Safety and immunogenicity of increasing doses of a Clostridium difficile toxoid vaccine administered to healthy adults

Clostridium difficile is a major cause of nosocomial diarrhea in industrialized countries. Although most illnesses respond to available therapy, infection can increase morbidity, prolong hospitalization, and produce life-threatening colitis. Vaccines are being explored as an alternative means for protecting high-risk individuals. We assessed the safety, immunogenicity, and dose response of a parenteral vaccine containing C. difficile toxoids A and B. Thirty healthy adults were assigned to receive four spaced inoculations on days 1, 8, 30, and 60 with one of three doses of vaccine (6.25, 25, or 100 microg). At each dose level, subjects were randomized, in a double-blind fashion, to receive either the soluble toxoids (n = 5) or toxoids adsorbed to alum (n = 5). Subjects were monitored for clinical and immunologic responses to vaccination. Vaccination was generally well tolerated, with occasional, usually mild, systemic reactions (abdominal pain, arthralgia, and diarrhea). The most common local reaction, mild arm pain, was reported by all recipients of the toxoid-alum formulation. Nearly all subjects (> or = 90%) developed vigorous serum antibody responses to both toxins, as measured by immunoglobulin G (IgG) enzyme-linked immunosorbent assay and neutralization of cytotoxicity, whereas fecal IgA increases occurred in approximately 50%. Statistically significant effects of dose and formulation on immunogenicity were not seen, although antibody levels tended to be higher with the alum-adjuvanted formulations and with increasing doses of soluble toxoid. Serum antibody responses among the toxoid-alum group appeared to plateau at 25 microg. We concluded that the C. difficile toxoid vaccine is safe and immunogenic in healthy volunteers. Further development as a prophylactic vaccine or for producing C. difficile hyperimmune globulin is justified.     

Safety and tolerability of omalizumab

Background Omalizumab (Xolair^®) is a recombinant humanized monoclonal anti-IgE antibody with proven efficacy in patients with moderate-to-severe and severe persistent allergic (IgE-mediated) asthma.
Objective To review clinical study data to assess the safety profile of omalizumab.
Methods We analysed the safety of omalizumab using data from completed clinical studies (up to 1 year) involving more than 7500 patients with asthma, rhinitis or related conditions and up to 4 years in one study of patients with severe allergic asthma, as well as post-marketing safety data. Analysis focuses on the risk of immune-system effects, hypersensitivity reactions, malignant neoplasia, parasitic infections and thrombocytopenia.
Results Omalizumab exhibited a good safety and tolerability profile that was maintained up to 4 years in one study. The incidence of anaphylaxis was 0.14% in omalizumab-treated patients and 0.07% in control patients. No omalizumab-treated patient developed measurable anti-omalizumab antibodies. Post-marketing, based on estimated exposure of 57 300 patients (June 2003–December 2006), the frequency of anaphylaxis attributed to omalizumab use was estimated to be at least 0.2% of patients. Current clinical trial data do not support an increased risk of malignant neoplasia or thrombocytopenia with omalizumab.
Conclusion Data indicate that the proven efficacy of add-on omalizumab in patients with moderate-to-severe or severe allergic asthma is accompanied by a favourable safety and tolerability profile.     

Safety and tolerability of fexofenadine for the treatment of allergic rhinitis in children 2 to 5 years old.

BACKGROUND: The safety of fexofenadine has been examined extensively in adults and school-age children. However, the safety of fexofenadine in children younger than 6 years has not been reported to date. OBJECTIVE: To compare the safety and tolerability of twice-daily fexofenadine hydrochloride, 30 mg, and placebo in preschool children aged 2 to 5 years with allergic rhinitis. METHODS: This was a multicenter, double-blind, randomized, placebo-controlled, parallel-group study, conducted between February 29, 2000, and June 14, 2001. Participants were randomized to either fexofenadine hydrochloride, 30 mg, or placebo twice daily for a 2-week period. To facilitate dosing, capsule content was mixed with applesauce (approximately 10 mL). Safety assessments depended on date of entry into the study because of an amendment to the protocol. Before the amendment, assessments included physical examination, vital signs reporting (oral temperature, heart rate, and respiratory rate), and adverse event (AE) reporting. After the amendment, safety assessments included laboratory testing (blood chemistry and hematology profiles), physical examination, 12-lead electrocardiography, and vital signs (oral temperature, blood pressure, heart rate, and respiratory rate) and AE reporting. RESULTS: Treatment-emergent AEs were observed in 116 of 231 participants receiving placebo and 111 of 222 receiving fexofenadine. These AEs were possibly related to study medication in 19 (8.2%) and 21 (9.5%) of the participants receiving placebo and fexofenadine, respectively, and most frequently involved the digestive system. No clinically relevant differences in laboratory measures, vital signs, and physical examinations were observed. CONCLUSIONS: The findings show that fexofenadine hydrochloride, 30 mg, is well tolerated and has a good safety profile in children aged 2 to 5 years with allergic rhinitis.     

Pharmacokinetics of cefatrizine administered in repeated doses

Twelve healthy volunteers received cefatrizine orally at doses equal to 500 mg every 12 h for 5 days. Cefatrizine was assayed by high performance liquid chromatography in plasma and urines collected after the first and/or the last administration. Cefatrizine absorption was rapid; its peak plasma level was reached at time 1.79 +/- 0.07 h following the first dose, it was equal to 7.37 +/- 0.31 micrograms.ml-1. Its apparent elimination half-life was equal to 1.50 +/- 0.05 h, it explains the lack of accumulation with time during multiple administrations every 12 hours. Comparisons between peak plasma concentration and area under curves following the first and last dosing showed significant (p less than 0.01) but weak (close to 15%) reduction of these 2 parameters with time which could be explained by a slight reduction of cefatrizine absorption with time. In conclusion, cefatrizine does not accumulate when administered repeatedly at a dose equal to 500 mg every 12 h in young adult, and its pharmacokinetics is virtually linear with time.     

Subjective response to and tolerability of long-term supraphysiological doses of levothyroxine in refractory mood disorders

BACKGROUND: Although supplementation with supraphysiological doses of levothyroxine (T4) has been an effective treatment for refractory affective disorders in open studies, questions remain as to the tolerability of this treatment. This is the first study to investigate subjective patient response and tolerability to long-term treatment with adjunctive T4. METHODS: Of 24 patients with refractory affective disorders or schizoaffective disorder who were consecutively included into an open trial with supraphysiological T4, 16 were eligible for this study. Four measures were used to rate tolerability to T4 treatment. Subjective response was graded on a scale ranging from -33 (maximal negative response) to +33 (maximal positive response). Positive and negative effects were assessed on a structured questionnaire. Clinical tolerance was assessed with the clinician-rated Thyroid Symptom List and the self-rated Von Zerssen Complaint Lists. Outcome was assessed with the CGI for prophylactic ratings (CGI-BP). RESULTS: At the time of assessment, patients had been treated with supraphysiological T4 (mean dose 368 microg/d) for a mean of 54 months. The total subjective response score was +25.2. Positive subjective response and observer-rated treatment success were moderately correlated. Ratings on the Thyroid Symptom List indicated an overall favorable side effect profile. General physical and mental symptoms were only slightly higher than in the general population. LIMITATIONS: This was an open, cross-sectional study that only included responders and partial responders to T4 treatment. CONCLUSIONS: Subjective response and side-effect tolerability of long-term supraphysiological doses of T4 is favorable in patients with refractory mood and schizoaffective disorders who respond to the intervention.     

Safety and tolerability of ultra-rush induction, less than one hour, of sublingual immunotherapy in children

BACKGROUND: The safety and tolerability of sublingual immunotherapy (SLIT) has been documented in allergic patients both in the build-up phase as well as during maintenance, but only two studies have evaluated the occurrence of adverse reactions with an ultra-rush regimen of SLIT induction in a mixed paediatric/adult population. Moreover one of these two studies used a chemically modified extract (allergoid). The aim of the present study was to evaluate the occurrence of immediate or late adverse reactions in allergic children after a very fast (40 min) ultra-rush SLIT induction with two different allergen extract solutions. METHODS: We studied 100 children (64 boys, mean age of 9.6 years, range 3.5-16.8), with a history of intermittent/persistent rhinitis and/or intermittent/mild persistent asthma due to inhalant allergens. The ultra-rush build-up phase involved the administration, every 10 min, of increasing doses of the highest-concentration vial of SLIT of two different manufacturers (Anallergo and Stallergènes). RESULTS: All patients completed the treatment, side-effects have been recorded in 19% of the cases: 10% within 1 h after the build-up phase, 7% within 48 h and 2% mixed. A major difference (p = 0.0001) was recorded between Anallergo (6 patients, 8.7%) and Staloral (13 patients, 41.9%), but all the reactions were mild: principally oral symptoms, in 1 case rhinorrhoea and cough, and delayed abdominal pain and diarrhoea in another patient. CONCLUSIONS: No severe adverse reactions were observed with this ultra-rush SLIT induction also in the paediatric age; statistical differences have been documented between the two different extracts.     

Rat hepatocarcinogenesis induced by N-nitrosodiethylamine and N-nitrosomorpholine continuously administered at low doses. From basophilic areas of hepatocytes to hepatocellular tumors.

The development of hepatocellular tumors was investigated with histological, histochemical, and morphometrical methods in male Sprague-Dawley rats continuously administered N-nitrosodiethylamine (DEN) or N-nitrosomorpholine (NNM) in the drinking water at low doses (0.5 mg DEN/100 ml; 1 mg NNM/100 ml). Groups of control, DEN-, and NNM-treated rats were investigated at 5-week intervals. Similar results were obtained in DEN- and NNM-treated rats. Two types of areas composed of basophilic or glycogenotic hepatocytes were observed preceding the appearance of hepatocellular adenomas and carcinomas. Besides their cytologic differences, the basophilic and glycogenotic areas induced displayed distinct histochemical features. Both types of areas were detected simultaneously and increased in parallel with time to a similar incidence, but basophilic areas reached larger sizes than the glycogenotic ones. Furthermore, each type of area, which clustered around and along efferent veins, was differently linked to tumorigenesis. Basophilic areas frequently developed into basophilic adenomas and trabecular carcinomas through a characteristic sequence. Early basophilic areas consisted of hepatocytes with lamellar cytoplasmic hyperbasophilia and exhibited the normal laminar liver structure. With time, an increasing number of basophilic areas also contained hepatocytes with powdered diffuse hyperbasophilia, which frequently were arranged in thick trabeculae, showed abundant mitotic figures, and invaded efferent veins. Neither such signs of malignancy nor conversion into basophilic areas or tumors could be established for areas of clear and acidophilic glycogenotic hepatocytes. However, a few small glycogenotic adenomas probably developed from glycogenotic areas. Our data thus underline the central role of basophilic areas for hepatocarcinogenesis. Moreover, taking into account the data from other experiments, it seems likely that although glycogenotic areas may be associated with the application of some carcinogens at high doses, they are not obligatory precursors of hepatocellular tumors.     

High levels of resistance to metronidazole and clarithromycin in Helicobacter pylori strains in children

The aim of the study was to evaluate the prevalence of resistance to amoxicillin, metronidazole, and clarithromycin before treatment of Helicobacter pylori infection in children and to assess the evolution of resistance with time. The study was carried out between 1994 and 1999 with 150 H. pylori-positive children through gastric culture (antimicrobial susceptibility) and histology. All cultured H. pylori strains were sensitive to amoxicillin, 64 (43%) were resistant to metronidazole, 32 (21%) were resistant to clarithromycin, and 14 (9%) were resistant to both metronidazole and clarithromycin. The overall prevalence of resistance to metronidazole and clarithromycin did not change significantly with time. The study highlights the generalized high-level and stable metronidazole and clarithromycin resistance of H. pylori strains from children.     

Efficacy and tolerability of fully transdermal hormone replacement in sequential or continuous therapy at two doses of progestogen in postmenopausal women

OBJECTIVES: Two randomized open-label studies were performed to evaluate fully transdermal hormone replacement therapy (HRT) with oestradiol (E2) and norethisterone acetate (NETA) in postmenopausal women. METHODS: Both hormones were delivered by transdermal matrix patches changed twice weekly. Subjects received E2, 50 microg/day and NETA, 170 microg/day or 350 microg/day, either continuously or sequentially. A one-year study (13 cycles of 28 days), including a reference regimen of transdermal E2 and sequential oral progestogen, was followed by a continuation study for a further year in 367 women. RESULTS: All regimens were highly and equally effective in the prevention of hot flushes. The fully transdermal regimens were associated with beneficial changes in the lipid profile. The sequential regimens provided effective scheduling of bleeding around the end of the progestogen phase. The continuous regimens were associated with irregular bleeding, which was rarely severe, and a gradually increasing incidence of amenorrhoea. With sequential or continuous therapy, bleeding was less severe at the lower dose of progestogen than at the higher dose. No endometrial hyperplasia was detected by biopsy in any treatment group. One serous endometrial carcinoma and one endometrial adenocarcinoma were detected. An endometrial thickness >5 mm did not predict the presence of hyperplasia at biopsy. Hormone-related adverse events were typical of those expected for HRT and dermal tolerability of the patches was good. CONCLUSIONS: Fully transdermal sequential or continuous HRT is effective and well tolerated in postmenopausal women. The lower dose of NETA may be preferable, because it confers adequate endometrial protection at a lower dose of progestogen.     

ERCP用于老年患者诊断和治疗的安全性和耐受性分析

目的对内镜逆行胰胆管造影(ERCP)用于老年患者诊断及治疗的安全性和耐受性进行回顾性分析。方法回顾性分析2010年1月至2013年12月在我院接受诊断和治疗的1 560例患者资料,年龄(71.6±11.4)岁,其中60~69岁1 116例,70岁及以上444例,数据包括患者的临床和生化特征,ERCP诊断和并发症。结果对潜在的复合因素进行多变量Logistic回归分析,60~69岁和70岁2组中相关因素的差异未见统计学差异(P=0.039)。老年ERCP检查和治疗中,60~69岁和70岁及以上2组间在成功插管、插管困难和插管失败方面均有一定差异(P0.05);2组间胆总管结石发生胆道梗阻和临床诊断无明显差异(P0.05),但2组间ERCP诊断、术后并发症和急性胰腺炎并发症均有一定差异(P0.05),70岁及以上的患者耐受性较好,但胆管结石大约是60~69岁患者的2倍(P=0.004)。结论老年患者进行ERCP诊断和治疗是安全的,且耐受性良好,对70岁及以上的老年患者ERCP并发症风险相对更少。     

Safety and tolerability of extended-release venlafaxine in severe medical and surgical illness

OBJECTIVE: This study attempted to determine if extended-release venlafaxine is safe for use in severely medically and surgically ill depressed patients. METHOD: The charts of 16 patients who were admitted to medical and surgical inpatient services and given extended-release venlafaxine were retrospectively evaluated for dose and duration of drug treatment, blood pressure changes, medication changes, and side effects. RESULTS: There was 50%-75% improvement in depressive symptoms, with a statistically insignificant mean elevation in blood pressure. CONCLUSIONS: Extended-release venlafaxine appears to be a safe and tolerable agent for the medical-surgical depressed inpatient.     

Safety and tolerability of fexofenadine hydrochloride, 15 and 30 mg, twice daily in children aged 6 months to 2 years with allergic rhinitis.

BACKGROUND: Antihistamines are an established first-line treatment for allergic rhinitis and are widely prescribed in infants for allergic symptoms. OBJECTIVE: To establish the safety and tolerability of fexofenadine hydrochloride in children aged 6 months to 2 years in 2 studies (T/3001 and T/3002). METHODS: Both studies had a multicenter, randomized, placebo-controlled design. Mean treatment duration was 8 days. Subjects were randomized (T/3001, n = 174; and T/3002, n = 219) to twice-daily fexofenadine hydrochloride, 15 or 30 mg, or placebo mixed with a standard vehicle. RESULTS: In the combined population, the incidence of treatment-emergent adverse events (TEAEs) was comparable between groups (placebo, 48.2% [96/199]; fexofenadine hydrochloride, 15 mg, 40.0% [34/85]; and fexofenadine hydrochloride, 30 mg, 35.2% [38/108]). Vomiting was the most common TEAE (placebo, 13.6%; fexofenadine hydrochloride, 15 mg, 14.1%; and fexofenadine hydrochloride, 30 mg, 5.6%). Most TEAEs were unrelated to study medication, as evaluated by investigators; those possibly related to study medication were mild or moderate in intensity. No clinical differences were seen between fexofenadine and placebo for vital signs, electrocardiographic results, or physical examination results. CONCLUSION: Fexofenadine hydrochloride, 15 or 30 mg, given for a mean duration of 8 days is well tolerated, with a good safety profile, in children aged 6 months to 2 years.     

Pharmacological analysis of the activity of phenazepam and flunitrazepam administered in superlow doses

Benzodiazepine tranquilizers, phenazepam and flunitrazepam, administered to random-bred albino male rats in superlow doses (10⁻⁹–10⁻¹⁵ mol/kg), are shown to exert an anxiolytic effect in the conflict test. In contrast to the case with the usual doses, the above effect is not accompanied by marked myorelaxant or sedative effects. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 121, № 2, pp. 164–166, February, 1996     

Effects of artemether, artesunate and dihydroartemisinin administered orally at multiple doses or combination in treatment of mice infected with Schistosoma japonicum

Artemether and artesunate, derivatives of the antimalarial artemisinin, as well as their main metabolite, dihydroartemisinin, all exhibit antischistosomal activities. The purpose of the current study was to compare the effects of artemether, artesunate and dihydroartemisinin administered orally at multiple doses or combination in treatment of mice infected with Schistosoma japonicum. We carried out experiments with mice, infected with 40 cercariae of S. japonicum, and treated with artemether, aretesunate and dihydroartemisinin (all at a single dose of 300 mg/kg, and the dose of the mixed three drugs is also 300 mg/kg) at multiple doses or combination therapy on days 6–8 or 34–36 post-infection. Administration with artemether, artesunate or dihydroartemisinin for 3 successive days reduced total worm burdens by 79.5−86% (30.86 ± 4.98 of mean total worm burden in control), female worm burdens by 79.4−86.7% (11.29 ± 2.63 of mean female worm burden in control) (all P values <0.01 vs. control), depending on different treatment protocols given on days 6–8 post-infection. However, no differences were seen between each treatment group (all P > 0.05). While the same treatment was given on days 34–36 post-infection, total worm burden reductions of 73.8−75.8% were achieved (29.44 ± 3.36 of mean total worm burden in control), which were significant when compared with the untreated control group (all P values <0.01). In all different treatment groups, female worm reductions (ranging from 88.7% to 93.1%, while the mean female worm burden in control is 10.33 ± 1.80) were consistently higher than the total worm reductions, resulting always in significantly lower female worm burdens when compared to the corresponding control (all P values < 0.01). However, there were no significant differences found between each treatment group (all P values >0.05). It is concluded that artemether, artesunate and dihydroartemisinin can be used to control schistosomiasis japonica, as a strategy to prevent S. japonicum infection. Administration with artemether, artesunate and dihydroartemisinin at multiple doses or in combined treatment damages both juvenile and adult S. japonicum, without statistically significant differences among the three drugs at the same dose.     

Safety and immunogenicity of an oral inactivated whole-cell pseudomonas aeruginosa vaccine administered to healthy human subjects

This study examines the safety and immunogenicity of an oral, whole-cell Pseudomonas aeruginosa vaccine administered to healthy volunteers. Thirty subjects received an oral dose of Pseudostat in two timed, measured doses with serological follow-up to 56 days postvaccination. Following vaccination, several individuals were identified as antibody responders for all three immunoglobulin (Ig) isotypes tested, specifically against whole-cell P. aeruginosa extract and outer membrane proteins F and I. The mean pooled lipopolysaccharide antigen-specific IgA showed the most significant and constant increases in titer postdose, with a similar increase in titer for whole-cell P. aeruginosa extract-specific IgA. The results demonstrated an increased phagocytic ability of the selected macrophage cell line in post vaccination sera. Furthermore a significant increase in intracellular macrophage killing of opsonized P. aeruginosa was also demonstrated (82% on day 14 postdose) in the presence of the postvaccination sera. The safety component of the study did not show any vaccine-attributable adverse effects in any of the subjects, as documented by clinical evidence, hematology, and biochemistry profiles. We conclude that Pseudostat is safe and immunogenic in humans at this dose and that further studies to determine the appropriate dosage and efficacy are needed. In our study, we have shown that the most significant and sustained responses to oral vaccination in human adult volunteers were serum IgA levels and that pooled sera collected postimmunization have an increased capacity to promote opsonophagocytotic killing of P. aeruginosa.     

Safety and immunogenicity of a proteosome-Shigella flexneri 2a lipopolysaccharide vaccine administered intranasally to healthy adults

We studied the safety and immunogenicity of a Shigella flexneri 2a vaccine comprising native S. flexneri 2a lipopolysaccharide (LPS) complexed to meningococcal outer membrane proteins-proteosomes-in normal, healthy adults. A two-dose series of immunizations was given by intranasal spray, and doses of 0.1, 0.4, 1.0, and 1.5 mg (based on protein) were studied in a dose-escalating design. The vaccine was generally well tolerated. The most common reactions included rhinorrhea and nasal stuffiness, which were clearly dose related (P < or = 0.05). These reactions were self-limited and generally mild. The vaccine elicited S. flexneri 2a LPS-specific immunoglobulin A (IgA), IgG, and IgM antibody-secreting cells (ASCs) in a dose-responsive manner. At doses of 1.0 or 1.5 mg, highly significant (P < 0.001) increases in ASCs of all antibody isotypes occurred and 95% of subjects had an ASC response in at least one antibody isotype. Dose-related serum antibody responses were observed, with geometric mean two- to fivefold rises in specific serum IgA and IgG titers and two- to threefold rises in IgM in the 1.0- and 1.5-mg-dose groups (P < 0.0001 for each isotype). Elevated serum antibody levels persisted through day 70. Increases in fecal IgG and IgA and also in urinary IgA specific for S. flexneri 2a LPS were demonstrated. These were most consistent and approached statistical significance (P = 0.02 to 0.12 for various measures) on day 70 after the first dose. The magnitude of immune responses to intranasally administered proteosome-S. flexneri 2a LPS vaccine is similar to those reported for live vaccine candidates associated with protective efficacy in human challenge models, and further evaluation of this product is warranted.