A 12-month audit of clozapine associated myocarditis in a South Australian Local Health Network: The importance of screening and personalised titration.

Clozapine is effective in up to 50 % of patients resistant to other antipsychotics. Its use is restricted to third-line due to adverse effects which include myocarditis. Australia reports the highest incidence of clozapine-associated myocarditis (CAM) in the context of pharmacovigilance and relatively rapid titration. An audit of patients commenced on clozapine within the Central Adelaide Local Health Network (CALHN) between 2012 and 2015 found an incidence of 8.6 %. We present here a case series from a follow up audit considering titration relevant risk factors for CAM. We reviewed anecdotal cases and data from all hospital-based commencements of clozapine across CALHN for the period July 2021 to June 2022 using pharmacy and medical record databases. We identified 5 cases of CAM and all had risk factors impacting on clozapine metabolism, including rapid titration, elevated baseline CRP, Asian ethnicity and concomitant treatment with inhibitors of clozapine metabolism. While personalisation of clozapine treatment needs further investigation in prospective trials, slower titration to lower targets for risk groups may not impact on hospital length of stay and has the potential to significantly reduce the burden of adverse events. Australian manufacturer approved titration rates exceed those recommended for personalised dosing and may not be safe for patients with risk factors. Early clozapine levels at week two could identify slow metabolisers for dose adjustment. Closer ties between psychiatrists and cardiologists are critical for the development of protocols for safely maintaining clozapine treatment during low level cardiac inflammation and to support safe rechallenge.

Aspirin deprescribing in primary prevention of cardiovascular disease: a prospective risk-benefit approach.

BACKGROUND: Current evidence and practice guidelines do not recommend aspirin for primary prevention of cardiovascular disease (CVD). Insufficient all-cause mortality benefits juxtaposed to increased gastrointestinal bleeding rates are well established. Pharmacists are well placed to assess the clinical appropriateness of aspirin in CVD and initiate deprescribing as required with medical colleagues. AIM: The aim of this study was to identify medical inpatients taking aspirin for primary prevention of CVD and initiate deprescribing utilising a risk-benefit approach. METHODS: A single-arm prospective feasibility study of general medicine patients admitted to a major tertiary hospital over 5 weeks (July-August 2020) was conducted. Screened patients were categorised as either taking aspirin for primary or secondary prevention. A 5-year benefit-risk analysis of bleeding and cardiovascular risk was calculated using a validated tool from the Cardiac Society of Australia and New Zealand to guide recommendations. RESULTS: This study screened 277 patients, of which 71 patients were identified as taking aspirin. Ten of these patients (14%) were categorised as taking aspirin for primary prevention and thus were deemed suitable for deprescribing. The analysis showed that aspirin continuance would, on average, increase major bleeding events by 39%, whilst reducing major cardiovascular events by 13.4%. Pharmacists recommended aspirin cessation in seven of the cases identified, and deprescribing was successful in five cases. CONCLUSIONS: This study described an impactful pharmacist-led initiative utilising a validated aspirin-specific tool to conduct risk-benefit analysis to reduce potential major bleeding associated with inappropriate aspirin use.

Continuation of Buprenorphine to Facilitate Postoperative Pain Management for Patients on Buprenorphine Opioid Agonist Therapy.

BACKGROUND: Acute pain management in patients on buprenorphine opioid agonist therapy (BOAT) can be challenging. It is unclear whether BOAT should be continued or interrupted for optimization of postoperative pain control. OBJECTIVES: To determine an evidence-based approach for pain management in patients on BOAT in the perioperative setting, particularly whether BOAT should be continued or interrupted with or without bridging to another mu opioid agonist and to identify benefits and harms of either perioperative strategy. STUDY DESIGN: Systematic literature review with qualitative data synthesis. SETTING: Hospital, perioperative. METHODS: The study protocol was registered on PROSPERO (Registration number 9030276355). Medline via OVID, EMBASE, CINAHL, and the Cochrane CENTRAL register of trials were searched for prospective or retrospective observational or controlled studies, case series, and case reports that described perioperative or acute pain care for patients on BOAT. References of narrative and systematic reviews addressing acute pain management in patients on BOAT and references of included articles were hand-searched to identify additional original articles for inclusion. The full text of publications were reviewed for final inclusion, and data were extracted using a standardized data extraction form. Results were summarized qualitatively. Primary outcomes were postoperative pain intensity and total opioid use and identification of benefits and harms of perioperative strategies. RESULTS: Eighteen publications presenting data on the perioperative management of patients on BOAT were identified: 10 case reports, 5 case series, and 3 retrospective cohort studies. Eleven articles reported continuation of BOAT, 2 concerned bridging BOAT, and 4 articles described stopping BOAT without planned bridging. In one retrospective cohort study, BOAT was continued in half and interrupted in half of patients. Patients on BOAT may have pain that is more difficult to treat than those who are not on OAT. There is no clear evidence that one particular strategy provides superior postoperative pain control, but interruption of BOAT may result in harm, including failure to return to baseline BOAT doses, continuing non-BOAT opioid use, or relapse of opioid use disorder. LIMITATIONS: There were a limited number of articles relevant to the study question consisting of case reports and retrospective observational studies. Some omitted relevant details. No prospective studies were found. CONCLUSIONS: There is no clear benefit to bridging or stopping BOAT but failure to restart it may pose concerns for relapse. We recommend continuing BOAT in the perioperative period when possible and incorporating an interdisciplinary approach with multimodal analgesia. KEY WORDS: Opioid use disorder, opiate substitution treatment, buprenorphine, buprenorphine-naloxone, buprenorphine opioid agonist therapy, postoperative pain, acute pain, multimodal analgesia.

Clinical characteristics and outcome of lone atrial fibrillation at a tertiary referral centre: the Groote Schuur Hospital experience.

INTRODUCTION: Atrial fibrillation (AF) is a relatively common arrhythmia. When AF represents an electrophysiological phenomenon in structurally normal hearts, it is termed lone AF. This study was a retrospective, case-based analysis of patients attending the Cardiac Clinic at Groote Schuur Hospital (GSH) and describes the clinical characteristics and outcomes of patients classified as having lone atrial fibrillation. To the best of our knowledge there are no such studies reported from Africa. METHODS: This was a retrospective, descriptive study in which 289 medical records of patients with AF at the GSH Cardiac Clinic were reviewed from 1992 to 2006. The clinical data were interrogated to exclude identifiable causes of AF. Information on clinical characteristics and outcomes were entered into a data-entry form. Baseline descriptive statistics were expressed as means and range for continuous variables, and counts with percentages for categorical variables. RESULTS: Fifteen per cent (n = 42) of patients were identified as having lone AF, with a mean follow-up time of 5.8 years. Males comprised 57% (n = 24) and females 43% (n = 18). Fifty per cent (n = 21) of the patients had paroxysmal AF, 29% (n = 12) had persistent AF, and 12% (n = 5) progressed from paroxysmal to permanent AF. Subsets of lone AF included concomitant atrial flutter (17%) (n = 7) and sick sinus syndrome (21%) (n = 9). Complications were stroke (10%) (n = 4), tachycardia-related cardiomyopathy (17%) (n = 7) and bleeding complications on warfarin (11%) (n = 3). CONCLUSIONS: Lone AF is not an uncommon arrhythmia, with a preponderance in thin, middle-aged males. The symptoms of lone AF can be debilitating. It has associated morbidity, including tachycardia-related cardiomyopathy and thromboembolism. Rate control and appropriate anticoagulation are the cornerstones of patient management.

Serratia marcescens Bullous Cellulitis in a Splenectomized Patient: A Case Report and Review of the Literature.

Serratia marcescens is a Gram-negative bacillus belonging to the Enterobacteriaceae family. Cutaneous infection with Serratia is rare, and usually occurs in immunocompromised individuals. Primary cutaneous infections are uncommon, but they are typically severe and are associated with significant morbidity and mortality. The pathogenetic factors leading to S. marcescens infection are not fully understood, but contributing virulence factors include proteases, secreted exotoxins, and the formation of biofilm. We report a case of cellulitis occurring in a splenectomized patient, which led to multiple wound debridements and a transmetatarsal amputation. This dramatic case led us to review the published literature on soft tissue infections caused by S. marcescens.

Gene-gene interactions of drug metabolizing enzymes and transporter protein in the risk of upper aerodigestive tract cancers among Indians.

BACKGROUND: The combined genetic effects of single nucleotide polymorphisms may additively or synergistically contribute to the increased cancer risk. The interactions associated with xenobiotic metabolizing enzymes and transporter protein involved in the biotransformation and transport of xenobiotics could determine the functional outcomes over the independent effects of a single susceptibility gene in the risk of upper aerodigestive tract cancers. METHODS: The hospital-based case-control study evaluated CYP1A1 (*2A and *2C), CYP2E1 (*1B, *5B, and *6), GST (M1, T1, and P1) and ABCB1 3435C>T polymorphisms among 408 histopathologically confirmed cases and 220 controls using polymerase chain reaction based methods in an Indian population. RESULTS: The multivariate logistic regression analyses demonstrated potentially high risk gene-gene interactions with the concurrent deletions of the GSTT1 and GSTM1 genes and GSTP1 variant genotypes (OR 5.81; 95% CI 1.01-40.28), the deletions of GSTT1 and GSTM1 genotypes with variant genotypes of CYP1A1*2A (OR 8.21; 95% CI 1.91-49.48), GSTT1 and GSTM1 deficient genotypes along with CYP2E1*1B variant genotypes (OR 6.73; 95% CI 1.32-22.81), the polymorphic genotypes of ABCB1 and deficient GSTT1 (OR 6.08; 95% CI 2.21-16.76) and an enhanced risk with the combined variant genotypes of CYP1A1*2A, GSTT1 and ABCB1 (OR 11.14; 95% CI 2.70-46.02). CONCLUSION: The findings indicate that the interactions associated with various drug metabolizing enzymes and transporter protein exhibit high risk for UADT cancers than that ascribed to a single susceptible gene. This was particularly established among the polymorphic carriers of CYP1A1*2A, GSTT1 and ABCB1 genes in the population investigated.

Gene-environment interactions associated with CYP1A1 MspI and GST polymorphisms and the risk of upper aerodigestive tract cancers in an Indian population.

PURPOSE: Genetic risk to tobacco related cancers are associated with polymorphisms in CYP1A1 and GST, which are involved in the metabolic activation and detoxification of carcinogens. The genetic variations in these drug-metabolizing enzymes may alter the susceptibility to UADT cancers triggered by environmental exposures. The hospital-based case-control study evaluated the impact of combined CYP1A1 MspI and GST (M1 & T1) polymorphisms among the individuals exposed to environmental risk factors as modulators in the risk of UADT cancers in Tamilians, a population of south India. METHODS: The unrelated histopathologically confirmed 408 cases and 220 population-based controls matched by age and gender were genotyped for CYP1A1 MspI, GSTM1 and GSTT1 polymorphisms using PCR based methods. To investigate the potential gene-environment interactions, analyses were carried out stratifying by smoking and tobacco chewing status using SPSS software. RESULTS: The combination of genes and environment interactions by stratified analyses revealed significant interactions among the habitual tobacco smokers (CYP1A1 MspI & GSTM1 null: OR 14.06; 95% CI 3.90-50.68, CYP1A1 MspI & GSTT1 null: OR 33.28; 95% CI 4.24-261.19) and tobacco chewers (CYP1A1 MspI & GSTM1 null: OR 20.51; 95% CI 6.77-62.13, CYP1A1 MspI & GSTT1 null: OR 79.35; 95% CI 10.40-605.55) on the multiplicative scale. CONCLUSION: Our findings have indicated that the individuals polymorphic for CYP1A1 MspI either with GSTM1 null or with GSTT1 null genotypes revealed an increased risk for UADT cancers than that ascribed to a single susceptible gene among the tobacco users in the population [single gene risk among smokers and chewers, respectively, for CYP1A1 MspI (OR 6.43; 95% CI 3.69-11.21); (OR 10.24; 95% CI 5.95-17.60), GSTM1*0 (OR 3.77; 95% CI 1.94-7.37); (OR 7.97 95% CI 4.10-15.76) and GSTT1*0 (OR 6.95 95% CI 2.88-16.77); (OR 25.83 95% CI 7.78-85.76).

CYP1A1 polymorphisms and the risk of upper aerodigestive tract cancers in an Indian population.

BACKGROUND: The inter-individual differences in upper aerodigestive tract (UADT) cancer risk may be partly attributed to the polymorphic variability in the CYP1A1 gene that is involved in the metabolic activation of xenobiotics to carcinogenic reactive metabolites. METHODS: The hospital-based case-control study evaluated CYP1A1*2A and CYP1A1*2C polymorphisms in 408 histopathologically confirmed cases and 220 controls using polymerase chain reaction-restriction fragment length polymorphism methods. RESULTS: The multivariate logistic regression analyses demonstrated that CYP1A1 *1A/*2A (odds ratio [OR] 1.76; 95% Confidence interval [CI] 1.19-2.60) and *2A/*2A (OR 2.83; 95% CI 1.43-5.61) genotypes were significantly associated with increased risk for UADT cancers. The gene-environment interaction analyses revealed a significant interaction among tobacco smokers and chewers carrying CYP1A1*2A mutant genotypes on the multiplicative scale. CONCLUSION: CYP1A1*2A polymorphic genotypes are associated with an enhanced risk to UADT cancers, in particular, among the habitual tobacco smokers and chewers carrying mutant genotypes in the Tamilians of the Indian population.

ABCB1 genetic polymorphism and risk of upper aerodigestive tract cancers among smokers, tobacco chewers and alcoholics in an Indian population.

BACKGROUND AND OBJECTIVE: Upper aerodigestive tract (UADT) cancers are associated with the tobacco use and alcohol consumption. Certain toxins and carcinogens causing UADT cancers are found to be substrates of polymorphic ABCB1 gene encoded P-glycoprotein efflux pump. This study investigates the association between ABCB1 gene polymorphism at exon 26 (3435C>T) and risk to UADT cancers in Tamilians, a population of south India. METHODS: The study included 219 unrelated histopathologically confirmed cases and 210 population-based controls. Genomic DNA was extracted from peripheral leukocytes and genotyped for ABCB1 3435C>T polymorphism by PCR-restriction fragment length polymorphism method. RESULTS: The multivariate logistic regression analyses demonstrated that the homozygous ABCB1 TT genotype was significantly associated with an overall increased risk for developing UADT cancers [odds ratio (OR): 2.53; 95% confidence interval (CI): 1.28-5.02]. Further, the determination of gene-environment interaction by stratified analyses have revealed a significant interaction between the smoking and homozygous TT genotype [(OR: 7.52; CI: 1.50-37.70) and (OR: 16.89; CI: 3.87-73.79) for 11-20 and >20 pack-years, respectively]. The strongest interaction was observed among the regular tobacco chewers (OR: 45.29; CI: 8.94-130.56) homozygous for TT genotype. No suggestion, however, of an interaction between the genotypes and the alcohol consumption on the multiplicative scale was made. CONCLUSION: The ABCB1 gene polymorphism at exon 26 (3435C>T) may be one of the risk factors for susceptibility to UADT cancers. Furthermore, the significant interaction among habitual smokers and tobacco chewers, homozygous for TT genotype modulates the risk to UADT cancers in the Tamilian population of south India.

A rare association of Ebstein's anomaly of tricuspid valve with rheumatic mitral stenosis.

Mitral valve abnormalities have been described in Ebstein's anomaly, but acquired rheumatic mitral valve disease is an extremely rare association. We describe a classical case of Ebstein's anomaly of tricuspid valve with severe rheumatic mitral stenosis. This patient had mild mitral regurgitation, pulmonary hypertension and atrial fibrillation.