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Summary: Background: Thiopurine hypermethylation towards 6‐methylmercaptopurine (6MMP) instead of 6‐thioguanine nucleotides (6TGN) is associated with inefficacy in patients with IBD. Allopurinol reverses such hypermethylation. Aims: To prospectively determine efficacy of allopurinol‐thiopurine combination and to compare 2 doses of allopurinol. Design: In a multicentre, double‐blind trial, patients with clinically active or steroid‐dependent IBD and thiopurine shunting were randomised to 50 or 100 mg/d allopurinol and 25% of their screening thiopurine dose, which was subsequently optimised, aiming for 6TGN of 260‐500 pmol/8x108RBCs. The primary endpoint was steroid‐free clinical remission at 24 weeks. Results: Of 73 patients, 39 (53% [95% CI 42‐65]) achieved steroid‐free remission, (54% with 50 mg/d and 53% with 100 mg/d). 81% were able to discontinue steroids. Therapeutic 6TGN levels were achieved in both groups. Final thiopurine doses were lower with 100 mg/d allopurinol (P < 0.005). 6MMP: 6TGN ratio decreased from mean 64 to 4 (P < 0.001), being higher with 50 mg/d (6 ± 1.83) than for 100 mg/d ([1 ± 0.16], P = 0.003). Three patients on 50 mg/d failed to sustain low ratios at 24 weeks. Toxicity was minimal; three patients on 50 mg/d allopurinol developed transient leukopenia. Alanine aminotransferase concentrations decreased (P < 0.001) similarly in both arms. Faecal calprotectin levels at study end were lower in patients who achieved the primary endpoint (median 171 [85‐541] vs 821[110‐5892] ug/g, P = 0.03). Conclusions: Low‐dose allopurinol‐thiopurine combination safely reverses shunting and optimises 6TGN with associated improvement in disease activity. 100 mg/d allopurinol is preferable due to greater metabolite profile stability and lower thiopurine dose without additional toxicity. [ABSTRACT FROM AUTHOR]

Background Therapeutic drug monitoring ( TDM) in inflammatory bowel disease ( IBD) patients receiving anti-tumour necrosis factor ( TNF) agents can help optimise outcomes. Consensus statements based on current evidence will help the development of treatment guidelines. Aim To develop evidence-based consensus statements for TDM-guided anti- TNF therapy in IBD. Methods A committee of 25 Australian and international experts was assembled. The initial draft statements were produced following a systematic literature search. A modified Delphi technique was used with 3 iterations. Statements were modified according to anonymous voting and feedback at each iteration. Statements with 80% agreement without or with minor reservation were accepted. Results 22/24 statements met criteria for consensus. For anti- TNF agents, TDM should be performed upon treatment failure, following successful induction, when contemplating a drug holiday and periodically in clinical remission only when results would change management. To achieve clinical remission in luminal IBD, infliximab and adalimumab trough concentrations in the range of 3-8 and 5-12 μg/mL, respectively, were deemed appropriate. The range may differ for different disease phenotypes or treatment endpoints-such as fistulising disease or to achieve mucosal healing. In treatment failure, TDM may identify mechanisms to guide subsequent decision-making. In stable clinical response, TDM-guided dosing may avoid future relapse. Data indicate drug-tolerant anti-drug antibody assays do not offer an advantage over drug-sensitive assays. Further data are required prior to recommending TDM for non-anti- TNF biological agents. Conclusion Consensus statements support the role of TDM in optimising anti- TNF agents to treat IBD, especially in situations of treatment failure. [ABSTRACT FROM AUTHOR]

Background Plasma concentrations of the anticoagulant dabigatran are correlated with clinical outcomes, and are affected by renal function, intestinal P-glycoprotein ( P-gp) activity and stomach acidity. Aims To determine the adherence to dabigatran etexilate renal dosing guidelines, the frequency of co-prescription of potentially interacting drugs in patients on dabigatran, and how these related to dabigatran dosing. Methods A retrospective chart review of 204 patients discharged from a tertiary hospital on dabigatran etexilate over a 12-month period. Creatinine clearance, using the Cockcroft- Gault equation, was used as the surrogate of renal function in the 86 patients where this was calculable. Results Prescribed dabigatran etexilate dose rates in relation to creatinine clearance and the manufacturer's guidelines were classified as 'standard', 'low' and 'high' in 47% (40/86), 49% (42/86) and 5% (4/86) of patients respectively. Co-prescribed drugs that potentially interact with dabigatran etexilate were present in 75% (154/204) of patients and included strong P-gp inhibitors (16%, 32/204), proton-pump inhibitors (46%, 94/204) and anti-platelet drugs (47%, 95/204). Co-prescription of strong P-gp inhibitors was associated with the prescription of 'low' dose rates relative to renal function ( P = 0.025). Conclusions Few patients were dosed excessively in relation to creatinine clearance. Around 50% was prescribed with 'low' dose rates in relation to creatinine clearance, which because of the association with co-prescription of strong P-gp inhibitors may be clinically appropriate. Most patients were co-prescribed with drugs that potentially interact with dabigatran etexilate. [ABSTRACT FROM AUTHOR]

Background Up to 20% of patients on thiopurine therapy fail to achieve adequate drug response. Many of these patients preferentially produce the toxic 6-methylmercaptopurine metabolites (6-MMP) rather than the active 6-thioguanine nucleotides (6-TGN) resulting in a high 6-MMP/6-TGN ratio (>20) and increased risk of hepatotoxicity. Aim To determine the prevalence of preferential 6-MMP producers and define the relationships between 6-TGN, 6-MMP and thiopurine methyltransferase (TPMT). Methods The database of 6-TGN, 6-MMP and TPMT measurements from patients throughout New Zealand was used to calculate patients' 6-MMP/6-TGN ratios and identify those with high (>20) or normal ratio (≤20).The TPMT enzyme activity was compared amongst the groups. Results Of 1879 patients with TPMT, 6-TGN and 6-MMP results, 349 (19%) had a 6-MMP/6-TGN ratio >20. The mean TPMT enzyme activity was slightly lower for those with a 6-MMP/6-TGN ratio ≤20 vs. >20, which achieved statistical significance (12.2 vs. 13.2; P < 0.001). However, the distributions of TPMT enzyme activity were similar, with 97% of TPMT results falling between 5.0 and 17.6 IU/mL for both groups. In all, 17% of those with 6-MMP/6-TGN ratio ≤20 were intermediate TPMT metabolisers (TPMT 5.0-9.2 IU/mL) vs. 7% in those with a ratio >20. Conclusions In this patient population with measured 6-MMP/6-TGN ratios, 19% of patients were preferential 6-MMP producers. The results show that high TPMT enzyme activity is not the major reason for preferential 6-MMP production in most patients with a high metabolite ratio. This suggests that there are one or more important alternative mechanisms for preferentially producing 6-MMP. [ABSTRACT FROM AUTHOR]

The treatment of gout requires a lowering of serum urate (SU) levels, and allopurinol is the drug that is most commonly used for this purpose. The objectives of this study were to define the relationships between allopurinol dose on the one hand and plasma oxypurinol, renal function, and SU levels on the other and to determine the minimum plasma oxypurinol concentration that would result in a target level of <6 mg/dl (0.36 mmol/l) of SU. For this purpose, 82 patients who had been receiving allopurinol for at least 1 month were recruited. Patients with SU <6 mg/dl were followed up quarterly for 12 months. In patients with SU ≥6 mg/dl, the dose of allopurinol was increased to bring the level of SU to <6 mg/dl. These patients were followed up once a month until the SU level remained at <6 mg/dl for 3 consecutive months; thereafter they were seen quarterly. SU, creatinine, and plasma oxypurinol were measured 6-9 hours after administration of the allopurinol dose. There were significant inverse correlations between creatinine clearance (CrCl) and plasma oxypurinol (P = 0.002), between allopurinol dose and SU (P < 0.0001) and between plasma oxypurinol and SU (P < 0.0001). Using receiver operating characteristic analysis, the target SU of <6 mg/dl was achieved in 75% of serum samples with plasma oxypurinol levels of >100 µmol/l (15.2 mg/l). Increasing the allopurinol dose resulted in increased plasma oxypurinol and reduced SU concentrations. Plasma oxypurinol concentrations >100 µmol/l were required to achieve SU <6 mg/dl. [ABSTRACT FROM AUTHOR]

The article focuses on adolescent clinical pharmacology. It notes that puberty is both a physiological and psychological transition wherein teenagers are prone to drinking, smoking, unprotected sexual intercourse, and prohibited drugs. They are likely to acquire nutritional disorders that can affect their quality of life such as obesity and anorexia nervosa. The authors suggest that the development of new drugs for adolescents require an analysis of their physiological and psychosocial changes.

Background: ECG and BNP have been assessed as screening tests for LVSD and heart failure. However, echocardiography also provides information about valvular disease and LVH. We assessed how good these screening tests are in identifying whether the subsequent echocardiogram will have any significant abnormality. Aims: To re-appraise the ECG and BNP as screening tests for echocardiography since there are important practical deficiencies in our current knowledge in this area. Methods: General practitioners referred suspected heart failure patients for clinical assessment, echocardiography, electrocardiography, and BNP measurement. The accuracy of each screening test and combinations of screening tests were calculated for LVSD, heart failure, valvular disease, and LVH. Results: The sensitivities of the ECG for LVSD, heart failure, LVH and valvular disease were 97%, 95%, 76%, and 69%, respectively. The corresponding figures for BNP were 86%, 82%, 59%, and 48%, respectively. When patients with atrial fibrillation and murmurs were excluded, the values for ECG were 94%, 87%, 53%, and 55%, while for BNP they were 83%, 73%, 50%, and 32%. Conclusions: ECG interpretation and BNP are adequate screening tests to detect LVSD or heart failure but fail to screen for other echocardiographic abnormalities, like valvular disease and LVH. This remains the case even if patients with atrial fibrillation or heart murmurs are excluded on the basis that they require echocardiography anyway. [ABSTRACT FROM AUTHOR]

Abstract Background: Azathioprine and 6-mercaptopurine (6‐MP) are well established for the treatment of inflammatory bowel disease (IBD). Assessing thiopurine methyltransferase (TPMT) status has been recommended to reduce the risk of serious toxicity. Measuring red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) concentrations has been recommended for dose adjustment. Aim: To describe the results of measuring TPMT activity and genotype, and 6-TGN concentration in New Zealand. Methods: Canterbury Health Laboratories provided these analyses for New Zealand. Those with low TPMT activity also underwent genotyping. All results were collated and analysed descriptively. 6-TGN concentrations were correlated with the dose of thiopurine when known. Results: TPMT enzyme activity (range 1–22 U/mL) from 574 patients showed a trimodal distribution. Genotyping results matched this distribution with only mild overlap between *1/*1 homozygote and *1/*3 heterozygote groups. One patient without TPMT measurement before therapy had life-threatening neutropenia and was later found to have *3/*3 genotype. TPMT analysis probably prevented two further such cases. Of 884 6-TGN concentrations (range 0–1434 pmol/108 RBC), 41, 39 and 20% were within, below, and above the therapeutic range of 235–450 pmol/108 RBC, respectively. Leucopenia was seen in some patients with high 6-TGN. 6‐MMP concentrations in 177 patients with low 6-TGN suggested non-compliance in 31, underdosing in 130, and preferential metabolism of 6-MP to 6-methylmercaptopurine in 16. There was poor correlation between azathioprine dose and 6-TGN concentration ( r2 = 0.002), supporting 6-TGN monitoring. Conclusions: Measurement of TPMT enzyme activity and 6-TGN concentration has been well-integrated into clinical practice. These tests should reduce the risk of toxicity and improve efficacy with thiopurines in patients with IBD. (Intern Med J 2005; 35: 580–585) [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the effect of a novel pudendal nerve stimulator on clinical and anorectal manometric parameters in patients with faecal incontinence. Retrospective cohort analysis of consecutive patients presenting with faecal incontinence who had failed initial conservative treatment and were not suitable for surgical intervention in a university hospital incontinence clinic. Biofeedback using a pudendal nerve stimulator comprising a bipolar electrode applied to the base of the clitoris or penis. Electrical pulse voltage was self-titrated and defined periods of treatment were prescribed. Anorectal manometry and Cleveland incontinence scores were assessed. There was a significant reduction in incontinence symptom score after pudendal nerve stimulator treatment in the 42 patients treated and who had a complete set of data (median age 57 years (range 37–81); 39 female, 3 male). This was accompanied by significant improvements ( P < 0.05) in anal sphincter tone, maximal tolerated rectal volume and the sustained rectoanal inhibitory reflex. An externally applied pudendal nerve stimulator improves symptoms and physiological evidence of faecal incontinence but long-term follow up is not available for these patients. [ABSTRACT FROM AUTHOR]

Summary Background : Azathioprine and mercaptopurine (MP) are well established treatments for inflammatory bowel disease but they have severe adverse effects that prevent their use in some patients. The likelihood and type of adverse effect may relate to thiopurine methyltransferase (TPMT) enzyme activity and genotype. Aim : To compare the TPMT genotype frequencies in patients with inflammatory bowel disease who have had severe adverse effects to those who tolerate azathioprine or MP (controls). Methods : Patients with inflammatory bowel disease who had been treated with azathioprine or MP in Christchurch between 1996 and 2002 were identified. Patients with adverse effects, and controls, were invited to provide a peripheral blood sample for analysis of TPMT genotype. The genotype frequencies were then compared between the two groups. Results : Fifty-six patients were identified with adverse effects requiring cessation of therapy, of which 50 were genotyped. Reactions included allergic-type (25%), hepatitis (33%), nausea/vomiting (14%), bone marrow suppression (10%), pancreatitis (6%) and other (12%). Five of 50 patients with reactions had TPMT genotype *1 /*3 , one had *3 /*3 , and the rest had the wildtype genotype *1 /*1 . The patient with genotype *3 /*3 had severe pancytopenia requiring hospitalization. Three of 50 controls had the *1 /*3 genotype and the rest were *1 /*1 . Conclusions : The TPMT allele frequency in our population with inflammatory bowel disease is similar to that reported elsewhere. There was a slight trend for more frequent TPMT mutations in the patients with adverse reactions, but this was not statistically significant. Most patients with reactions did not have gene mutations. [ABSTRACT FROM AUTHOR]

Summary: The fungus Fusarium solani detoxifies cyanide through induction of the cyanide hydratase gene activity (chy ) in the presence of either KCN or the metal-complexed cyanides, K[sub 2] Ni(CN)[sub 4] or K[sub 4] Fe(CN)[sub 6] , at pH 7.0 and 4.0 respectively. Sequence analysis of the chy gene identified primers for reverse transcriptase–polymerase chain reaction (RT–PCR)-directed analysis of mRNA transcripts, which demonstrated that activity correlated to the substrate-specific induction of gene expression. chy transcription was initiated 30–60 min after exposure of F. solani cultures to cyanide complexes. Maximum expression was detected within 4.5 h, after which chy mRNA synthesis declined below the limits of detection within 26 h. A lag period of approx. 2 h, following initial transcription, was recorded before cyanide complexes were converted to formamide. mRNA transcripts of chy were not detected in the absence of cyanide or cyanide complexes. The presence of introns within the gene resulted in a difference in size of 100 bp for DNA compared with mRNA of the corresponding 5′ region. This size difference facilitated PCR detection of gene and transcript respectively. Comparisons of the predicted amino acid sequence of the F. solani chy gene and those of Gloeocerospora sorghi , Fusarium lateritium and Leptosphaeria maculans demonstrate that cyanide hydratase genes are highly conserved and of a similar evolutionary origin. These data predict that the functional assay described here to monitor the induction of chy gene expression and, potentially, cyanide degradation would be applicable to a variety of polluted environments. [ABSTRACT FROM AUTHOR]

Proton pump inhibitors have dramatically influenced the management of acid-peptic disorders in recent years. They all have a broadly similar mechanism of action and are extensively metabolized in the liver via cytochromes P450 2C19 and 3A4. There is some variation in their potential for drug interactions due to differences in enzyme inhibition. Relatively few serious adverse effects have been reported for the proton pump inhibitors. Comparative studies of acid suppression suggest that lansoprazole and pantoprazole have a potency similar to that of omeprazole on a mg for mg basis; however, rabeprazole may have a greater potency than omeprazole. Lansoprazole and rabeprazole display a more rapid onset of maximal acid suppression than the other proton pump inhibitors. Comparative studies using proton pump inhibitors for the treatment of reflux oesophagitis, duodenal ulcer healing and Helicobacter pylori eradication show little overall difference in outcome between the proton pump inhibitors when used in their standard doses. Lansoprazole and rabeprazole provide earlier and better symptom relief than the other proton pump inhibitors in some studies of peptic ulcer treatment. The few studies of gastric ulcer treatment suggest that there is an advantage in using the proton pump inhibitors that have a higher standard daily dose. [ABSTRACT FROM AUTHOR]

The authors discuss a study published in an issue of the periodical focusing on the role of vedolizumab in treatment and cause of extra-intestinal manifestations of inflammatory bowel disease. Topics discussed include the lesions such as pyoderma gangrenosum, erythema nodosum and aphthous stomatitis; the prevalence of peripheral arthritis, ankylosing spondylitis and sacroiliitis; and the lack of efficacy of anti-rheumatic agents (DMARDs) such as methotrexate and sulphasalazine in treatment.

A response by P. Chin and colleagues to a letter to the editor on their article "High TPMT enzyme activity does not explain drug resistance due to preferential 6-methylmercaptopurine production in patients on thiopurine treatment" in the 2012 issue is presented.

A letter to the editor is presented regading Vitamin D receptor gene polymorphism linked with inflammatory bowel disease among male patients in New Zealand.

Reports a case of Mycobacterium avium paratuberculosis (MAP) infection in Crohn's disease patients. Hypotheses on the cause Crohn's disease; Characteristics of MAP; Performance of a duplex polymerase chain reaction to confirm the identity of the organism.

Background: Azathioprine and mercaptopurine are considered safe during pregnancy. However, the pharmacokinetic effects of pregnancy on thiopurine metabolism are undefined., Aims: To characterise thiopurine metabolism in pregnancy and measure infant metabolite levels and outcomes., Methods: Women with IBD who were taking a thiopurine and pregnant or trying to conceive were recruited. Maternal thiopurine metabolites were measured pre-conception, in each trimester, at delivery and post-partum. Infant metabolite levels, full blood examination and liver function testing were performed at birth, and repeated until levels undetectable and haematological and biochemical abnormalities resolved., Results: Forty patients were included with measurements on at least two occasions, and two with only mother-baby levels at delivery. The median maternal 6-TGN level dropped in the second trimester compared with post-partum (179.0 vs 323.5 pmol/8 × 10 8 RBCs, P < 0.001) and the median 6-MMP level increased in the second trimester compared with post-partum (1103.0 vs 329.5 pmol/8 × 10 8 RBCs, P < 0.01). At delivery, the median 6-TGN level was lower in infants (n = 20) than mothers (78.5 vs 217 pmol/8 × 10 8 RBCs) (P < 0.001). Metabolites were not detected at 6 weeks in any infants. Anaemia was not seen, but thrombocytosis and abnormal liver biochemistry were detected in 80% of infants from 6 weeks, which gradually improved., Conclusions: 6-TGN levels decrease and 6-MMP levels increase in the second trimester of pregnancy. Infants are exposed to thiopurine metabolites at low levels with clearance by 6 weeks and no anaemia. The cause of infant thrombocytosis and abnormal liver biochemistry in the absence of metabolites is unclear., (© 2021 John Wiley & Sons Ltd.)

Introduction: Glycaemic control in women with gestational diabetes mellitus (GDM) has typically been achieved with diet, exercise and insulin therapy. Controversy exists in the literature about a potential role for metformin., Methods: A literature review was completed aiming to compare the glycaemic control, maternal and fetal out comes of metformin therapy with insulin. Searches were completed on databases, including Medline, PubMed and ScienceDirect. Seven randomised control trials (RCTs) fit the inclusion criteria, with a total sample size of 1514 women., Results: The majority of studies found no difference in glycaemic control between metformin and insulin groups. When comparing maternal outcomes, those receiving metformin therapy recorded less maternal weight gain in four studies. A number of studies reported lower rates of neonatal hypoglycaemia, and one reported higher rates of preterm birth in the metformin group. There were no other differences in the recorded maternal and fetal outcomes., Discussion: The Jadad score for assessing risk of bias for most included studies was either 3 or 4. The criteria for diagnosis of GDM, maternal and neonatal complications varied between studies. Only one study has published follow-up data, and most are single-centre trials with relatively small sample sizes., Conclusion: Though there is a growing body of evidence to suggest a role for metformin in GDM management, further large-scale, multicentre RCTs are needed before guidelines can be altered., (© 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Background: Up to 20% of patients on thiopurine therapy fail to achieve adequate drug response. Many of these patients preferentially produce the toxic 6-methylmercaptopurine metabolites (6-MMP) rather than the active 6-thioguanine nucleotides (6-TGN) resulting in a high 6-MMP/6-TGN ratio (>20) and increased risk of hepatotoxicity., Aim: To determine the prevalence of preferential 6-MMP producers and define the relationships between 6-TGN, 6-MMP and thiopurine methyltransferase (TPMT)., Methods: The database of 6-TGN, 6-MMP and TPMT measurements from patients throughout New Zealand was used to calculate patients' 6-MMP/6-TGN ratios and identify those with high (>20) or normal ratio (≤20).The TPMT enzyme activity was compared amongst the groups., Results: Of 1879 patients with TPMT, 6-TGN and 6-MMP results, 349 (19%) had a 6-MMP/6-TGN ratio >20. The mean TPMT enzyme activity was slightly lower for those with a 6-MMP/6-TGN ratio ≤20 vs. >20, which achieved statistical significance (12.2 vs. 13.2; P < 0.001). However, the distributions of TPMT enzyme activity were similar, with 97% of TPMT results falling between 5.0 and 17.6 IU/mL for both groups. In all, 17% of those with 6-MMP/6-TGN ratio ≤20 were intermediate TPMT metabolisers (TPMT 5.0-9.2 IU/mL) vs. 7% in those with a ratio >20., Conclusions: In this patient population with measured 6-MMP/6-TGN ratios, 19% of patients were preferential 6-MMP producers. The results show that high TPMT enzyme activity is not the major reason for preferential 6-MMP production in most patients with a high metabolite ratio. This suggests that there are one or more important alternative mechanisms for preferentially producing 6-MMP., (© 2012 Blackwell Publishing Ltd.)

Aims: The aim of this study was to explore whether genetic variation of cytochrome P450 2C9 (CYP2C9) contributes to NSAID-associated gastric ulceration. The hypothesis tested was that CYP2C9 poor metabolizer genotype would predict higher risk of gastric ulceration in patients on NSAIDs that are metabolized by CYP2C9, due to higher plasma NSAID concentrations., Methods: Peripheral blood DNA samples from 23 people with a history of gastric ulceration attributed to NSAIDs metabolized by CYP2C9, and from 32 people on NSAIDs without gastropathy, were analysed to determine CYP2C9 genotype., Results: The following genotypes were found: *1/*1 (wild type) in 70% of cases and 58% of controls, *1/*2 in 17% of cases and 29% of controls, *1/*3 in 13% of cases and 13% of controls. The difference between case and control nonwild-type genotype frequency was 11.5% (95% CI -14,37%), with the direction of the difference being against the hypothesis. No individuals with homozygote poor metaboliser genotype were identified. The differences in genotype frequencies between the two groups were not significant and the frequencies were similar to those in a large published population study. Ninety-five percent binomial confidence interval analysis confirms that there is no apparent clinically significant relationship between CYP2C9 genotype and risk of gastric ulceration although a small difference in risk in poor metabolizers cannot be excluded., Conclusions: These results do not support the hypothesis that gastric ulceration resulting from NSAID usage is linked to the poor metabolizing genotypes of CYP2C9.

Aims: To review the basis and optimal use of therapeutic drug monitoring of antimicrobial agents., Methods: Antimicrobial agents for which a reasonable case exists for therapeutic drug monitoring are reviewed under the following headings: pharmacokinetics, why monitor, therapeutic range, individualization of therapy, sampling times, methods of analysis, interpretative problems and cost-effectiveness of monitoring., Results: There is a strong historical case for monitoring aminoglycosides. The recent move to once-daily dosing means that criteria for therapeutic drug monitoring need to be redefined. Vancomycin has been monitored routinely but many questions remain about the most appropriate approach to this. A case can be made for monitoring teicoplanin, flucytosine and itraconazole in certain circumstances., Conclusions: The approach to monitoring aminoglycosides is being redefined in the light of once daily dosing. It may be that less stringent monitoring is required in some circumstances but toxicity, especially ototoxicity, remains a problem with these drugs. Monitoring to avoid high AUCs (areas under the concentration-time curve) is recommended. The ideal method for monitoring vancomycin remains to be defined although a reasonable case exists for measuring trough concentrations, mainly to ensure efficacy. Teicoplanin is sometimes monitored to ensure efficacy while flucytosine may be monitored to avoid high concentrations associated with toxicity. Itraconazole has various pharmacokinetic problems and monitoring has been suggested to ensure that adequate concentrations are achieved.

Aim: To compare the pharmacokinetics of lansoprazole in patients with reflux oesophagitis and in healthy volunteers, after a single dose and at steady-state., Patients and Methods: A 30 mg dose of lansoprazole was administered orally daily for 7 days in eight healthy male volunteers aged 21-24 years, and in 16 patients aged 29-65 years with grade 2 or 3 reflux oesophagitis. The pharmacokinetics were assessed over the 24 h dose interval following the first dose and again after the 7th dose., Results: Within both the patient and volunteers groups, there were no significant differences between day 1 and day 7 in any of the pharmacokinetic parameters including maximum concentration (Cmax), area under the concentration-time curve (AUC), and terminal half-life of elimination (t(1/2)). However, on both days 1 and 7, values were significantly higher in the patients than in the healthy volunteers. On day 7, Cmax was 1343 ng/mL in patients compared with 765 ng/mL in healthy volunteers, AUC was 3458 ng.h/mL vs. 1350 ng.h/mL and t(1/2) was 1.62 h vs. 0.90 h., Conclusion: The differences in results for the pharmacokinetics reflect reduced lansoprazole clearance in the patient group. Other research has not found a difference in pharmacokinetics when comparing healthy volunteers with patients with acid-related disorders. The difference in lansoprazole clearance in this study may be related to a variety of factors that are different in patients compared with young normal volunteers, such as age, gender, other drugs, and reduced general well-being.

Aims: To review the basis and optimal use of therapeutic drug monitoring of antimicrobial agents., Methods: Antimicrobial agents for which a reasonable case exists for therapeutic drug monitoring were reviewed under the following headings: pharmacokinetics, why monitor, therapeutic range, individualisation of therapy, sampling times, methods of analysis, interpretative problems and cost-effectiveness of monitoring., Results: There is a strong historical case for monitoring aminoglycosides. The recent move to once-daily dosing means that criteria for therapeutic drug monitoring need to be redefined. Vancomycin has been monitored routinely but many questions remain about the most appropriate approach to this. A case can be made for monitoring teicoplanin, flucytosine and itraconazole in certain circumstances., Conclusions: The approach to monitoring aminoglycosides needs to be redefined in the light of once-daily dosing. It is premature to suggest that less stringent monitoring is necessary as toxicity remains a problem with these drugs. The ideal method of monitoring vancomycin remains to be defined although a reasonable case exists for measuring trough concentrations, mainly to ensure efficacy. Teicoplanin is monitored occasionally to ensure efficacy while flucytosine is monitored occasionally to avoid high concentrations associated with toxicity. Itraconazole has various pharmacokinetic problems and monitoring has been suggested to ensure that adequate concentrations are achieved.

1. Once-daily aminoglycoside dosing has many advantages and has been widely advocated. However, existing guidelines for methods of administration and monitoring are non-specific and may lead to excessive dosing. 2. The traditional approach of aiming for target peak and trough concentrations is not appropriate for once-daily dosing. 3. A method is proposed which uses a target area under the concentration-time curve (AUC) for the aminoglycoside based on the 24 h AUC that would result with conventional dosing. This method requires measurement of two drug concentrations, one approximately 0.5 h after the end of the infusion and another at a later time (6-22 h) depending on renal function. 4. A simpler, graphical method is also proposed for patients with normal renal function, which requires the measurement of a single concentration at a time between 6 and 14 h. 5. Both methods are likely to be safer than existing guidelines.

1. The aminoglycoside antibiotics are 50 years old. Their success and continuing use can be attributed to various factors including rapid concentration-dependent bactericidal effect, synergism with beta-lactam antibiotics, clinical effectiveness, a low rate of true resistance and low cost. 2. The aminoglycosides remain drugs of choice in many circumstances including septicaemia, other serious infections due to Gram negative bacilli, and bacterial endocarditis. 3. Nephrotoxicity and ototoxicity have been the main drawbacks clinically for the aminoglycosides. 4. There has been an evolution in dosing strategies largely aimed at reducing toxicity. Therapeutic drug monitoring has been used extensively to assist dosing, and target concentrations have been advocated, such as peak concentrations of between 6 and 10 mg l-1 and through concentrations of < 2 mg l-1 for gentamicin, tobramycin and netilmicin. 5. Recently there has been a minor revolution in the approach to aminoglycoside dosing, with a change to larger doses, given less frequently. In its most convenient form this is 'Once-daily aminoglycoside dosing'. It offers the hope of better efficacy, less toxicity, and easier administration and monitoring. 6. This article summarises the background of aminoglycoside usage, leading up to the recent changes in dosing strategy.