Risk Of Severe Adverse Events Research Articles

Mefloquine prescriptions in the presence of contraindications: prevalence among US military personnel deployed to Afghanistan, 2007

Contraindications to mefloquine use include a history of certain prevalent neuropsychiatric disorders, which are thought to increase the risk of severe adverse events including anxiety, paranoia, depression, hallucinations, psychosis, and possibly suicide. Within the US military, the continued availability and use of mefloquine is subject to administrative policies dating to 2002 that require clinicians to exercise added caution during prescribing. This analysis was performed to quantify the effectiveness of these policies in ensuring health care provider compliance with package insert prescribing guidance. A previously identified cohort consisting of 11,725 active duty US military personnel, among whom 1127 (9.6%) had contraindications to mefloquine use identified through medical surveillance and pharmaceutical databases, was examined to identify individuals receiving prescriptions for mefloquine in the 45 days prior to a combat deployment in 2007. Among the 11,725 cohort members, 4505 (38.4% of the cohort) received a prescription for mefloquine. Among the 1127 cohort members with contraindications, 155 (1.3% of the cohort) were prescribed mefloquine, comprising 13.8% of those with contraindications. Despite the longstanding administrative policies meant to reduce such events, approximately one in seven individuals with neuropsychiatric contraindications received a prescription for mefloquine prior to a recent combat deployment, significantly increasing the risk of subsequent adverse events. Given the prevalence of neuropsychiatric disorders among US military personnel and the continued availability of mefloquine, additional study is recommended to describe and quantify the nature and extent of mefloquine-associated adverse events experienced among this group.

Fatal hemorrhage after attempted treatment of a basilar artery stenosis

Interventional treatment of severe intracranial stenoses using angioplasty and stent placement carries a significant risk of severe adverse events. These events are frequently caused by the intraarterial dilation but may also be precipitated by other causes related to the procedure. The authors describe a fatal subarachnoid hemorrhage during the treatment of a basilar artery (BA) stenosis caused by a vascular rupture distant from the site of angioplasty. After successful balloon dilation, an attempt to deploy a self-expanding stent failed due to the severe kinking of the stenotic segment of the BA. The angiogram performed during the intervention revealed a fatal rupture of the BA in a location not related to the angioplasty or guide wire tip. The technical aspects of the intervention are analyzed on the basis of the postmortem findings.

Randomised double-blind, placebo-controlled trial of the effects of the ‘party pills’ BZP/TFMPP alone and in combination with alcohol

The objective of this study was to determine the clinical effects of party pills containing benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) when taken alone and in combination with alcohol. The study was a randomised, double-blind, placebo-controlled trial conducted in a hospital-based clinic in Wellington, New Zealand. Thirty-five volunteers who had previously used party pills containing BZP were included in this trial. Participants received one of the following four treatments: 300 mg/74 mg BZP/TFMPP and placebo, 300 mg/74 mg BZP/TFMPP and 57.6 g (6 units) alcohol, placebo and 57.6 g (6 units) alcohol and double placebo. The primary outcome variable was a measure of driving performance, the standard deviation of lateral position (SDLP) measured at 6.5 h. Secondary measures included adverse events, cardiovascular effects, psychological function and delayed effects on sleep. The study was stopped early, after 35 of the planned 64 subjects had undertaken testing, because of severe adverse events that occurred in four of 10 BZP/TFMPP-only subjects, three of seven combined BZP/TFMPP and alcohol subjects, none of the 6 placebo subjects, and none of the 12 alcohol-only subjects. The overall rate of severe adverse events (defined as causing considerable interference with usual activity and/or rated by subject as severe) in those receiving BZP/TFMPP was seven of 17 (41.2%, 95% CI 18.4-67.1). The severe events included agitation, anxiety, hallucinations, vomiting, insomnia and migraine. BZP/TFMPP significantly improved the driving performance, decreasing SDLP at -4.2 cm (95% CI -6.8 to -1.6, P = 0.002). The effect of alcohol was to increase SDLP: 2.3 cm (95% CI -0.3 to 4.9, P = 0.08). BZP/TFMPP also resulted in increased heart rate and blood pressure and in difficulty in getting to sleep. BZP/TFMPP alone or with alcohol carries a significant risk of severe adverse events when taken in similar doses to those recommended by manufacturers.

IMVAMUNE®: modified vaccinia Ankara strain as an attenuated smallpox vaccine

Smallpox vaccines based on replicating vaccinia virus are known to elicit rare yet serious adverse events, particularly in human populations with immune deficiency, atopic dermatitis and at the extremes of age. A vaccine that induces protective immune responses equivalent to first-generation smallpox vaccines while reducing the risk for severe adverse events is critical for a national stockpile of smallpox vaccines. Modified vaccinia Ankara (MVA) has been proposed as an immediate solution for vaccination of high-risk individuals. Bavarian Nordic’s vaccine MVA-BN® (IMVAMUNE®) is a MVA strain that is replication incompetent in mammalian cell lines. IMVAMUNE has been administered to more than 1900 human subjects to date, including high-risk populations (e.g., people diagnosed with atopic dermatitis or infected with HIV) in which standard replicating vaccines are contraindicated. We review the Phase I clinical trial safety profile and immune responses and compare them with other smallpox vaccines, including ACAM2000™ and Dryvax®.

Oral and cutaneous lichenoid reaction with nail changes secondary to imatinib: Report of a case and literature review

Imatinib mesylate--Gleevec (US), Glivec (worldwide), STI571--is an oral cancer drug that selectively inhibits several protein tyrosine kinases associated with human malignancy. The drug is used for the treatment of chronic myeloid leukemia, malignant gastrointestinal stromal tumors, and some other conditions. Treatment with imatinib is generally well tolerated but not without the risk of adverse effects. The risk of severe adverse events is low. Cutaneous side effects of this drug are common but muco-cutaneous lichenoid eruption with nail changes is very rare. We report a case of lichenoid eruption during imatinib therapy involving the skin, mucous membranes, and nails that cleared in spite of ongoing imatinib therapy.

Safety of Ultrasound Contrast Agents in Stress Echocardiography

Definity and Optison are perflutren-based ultrasound contrast agents used in echocardiography. United States Food and Drug Administration warnings regarding serious cardiopulmonary reactions and death after Definity administration highlighted the limited safety data in patients who undergo contrast stress echocardiography. From 1998 and 2007, 2,022 patients underwent dobutamine stress echocardiography and 2,764 underwent exercise stress echocardiography with contrast at the Cleveland Clinic. The echocardiographic database, patient records, and the Social Security Death Index were reviewed for the timing and cause of death, severe adverse events, arrhythmias, and symptoms. Complication rates for contrast dobutamine stress echocardiography and exercise stress echocardiography were compared with those in a control group of 5,012 patients matched for test year and type who did not receive contrast. Ninety-five percent of studies were performed in outpatients. There were no differences in the rates of severe adverse events (0.19% vs 0.17%, p = 0.7), death within 24 hours (0% vs 0.04%, p = 0.1), cardiac arrest (0.04% vs 0.04%, p = 0.96), and sustained ventricular tachycardia (0.2% vs 0.1%, p = 0.32) between patients receiving and not receiving intravenous contrast, respectively. In conclusion, severe adverse reactions to intravenous contrast agents during stress echocardiography are uncommon. Contrast use does not add to the baseline risk for severe adverse events in patients who undergo stress echocardiography.

Treatment of Chronic Hepatitis C Virus Infection With Pegylated Interferon and Ribavirin in Cirrhotic Patients Awaiting Liver Transplantation

Successful treatment of chronic hepatitis C virus (HCV) infection can prevent reinfection after orthotopic liver transplantation (OLT). Pegylated interferon (PEG-IFN) may ameliorate virological response (VR), making the risk-to-benefit ratio of therapy favorable in waiting list patients. From January 2001 to April 2006, we treated 15 HCV cirrhotics with PEG-IFN alpha-2b (1.5 μg/kg/week) and ribavirin (RIBA; ≥10.6 mg/kg/d). Their mean age was 51.5 years. There were 9 men. In 6 cases the genotype was 1b. With Child-Pugh scores ≥9 (range 9–12) and Model for End-Stage Liver Disease (MELD) scores ≥14 (range, 14–22). Adverse events occurred in all subjects: thrombocytopenia (<40,000/μL) in 8; neutropenia (<700/μL) in 10; anemia (Hb <8.5 g/dL) in 1; grade III hepatic encephalopathy in 2; pelvic infection in 1; variceal hemorrhage in 1; and hepatocellular carcinoma (HCC) recurrence in 1. Adverse events caused treatment withdrawal in 6 (40.0%) and RIBA and/or PEG-IFN dose reduction in 10 (66.6%). Early VR (EVR) was obtained in 9 subjects (60.0%), end-of-treatment (EOT) VR in 7 (46.6%), and sustained VR (SVR) in 3 (20.0%). Three subjects—2 nonresponder and 1 breakthrough—were transplanted at 25, 23, and 16 months after the EOT, respectively. Three subjects died at 6, 8, and 15 months after the EOT due to HCC, spontaneous bacterial peritonitis, and liver failure. Nine patients are awaiting OLT. The risk-to-benefit ratio is against PEG-INF and RIBA treatment of severely decompensated cirrhotics infected with genotype 1 awaiting OLT, but therapy is probably beneficial in genotype 2 subjects, due to an expected SVR rate of more than 40%. However, one must carefully consider the high risk for severe adverse events.

Does alcohol consumption increase the risk of severe adverse events to ivermectin treatment

The present investigation is a case-control study designed to assess the level of association between alcohol consumption and the occurrence of severe adverse reaction (SAE) following ivermectin consumption. Thirty-six (36) cases of SAE occurred in the health districts of Bankim, Nanga Eboko, Obala, Okola and Sa’a. Case and control (43) individuals were submitted to a questionnaire related to their alcohol consumption 24 before and 24 to 48 h following ivermectin intake. An in-depth interview of siblings and local health worker was conducted to assess alcohol consumption around Mectizan intake. The degree of alcohol use was assessed using the level of serum transaminases and the alcohol use disorder identification test (AUDIT). The alcoholic beverages of the study communities were conventional such as beer, whisky, or locally made. Locally produced beverages included “arki” (“Odontol”, “Hah”, ...) and palm wine. The bark, sap or fruit of plants adjuvant are known to contain alkaloids and tannins which are potent neurotropic substances. The likelihood of developing SAE among cases and controls did not differ significantly with history of consumption of alcoholic beverages. Nor did it differ for other indicators of chronic alcohol consumption. Key words: Alcohol consumption, onchocerciasis, AUDIT, serious adverse events, encephalopathy.

Safety of sublingual grass pollen immunotherapy after anaphylaxis

To demonstrate that sublingual immunotherapy is a safe treatment option in patients who have previously suffered anaphylaxis when undergoing subcutaneous grass pollen immunotherapy. We report two patients who developed a systemic anaphylactic reaction following subcutaneous grass pollen immunotherapy, resulting in discontinuation of treatment. Following treatment of the acute anaphylactic episode, both patients were subsequently safely commenced on sublingual grass pollen immunotherapy. Injection immunotherapy has a relatively low risk of severe adverse events, although anaphylaxis is a potentially fatal complication and usually results in termination of the immunotherapy programme. Sublingual immunotherapy has a safer side effect profile than subcutaneous immunotherapy, with no reported cases of anaphylaxis.

The use of central nervous system drugs and analgesics among very old people with and without dementia

Old people in general, and particularly those with dementia, are more sensitive to adverse drug effects than younger people. Despite this, the use of central nervous system (CNS) drugs among old people is common. The aim of the present study was to compare the use of central nervous system drugs and analgesics among people aged 85 years or older, with and without dementia. One half of all people aged 85 years old and all those aged 90, 95 and above in Umeå, Sweden and Vaasa and Mustasaari, Finland, were asked to participate in this part of the GERDA/Umeå 85+ study. Both those living in their own homes and those in institutions were included. Trained investigators performed structured interviews and assessments. Medication data were obtained from the participants and medical records. Dementia disorders were diagnosed according to DSM-IV. Dementia was diagnosed in 247/546 participants (45.2%). A higher proportion of the participants with dementia used paracetamol (50.6% compared to 21.4%, p < 0.001), antipsychotics (22.3% and 2.7%, p < 0.001), antidepressants (33.6% and 11.4%, p < 0.001) and anxiolytics (19.0% and 8.0%, p < 0.001). There were no differences in the use of opioid analgesics, anticonvulsants and hypnotics. The use of CNS drugs and analgesics was common among this population of very old people. Furthermore, the prescription of CNS drugs was more common among people with dementia. The use of antipsychotics in people with dementia should arouse particular concern, because of the high risk of severe adverse events and the limited evidence of positive effects.

Allergen injection immunotherapy for seasonal allergic rhinitis

Allergic rhinitis is the most common of the allergic diseases. Despite improved understanding of the pathophysiology of allergic rhinitis and advances in its pharmacological treatment, its prevalence has increased worldwide. For patients whose symptoms remain uncontrolled despite medical treatment, allergen injection immunotherapy is advised. An allergen-based treatment may reduce symptoms, the need for medication and modify the natural course of this disease. To evaluate the efficacy and safety of subcutaneous specific allergen immunotherapy, compared with placebo, for reducing symptoms and medication requirements in seasonal allergic rhinitis patients. We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1 2006), MEDLINE (1950 to 2006), EMBASE (1974 to 2006), Pre-MEDLINE, KOREAMED, INDMED, LILACS, PAKMEDINET, Scisearch, mRCT and the National Research Register. The date of the last search was February 2006. All studies identified by the searches were assessed to identify randomised controlled trials involving participants with symptoms of seasonal allergic rhinitis and proven allergen sensitivity, treated with subcutaneous allergen specific immunotherapy or corresponding placebo. Two independent authors identified all studies reporting double-blind, placebo controlled randomised trials of specific immunotherapy in patients with seasonal allergic rhinitis due to tree, grass or weed pollens. Two authors independently performed quality assessment of studies. Data from identified studies were abstracted onto a standard extraction sheet and subsequently entered into RevMan 4.2.8. Analysis was performed using the Standardised Mean Difference (SMD) method and a random-effects model; P values < 0.05 were considered statistically significant. The primary outcome measures were symptom scores, medication use, quality of life and adverse events. We retrieved 1111 publications of which 51 satisfied our inclusion criteria. In total there were 2871 participants (1645 active, 1226 placebo), each receiving on average 18 injections. Duration of immunotherapy varied from three days to three years. Symptom score data from 15 trials were suitable for meta-analysis and showed an overall reduction in the immunotherapy group (SMD -0.73 (95% CI -0.97 to -0.50, P < 0.00001)). Medication score data from 13 trials showed an overall reduction in the immunotherapy group (SMD of -0.57 (95% CI -0.82 to -0.33, p<0.00001)). Clinical interpretation of the effect size is difficult. Adrenaline was given in 0.13% (19 of 14085 injections) of those on active treatment and in 0.01% (1 of 8278 injections) of the placebo group for treatment of adverse events. There were no fatalities. This review has shown that specific allergen injection immunotherapy in suitably selected patients with seasonal allergic rhinitis results in a significant reduction in symptom scores and medication use. Injection immunotherapy has a known and relatively low risk of severe adverse events. We found no long-term consequences from adverse events.

Adding pharmacogenetics information to drug labels: lessons learned

The US Food and Drug Administration approved a revised package insert for two cancer drugs to include information about the increased risk of severe adverse events owing to enzyme deficiencies caused by genetic variants. The label revisions stopped short of recommending or requiring pharmacogenetic testing prior to or following an adverse event. Despite (or because of) the lack of specific recommendations, we believe the actions taken by US Food and Drug Administration will have implications for pharmacogenetics research, clinical integration, and other policy considerations. We review the reasons behind the cautious label changes and discuss some of the lessons that can be learned from these experiences.

Short communication: High prevalence of the cytochrome P450 2C8*2 mutation in Northern Ghana

Recently, Ghana has changed the first-line treatment of uncomplicated malaria from chloroquine to amodiaquine (AQ) plus artesunate. AQ may cause adverse events such as agranulocytosis and hepatoxicity. The pro-drug AQ is transformed by cytochrome P450 CYP2C8 to the active metabolite N-desethylaminodiaquine. Several polymorphic variants of CYP2C8 are known, some with reduced activity. In 200 randomly selected children from Northern Ghana, we determined the allele frequencies of the CYP2C8 variants CYP2C8*1 (wild type), CYP2C8*2, CYP2C8*3, and CYP2C8*4. We did not detect CYP2C8*3 and CYP2C8*4, but CYP2C8*2 showed an allele frequency of 0.1675. AQ metabolism in patients with CYP2C8*2 may be impaired, and with an increase of AQ based treatment the risk of severe adverse events may mount.

Opsonization with a trifunctional bispecific (alphaCD3 x alphaEpCAM) antibody results in efficient lysis in vitro and in vivo of EpCAM positive tumor cells by cytotoxic T lymphocytes.

Removab is a trifunctional bispecific antibody which can bridge CD3+ T cells and epithelial cell adhesion molecule positive (EpCAM+) tumor cells, and binds with its Fc fragment to antigen presenting cells. To explore a new approach for the treatment of patients with carcinoma of the upper aerodigestive tract, we investigated whether Removab can induce specific cellular responses to the EpCAM+ carcinoma cell line BHY. Particular emphasis was put on the opsonization of peripheral blood mononuclear cells (PBMN) with respect to clinical application. Tumor cells and allogeneic PBMN of healthy volunteers were incubated with or without Removab. In a third group, PBMN were opsonized with Removab and washed before incubation with tumor cells. Inverse microscopy, ELISPOT, flow cytometry analysis and cytotoxicity assays on the chorioallantois membrane (CAM) were performed. In comparison with PBMN alone, opsonization with Removab resulted in: a) activation of CD83+ antigen presenting cells, b) secretion of interferon gamma, and c) granzyme B mediated lysis of targeted BHY cells by EpCAM specific CD8+ T cells. The secretion of tumor necrosis factor alpha, interferon gamma and interleukin-2 by opsonized PBMN was significantly reduced after 24 h. Washed opsonized PBMN maintained their lytic activity against tumor cells as tested on the CAM. Removab is an appropriate agent for the therapeutic amplification of T cell responses against EpCAM+ tumor cells by opsonization of PBMN without putting patients at risk for severe adverse events caused by a cytokine storm.

Sublingual immunotherapy: what lessons can we draw from recent studies?

Allergen-specific immunotherapy, together with drugs and allergen avoidance, is a cornerstone in the management of respiratory allergy. The traditional subcutaneous route is burdened by the risk of severe adverse events; therefore, safer routes of administration (e.g. local routes) have been developed and are being investigated. Controlled clinical trials have failed to demonstrate the clinical efficacy and the safety of oral or bronchial administration, and these routes have been abandoned. Local nasal immunotherapy proved effective and safe in 17 of 18 controlled trials; thus it could be considered to be a viable route of immunotherapy. Nevertheless, nasal immunotherapy is effective in rhinitis only and requires a particular administration technique; therefore, its use is slowly declining. In contrast, the efficacy of sublingual administration in the treatment of asthma and rhinitis in adults and children is supported by numerous controlled trials. The safety profile, assessed in clinical trials and post-marketing surveillance studies, is satisfactory; the most frequent side effects are gastrointestinal complaints, which can be easily managed by proper adjustment of the dose. The World Health Organization now considers sublingual immunotherapy as a valid alternative to the subcutaneous route, including its use in children. The long-lasting efficacy of treatment via the sublingual route has been documented recently but a number of points still need to be investigated, including mechanisms of action, optimal dosage, cost-effectiveness and patient's adherence.

Immunothérapie spécifique : acquis et avenir

Specific immunotherapy involves the administration of allergen extracts to achieve clinical tolerance of the allergens which cause symptoms in patients with allergic conditions. Immunotherapy has been shown to be effective in patients with mild forms of allergic diseases, specially in upper airway diseases. Recent studies suggest that specific immunotherapy may also modify the course of allergic disease, by reducing the risk of developing new allergic sensitizations, and also inhibiting the development of clinical asthma in children treated for allergic rhinitis. The traditional subcutaneous route is burdened with the risk of severe adverse events, therefore, local routes have been investigated and developed. The sublingual route is supported by numerous controlled trials showing its efficacy in rhinitis. The safety profile, assessed in clinical trials studies, is satisfactory. Several points still need to be elucidated, including mechanisms of action, optimal dosage, cost-effectiveness, and adherence. New approaches using mimic bacterial DNA vaccines alone or associated to modified allergen, which enhances immunogenicity in terms of eliciting a Th1-type response vaccines, are also undergoing serious consideration.

REPORTS OF ADVERSE EVENTS TO BLOOD TRANSFUSION IN SLOVENIA IN 2002

Background. The risk of severe adverse events to blood transfusion is very low. More frequent are adverse events to transfusion, which are not severe, but must also be treated. Introduction of the haemovigilance system is a way of detecting and analysing them in order to correct their cause and to prevent their recurrence. Methods. In 2002 we collected data on transfusion adverse events registered by the Blood Transfusion Centre of Slovenia and blood transfusion departments in Slovene general hospitals. Results. 86 adverse events to transfusion were reported in 2002. The most frequent were non-haemolytic fever (42 cases) and allergic reactions (27 cases). 5 cases of haemolysis and 1 of pulmonary oedema were also reported. 11 cases were not categorised. Conclusions. We suppose that the collected data is not complete. However, it does give us insight into the clinical part of the transfusion chain. The most frequently registered adverse events in Slovenia are the same as in other countries. The presented data is the beginning of a systematic registration, using standard forms and reporting. Analysis and a followup activities are the basis for improvement of the blood transfusion safety and quality of treatment.

Adherence to treatment regimen in depressed patients treated with amitriptyline or fluoxetine

Objective: Non-compliance presents a constant challenge to effective therapy. Many studies only investigate early treatment discontinuation and not other measures like adherence to treatment regimen. We compared adherence in depressed patients using either a selective serotonin reuptake inhibitor (fluoxetine) or a tricyclic antidepressant (amitriptyline), and examined its clinical relevance through adverse events, drop-out rates, and outcome. Adherence was measured electronically with the MEMS (Medication Event Monitoring System). Design: Nine-week double blind, randomized controlled trial. Setting: Ambulatory psychiatric care. Patients: Random sample of 66 depressed (DSM-III-R criteria) patients. Intervention: Fluoxetine 20 mg or amitriptyline 150 mg. Main outcome measures: Time course of adherence and its relation to severe adverse events, drop-outs and outcome. Results: Non-adherence to the treatment regimen occurred frequently in both treatment groups: 31% of patients had at least one 3-day drug holiday, and 34% of patients had at least one episode of three pills in a 24-h period. Over-consumption occurred more frequently during the early phases of treatment while under-consumption occurred more frequently during the later phases. Patients on amitriptyline ( P=0.03) and patients with a higher pill intake ( P=0.01) experienced more severe adverse events. Patients on amitriptyline ( P=0.009) and patients with a lower adherence to the treatment regimen ( P=0.004) discontinued from treatment more frequently. The final Hamilton score was significantly predicted by a longer duration of treatment and by a better adherence, but only in amitriptyline users. Conclusions: Non-adherence to the treatment regimen has important clinical consequences. Pharmacodynamics and human behavior predict risk for severe adverse events and drop-outs. Moreover, in amitriptyline users but not in fluoxetine users, better adherence predicts a better outcome.

Pharmacokinetic and Metabolic Investigations of Mycophenolic Acid in Pediatric Patients After Renal Transplantation: Implications for Therapeutic Drug Monitoring

The need for mycophenolic acid (MPA) monitoring is still under discussion. Key issues for the PK/PD relationships of this drug are: the role of metabolites, the usefulness of AUC versus predose levels, and the need to monitor the free concentration of MPA (f-MPA). Recent advances have revealed that, in addition to 7-O-MPAG, three additional MPA metabolites are present in the plasma of transplant recipients. One of these metabolites (M-2), identified as an acyl glucuronide of MPA, was found to inhibit IMPDH-II in vitro. This active metabolite was also found to cross-react in the Emit assay for MPA. In an ongoing multicenter study, the authors are evaluating the relevance of monitoring total (t-MPA) and free mycophenolic acid (f-MPA) in pediatric renal transplant recipients. As in adults, a time-dependent increase of t-MPA-AUC(0-12h) within the first 3 months posttransplant (35 versus 64 mg x h/L, [corrected] 3 weeks versus 3 months respectively; daily dosage: 0.6 g/m2 bid) was seen. Receiver operating characteristics curve analyses were used to test the ability of predose levels or AUC(0-12h) to discriminate between cases with no complications and those with acute rejection, adverse events (severe infections, leukopenia), or gastrointestinal disorders observed during the early posttransplant course. In agreement with observations in adults, a significant (p = 0.001) association was observed between AUC(0-12h) and acute rejection. A t-MPA-AUC(0-12h) of approximately 30-60 mg x h/L [corrected], as determined by HPLC, seems to be a reasonable target for the early posttransplant period. It remains to be elucidated whether regular predose level monitoring may be of more practical value. A higher incidence of rejection was observed at predose MPA concentrations < or = 1 mg/L, as measured by HPLC. In contrast to t-MPA, f-MPA-AUC(0-12h) was significantly related to severe infections and leukopenia. The risk for severe adverse events was increased at f-MPA- AUC(0-12h) values > or =600 microg x h/L [corrected]. On the basis of these data and the observed variability in the pharmacokinetics of MPA, the development of monitoring strategies for this drug appears to be promising.

Diphtheria-tetanus-acellular pertussis vaccine adsorbed (Triacelluvax; DTaP3-CB): a review of its use in the prevention of Bordetella pertussis infection.

DTaP3-CB (Triacelluvax) is an acellular pertussis (aP) vaccine containing 3 antigens from purified Bordetella pertussis bacteria combined with diphtheria and tetanus toxoids (DT). In addition to purified filamentous haemagglutinin and pertactin, DTaP3-CB contains pertussis toxin which has been genetically rather than chemically detoxified. As shown in randomised, double-blind clinical trials in infants, DTaP3-CB elicits an immune response similar to or greater than that of whole cell (DTwP) vaccines. Results of a large multicentre study comparing DTaP3-CB with 12 acellular and 1 DTwP vaccine indicate that DTaP3-CB, like all acellular vaccines, induces variable immune responses to different pertussis antigens; however, antibody titres to pertussis toxin are normally higher after immunisation with the genetically detoxified vaccine than with other 3- or 4-component vaccines. When given as a fourth or fifth booster dose, DTaP3-CB produced a significant immune response in infants primed with 3 doses of either a DTaP or DTwP vaccine. Virtually all infants immunised with DTaP3-CB had a serological response to diphtheria and tetanus toxoids. Data from 2 very large efficacy studies indicate that DTaP3-CB has high and long lasting protective efficacy against culture-confirmed pertussis which is greater than that of a 2-component vaccine (DTaP2-SB) and the whole cell DTwP-CON vaccine after a 3-, 5- and 12-month immunisation schedule and after a 2-, 4- and 6-month schedule with the DTwP-CON vaccine. However, the DTwP-CON whole cell vaccine has been noted for its low immunogenicity in 1 study and low efficacy and immunogenicity in another study. On the other hand, DTaP3-CB vaccine has similar efficacy to DTaP3-SB (after immunisation at 2, 4 and 6 months), DTaP5-CON and DTwP-EVANS against culture-confirmed pertussis with > or =21 days cough in infants immunised according to a 3-, 5- and 12-month schedule. Infants immunised with DTaP3-CB experienced significantly fewer adverse events such as pain, redness, swelling and irritability than infants given DTwP. DTaP3-CB has a similar tolerability profile to other acellular vaccines and is associated with similar rates of local tenderness, irritability, fever (> or =40 degrees C) and persistent crying. Comparative trials have shown that infants immunised with DTaP3-CB had a lower incidence of pain at the site of injection and fever (> or =38 degrees C) compared with other acellular vaccines, although this may have little clinical significance. Concomitant administration of DTaP3-CB with hepatitis B, oral polio or Haemophilus influenzae type B vaccines did not affect the immunogenicity of these other paediatric vaccines. Data from clinical trials with DTaP3-CB vaccine indicate that this vaccine induces high and long lasting efficacy. It is at least as efficacious as most whole cell vaccines and generally similar in efficacy to the most efficacious acellular pertussis vaccines containing 3 or more pertussis antigens. DTaP3-CB is better tolerated than whole cell vaccines and has a similar tolerability profile to other acellular vaccines; the possible lower risk of severe adverse events remains to be confirmed. The low reactogenicity of DTaP3-CB is likely to make it well tolerated and therefore well accepted for the immunisation of infants, thereby enabling wider implementation of vaccination programmes.