Excellent Safety Record Research Articles

Use of IGIV in the treatment of atopic dermatitis, urticaria, scleromyxedema, pyoderma gangrenosum, psoriasis, and pretibial myxedema

There has been a rapid expansion in the use of IGIV for an ever-growing number of conditions. It is a product with an excellent safety record without the side effects of steroids or other immunosuppressive agents. There have been numerous recent advances in our understanding of the mechanisms of action of IGIV in many of the conditions for which it is being used, but there is still much to be learned. IGIV has had a major impact in neurology, haematology, immunology, rheumatology and dermatology. The limitations for IGIV are cost of the preparation itself and the logistical problems associated with its administration. Here we describe the published evidence for the use of high-dose IGIV in the dermatological conditions atopic dermatitis, urticaria, scleromyxedema, pyoderma gangrenosum, psoriasis and pretibial myxedema. These conditions have an emerging evidence base for hdIGIV which is relatively small consisting mainly of case reports and small case series. The outcomes in a number of these conditions appear encouraging, but as the reports are likely to reflect a bias for positive results, one must be cautious about drawing firm conclusions.

Is herniography useful?

Herniography has been used for 25 years in the diagnosis of occult herniation but has not gained widespread acceptance in the UK, despite studies confirming its high sensitivity and specificity for occult hernias and an excellent record of safety and patient acceptability. The traditional approach in the UK to suspected occult groin herniation has been surgical exploration. This study examined the use of herniography in a single district general hospital to assess its impact in limiting unnecessary groin explorations and allowing discharge of patients without hernias. The case notes of 90 successive patients referred for herniography by the department of general surgery in a single UK district general hospital over an 18-month period were reviewed. Eighty-seven completed examinations were analysed in which 23 hernias were diagnosed in 20 patients. Thirteen patients have undergone hernia repair with resolution of symptoms. There were no false positive examinations, although two inguinal hernias were incorrectly diagnosed radiologically as femoral hernias; there were two false negative examinations where additional hernias were found at laparoscopic repair. There were no reported complications. Twenty-four patients were discharged directly from the surgical clinic after a negative herniogram. Thirty patients were referred to other specialities. No patient had undergone groin exploration after a negative herniogram. Herniography is a useful tool in assessing obscure groin pain and potential occult herniation. It can reliably rule out the presence of a hernia and avoid the need for surgical exploration. Many patients with a negative herniogram can be reassured and discharged, whilst others may be referred on to other specialities safe in the knowledge that an occult hernia has been excluded.

Isolation of Vaccinia MVA Recombinants Using the Viral F13L Gene as the Selective Marker

Modified vaccinia Ankara (MVA) is a highly attenuated vaccine vector that has an excellent vaccine safety record. Also, as a eukaryotic gene expression vector, MVA can be used in a biosafety level 1 setup, in contrast to more virulent vaccinia virus strains. Isolation of recombinant MVA involves repeated plaquing of the virus and is burdensome because virus plaques are slow to develop and difficult to recognize. To facilitate the generation of MVA recombinants, we have developed a cloning system for MVA based on the selection of the viral F13L gene. Deletion of F13L in MVA produced a small plaque phenotype and a reduction in extracellular virus formation, indicating a severe block in cell-to-cell spread. When using the F13L knockout virus as the parental virus, reintroduction of the F13L gene in the original locus was used as an efficient selection for the isolation of virus recombinants. The selection procedure can be done entirely in the permissive baby hamster kidney (BHK)-21 cell line, does not require plaque isolation, and rendered close to 100% recombinant virus.

LNG safety: An issue of increasing importance

AbstractThe emergence of liquefied natural gas (LNG) to fill the growing gap in natural gas supply has led to a renewed interest in LNG safety. LNG regulations, which developed primarily in the 1970s, do not contain many process safety management concepts currently practiced by the rest of the process industry. Rather than continuous patching of federal LNG rules, a complete revamp using process safety concepts is long overdue, to maintain the excellent safety record that the LNG industry has enjoyed. © 2005 American Institute of Chemical Engineers Process Saf Prog 24, 2005

Clinical uses of intravenous immunoglobulin

There has been a rapid expansion in the use of intravenous immunoglobulin (IVIG) for an ever growing number of conditions. It is a product with an excellent safety record without the side effects of steroids or other immunosuppressive agents. There have been numerous recent advances in our understanding of the mechanisms of action of IVIG in many of the conditions for which it is being used, but there is still much to be learned. IVIG has had a major impact in neurology, haematology, immunology, rheumatology and dermatology. The limitations for IVIG are cost of the preparation itself and the logistical problems associated with its administration. Many of the side effects are managed easily by careful screening of the patient prior to treatment, premedication with analgesics and antihistamines and adjustment of infusion rate. It is likely, however, that side effects will be more frequent as the dose given increases and effects on plasma viscosity become greater [122]. It will be important to increase the evidence base for IVIG in many conditions to define its therapeutic role. In addition, there have been very few dose-ranging studies for hdIVIG and fewer still of which adjunctive agents (including biological agents such as rituximab and daclizumab) might offer the best therapeutic combinations. Although not established, the use of IVIG is being studied in a range of conditions including heart failure, mycobacterial infection, adult respiratory distress syndrome, transplantation, fibrosis, connective tissue disease, encephalitis, epilepsy and even Alzheimer's disease. Should IVIG prove to be of efficacy in these settings it is likely to have major implications for drug budgets as many of the conditions are very common and place great strain on the world's supply of IVIG itself. Future studies will therefore need to address questions of efficacy, pharmacoeconomics, dose, adjunctive therapies and mechanism of action which may point the way to novel treatment strategies beyond IVIG. It is also clear, however, that controlled trials in many of the rare conditions may be very difficult to carry out and approaches such as prospective disease registries may be needed.

Past, present, and future: a 7-year update of Viagra® (sildenafil citrate)

More than 30 million men are estimated to have erectile dysfunction (ED) in the United States. Worldwide, ED is estimated to affect more than 150 million men, and that number is expected to exceed 300 million men by the year 2025. The prevalence of ED ranges from 7% in men aged 18-29 years to 85% in men aged 76-85 years. In addition, a recent report showed that 68% of patients with ED aged 18 years and older have at least one comorbid diagnosis of hypertension, hyperlipidaemia, diabetes or depression, and research suggests that ED may be an early indicator of systemic vascular disease. Viagra (sildenafil citrate), the first-in-class phosphodiesterase type 5 (PDE5) inhibitor, was introduced in 1998 for the treatment of ED. In the 7 years since its market launch, more than 750,000 physicians have prescribed sildenafil to more than 23 million men, helping establish an excellent safety and efficacy record. Clinical studies have demonstrated that sildenafil successfully treats ED of varied organic, psychogenic or mixed aetiology, and is effective in men with ED and comorbidities such as hypertension, hyperlipidaemia, diabetes or depression. Sildenafil was a breakthrough medication that addressed a previously unfulfilled medical need. The impact of sildenafil has stimulated academic, clinical and industrial research to better understand the nature of sexual function and develop better treatment and management for sexual dysfunctions such as ED. With the advent of other erectogenic therapies for the treatment of ED, this 7-year update will focus on the unique history and development of sildenafil, its current use and applications and its future directions and indications. Special emphasis is placed on the impact of sildenafil on our understanding of sexual health and on the extensive safety and efficacy data that have been amassed from numerous clinical trials.

Tinea Capitis: A Treatment Update

Currently, many experts consider griseofulvin to be the drug of choice for tinea capitis. It is FDA approved for this indication, highly efficacious, and has an excellent long-term safety record. Nonetheless, there is now ample evidence documenting the efficacy and safety of other antifungal agents. Terbinafine, itraconazole, and fluconazole have been used off-label in the United States and United Kingdom for tinea capitis. Several studies have shown that short-term terbinafine, itraconazole, or fluconazole each are comparable in efficacy and safety to griseofulvin. High-dose griseofulvin is still the first-line therapy for tinea capitis in our practice, but a large-scale, multicenter trial of higher dose terbinafine is now ongoing, and positive efficacy and safety results from that study may lead to a change in our standard of care. Terbinafine, itraconazole, or fluconazole currently are used in patients who have either failed griseofulvin or developed adverse reactions to this medication. Families must be informed that these other antifungal agents are not FDA-approved for this indication when they are used. Guidelines for therapy with each of these agents are summarized in Table 5. In addition, the adjuvant use of antifungal shampoos is recommended for all patients in order to decrease the viability of fungal spores present on the hair, as well as for all household contacts to prevent infection or eliminate the carrier state.

Role of pantoprazole in the treatment of gastro-oesophageal reflux disease

The diagnosis and treatment of gastro-oesophageal reflux disease (GERD) presents many problems, despite the fact that significant advances have been made in recent years in the understanding of its pathogenesis and symptomatology. GERD affects many people and has a significant negative impact on patient quality of life. Heartburn is the most common symptom of GERD which occurs with and without oesophagitis. The predominant causative factor for symptoms is prolonged contact of oesophageal mucosa with refluxed acid and pepsin. Proton pump inhibitors (PPIs) are the most effective treatment for GERD: overall proportions of patients with healing and complete heartburn relief are markedly higher with PPIs than with alternative treatment strategies. Furthermore, the speed of healing and heartburn relief with PPIs is almost twice as rapid as with any other form of therapy. The present review focuses on the effectiveness and safety of the PPI, pantoprazole. The data show that the compound is highly effective in GERD patients with and without oesophagitis. Pantoprazole has an excellent safety record and shows only minor interaction with other drugs.

A Bayesian approach to the assessment of inhibitor risk in studies of factor VIII concentrates

The assessment of inhibitor risk is a crucial component in the clinical development of new and modified factor VIII (FVIII) preparations. There has been a recent discussion about the design of studies and the assessment of inhibitors and inhibitor risk in such studies at a recent FDA-sponsored FVIII Inhibitor Workshop, and new requirements for the success of these trials have been proposed to evaluate inhibitor data based on the use of an upper 95% confidence bound. We review the consequences of these requirements and demonstrate that for any product to succeed, it must have an extremely low underlying risk of inhibitor development. Furthermore, several existing commercially available FVIII products with an excellent safety record would not necessarily pass these endpoints. As a result, we propose an alternative set of acceptance criteria based on a Bayesian statistical paradigm. This approach is based on the determination of a probability that the product in question actually has an inhibitor risk below some pre-set limit, a concept that we believe is more intuitive than the traditional confidence interval method. We show that all existing products would pass this approach, but a product (Bisinact) with known inhibitor risk would not.

Clinical review: Percutaneous dilatational tracheostomy

As the number of critically ill patients requiring tracheotomy for prolonged ventilation has increased, the demand for a procedural alternative to the surgical tracheostomy (ST) has also emerged. Since its introduction, percutaneous dilatational tracheostomies (PDT) have gained increasing popularity. The most commonly cited advantages are the ease of the familiar technique and the ability to perform the procedure at the bedside. It is now considered a viable alternative to (ST) in the intensive care unit. Evaluation of PDT procedural modifications will require evaluation in randomized clinical trials. Regardless of the PDT technique, meticulous preoperative and postoperative management are necessary to maintain the excellent safety record of PDT.

Recommendations on haematological criteria for the diagnosis of epoetin‐induced pure red cell aplasia

Pure red cell aplasia (PRCA) is a rare condition characterised by an arrest in red blood cell production, which may be congenital or acquired. Recombinant human erythropoietin (epoetin) was introduced in 1989 for the treatment of anaemia of chronic kidney disease patients and has maintained an excellent therapeutic and safety record while treating hundreds of thousands of patients. A very rare, but serious adverse event associated with epoetin administration is a condition in which patients develop neutralising anti-erythropoietin antibodies and, consequently, PRCA. This condition is referred to as epoetin-induced PRCA (epo-PRCA). Since it is a rare condition, many haematologists and nephrologists around the world see the condition infrequently and may be uncertain about the diagnosis. For this reason, an ad hoc international working group of expert haematologists and nephrologists met together to derive new recommendations for the haematological diagnosis of epo-PRCA. These recommendations, which represent the consensus opinions of the working group, address haematological approaches to monitor and investigate suspected epo-PRCA and should help physicians differentiate between PRCA and other bone marrow diseases, as well as, between PRCA and epo-PRCA.

Inter‐patient variation in efficacy of five oncolytic adenovirus candidates for ovarian cancer therapy

Gene therapy offers a new strategy for cancer treatment. Adenoviruses represent the most widely used gene therapy vector and feature an excellent safety record. Conditionally replicative adenoviruses (CRAds) effect solid tumor penetration and tumor selective oncolysis and consequently offer potential efficacy for metastatic disease treatment. We evaluated five CRAds as candidate clinical agents for ovarian cancer therapy: RGDCRADcox-2R, Ad5VEGFE1, Ad5/3VEGFE1, Ad5-Delta24RGD, and Ad5/3-Delta24. DNA replication by these five CRAds, wild-type adenovirus, and an E1-deleted control was measured in purified primary ovarian cancer cell spheroids by quantitative PCR. CRAd-mediated oncolysis was quantified in ovarian cancer cell monolayers and three-dimensional spheroids by cellular viability assays. The therapeutic efficacy of each CRAd was tested by intraperitoneal administration in mice with peritoneally disseminated human ovarian cancer. An increase in viral DNA was noted in primary tumor cell spheroids for all replicative viruses tested. Variation was noted in viral DNA replication between patient samples. All five CRAds induced remarkable oncolysis. They also prolonged survival in vivo compared with the wild-type control group. All five CRAds tested showed robust DNA replication, oncolysis, and in vivo therapeutic efficacy. Each virus has potential for clinical testing, and such further testing will ultimately determine its safety and relative usefulness. Variation of CRAd DNA replication between different patient samples suggests that target tissue features, such as surface receptors and endogenous transcription factors, may affect CRAd infectivity and replicativity. Evaluation of such factors may become important to optimize cancer therapy for individual patients.

Recombinant Activated Factor VII in Patients at High Risk of Bleeding

Currently, recombinant activated factor VII (rFVIIa) (NovoSeven ® ) is indicated for the treatment of spontaneous and surgical bleeding in congenital haemophilia A and B patients with inhibitors to factors VIII (FVIII) and IX (FIX) >5 Bethesda units (BU) worldwide, and in patients with acquired haemophilia, congenital FVII deficiency and Glanzmann's thrombasthenia in Europe. Until April 2003, almost three-quarters of a milion doses of rFVIIa have been administered proving its efficacy and excellent safety record. According to results from initial clinical trials and a large number of case reports, the rFVIIa may be effective not only in treating haemophilia patients but also in treatment of bleeding in patients on oral anticoagulation or heparin, patients with liver diseases, von Willebrand disease (vWD), thrombocytopenia, various platelet defects, congenital or acquired deficiency of FVII, and in subjects without any pre-existing coagulopathy with diffuse life-threatening bleeding triggered by surgery or trauma. This review will briefly summarize rFVIIa mode of action in haemostasis, the current clinical experience with rFVIIa and focus on the alternative use of rFVIIa in patients at the high risk of bleeding in both spontaneous cases and clinical trials reports. † stasko@jfmed.uniba.sk

Rapid administration of ibandronate does not affect renal functioning: evidence from clinical studies in metastatic bone disease and hypercalcaemia of malignancy.

Ibandronate is a third-generation aminobisphosphonate that has an excellent safety record in hypercalcaemia of malignancy, and has recently been approved for the prevention of skeletal events from metastatic breast cancer. This paper reviews the safety data from clinical studies of intravenous ibandronate by infusion or injection, focusing on renal adverse events (AEs). In clinical trials of patients with hypercalcaemia of malignancy, 2-h infusions of ibandronate at doses of up to 6 mg had a low potential for renal events. In a phase III trial of patients with metastatic bone disease from breast cancer, 6 mg ibandronate infused over 1-2 h had a renal safety profile comparable to that of placebo. In pilot studies, repeated daily infusions of ibandronate (4 mg infused over 2 h for four consecutive days, or 6 mg infused over 1 h for three consecutive days) for severe metastatic bone pain were not associated with any renal AEs. The safety of single 15-min infusions of 6 mg ibandronate has been demonstrated in healthy volunteers and patients with metastatic bone disease from breast cancer or multiple myeloma. Furthermore, single and rapid bolus injections of 2 or 3 mg ibandronate did not increase the risk of renal dysfunction in patients with skeletal metastases. Implications for the renal safety of ibandronate in the management of patients with metastatic bone disease are discussed.

Statins as potential therapeutic agents in multiple sclerosis.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (ie, statins) are oral cholesterol-lowering drugs. Statins are well tolerated and have an excellent safety record. These agents competitively inhibit HMG CoA reductase, which is the enzyme that catalyzes the conversion of HMG CoA to L-mevalonate. Although L-mevalonate is a key intermediate in cholesterol synthesis, several of its metabolites are involved in post-translational modification of specific proteins involved in cell proliferation and differentiation. Thus, independent of their cholesterol-reducing properties, statins have important pleiotropic biologic effects. Recent reports indicate that statins have anti-inflammatory and neuroprotective properties. Whether statins will be of clinical benefit for patients with multiple sclerosis and other neurodegenerative diseases of the central nervous system will only be known after they are evaluated in prospective randomized clinical trials.

Analysis of outpatient surgery center safety using an internet-based quality improvement and peer review program.

Assessing the quality of care delivered in office-based outpatient surgery centers is difficult because formerly there was no central data collection system. The American Association for Accreditation of Ambulatory Surgery Facilities (AAAASF), in its ongoing effort to assess and improve patient care, has developed an Internet-based quality improvement and peer review program to analyze outcomes for surgery centers it accredits. Reporting is mandatory for all surgeons operating in AAAASF-accredited facilities. Each surgeon must report all unanticipated sequelae and at least six random cases reviewed by an accepted peer review group biannually. A total of 411,670 procedures were analyzed during a 2-year period (from 2001 to 2002). There were 2597 sequelae reported during this period. The most common sequela was hematoma formation following breast augmentation. Infection occurred in 388 cases. Deep vein thrombosis, pulmonary embolism, and intraoperative cardiac arrhythmias were found to occur in a frequency consistent with previous reports. Significant complications (hematoma, hypertensive episode, wound infection, sepsis, and hypotension) were infrequent. A total of 1378 significant sequelae were reported for 411,670 procedures. This calculates to one unanticipated sequela in 299 procedures (an incidence of 0.33 percent). Seven deaths were reported. A death occurred in one in 58,810 procedures (0.0017 percent). The overall risk of death was comparable whether the procedure was performed in an AAAASF-accredited office surgery facility or a hospital surgery facility. This study documents an excellent safety record for surgical procedures performed in accredited office surgery facilities by board-certified surgeons.

Bexxar: novel radioimmunotherapy for the treatment of low-grade and transformed low-grade non-Hodgkin's lymphoma.

Immunotherapy using monoclonal antibodies to specifically target B cells has provided new hope to many patients with indolent lymphomas, particularly those with chemotherapy-refractory disease. Lymphomas are extremely sensitive to radiation, and significant progress has been made over the last decade in the development of radioimmunotherapy with anti-CD20 antibodies. Herein we review clinical experience with tositumomab and iodine I 131 tositumomab (Bexxar; Corixa Corporation; South San Francisco, CA; and GlaxoSmithKline; Philadelphia, PA) in patients with non-Hodgkin's lymphoma. Therapy with Bexxar has demonstrated high response rates and long durations of response compared with unconjugated anti-CD20 antibodies in patients with relapsed low-grade and transformed low-grade non-Hodgkin's lymphomas. Iodine-131 (I-131) has a long history of clinical experience, an excellent safety record, and favorable nuclear and pharmacologic properties. Importantly, the gamma emissions of iodine-131 facilitate accurate dosimetry to calculate the appropriate patient-specific therapeutic activity to deliver a predetermined total-body dose of radiation, thereby minimizing hematologic toxicity. In clinical trials of Bexxar, objective response rates ranged from 54%-71% in heavily pretreated patients. In the pivotal trial, the number of patients with a longer duration of response after treatment with Bexxar was significantly greater than the number of patients with a longer duration of response after their last qualifying chemotherapy regimen. In 76 newly diagnosed patients, the objective response rate was 97%, and 63% of patients achieved complete responses. These data suggest that Bexxar will become an important new option in the treatment of indolent lymphoma.

Fostering Member State Implementation of the Iaea's Transport Regulations

AbstractIn the area of radioactive material transport, the IAEA has concentrated its efforts since the 1950s on developing and keeping up-to-date its 'Regulations for the Safe Transport of Radioactive Material'. The transport regulations were first published in 1961 and revised in 1967, 1973, 1985 and 1996. Many countries throughout the world apply the safety requirements embodied in the transport regulations. This high level of implementation has resulted in an excellent safety record, there having been no transport accident with radiological consequences for people, property or the environment arising from the radioactive nature of the material being transported. Nevertheless, the IAEA has not relaxed its efforts to ensure that its transport regulations stay abreast of scientific and technical developments; on the contrary, it has been undertaking a regular and vigorous review of its safety requirements, and continues to do so with the assistance of Member States and relevant international organisations...

Extended-release ciprofloxacin (Cipro XR) for treatment of urinary tract infections

Symptomatic urinary tract infections (UTIs) constitute a major health problem throughout the Western world. In the USA, UTIs are responsible for 7–8 million outpatient visits each year and for over one-third of all hospital-acquired infections. Empiric antimicrobial therapy for UTIs, which are primarily caused by Escherichia coli, is increasingly being complicated by the emergence of resistance to the most widely used agents. Recent studies indicate that the prevalence of E. coli resistance to trimethoprim/sulphamethoxazole (TMP/SMX), the current first-line therapy for UTIs, exceeds 20% in many North American regions. Importantly, antibiotic resistance often translates into clinical failure. The use of antibiotics with favourable pharmacokinetic/pharmacodynamic profiles and convenient dosing schedules, which effectively increase bacterial eradication and patient compliance, can help to curb the current epidemic of resistance and reduce the rate of clinical failure associated with resistance. Fluoroquinolones have well-established efficacy in the treatment of multiple bacterial infections and, over the years, the rates of resistance to these antibiotics have remained very low. Fluoroquinolones are currently recommended for therapy of uncomplicated UTIs when the local incidence of TMP/SMX resistance is ≥10–20%, as well as for the treatment of complicated UTIs and acute pyelonephritis. Ciprofloxacin, one of the most widely used fluoroquinolones, has a potent bactericidal effect across the full spectrum of uropathogens, as well as a long and excellent efficacy and safety record in the management of UTI and other infections. A recently developed extended (modified)-release formulation of ciprofloxacin (Cipro XR or Cipro XL) provides higher maximum plasma concentrations with lower inter-patient variability than the conventional, immediate-release, twice-daily formulation. Additionally, therapeutic drug levels with extended-release ciprofloxacin are achieved rapidly and maintained over the course of 24 h, allowing once-daily dosing. Clinical trials in patients with cystitis and those with complicated UTIs or acute uncomplicated pyelonephritis indicate that extended-release ciprofloxacin is at least as effective as the immediate-release formulation. These studies have also confirmed good tolerability and safety of extended-release ciprofloxacin, similar to the immediate-release formulation. Therefore, extended-release ciprofloxacin is a convenient, well-tolerated and effective therapy for UTIs that may improve patients’ compliance with treatment and thus decrease the risk of treatment failure and the spread of antibiotic resistance.

Development of a new 10% liquid, triple virus reduced intravenous immune globulin product, new generation IGIV

Rationale While immune globulin products after introduction of dedicated virus inactivation steps have an excellent safety record, patient concerns around transmission of particularly viruses still exist, and are fueled by newly emerging viruses. Methods To address these concerns, the manufacturing process of this new liquid IGIV contains three dedicated virus reduction steps: (1) a three component solvent-detergent (SD) treatment, (2) a 35 N nanofiltration step, and (3) a prolonged incubation period at low pH and elevated temperature. Results (1) SD treatment resulted in complete inactivation of all the lipid-enveloped viruses tested, already after only 1 minute of the 60 minutes treatment, and also at drastically reduced concentrations of the SD reagents. (2) Nanofiltration effectively removed lipid-enveloped viruses. Also, HAV and parvovirus B19, viruses which are smaller than the nominal pore size of the filter used, were reproducibly and robustly removed by antibody-enhanced nanofiltration which occurred at a wide range of HAV and B19 antibody concentrations. (3) Incubation at low pH and elevated temperature effectively inactivated lipid-enveloped viruses, and resulted in significant levels of inactivation for non-lipid enveloped viruses, including parvoviruses. Inactivation was shown to depend on a combination of low pH and elevated temperature. Conclusions The incorporation of three dedicated and mechanistically different virus reduction steps for this new liquid immunoglobulin product results in unprecedented safety margins.