Vaccinia immune globulin: current policies, preparedness, and product safety and efficacy.

In 1980 the World Health Organization declared that smallpox was eradicated from the world, and routine smallpox vaccination was discontinued. Nevertheless, samples of the smallpox virus (variola virus) were retained for research purposes, not least because of fears that terrorist groups or rogue states might also have kept samples in order to develop a bioweapon. Variola virus represents an effective bioweapon because it is associated with high morbidity and mortality and is highly contagious. Since September 11, 2001, countries around the world have begun to develop policies and preparedness programs to deal with a bioterror attack, including stockpiling of smallpox vaccine. Smallpox vaccine itself may be associated with a number of serious adverse events, which can often be managed with vaccinia immune globulin (VIG). VIG may also be needed as prophylaxis in patients for whom pre-exposure smallpox vaccine is contraindicated (such as those with eczema or pregnant women), although it is currently not licensed in these cases. Two intravenous formulations of VIG (VIGIV Cangene and VIGIV Dynport) have been licensed by the FDA for the management of patients with progressive vaccinia, eczema vaccinatum, severe generalized vaccinia, and extensive body surface involvement or periocular implantation following inadvertent inoculation.

Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety

Background and purpose: The major drug-metabolizing enzymes for the oxidation of oxycodone are CYP2D6 and CYP3A. A high interindividual variability in the activity of these enzymes because of genetic polymorphisms and/or drug-drug interactions is well established. The possible role of an active metabolite in the pharmacodynamics of oxycodone has been questioned and the importance of CYP3A-mediated effects on the pharmacokinetics and pharmacodynamics of oxycodone has been poorly explored. Experimental approach: We conducted a randomized crossover (five arms) double-blind placebo-controlled study in 10 healthy volunteers genotyped for CYP2D6. Oral oxycodone (0.2 mg·kg−1) was given alone or after inhibition of CYP2D6 (with quinidine) and/or of CYP3A (with ketoconazole). Experimental pain (cold pressor test, electrical stimulation, thermode), pupil size, psychomotor effects and toxicity were assessed. Key results: CYP2D6 activity was correlated with oxycodone experimental pain assessment. CYP2D6 ultra-rapid metabolizers experienced increased pharmacodynamic effects, whereas cold pressor test and pupil size were unchanged in CYP2D6 poor metabolizers, relative to extensive metabolizers. CYP2D6 blockade reduced subjective pain threshold (SPT) for oxycodone by 30% and the response was similar to placebo. CYP3A4 blockade had a major effect on all pharmacodynamic assessments and SPT increased by 15%. Oxymorphone Cmax was correlated with SPT assessment (ρS= 0.7) and the only independent positive predictor of SPT. Side-effects were observed after CYP3A4 blockade and/or in CYP2D6 ultra-rapid metabolizers. Conclusions and implications: The modulation of CYP2D6 and CYP3A activities had clear effects on oxycodone pharmacodynamics and these effects were dependent on CYP2D6 genetic polymorphism.

Safety of combined heat and moisture exchanger filters in long-term mechanical ventilation.

STUDY OBJECTIVE: To evaluate the safety of a combined heat and moisture exchanger filter (HMEF) for the conditioning of inspired gas in long-term mechanical ventilation (MV). DESIGN: Randomized controlled trial. SETTING: Medical ICU in a large teaching hospital. PATIENTS: One hundred fifteen consecutive patients who required > or = 48 h of MV. INTERVENTIONS: Patients were randomized at intubation time (day 1) to receive inspired gas conditioned either by a water-bath humidifier heated at 32 degrees C (HWBH) or by an HMEF (Hygroster; DAR; Mirandola, Italy). MEASUREMENTS AND MAIN RESULTS: The two study groups were comparable in terms of primary pathologic condition at the time of hospital admission, disease severity as measured by the Simplified Acute Physiology Score, and ICU mortality. They did not differ with respect to ventilator days per patient (mean +/- SD: HMEF, 7.6 +/- 6.5; HWBH, 7.8 +/- 5.8), incidence of endotracheal tube obstruction (HMEF, 0/59; HWBH, 1/56), and incidence of hypothermic episodes (HMEF, five; HWBH, two). In 41 patients receiving MV for > or = 5 days, the morphologic integrity of respiratory epithelium was evaluated on day 1 and day 5, using a cytologic examination of tracheal aspirate smears. The state of ciliated epithelium was scored on a scale from 0 (poorest integrity) to 1,200 (maximum integrity), according to a well-described method. In both patient groups, the scores slightly but significantly decreased from day 1 to day 5 (mean +/- SD: HWBH, from 787 +/- 104 to 745 +/- 88; HMEF, from 813 +/- 79 to 739 +/- 62; p < 0.01 for both groups); there were no statistically significant differences between groups. CONCLUSIONS: These data indicate acceptable safety of HMEFs of the type used in the present study for long-term mechanical ventilation.

State-of-the-art of 3D cultures (organs-on-a-chip) in safety testing and pathophysiology.

Integrated approaches using different in vitro methods in combination with bioinformatics can (i) increase the success rate and speed of drug development; (ii) improve the accuracy of toxicological risk assessment; and (iii) increase our understanding of disease. Three-dimensional (3D) cell culture models are important building blocks of this strategy which has emerged during the last years. The majority of these models are organotypic, i.e., they aim to reproduce major functions of an organ or organ system. This implies in many cases that more than one cell type forms the 3D structure, and often matrix elements play an important role. This review summarizes the state of the art concerning commonalities of the different models. For instance, the theory of mass transport/metabolite exchange in 3D systems and the special analytical requirements for test endpoints in organotypic cultures are discussed in detail. In the next part, 3D model systems for selected organs--liver, lung, skin, brain--are presented and characterized in dedicated chapters. Also, 3D approaches to the modeling of tumors are presented and discussed. All chapters give a historical background, illustrate the large variety of approaches, and highlight up- and downsides as well as specific requirements. Moreover, they refer to the application in disease modeling, drug discovery and safety assessment. Finally, consensus recommendations indicate a roadmap for the successful implementation of 3D models in routine screening. It is expected that the use of such models will accelerate progress by reducing error rates and wrong predictions from compound testing.

Indicateurs sécurité en obstétrique : une étude Delphi [Patient safety indicators for obstetrics: a Delphi based study]

OBJECTIVE: Clinical indicators are increasingly used to assess safety of patient care. In obstetrics, only a few indicators have been validated to date and none is used across specialties. The purpose of this study was to identify and assess for face and content validity a group of safety indicators that could be used by anaesthetists, obstetricians and neonatologists involved in labour and delivery units. MATERIALS AND METHODS: We first conducted a systematic review of the literature to identify potential measures. Indicators were then validated by a panel of 30 experts representing all specialties working in labour and delivery units. We used the Delphi method, an iterative questionnaire-based consensus seeking technique. Experts determined on a 7-point Likert scale (1=most representative/7=less representative) the soundness of each indicator as a measure of safety and their possible association with errors and complications caused by medical management. RESULTS: We identified 44 potential clinical indicators from the literature. Following the Delphi process, 13 indicators were considered as highly representative of safety during obstetrical care (mean score</=2.3). Experts ranked 6 of these indicators as being strongly associated to potential errors and complications. CONCLUSIONS: We identified and validated for face and content, a group of six clinical indicators to measure potentially preventable iatrogenic complications in labour and delivery units.

Effect of computerisation on the quality and safety of chemotherapy prescription.

BACKGROUND: Chemotherapy is prescribed according to protocols of several cycles. These protocols include not only therapeutic agents but also adjuvant solvents and inherent supportive care measures. Multiple errors can occur during the prescription, the transmission of documents and the drug delivery processes, and lead to potentially serious consequences. OBJECTIVE: To assess the effect of a computerised physician order entry (CPOE) system on the number of errors in prescription recorded by the centralised chemotherapy unit of a pharmacy service in a university hospital. PATIENTS AND METHODS: Existing chemotherapy protocols were standardised by a multidisciplinary team (composed of a doctor, a pharmacist and a nurse) and a CPOE system was developed from a File Maker Pro database. Chemotherapy protocols were progressively introduced into the CPOE system. The effect of the system on prescribing errors was measured over 15 months before and 21 months after starting computerised protocol prescription. Errors were classified as major (dosage and drug name) and minor (volume or type of infusion solution). RESULTS: Before computerisation, 141 errors were recorded for 940 prescribed chemotherapy regimens (15%). After introduction of the CPOE system, 75 errors were recorded for 1505 prescribed chemotherapy regimens (5%). Of these errors, 69 (92%) were recorded in prescriptions that did not use a computerised protocol. A dramatic decrease in the number of errors was noticeable when 50% of the chemotherapy protocols were prescribed through the CPOE system. CONCLUSION: Errors in chemotherapy prescription nearly disappeared after implementation of CPOE. The safety of chemotherapy prescription was markedly improved.

Safety and effectiveness of amphotericin B deoxycholate for the treatment of visceral leishmaniasis in Uganda

Between September 2003 and April 2004, the supply of antimonial drugs to Amudat Hospital, in north-eastern Uganda, was interrupted and all cases of visceral leishmaniasis presenting at the hospital could only be treated with amphotericin B deoxycholate (AmB). This allowed the safety and effectiveness of the AmB to be evaluated, in comparison with an historical cohort of patients treated, at the same hospital, with meglumine antimoniate (Sb-V). Demographic and clinical data were collected before and after treatment. Adverse effects were recorded passively in all the subjects, and actively, using a standardized questionnaire, in a sub-group of the patients given AmB. The in-hospital case-fatality 'rates' were 4.8% [95% confidence interval (CI) =2.4%-8.8%] among the 210 patients treated with AmB and 3.7% (CI=1.4%-7.9%) among the 161 patients treated with Sb-V (P>0.20). Adverse effects requiring treatment interruption were rare in both cohorts. Treatment failures (i.e. non-responses or relapses) were observed in 2.9% (CI= 1.2%-6.4%) of the patients treated with AmB and 1.2% (CI=0.1%-4.4%) of the patients treated with Sb-V (P>0.20). For the treatment of visceral leishmaniasis in Uganda, AmB therefore had a similar effectiveness and safety profile to that of meglumine antimoniate.

The 5th anniversary of "Patient Safety in Surgery" - from the Journal's origin to its future vision.

A prospective study was undertaken to determine prognostic markers for patients with obstructive jaundice. Along with routine liver function tests, antipyrine clearance was determined in 20 patients. Four patients died after basal investigations. Five patients underwent definitive surgery. The remaining 11 patients were subjected to percutaneous transhepatic biliary decompression. Four patients died during the drainage period, while surgery was carried out for seven patients within 1-3 weeks of drainage. Of 20 patients, only six patients survived. Basal liver function tests were comparable in survivors and nonsurvivors. Discriminant analysis of the basal data revealed that plasma bilirubin, proteins and antipyrine half-life taken together had a strong association with mortality. A mathematical equation was derived using these variables and a score was computed for each patient. It was observed that a score value greater than or equal to 0.84 indicated survival. Omission of antipyrine half-life from the data, however, resulted in prediction of false security in 55% of patients. This study highlights the importance of addition of antipyrine elimination test to the routine liver function tests for precise identification of high risk patients.

Long-Term Safety of Canakinumab in Patients with Gouty Arthritis.

Background/Purpose: Gouty arthritis (GA) is a chronic inflammatory disease. Targeting the inflammatory pathway through IL-1_ inhibition with canakinumab (CAN) may provide significant long-term benefits. CAN safety versus triamcinolone acetonide (TA) over initial 24 weeks (blinded study) for patients (pts) with history of frequent attacks (_3 in year before baseline) was reported earlier from core (_-RELIEVED [_-REL] and _-REL-II) and first extension (E1) studies1. Herein we present full 18-month long-term CAN safety data, including open-label second extension (E2) studies. Methods: GA pts completing _-REL E1 and _-REL-II E1 studies1 were enrolled in these 1-year, open-label, E2 studies. All pts entering E2, whether randomized to CAN or TA, received CAN 150 mg sc on demand upon new attack. Data are presented only for pts randomized to CAN, and are reported cumulatively, i.e. including corresponding data from previously reported core and E1 studies. Long-term safety outcomes and safety upon re-treatment are presented as incidence rate per 100 patient-years (pyr) of study participation for AEs and SAEs. Deaths are reported for all pts (randomized to CAN or TA). Selected predefined notable laboratory abnormalities are shown (neutrophils, platelets, liver and renal function tests). Long-term attack rate per year is also provided. Results: In total, 69/115 (60%) and 72/112 (64.3%) of the pts randomized to CAN in the two core studies entered the two E2 studies, of which 68 and 64 pts, respectively completed the E2 studies. The 2 study populations had differing baseline comorbidity and geographic origin. Lab data (not time adjusted) for neutropenia appears worse after retreatment in _-REL E2, and deterioration of creatinine clearance appears worse after retreatment (Table 1). The time-adjusted incidence rates for AEs were 302.4/100 pyr and 360/100 pyr, and for SAEs were 27.9/100 pyr and 13.9/100 pyr in _-REL E2 and _-REL-II E2 respectively (Table 1). The time-adjusted incidence rates of any AEs, infection AEs, any SAEs, and selected SAEs before and after re-treatment are presented in Table 1. Incidence rates for AEs and SAEs declined after re-treatment, with the exception of SAEs in _-REL-II E2, which increased from 2.9/100 pyr to 10.9/100 pyr (no infection SAEs after retreatment in _-REL-II E2, and other SAEs fit no special pattern). In the total safety population (N_454, core and all extensions), there were 4 deaths, 2 in the core studies previously reported1 and 2 during the _-REL E2 study (one patient in the CAN group died from pneumonia; one patient in the TA group who never received CAN died of pneumococcal sepsis). None of the deaths was suspected by investigators to be study drug related. The mean rates of new attacks per year on CAN were 1.21 and 1.18 in _-REL E2 and in _-REL-II E2. Conclusion: The clinical safety profile of CAN upon re-treatment was maintained long-term with no new infection concerns

Immunogenicity and safety of an intradermal boosting strategy for vaccination against influenza in lung transplant recipients.

The immunogenicity of influenza vaccine is suboptimal in lung transplant recipients. Use of a booster dose and vaccine delivery by the intradermal rather than intramuscular route may improve response. We prospectively evaluated the immunogenicity and safety of a 2-dose boosting strategy of influenza vaccine. Sixty lung transplant recipients received a standard intramuscular injection of the 2006-2007 inactivated influenza vaccine, followed 4 weeks later by an intradermal booster of the same vaccine. Immunogenicity was assessed by measurement of geometric mean titer of antibodies after both the intramuscular injection and the intradermal booster. Vaccine response was defined as 4-fold or higher increase of antibody titers to at least one vaccine antigen. Thirty-eight out of 60 patients (63%) had a response after intramuscular vaccination. Geometric mean titers increased for all three vaccine antigens following the first dose (p &lt; 0.001). However, no significant increases in titer were observed after the booster dose for all three antigens. Among nonresponders, 3/22 (13.6%) additional patients responded after the intradermal booster (p = 0.14). The use of basiliximab was associated with a positive response (p = 0.024). After a single standard dose of influenza vaccine, a booster dose given by intradermal injection did not significantly improve vaccine immunogenicity in lung transplant recipients.

Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety.

BACKGROUND AND PURPOSE: The major drug-metabolizing enzymes for the oxidation of oxycodone are CYP2D6 and CYP3A. A high interindividual variability in the activity of these enzymes because of genetic polymorphisms and/or drug-drug interactions is well established. The possible role of an active metabolite in the pharmacodynamics of oxycodone has been questioned and the importance of CYP3A-mediated effects on the pharmacokinetics and pharmacodynamics of oxycodone has been poorly explored. EXPERIMENTAL APPROACH: We conducted a randomized crossover (five arms) double-blind placebo-controlled study in 10 healthy volunteers genotyped for CYP2D6. Oral oxycodone (0.2 mg x kg(-1)) was given alone or after inhibition of CYP2D6 (with quinidine) and/or of CYP3A (with ketoconazole). Experimental pain (cold pressor test, electrical stimulation, thermode), pupil size, psychomotor effects and toxicity were assessed. KEY RESULTS: CYP2D6 activity was correlated with oxycodone experimental pain assessment. CYP2D6 ultra-rapid metabolizers experienced increased pharmacodynamic effects, whereas cold pressor test and pupil size were unchanged in CYP2D6 poor metabolizers, relative to extensive metabolizers. CYP2D6 blockade reduced subjective pain threshold (SPT) for oxycodone by 30% and the response was similar to placebo. CYP3A4 blockade had a major effect on all pharmacodynamic assessments and SPT increased by 15%. Oxymorphone C(max) was correlated with SPT assessment (rho(S)= 0.7) and the only independent positive predictor of SPT. Side-effects were observed after CYP3A4 blockade and/or in CYP2D6 ultra-rapid metabolizers. CONCLUSIONS AND IMPLICATIONS: The modulation of CYP2D6 and CYP3A activities had clear effects on oxycodone pharmacodynamics and these effects were dependent on CYP2D6 genetic polymorphism.