ABSTRACT
OBJECTIVE: Past studies have suggested a potential "J shaped" relationship between infrarenal aortic diameter and both cardiovascular disease (CVD) prevalence and all cause mortality. However, screening programmes have focused primarily on large (aneurysmal) aortas. In addition, aortic diameter is rarely adjusted for body size, which is particularly important for women. This study aimed to investigate specifically the relationship between body size adjusted infrarenal aortic diameter and baseline prevalence of CVD. METHODS: A retrospective analysis was performed on a total of 4882 elderly (>50 years) participants (mean age 69.4 ± 8.9 years) for whom duplex ultrasound to assess infrarenal abdominal aortic diameters had been performed. History of CVDs, including ischaemic heart disease (IHD), and associated risk factors were collected at the time of assessment. A derivation cohort of 1668 participants was used to select cut offs at the lower and upper 12.5% tails of the aortic size distributions (aortic size index of <0.84 and >1.2, respectively), which was then tested in a separate cohort. RESULTS: A significantly elevated prevalence of CVD, and specifically IHD, was observed in participants with both small and large aortas. These associations remained significant following adjustment for age, sex, diabetes, hypertension, dyslipidaemia, obesity (body mass index), and smoking. CONCLUSION: The largest and smallest infrarenal aortic sizes were both associated with prevalence of IHD. In addition to identifying those with aneurysmal disease, it is hypothesised that screening programmes examining infrarenal aortic size may also have the potential to improve global CVD risk prediction by identifying those with small aortas.
Subject(s)
Aorta, Abdominal/diagnostic imaging , Myocardial Ischemia/epidemiology , Ultrasonography, Doppler, Duplex , Aged , Female , Humans , Male , Middle Aged , Myocardial Ischemia/diagnostic imaging , New Zealand/epidemiology , Predictive Value of Tests , Prevalence , Prognosis , Retrospective Studies , Risk Assessment , Risk Factors , Time FactorsABSTRACT
OBJECTIVE: Recently, the prevalence of abdominal aortic aneurysm (AAA) using screening strategies based on elevated cardiovascular disease (CVD) risk was reported. AAA was defined as a diameter ≥30 mm, with prevalence of 6.1% and 1.8% in men and women respectively, consistent with the widely reported AAA predominant prevalence in males. Given the obvious differences in body size between sexes this study aimed to re-evaluate the expanded CVD risk based AAA screening dataset to determine the effect of body size on sex specific AAA prevalence. METHODS: Absolute (26 and 30 mm) and relative (aortic size index [ASI] equals the maximum infrarenal aorta diameter (cm) divided by body surface area (m2), ASI ≥ 1.5) thresholds were used to assess targeted AAA screening groups (n = 4115) and compared with a self reported healthy elderly control group (n = 800). RESULTS: Male AAA prevalence was the same using either the 30 mm or ASI ≥1.5 aneurysm definitions (5.7%). In females, AAA prevalence was significantly different between the 30 mm (2.4%) and ASI ≥ 1.5 (4.5%) or the 26 mm (4.4%) thresholds. CONCLUSION: The results suggest the purported male predominance in AAA prevalence is primarily an artefact of body size differences. When aortic size is adjusted for body surface area there is only a modest sex difference in AAA prevalence. This observation has potential implications in the context of the ongoing discussion regarding AAA screening in women.
Subject(s)
Aortic Aneurysm, Abdominal/epidemiology , Body Surface Area , Mass Screening , Age Distribution , Confounding Factors, Epidemiologic , Female , Humans , New Zealand/epidemiology , Prevalence , Risk Assessment/methods , Sex DistributionABSTRACT
A case series of hepatotoxicity associated with an extract of Artemisia annua L. was identified through the New Zealand spontaneous adverse drug reaction reporting system. A. annua extract, produced using a supercritical carbon dioxide extraction method and formulated with grapeseed oil, has been marketed in New Zealand as a natural product for joint health. As of 31 January 2019, the New Zealand Pharmacovigilance Centre had received 29 reports of hepatic adverse reactions occurring in patients taking A. annua extract in grapeseed oil. The case reports were assessed for patient and adverse reaction characteristics, patterns of A. annua extract use and causality (based on the WHO-UMC system for standardized case causality assessment). Patients were aged 47 to 93 years (median 67). Time to onset of hepatotoxicity from starting A. annua extract was 7 days to approximately 12 months in the 23 reports with this information. Nineteen of these reports indicated onset within 12 weeks. A. annua extract was the sole suspect medicine in 27 reports. A few patients had possible predisposing conditions. Twenty-seven patients were reported to have recovered or improved on stopping A. annua extract. Nine patients required hospital admission. The pattern of hepatic injury varied. Jaundice, often with pruritus and dark urine, was experienced by 16 patients. There was considerable consistency across case reports from various reporters. We assessed the case reports as a series using the Bradford Hill guidelines for causal inference and concluded that there was a safety signal of a causal association between the A. annua extract and hepatotoxicity sufficient to be communicated and investigated further.
ABSTRACT
RATIONALE: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. OBJECTIVE: To identify additional AAA risk loci using data from all available genome-wide association studies. METHODS AND RESULTS: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. CONCLUSIONS: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.
Subject(s)
Aortic Aneurysm, Abdominal/diagnosis , Aortic Aneurysm, Abdominal/genetics , Genetic Loci/genetics , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study/methods , Aortic Aneurysm, Abdominal/epidemiology , Genetic Predisposition to Disease/epidemiology , Genetic Variation/genetics , Genome-Wide Association Study/trends , HumansABSTRACT
OBJECTIVE: This prospective study sought to track the natural history of duplex ultrasound (DUS) detected varicose vein recurrence in the groin after surgical intervention during a 5-year period. METHODS: Patients were recruited from a previous prospective trial investigating outcomes after high ligation and stripping with and without patch saphenoplasty. Follow-up examinations of the lower limb venous systems using DUS, air plethysmography, and clinical assessment were carried out at 1, 6, 12, and 36 months. At 60 months, an additional detailed DUS scan of the groin was performed on those with recurrence, including vessel numbers, diameter, and reflux velocity, to characterize the state of this groin recurrence. RESULTS: In the 130 limbs at 5 years, ultrasound groin recurrence was detected in 82%, and visible varicose veins occurred in 83% (108 limbs). In contrast, recurrence with severe varices occurred in 47% (61 limbs) as clinical recurrence (Venous Clinical Severity Score less the stocking component >3) in 22% (29 limbs) and functional recurrence (venous filling index >2 mL/s) in 34% (43/125 limbs). The DUS pattern was junctional in 29 limbs (22%), nonjunctional in 37 limbs (29%), and mixed pattern in 40 limbs (31%). Compared with the 24 (19%) with no ultrasound-detected recurrence, severe visible varicose veins were significantly more common with each of these patterns and especially with multiple connecting vessels (odds ratio, 5.4; confidence interval, 1.5-19.5). The diameter and velocity of reflux through recurrent vessels in the groin did not correlate with disease severity, and no DUS feature in the groin was predictive of Venous Clinical Severity Score >3 or a venous filling index >2 mL/s. The appearance of DUS recurrence within the first year and other features, including residual lower leg reflux, body mass index, gender, and previous treatment, were more consistent predictors. CONCLUSIONS: Early ultrasound recurrence is predominantly evidence of neovascularization and some small-vessel remodeling at the site of treatment. When it occurs, some visible varicose veins are inevitable. However, these appearances alone are not good predictors of severe clinical recurrence.
Subject(s)
Groin/blood supply , Saphenous Vein/surgery , Varicose Veins/diagnostic imaging , Varicose Veins/surgery , Vascular Surgical Procedures , Aged , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prospective Studies , Recurrence , Treatment Outcome , Ultrasonography, Doppler, DuplexABSTRACT
BACKGROUND AND OBJECTIVE: Artemisinin combination therapies such as artemether-lumefantrine (AL) are effective for first-line treatment of uncomplicated acute Plasmodium falciparum malaria. However, the safety profile of AL in large populations has not been fully assessed. The objective of this study was to establish the safety of AL in public health facilities in Tanzania using the Cohort Event Monitoring (CEM) method. METHODOLOGY: Patients who presented to public health facilities in four regions of Tanzania who were prescribed AL were enrolled in a CEM study, a prospective, observational cohort study to establish a profile of adverse events (AEs) for the medicine when used in routine clinical practice. Pre- and post-treatment forms were used to record baseline information and new health events before and 7 days after treatment. RESULTS: A total of 8040 patients were enrolled in the study, of whom 6147 were included in the analysis. Following treatment initiation, a total of 530 AEs were reported in 6% (383) of the patients. The most frequent post-treatment AEs were in alimentary system (42%), including vomiting, nausea, diarrhoea, abdominal pain and anorexia, followed by AEs in the neurological system (25%). Causality assessment of the events showed that 51.9% (275/530) were possibly related to AL. There was a significant difference in the frequency of AEs by age-group with an increase in the number of AEs as age increased (P < 0.001). There was no statistically significant difference in the frequency of the events between males and females (P = 0.504). The AE profile was consistent with the AEs reported in the product information and in other studies; no new adverse drug reactions were identified. The majority of the reported AEs were the same as the symptoms of malaria and therefore indistinguishable from the underlying disease. CONCLUSIONS: The safety profile of AL for treatment of malaria continues to be favourable. CEM as a pharmacovigilance tool has proven to provide reliable safety data in a short period.
Subject(s)
Antimalarials/administration & dosage , Antimalarials/adverse effects , Artemisinins/administration & dosage , Artemisinins/adverse effects , Drug Monitoring/methods , Ethanolamines/administration & dosage , Ethanolamines/adverse effects , Fluorenes/administration & dosage , Fluorenes/adverse effects , Malaria/drug therapy , Adolescent , Adult , Artemether, Lumefantrine Drug Combination , Child , Child, Preschool , Cohort Studies , Drug Combinations , Drug Monitoring/trends , Drug-Related Side Effects and Adverse Reactions/diagnosis , Drug-Related Side Effects and Adverse Reactions/epidemiology , Female , Health Facilities/trends , Humans , Infant , Malaria/epidemiology , Male , Middle Aged , Nausea/chemically induced , Prospective Studies , Tanzania/epidemiology , Vomiting/chemically induced , Young AdultABSTRACT
INTRODUCTION: Cohort event monitoring (CEM) is an intensive method of post-marketing surveillance for medicines safety. The method is based on prescription event monitoring, which began in the 1970s, and has since been adapted by WHO for monitoring the safety of medicines used in Public Health Programmes. CEM aims to capture all adverse events that occur in a defined group of patients after starting treatment with a specific medicine during the course of routine clinical practice. OBJECTIVE: The aims of this study were to describe the experiences of National Pharmacovigilance Centres (NCs) that have used CEM to monitor artemisinin-based combination therapy (ACT) for uncomplicated malaria in the African setting, to raise awareness of some of the challenges encountered during implementation and to highlight aspects of the method that require further consideration. METHOD: A questionnaire-based survey was conducted to capture the experiences of NCs that have implemented CEM for active post-marketing surveillance of antimalarial medicines in sub-Saharan Africa. Six NCs were identified as having implemented CEM programmes and were invited to participate in the survey; five NCs indicated willingness to participate and were sent the questionnaire to complete. RESULTS: Four NCs responded to the survey-Ghana, Kenya, Nigeria and Zimbabwe-providing information on the implementation of a total of six CEM programmes. Their experiences indicate that CEM has helped to build pharmacovigilance capacity within the participating NCs and at the monitoring sites, and that healthcare providers (HCPs) are generally willing to participate in implementing the CEM method. All of the programmes took longer than expected to complete: contributing factors included a prolonged enrolment period and unexpectedly slow data entry. All of the programmes exceeded their budget by 11.1-63.2 %. Data management was identified as a challenge for all participating NCs. CONCLUSIONS: The reported experiences of four NCs that have undertaken CEM studies on ACTs indicate that CEM has helped to build pharmacovigilance capacity within NCs and monitoring sites and that HCPs are willing to participate in CEM programmes; however, the method was found to be labour intensive and data management was identified as a challenge. Reducing the workload associated with CEM, particularly in relation to data management, and integrating the method into the routine work of HCPs and NCs should be considered for future implementation.
Subject(s)
Antimalarials/adverse effects , Pharmacovigilance , Surveys and Questionnaires , Cohort Studies , Ghana/epidemiology , Humans , Kenya/epidemiology , Nigeria/epidemiology , Prospective Studies , Zimbabwe/epidemiologySubject(s)
Adverse Drug Reaction Reporting Systems , Antitubercular Agents/adverse effects , Thioacetazone/adverse effects , Tuberculosis/drug therapy , Antitubercular Agents/pharmacokinetics , Drug Resistance, Multiple, Bacterial/drug effects , Global Health , Humans , Pharmacovigilance , Thioacetazone/pharmacology , World Health OrganizationABSTRACT
BACKGROUND: Highly trained vascular sonographers make up a significant cost of abdominal aortic aneurysm (AAA) ultrasound screening. However, they are over-trained for this very limited task. Others have reported that health workers (e.g. emergency room staff and nurses) with far less training may be able to perform these scans. The national AAA screening programme in the UK uses staff with limited training. Whether individuals without a health professional qualification could be trained to perform the scan accurately to improve cost-effectiveness is not known. We aimed to investigate whether a short, well-supervised course in ultrasonography could train novices to detect AAA for screening purposes. METHODS: Three novices were trained by an experienced sonographer for 15 days to perform abdominal aortic ultrasound examinations and detect AAA using a portable ultrasound system. The examination included four anterior-posterior aortic measurements: a maximal diameter in the coronal plane and three diameters of the suprarenal, mid and distal infrarenal aorta in the transverse plane. The novices independently scanned 215 subjects following training; experienced sonographers repeated the measurements on the same subject in the same session. Using Bland-Altman plots and CUSUM analysis, the novices' and experienced sonographers' accuracy and efficiency measurements were compared. Factors influencing performance were recorded. RESULTS: The novices measured the maximal coronal aortic diameter accurately, to within 0.46-0.52 cm of the true diameter; 85-97% of their coronal measurements were within 0.5 cm of the assessors; kappa statistic and Bland-Altman plots show a high agreement with the assessor's measurements. However, the novices' measurements of the three diameters in the transverse plane were outside clinically acceptable limits. Assuming a referral policy for a second scan for scans recorded as 'difficult', only one novice missed a 3.13 cm aneurysm.A CUSUM quality improvement analysis demonstrated substantial improvements in the scanning efficiency of the novices with continued scanning experience. CONCLUSION: This study showed that novices could be trained to screen for AAA over 15 days. However, the need for continuing quality improvement is critical, especially in more technically demanding cases. Measuring the maximal infrarenal diameter instead of specific segmental diameters may be more appropriate for AAA screening using novices.
Subject(s)
Aortic Aneurysm, Abdominal/diagnostic imaging , Cardiology/education , Mass Screening , Professional Competence , Radiology/education , Female , Humans , Male , New Zealand , Reproducibility of Results , Sensitivity and Specificity , UltrasonographyABSTRACT
OBJECTIVE: To determine the role of microvenous valves in the superficial venous system in the prevention of reflux and skin changes in the progression of venous insufficency. METHODS: The venous anatomy of 15 amputated lower limbs, eight free from clinical venous disease and seven with varicose veins and ulcers, was examined using retrograde venography corrosion casting. Prior to amputation, all limbs were scanned by duplex ultrasound to confirm the presence or absence of reflux in the great (GSV) and small saphenous veins or their tributaries. The resulting resin casts were photographed and mapped to show the position, orientation, and competency of valves in the superficial venous network. Casts were also examined by scanning electron microscopy. RESULTS: Retrograde venous filling was demonstrated in the "normal" limbs despite a competent GSV. Microvalves were identified down to the sixth generation of tributaries from the GSV. Only in regions where incompetence existed in microvalves out to the third (ie, the "boundary") generation was the resin able to penetrate deeper into microvenous networks of the dermis. This was despite the presence of subsequent competent valves, which were able to be bypassed in the network. In limbs with varicose veins and venous ulcers, reflux into the small venous networks and capillary loops was more extensive with more dense networks and greater tortuousity. CONCLUSIONS: This study demonstrates that valvular incompetence can occur independently in small superficial veins in the absence of reflux within the GSV and the major tributaries. We have shown that once there is incompetence of the third generation "boundary" microvalves, reflux can extend into the microvenous networks in the skin. These effects are markedly worse in the presence of GSV incompetence. We propose that degenerative changes with valve incompetence are required in both the larger proximal vessels and the small superficial veins, in particular at the "boundary" valve level, for the severe skin changes in venous insufficiency to occur.
Subject(s)
Leg/blood supply , Skin/blood supply , Venous Insufficiency/physiopathology , Venous Valves/physiopathology , Venules/physiopathology , Aged , Aged, 80 and over , Cadaver , Female , Humans , Male , Middle AgedABSTRACT
The alpha-7 neuronal nicotinic receptor is a novel pharmacological target for psychiatric and cognitive disorders. Selective radiotracer tools for pre-clinical receptor occupancy can facilitate the interpretation of the biological actions of small molecules at a target receptor. We discovered a high affinity nicotinic alpha-7 subtype-selective ligand, AZ11637326, with physical-chemical and pharmacokinetic properties suitable for an in vivo radioligand tool. [(3)H]AZ11637326 synthesis by tritiodehalogenation of the corresponding tribromide precursor yielded a high specific activity radiotracer with high affinity alpha-7 receptor binding in the rat hippocampus determined by autoradiography (Kd = 0.2 nM). When [(3)H]AZ11637326 was administered to rats by intravenous bolus, rapid uptake was measured in the brain followed by a 3-4 fold greater specific binding in regions containing the alpha-7 receptor (frontal cortex, hippocampus, hypothalamus and midbrain) when compared to non-target regions (striatum and cerebellum). Systemic administration of the high affinity alpha-7 receptor antagonist, methyllycaconitine (MLA), or pretreatment with alpha-7 selective agonists (AR-R17779, PyrQTC, DBCO-4-POM, and DBCO-3-POM) significantly blocked the alpha-7 specific binding of [(3)H]AZ11637326 in the rat brain. The rank order of ligand ED(50) values for in vivo alpha-7 receptor occupancy in rat hippocampus was: DBCO-4-POM > DBCO-3-POM â¼ MLA > PyrQTC > AR-R17779. The occupancy affinity shift was consistent with in vitro binding affinity in autoradiography. Our studies established the optimal conditions for [(3)H]AZ11637326 in vivo specific binding in the rat brain and support the use of [(3)H]AZ11637326 as a pre-clinical tool for assessment of novel alpha-7 compounds in drug discovery.
Subject(s)
Azabicyclo Compounds/metabolism , Brain/metabolism , Drug Delivery Systems/methods , Receptors, Nicotinic/metabolism , Spiro Compounds/metabolism , Tritium/metabolism , Animals , Azabicyclo Compounds/administration & dosage , Azabicyclo Compounds/chemistry , Brain/drug effects , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Ligands , Male , Protein Binding/physiology , Rats , Rats, Sprague-Dawley , Spiro Compounds/administration & dosage , Spiro Compounds/chemistry , Tissue Distribution/drug effects , Tissue Distribution/physiology , Tritium/administration & dosage , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
Radiotracers suitable for positron emission tomography studies often serve as preclinical tools for in vivo receptor occupancy. The serotonin 1B receptor (5-HT(1B)) subtype is a pharmacological target used to discover treatments for various psychiatric and neurological disorders. In psychiatry, 5-HT(1B) antagonists may provide novel therapeutics for depression and anxiety. We report on the in vitro and in vivo evaluation of tritiated 5-methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylicacid (4-morpholin-4-yl-phenyl)-amide ([N-methyl-(3)H(3)]AZ10419369), a potent 5-HT(1B) radiotracer. [N-methyl-(3)H(3)]-AZ10419369 showed saturable single-site high-affinity in vitro binding (guinea pig, K(d) = 0.38 and human, K(d) = 0.37) to guinea pig or human 5-HT(1B) receptors in recombinant membranes and high-affinity (K(d) = 1.9 nM) saturable (B(max) = 0.099 pmol/mg protein) binding in membranes from guinea pig striatum. When [N-methyl-(3)H(3)]AZ10419369 was administered to guinea pigs by intravenous bolus, the measured radioactivity was up to 5-fold higher in brain areas containing the 5-HT(1B) receptor (striatum/globus pallidus, midbrain, hypothalamus, and frontal cortex) compared with the cerebellum, the nonspecific binding region. Specific uptake peaked 30 min after injection with slow dissociation from target regions, as suggested by the in vitro binding kinetic profile. Pretreatment with 6-fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin-1-yl)-phenyl]-amide (AZD1134) and 2-aminotetralin (AR-A000002), 5-HT(1B)-selective ligands, inhibited [N-methyl-(3)H(3)]AZ10419369-specific binding in a dose-dependent manner. In the guinea pig striatum, AZD1134 (ED(50) = 0.017 mg/kg) occupies a greater percentage of the 5-HT(1B) receptors at a lower administered dose than AR-A000002 (ED(50) = 2.5 mg/kg). In vivo receptor occupancy is an essential component to build binding-efficacy-exposure relationships and compare novel compound pharmacology. [N-methyl-(3)H(3)]AZ10419369 is a useful preclinical tool for investigating 5-HT(1B) receptor occupancy for novel compounds targeting this receptor.
Subject(s)
Benzopyrans/metabolism , Morpholines/metabolism , Piperazines/metabolism , Radiopharmaceuticals/metabolism , Receptor, Serotonin, 5-HT1B/metabolism , Serotonin 5-HT1 Receptor Antagonists , Serotonin Antagonists/metabolism , Tritium/metabolism , Animals , Benzopyrans/chemical synthesis , Benzopyrans/pharmacology , CHO Cells , Cell Line , Cricetinae , Cricetulus , Guinea Pigs , Haplorhini , Humans , Male , Morpholines/chemical synthesis , Morpholines/pharmacology , Piperazines/chemical synthesis , Piperazines/pharmacology , Protein Binding/drug effects , Protein Binding/physiology , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/pharmacology , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacologyABSTRACT
AIM: To examine a New Zealand case series of clozapine-associated myocarditis. METHODS: All cases of myocarditis in the Intensive Medicines Monitoring Programme's (IMMP) clozapine database were identified and reviewed. RESULTS: 25 cases of myocarditis associated with the use of clozapine have been reported to the IMMP. The majority of cases (84%) were male and the mean age was 35.5 years. Myocarditis occurred at daily clozapine doses ranging from 12.5 mg to 500 mg. Eighty percent of the cases developed within 1 month of starting the medicine, although in three cases the onset was more than a year after commencing clozapine. Of the 25 cases, 2 patients died. CONCLUSIONS: This New Zealand case series of clozapine-associated myocarditis is similar to a recent Australian case series. Clozapine-associated myocarditis most often occurs within 1-2 months of starting clozapine, but it may develop at any time while on the medicine, and can occur even at very low doses. A data-linkage study using national morbidity and mortality datasets could estimate the incidence of clozapine-associated myocarditis in New Zealand.
Subject(s)
Adverse Drug Reaction Reporting Systems , Antipsychotic Agents/adverse effects , Clozapine/adverse effects , Myocarditis/chemically induced , Myocarditis/epidemiology , Adolescent , Adult , Aged , Antipsychotic Agents/administration & dosage , Clozapine/administration & dosage , Cohort Studies , Databases, Factual , Female , Humans , Male , Middle Aged , Myocarditis/therapy , New Zealand/epidemiology , Retrospective Studies , Risk Factors , Survival RateABSTRACT
PURPOSE: To describe patterns of sibutramine usage in New Zealand during the first 3 years of marketing using data acquired during post-marketing safety surveillance. METHODS: Demographic and prescription data were examined from a nationwide cohort of 17 298 patients prescribed sibutramine between 1 February 2001 and 31 March 2004. Outcome measures were age and sex distribution of the cohort; period prevalence of sibutramine usage for each ethnic group; duration of treatment and reasons for cessation of therapy. Limited BMI data were also examined. RESULTS: About 0.5% of the NZ population were prescribed sibutramine in the period studied. Overwhelmingly, the highest users of sibutramine were NZ European women aged 30-59 years. Maori and Pacific Peoples were under-represented in the cohort, despite the higher prevalence of obesity among these populations. Sibutramine usage was predominantly short-term: 59% of the cohort used sibutramine for 90 days or less, half of whom used it for only 1 month. CONCLUSIONS: There has been extensive use of sibutramine in New Zealand. Sibutramine has been relatively under-utilised by Maori and Pacific ethnic groups, compared to New Zealand Europeans, despite their higher prevalence of obesity. A number of factors may have contributed to the predominantly short-term use of this medicine, including the cost of the medicine to the consumer, weight loss not meeting expectations and adverse effects of the medicine.
Subject(s)
Appetite Depressants/therapeutic use , Cyclobutanes/therapeutic use , Obesity/drug therapy , Practice Patterns, Physicians'/statistics & numerical data , Adult , Adverse Drug Reaction Reporting Systems , Age Factors , Cohort Studies , Female , Humans , Male , Middle Aged , Native Hawaiian or Other Pacific Islander/statistics & numerical data , New Zealand , Product Surveillance, Postmarketing , Racial Groups/statistics & numerical data , Sex Factors , Time FactorsABSTRACT
AIMS: To investigate a possible association of sibutramine with QT interval prolongation. METHODS: Post-marketing surveillance using prescription event monitoring in the New Zealand Intensive Medicines Monitoring Programme (IMMP) identified a case of QT prolongation and associated cardiac arrest in a patient taking sibutramine for 25 days. This patient was further investigated, including genotyping for long QT syndrome. Other IMMP case reports suggesting arrhythmias associated with sibutramine were assessed and further reports were obtained from the World Health Organisation (WHO) adverse drug reactions database. RESULTS: The index case displayed a novel mutation in a cardiac potassium channel subunit gene, KCNQ1, which is likely to prolong cardiac membrane depolarization and increase susceptibility to long QT intervals. Assessment of further IMMP reports identified five additional patients who experienced palpitations associated with syncope or presyncopal symptoms, one of whom had a QT(c) at the upper limit of normal. Assessment of reports from the WHO database identified three reports of QT prolongation and one fatal case of torsade de pointes in a patient also taking cisapride. CONCLUSIONS: This case series suggests that sibutramine may be associated with QT prolongation and related dysrhythmias. Further studies are required, but in the meantime we would recommend that sibutramine should be avoided in patients with long QT syndrome and in patients taking other medicines that may prolong the QT interval.
Subject(s)
Appetite Depressants/adverse effects , Arrhythmias, Cardiac/chemically induced , Cyclobutanes/adverse effects , Adult , Amino Acid Substitution , Arrhythmias, Cardiac/genetics , Arrhythmias, Cardiac/physiopathology , Electrocardiography/methods , Female , Genetic Testing/methods , Humans , KCNQ1 Potassium Channel/genetics , Long QT Syndrome/chemically induced , Long QT Syndrome/genetics , Long QT Syndrome/physiopathology , Mutation , Product Surveillance, Postmarketing/methods , Syncope/chemically induced , Syncope/physiopathologyABSTRACT
The in vitro pharmacological profile of a novel small molecule corticotropin-releasing factor 1 (CRF(1)) receptor antagonist, (+/-)-N-[2-methyl-4-methoxyphenyl]-1-(1-(methoxymethyl)propyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine (SN003), and the characteristics of its radioligand ([(3)H]SN003) are described. SN003 has high affinity and selectivity for CRF(1) receptors expressed in rat cortex, pituitary, and recombinant HEK293EBNA (HEK293e) cells with respective radiolabeled ovine CRF ([(125)I]oCRF) binding K(i) values of 2.5, 7.9, and 6.8 nM. SN003 was shown to be a CRF(1) receptor antagonist inasmuch as it inhibited CRF-induced cAMP accumulation in human CRF(1)HEK293e cells and CRF-stimulated adrenocorticotropin hormone release from rat pituitary cells without agonist activities. Significant decreases in the B(max) of [(125)I]oCRF binding by SN003 suggest that this antagonist is not simply competitive. To further explore the interaction of SN003 with the CRF(1) receptors, [(3)H]SN003 binding to rat cortex and human CRF(1)HEK293e cell membranes was characterized and shown to be reversible and saturable, with K(D) values of 4.8 and 4.6 nM, and B(max) values of 0.142 and 7.42 pmol/mg protein, respectively. The association and dissociation rate constants of [(3)H]SN003 (k(+1) 0.292 nM(-1) min(-1) and k(-1) 0.992 x 10(-2) min(-1)) were also assessed using human CRF(1)HEK293e cell membranes, giving an equilibrium dissociation constant of 3.4 nM. Moreover, [(3)H]SN003 binding displayed a single affinity state and insensitivity to 5'-guanylylimidodiphosphate, consistent with characteristics of antagonist binding. Incomplete inhibition of [(3)H]SN003 binding by CRF peptides also suggests that SN003 is not simply competitive with CRF at CRF(1) receptors. The distribution of [(3)H]SN003 binding sites was consistent with the expression pattern of CRF(1) receptors in rat brain regions. Small molecule CRF(1) antagonist radioligands like [(3)H]SN003 should enable a better understanding of small molecule interactions with the CRF(1) receptor.
Subject(s)
Pyridines/pharmacology , Radiopharmaceuticals/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Triazoles/pharmacology , Adrenocorticotropic Hormone/metabolism , Animals , Binding Sites , Cell Membrane/drug effects , Cell Membrane/metabolism , Cells, Cultured , Cyclic AMP/metabolism , Humans , Male , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Corticotropin-Releasing Hormone/metabolism , TritiumABSTRACT
4-(1,3-Dimethoxyprop-2-ylamine)-2,7-dimethyl-8-(2,4-dichlorophenyl)-pyrazolo[1,5-a]-1,3,5-triazine (DMP696) is a highly selective and potent, nonpeptide corticotropin-releasing factor 1 (CRF(1)) antagonist. In this study, we measured in vivo CRF(1) receptor occupancy of DMP696 by using ex vivo ligand binding and quantitative autoradiography and explored the relationship of receptor occupancy with plasma and brain exposure and behavioral efficacy. In vitro affinity (IC(50)) of DMP696 to brain CRF(1) receptors measured using the brain section binding autoradiography in this study is similar to that assessed using homogenized cell membrane assays previously. The ex vivo binding assay was validated by demonstrating that potential underestimation of receptor occupancy with this procedure could be minimized by identifying an appropriate in vitro incubation time (40 min) based upon the dissociation kinetics of DMP696. Orally administrated DMP696 dose dependently occupied CRF(1) receptors in the brain, with ~60% occupancy at 3 mg/kg. In the defensive withdrawal test of anxiety, this dose of DMP696 produced approximately 50% reduction in the exit latency. The time course of plasma and brain drug levels paralleled that of receptor occupancy, with peak exposure at 90 min after dosing. The plasma-free concentration of DMP696 corresponding to 50% CRF(1) receptor occupancy (in vivo IC(50), 1.22 nM) was similar to the in vitro IC(50) (~1.0 nM). Brain concentrations of DMP696 were over 150-fold higher than the plasma-free levels. In conclusion, doses of DMP696 occupying over 50% brain CRF(1) receptors are consistent with doses producing anxiolytic efficacy in the defense withdrawal test of anxiety, and the IC(50) value estimated in vivo based on plasma-free drug concentrations is consistent with the in vitro IC(50) value.