following vaccination with either vaccine alone, both vaccines administered concomitantly or as a combined vaccine (anti-Vi: 1307, 1247 and 942 EL.U/mL, respectively; anti-HAV: 462, 517 and 432 EL.U/mL, respectively) were not significantly different (p = .45 for anti-HAV, p = .18 for anti-Vi). Seroconversion rates were > 94.4% in all cases. CONCLUSIONS: The inactivated hepatitis A and Vi polysaccharide typhoid vaccines are safe and well tolerated when administered simultaneously (mixed or concomitant) and as a combined vaccine. Subjects seroconverted to both antigens to the same extent as the monovalent vaccines and there was no cross-interference in the immune profiles of the vaccines.

Clinical and immunological assessment of a candidate Lyme disease vaccine in healthy adults: antibody persistence and effect of a booster dose at month 12.

A candidate Lyme vaccine was administered to 20 adult volunteers following a 0, 1, 2 months vaccination schedule, with a booster at 12 months. An immune response, assessed as 'LA-2 equivalent' antibody titres using an inhibition ELISA, was induced in all vaccinees which persisted until the booster. Titres were increased 25-fold following the booster and persisted through month 24. There was a good correlation between 'LA-2 equivalent' antibody titres and a bactericidal assay (r2 = 0.86). Local symptoms were mild, resolving spontaneously within 72 h, with no reports of rash, arthralgia or other systemic symptoms. This Lyme vaccine was safe, well-tolerated and elicited an antibody response in all volunteers which persisted at least 12 months after the booster.

Evaluation of the safety, reactogenicity and immunogenicity of three recombinant outer surface protein (OspA) lyme vaccines in healthy adults.

The safety, reactogenicity and immunogenicity of three candidate Lyme vaccines based on recombinant outer surface protein (OspA) presented in either lipidated or unlipidated forms, were assessed in 300 seronegative volunteers. Subjects received three doses of one of the three formulations at monthly intervals and were evaluated for antibody levels and the presence of symptoms after each dose. All formulations proved to be safe, the majority of local reactions being reported as mild, and all general symptoms were perceived to be either-mild or moderate in intensity. No subject refused a subsequent vaccine dose. All subjects were tested for both anti-OspA IgG and LA-2 equivalent antibodies up until day 84. All three vaccines induced an immune response but subjects who received lipoprotein OspA had the highest anti-OspA IgG and LA-2 equivalent GMTs after each dose and this was also true for the subset of subjects tested on day 180. The lipoprotein OspA group also had the largest number of subjects who remained seropositive for anti-OspA IgG antibodies. As the lipoprotein formulation produced the strongest immune response, with symptoms which were acceptable to all the vaccinees, we suggest further development of this vaccine.

Oral bioavailability of CHF1194, an inclusion complex of piroxicam and beta-cyclodextrin, in healthy subjects under single dose and steady-state conditions.

CHF1194 is an inclusion complex of beta-cyclodextrin with the nonsteroidal anti-inflammatory drug piroxicam. In man, beta-cyclodextrin acts as a carrier of piroxicam. As the inclusion complex of piroxicam-beta-cyclodextrin is wettable and more water soluble, the absorption rate of the drug is increased whilst its other pharmacokinetic characteristics remain unchanged. The aim of the present study in 12 healthy subjects was to compare the oral bioavailability of 20 mg piroxicam in a CHF1194 tablet and a plain piroxicam capsule after a single dose and after two weeks of once daily administration, and also to assess the plasma levels and urinary excretion of beta-cyclodextrin after CHF1194 administration. The two treatments were administered in cross-over fashion, separated by a wash-out period of three weeks. Piroxicam, 5'-hydroxypiroxicam and beta-cyclodextrin were monitored in plasma and urine for 120 h after the first and last doses. Clinical tolerance was excellent and no adverse event occurred during either phase of the study. The extent of absorption of piroxicam from the CHF1194 tablet after the single dose was equivalent to that after the plain piroxicam capsule, within confidence limits of less than 80-125%. After repeated dosing, CHF1194 yielded the same steady-state systemic concentrations of piroxicam and 5'-hydroxypiroxicam as the reference capsule, and similar excretion pattern of the metabolite. After both single and multiple dosing, piroxicam was absorbed more rapidly after CHF1194, an expected consequence of the complexation of piroxicam with beta-cyclodextrin.(ABSTRACT TRUNCATED AT 250 WORDS)

Exploratory study of the decongestive effect of Rhinopront syrup in adults and in children with acute rhinitis.

The decongestive effect of Rhinopront syrup was assessed in 18 adults and 18 children with acute rhinitis, by comparison to a matching placebo syrup and to a commercial standard decongestant (Triaminic tablets or drops). The evolution of symptoms following single dose administration of each treatment was estimated both by objective measurements of nasal resistance using bilateral rhinomanometry and by subjective evaluation of nasal congestion and aspect of the mucosa. In children, the treatment was continued over the next 4 days and the global clinical efficacy of the formulations was subjectively evaluated by the parents. In adult patients, a significant decrease in nasal resistance was obtained after a single dose of Rhinopront (15 g). The effect was already important after 0.5 h and reached a minimum of approximately 50% of baseline within 1 to 2 h; the drop in nasal resistance was significantly less intense for Triaminic (p < 0.05; 0.5-1-h period) and for the placebo (p < 0.05; 0.5-2-h period). In children, the scatter of rhinomanometric measurements precluded the observation of any significant within- or between-group differences; however, a significantly lower nasal congestion score was observed for Rhinopront than placebo, between 4 and 10 h after single dose administration (1 g per year of age). The present work suggests that Rhinopront is an effective nasal decongestant in adults and children with acute congestive rhinitis and supports the adequacy of the proposed twice-daily dosing rate.

Pharmacokinetics of brodimoprim in special populations.

The pharmacokinetics of brodimoprim have been investigated after single oral dose administration in children, in healthy adults, and elderly subjects, as well as in patients with mild renal failure (creatinine clearance 40-70 mL/min) or liver insufficiency (Child-Pugh grade A or B). The plasma half-life increased moderately with age. The percent brodimoprim bound to plasma proteins, 93%, was identical in renally impaired patients and in healthy controls but decreased to 90% or less in liver insufficiency. The apparent distribution volume and clearance were much higher in children than in adults. Urinary excretion of unchanged brodimoprim amounted to 5-10% of the administered dose. The steady-state pharmacokinetics of brodimoprim has also been investigated in elderly subjects (400 mg loading dose followed by 7 days 200 mg once daily). There was no significant modification of elimination half-life and of clearance upon repeated dosing. Renal excretion of brodimoprim and hydroxy metabolite at steady-state reached 9% and 14% per 24 hours in the elderly, compared to 9% and 24% in young adults. The accumulation factor reached 3.3 +/- 0.4 and 2.7 +/- 0.3 respectively.

Relative bioavailability of carbinoxamine and phenylpropanolamine from a retard suspension after single dose administration in healthy subjects.

The plasma pharmacokinetics of carbinoxamine (CA, CAS 486-16-8) and phenylpropanolamine (PP, CAS 14838-15-4) after single dose administration of a retard suspension (Rhinopront), containing a resinate as sustained-release agent, were compared to those of the same active principles given as an aqueous solution. The study was performed in 20 healthy subjects who received the two formulations according to a standard crossover design with a one-week wash-out. Blood samples were obtained up to 24 h post-dose. PP and CA were assayed in the plasma samples by gas chromatography with electron-capture detection and HPLC with coulometric detection, respectively. The pharmacokinetic results indicated sustained release of the two active principles with the retard suspension: CA appeared in plasma at a much slower rate than with the solution, a 30% lower Cmax being reached after 8.0 h instead of 3.0 h post-dose. For PP, Cmax was 23% lower and occurred 3.0 post-dose instead of 1.5 h with the solution. The extent of absorption of the two drugs, as assessed by AUC (0-24 h), was slightly smaller with the retard suspension than with the aqueous solution. However, the test/reference ratio remained within 95% confidence intervals of 80-87% and 88-98% for CA and PP, respectively, indicating bioequivalence of the two formulations. A simulation of the plasma levels during repeated administration indicated that dosing with the retard suspension at 12-h intervals should yield the same steady-state plasma levels as a 5 times daily administration of a divided dose of the aqueous solution, for both drugs.

Neonatal lupus erythematosus with congenital heart block associated with maternal systemic lupus erythematosus.

We report the presence of complete heart block in a girl whose mother has anti-Ro antibodies and is suffering from systemic lupus erythematosus with Sjögren's syndrome. HLA antigens studies in the two patients support the hypothesis described recently that HLA DR3 is responsible for the production of anti-Ro antibodies and not for the phenotypic expression of the tissue injury.

Circulating lupus type anticoagulant and pulmonary hypertension associated with mixed connective tissue disease.

We report the case of a young woman, with mixed connective tissue disease (MCTD), associated with disabling pulmonary hypertension and presence of the "lupus anticoagulant". The "lupus anticoagulant", an antibody directed against phospholipid components, was linked in our patient to extensive thrombophlebitis and premature labor. Raynaud's phenomenon progressed towards finger necrosis in spite of optimal vasodilating treatment. The part played by the "lupus anticoagulant" in pulmonary hypertension remains to be established. Both these complications responded to prednisolone therapy, but the improvement was limited and short-lived.

[Preoperative localization of parathyroid adenomas: significance, indications and results]. / Localisation pré-opératoire des adénomes parathyroïdiens: intérêt, indications et résultats.

Preoperative localizing technics of a parathyroid tumour. The authors present a limited experience about preoperative localizing technics of a parathyroid tumour. Oesophagography and selenomethionine 75 scintigraphy were not useful. Ultrasonography and computed tomography localised 50% of the tumours. Selective thyroïd venous catheterization and radioimmunoassay are correctly predictive in 87,5% of the studied cases. The interest, morbidity and results of these different technics are discussed.

Early submaximal exercise stress test after myocardial infarction. Comparison with a late test and prognostic value.

An early exercise stress test was carried out in 116 patients 8 to 14 days after a myocardial infarction. This test is in good agreement with the late maximal stress test performed 8 weeks after the infarction, both tests being positive together in 86.4% and negative in 84.6% of the cases. Residual coronary insufficiency is present in 41.4% of the patients during the early test, 47.9% after inferior and 30.2% after anterior infarction. With beta blocking therapy, 28.2% of the patients had a positive test, and 48% without this treatment. The sensitivity of the early test is good after inferior infarction but poor after anterior infarction or during beta blocking therapy. A multivessel disease is disclosed by coronary angiography in 78.5% of the patients with a positive early stress test and in 53.3% in cases with a negative test. In the patients with a positive test, mortality at one year is higher (8.7% versus 2.9%). A coronary angiography should be performed relatively precociously in this group of patients.

Adriamycin cardiotoxicity. Prognostic value of the systolic time intervals.

The aim of this study was to detect the cardiotoxicity of Adriamycin (ADM) by the evolution of the systolic time intervals (STI). The PEP/LVET ratio represents an easy and reproducible index of myocardial function. The more important this increase, the greater the risk of developing heart failure. A significant correlation exists between the variation of this ratio and the total administered dose, but the correlation coefficient is low. A heart failure may appear for doses of ADM under 500 mg/m2 but it is preceded by an increase of the index. In the absence of a significant modification, the generally admitted maximum dose of 550 mg/m2 may be exceeded. In case of a ratio increase in excess of 0.08 it will be necessary to balance the potential benefits of treatment with the hazards of cardiac failure. The PEP/LVET ratio allows proceeding with the cytostatic treatment in increased security by selecting the patients at high risk for cardiac failure.

[Metaphyseal osteolysis. Unusual aspect of reflex algodystrophy in children (author's transl)]. / Ostéolyse métaphysaire. Aspect inhabituel de l'aldogystrophie réflexe de l'enfant.

Two children 7 and 14 years old respectively, presented with reflex neurovascular dystrophy. The salient feature of the disease consisted of osteolytic lesions of distal tibial and fibulal metaphyses. To out knowledge these were not previously reported. Complete recovery spontaneously occurred in a few weeks or months. Thus they do not require any treatment, which might be harmful.