Association between SCN1A polymorphism and carbamazepine-resistant epilepsy

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• The SCN1A gene encodes the α subunit of the neuronal voltage-gated sodium channel, which is a target for carbamazepine and other antiepileptic drugs (AEDs).
• Recent studies have demonstrated that a common polymorphism of SCN1A IVS5-91 G > A was associated with carbamazepine and phenytoin use in daily practice.
• However, it has not been determined whether the polymorphism affects carbamazepine or other AED responsiveness.
WHAT THIS STUDY ADDS
• This study demonstrated a significant association between the SCN1A IVS5-91 AA genotype and carbamazepine-resistant epilepsy, while the AA genotype did not affect carbamazepine use.  

AIMS

To establish whether the SCN1A IVS5-91 G > A polymorphism of the SCN1A gene, which encodes the neuronal sodium channel α subunit, affects responsivenss to the antiepileptic drugs (AEDS) carbamazepine and/or phenytoin.  

METHODS

SCN1A IVS5-91 G > A polymorphism was genotyped in 228 Japanese epileptic patients treated with AEDs. The association between AED responsiveness and the polymorphism was estimated by logistic regression analysis, adjusting for clinical factors affecting the outcome of AED therapy.  

RESULTS

The frequency of the AA genotype was significantly higher in carbamazepine-resistant patients (odds ratio, 2.7; 95% confidence interval (CI), 1.1, 7.1) and was insignificantly higher in AED-resistant patients.  

CONCLUSIONS

This is the first report demonstrating an association between the SCN1A polymorphism and carbamazepine-resistant epilepsy.     

Population pharmacokinetics and exploratory pharmacodynamics of ifosfamide according to continuous or short infusion schedules: an n = 1 randomized study

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• The optimal infusion duration for ifosfamide remains to be determined.
• No differences according to time of infusion have been identified in traditional pharmacokinetic endpoints, such as area under the curve.
• The impact on pharmacodynamics has never been modelled or correlated with pharmacokinetics.
WHAT THIS STUDY ADDS
• The pharmacokinetics and pharmacodynamics of ifosfamide and its main metabolites can both be modelled with no influence of infusion duration.
• Pharmacodynamic modelling (renal and haematological toxicity) allows further simulations of new schedules with favourable toxicity profiles.  

AIMS

To model the pharmacokinetics and pharmacodynamics of ifosfamide and its key metabolites. The pharmacodynamic parameters included were renal toxicity and myelosuppression measured using urinary β₂-microglobulin (BMG) and absolute neutrophil count (ANC), respectively.  

METHODS

Seventeen patients were enrolled into an n  = 1 randomized trial during two consecutive cycles of ifosfamide 9 g m⁻² during each cycle given by a 3 h or 72 h infusion. Data were analyzed using NONMEM.  

RESULTS

Ifosfamide and metabolite concentration–time profiles were described by a one-compartment open-model with auto-induction of clearance. BMG and ANC time-courses were related to ifosfamide concentration via indirect response models.  

CONCLUSIONS

This modelling allowed the simulation of weekly schedules of flat doses with favourable myelotoxic profiles.     

Cranberry juice suppressed the diclofenac metabolism by human liver microsomes, but not in healthy human subjects

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Cranberry juice has a significant inhibitory effect on CYP2C9 activity in vitro , whereas it shows a minimal effect on the pharmacokinetics and pharmacodynamics of warfarin, a CYP2C9 substrate in vivo .
• Information regarding the interaction between cranberry juice and other medications metabolized by CYP2C9 is limited.
WHAT THIS STUDY ADDS
• Cranberry juice suppressed the metabolism of diclofenac, another CYP2C9 substrate, by human liver microsomes.
• Pharmacokinetic parameters of diclofenac were not altered by cranberry juice consumption in human subjects.  

AIM

To investigate a potential interaction between cranberry juice and diclofenac, a substrate of CYP2C9.  

METHODS

The inhibitory effect of cranberry juice on diclofenac metabolism was determined using human liver microsome assay. Subsequently, we performed a clinical trial in healthy human subjects to determine whether the repeated consumption of cranberry juice changed the diclofenac pharmacokinetics.  

RESULTS

Cranberry juice significantly suppressed diclofenac metabolism by human liver microsomes. On the other hand, repeated consumption of cranberry juice did not influence the diclofenac pharmacokinetics in human subjects.  

CONCLUSIONS

Cranberry juice inhibited diclofenac metabolism by human liver microsomes, but not in human subjects. Based on the present and previous findings, we think that although cranberry juice inhibits CYP2C9 activity in vitro , it does not change the pharmacokinetics of medications metabolized by CYP2C9 in clinical situations.     

Limited frequency of the CYP2C19*17 allele and its minor role in a Japanese population

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• A novel CYP2C19 gene variant, CYP2C19 * 17 , is associated with increased metabolic activity.
• Ethnic differences in the frequency of the variant allele have been reported. However, the frequency of the CYP2C19 * 17 allele has not been studied in the Japanese population.
WHAT THIS STUDY ADDS
• In a population of 265 healthy Japanese subjects, a low frequency (1.3%) of the CYP2C19 * 17 allele was observed.
• The limited frequency of the * 17 allele and the absence of a subject homozygous for * 17 indicated that CYP2C19 * 17 would play a minor role in a Japanese population.  

AIMS

We investigated the CYP2C19 * 17 allelic frequency in Japanese subjects, and evaluated whether CYP2C19 * 17 is an important determinant of interindividual variability of CYP2C19 activity.  

METHODS

We enrolled 265 subjects to determine their CYP2C19 genotype and plasma metabolic ratio following a single dose of 40 mg omeprazole.  

RESULTS

Seven subjects heterozygous for CYP2C19 * 17 and no * 17/ * 17 subjects resulted in the CYP2C19 * 17 frequency being 1.3%. These heterozygotes had moderate metabolic activities when compared with the metabolic ratio of the other subjects.  

CONCLUSIONS

The low frequency of CYP2C19 * 17 and the absence of * 17/ * 17 indicates that CYP2C19 * 17 plays a minor role in the Japanese population.     

Transfer of isoniazid from circulation to breast milk in lactating women on chronic therapy for tuberculosis

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Isoniazid is the most widely used first line antituberculosis drug.
• It is considered safe during lactation, but limited data are available on the transfer of isoniazid from circulation to milk in lactating women, which can provide an assessment of extent of exposure to the nursling.
WHAT THIS STUDY ADDS
• The study documents the transfer pattern and milk to plasma (M : P) ratio of isoniazid at a steady state.
• Peak plasma and milk concentrations of isoniazid were reached within 1 h and the projected exposure of the drug to the infant is much lower than the prophylactic dose, supporting its safety during breast feeding.  

AIM

To determine milk to plasma (M : P) ratios and infant dose (absolute and relative) for isoniazid in lactating women on antituberculosis therapy.  

METHODS

Concentrations of isoniazid in plasma and milk were measured in exclusively breast feeding women taking 300 mg day⁻¹ as treatment for tuberculosis.  

RESULTS

Peak plasma and milk concentrations of isoniazid were observed at 1 h. A mean M : P_AUC value of 0.89 (95% CI 0.7, 1.1) was calculated for isoniazid from seven women over 24 h. The mean absolute infant dose was estimated to be 89.9 μg kg day⁻¹ (95% CI 65.6, 114) and the relative infant dose was 1.2% of the weight adjusted maternal dose.  

CONCLUSIONS

The mean relative dose of isoniazid (1.2%) transmitted to the infant via breast milk is below the 10% notional level of concern. These data suggest that isoniazid therapy is safe during breastfeeding.     

Effect of atorvastatin on hs-CRP in acute coronary syndrome

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Markers of inflammation are being investigated as predictors of coronary ischaemic events. All major statins have shown almost similar and significant efficacy in reducing C-reactive protein (CRP) concentrations in acute coronary syndrome (ACS), but atorvastatin was used in a high dose (80 mg).
• This study was designed to evaluate the effect of a lower dose (20 mg) of atorvastatin on hs-CRP concentrations in patients with ACS.
WHAT THIS STUDY ADDS
• A lower dose of atorvastatin (20 mg) was effective in decreasing hs-CRP and LDL concentrations in as short a duration as 4 weeks. The use of a lower dose of atorvastatin in patients of ACS can offer an attractive approach for early treatment of ACS patients.  

AIMS

To evaluate the effect of a lower dose (20 mg) of atorvastatin on hs-CRP concentrations in patients with ACS.  

METHODS

Group A ( n  = 50) patients received atorvastatin 20 mg day⁻¹ for 4 weeks in addition to standard anti-anginal treatment. Group B ( n  = 50) patients received standard anti-anginal treatment without atorvastatin.  

RESULTS

hs-CRP concentrations decreased in both groups, but the decrease was greater in group A. The decrease in hs-CRP was also significantly greater in the subgroups of smoking, hypertension and past history of cardiovascular disease with atorvastatin.  

CONCLUSIONS

The use of a lower dose (20 mg) of atorvastatin can offer an attractive approach for early treatment of patients with ACS.     

Choice of first antihypertensive – are existing guidelines ignored?

What is already known about this subject
• Recommended treatment guidelines for hypertension have been developed to assist GPs' decisions about appropriate therapies.
• The British Hypertension Society's (BHS) 2004 guidelines recommend initial drug choice based on age, and avoidance of β-adrenoceptor blockers in diabetes.
What this study adds
• Prescribing of first-line antihypertensives in Ireland appears guided by age, but mainly for those under 55 years.
• Adherence to the guidelines was in part related to patient gender.
• Presence of concomitant diabetes had a greater influence on the choice of therapy than age of patient.  

Aims

To determine adherence to hypertension guidelines in relation to age and diabetes.  

Methods

The Irish HSE-PCRS prescribing database identified patients initiating antihypertensive monotherapy in 2005. Logistic regression predicted the likelihood of therapy according to guidelines.  

Results

The odds ratio (OR) of receiving therapies according to the guideline recommendations in those <55 years vs.  ≥55 years was 1.31 (95% CI 1.26, 1.37). Diabetics were more likely than nondiabetics to receive antihypertensives other than β-adrenoceptor blockers (OR 2.97, 95% CI 2.74, 3.21).  

Conclusions

Our findings show some adherence to the guidelines in relation to age but selective prescribing of antihypertensives for diabetics.     

How well are general practice trainees prepared for paediatric prescribing?

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Children make up a significant proportion of a general practitioner's (GP's) prescribing workload.
• The realisation that children cannot be assumed to be little adults and may require specialized prescribing and therapeutic knowledge is relatively recent.
• Off-label medicines, which have been associated with an increased frequency of adverse drug reactions, are commonly prescribed by GPs to children.
WHAT THIS STUDY ADDS
• The majority of GP trainees believe that their undergraduate and postgraduate training in paediatric therapeutics is insufficient for their coming requirements in primary care.
• Approximately one-third of GP trainees do not undertake any paediatrics training prior to starting work as a GP.
• Off-label and unlicensed prescribing are the most poorly covered areas of paediatric therapeutics in universities/university hospitals.
• Those trainees who do undergo paediatric training during their vocational years report increased paediatric prescribing confidence.
AIMS AND METHODOLOGY We invited 232 General Practice Trainees to complete an on-line questionnaire to assess how they rated their training for the task of paediatric prescribing and therapeutics in the community.
RESULTS Of the 166 (71%) respondents who completed the questionnaire, 26.5% recalled specific teaching about paediatric prescribing and 59.6% covering one or more relevant topic during their undergraduate years. Undertaking a paediatric post during vocational training was associated with greater prescribing confidence ( P  < 0.001); however, 35% of respondents were not intending to undertake such a post.
CONCLUSION This study suggests that many GP trainees perceive their paediatric prescribing training as inadequate.     

A comparison of serum antivenom concentrations after intravenous and intramuscular administration of redback (widow) spider antivenom

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Widow spider antivenoms, including redback spider antivenom, are often given by the intramuscular route.
• No studies have measured widow spider antivenom following intramuscular or intravenous antivenom.
WHAT THIS STUDY ADDS
• Intramuscular redback spider antivenom is not detectable in serum for at least 3–5 h after treatment. Intravenous antivenom is detectable 30 min after intravenous infusion.
• Intramuscular antivenom may not be an effective administration route.
AIMS There are no studies measuring antivenom concentrations following intramuscular administration. This study aimed to compare antivenom concentrations following intravenous and intramuscular administration of redback spider antivenom (RBSAV).
METHODS Twenty patients recruited to a controlled trial comparing intramuscular and intravenous administration of antivenom had serial blood samples collected at 30 min intervals for 2 h after the administration of one or two doses of antivenom. Antivenom concentration was measured using an enzyme immunoassay.
RESULTS Ten patients received intramuscular antivenom but antivenom could not be detected in serum after either one or two vials, at any time point. The median time of the final sample after commencement of antivenom treatment in these patients was 3.2 h (1.8–5 h). Ten patients received intravenous antivenom (three one vial and seven two or more vials) and antivenom was detected in all patients.
CONCLUSIONS RBS AV given by the intramuscular route is unlikely to be effective in the treatment of redback (widow) spider bite.     

Polypharmacy and potential drug–drug interactions in emergency department patients in the Caribbean

Background Potential Drug–Drug Interactions (DDI) account for many emergency department visits. Polypharmacy, as well as herbal, over-the-counter (OTC) and combination medication may compound this, but these problems are not well researched in low-and-middle-income countries. Objective To compare the incidence of drug–drug interactions and polypharmacy in older and younger patients attending the Emergency Department (ED). Setting The adult ED of a tertiary teaching hospital in Trinidad. Methods A 4 month cross sectional study was conducted, comparing potential DDI in older and younger patients discharged from the ED, as defined using Micromedex 2.0. Main outcome measure The incidence and severity of DDI and polypharmacy (defined as the use of ≥5 drugs simultaneously) in older and younger patients attending the ED. Results 649 patients were included; 275 (42.3%) were ≥65 years and 381 (58.7%) were female. There were 814 DDIs, of which 6 (.7%) were contraindications and 148 (18.2%) were severe. Polypharmacy was identified in 244 (37.6%) patients. Older patients were more likely to have potential DDI (67.5 vs 48.9%) and polypharmacy (56 vs 24.1%). Herbal products, OTC and combination drugs were present in 8, 36.7 and 22.2% of patients, respectively. On multivariate analysis, polypharmacy and the presence of hypertension and ischaemic heart disease were associated with an increased risk of potential DDI. Conclusion Polypharmacy and potential drug–drug interactions are common in ED patients in the Caribbean. Older patients are particularly at risk, especially as they are more likely to be on multiple medications. The association between herbal medication and polypharmacy needs further investigation. This study indicates the need for a more robust system of drug reconciliation in the Caribbean.     

Predictive factors for generalized seizures after deliberate citalopram overdose

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Citalopram is a common means of self-poisoning in young adults.
• Generalized seizures are a recognised complication after selective serotonin reuptake inhibitor overdose (including citalopram overdose).

WHAT THIS STUDY ADDS

• The minimum stated citalopram dose associated with seizures in the absence of co-ingested drugs was 400 mg.
• Co-ingestion of a tricyclic antidepressant or venlafaxine confers a 15-fold increased risk of seizures.

AIMS

Seizures are a recognized complication of citalopram overdose. The present study sought to establish risk factors for seizures in this high-risk patient group, including stated dose ingested, co-ingested drugs or ethanol, and electrolyte disturbances.

METHODS

A retrospective casenote review was carried out of patients who attended the Emergency Department due to citalopram overdose between January 2000 and July 2007 inclusive. Stepwise logistic regression analysis considered age, gender, stated citalopram dose, acute ethanol consumption, co-ingested drugs, administration of activated charcoal, and hyponatraemia.

RESULTS

There were 241 patients (177 women), and the median (interquartile range) stated citalopram dose was 300 mg (200 to 600 mg). Generalized seizures occurred in 18 patients (7.5%). Logistic regression analysis found co-ingested tricyclic antidepressants or venlafaxine predicted seizures with odds ratio = 15 (95% confidence interval 3, 75). In the absence of co-ingested drugs, the minimum citalopram dose associated with seizures was 400 mg. Odds ratio for seizures = 1.1 (95% confidence interval 1.0, 1.2) for every 100 mg increment in citalopram dose. Seizures were associated with a greater need for invasive ventilatory support, higher creatine kinase activity, and prolonged hospital stay.

CONCLUSIONS

Generalized seizures are an important manifestation of citalopram toxicity, and cannot be explained solely by electrolyte disturbances or co-ingestion of other drugs or ethanol. The strongest predictors of seizures in this patient series were ingestion of high citalopram dosages and co-ingestion of drugs capable of lowering seizure threshold.     

Bromide as marker for drug adherence in hypertensive patients

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Insufficient drug adherence is an important reason for inadequate blood pressure control.
• Currently, methods that measure drug adherence objectively are lacking. Objective methods are needed to help improve blood pressure control and outcome in hypertensive patients.
WHAT THIS STUDY ADDS
• Potassium bromide added to antihypertensive drugs can be used to monitor drug adherence in individual patients.
• However, although this method is objective, it is rather time-, cost- and work-consuming.
AIMS Adherence to antihypertensive medication is essential for adequate long-term control of blood pressure (BP). This study investigated different methods of measuring adherence in hypertensive patients.
METHODS Patients were included if BP was insufficiently controlled on monotherapy. After a placebo period patients were treated with trandolapril 2 mg/verapamil SR 180 mg (TV). BP was determined using a mercury sphygmomanometer and ambulatory BP monitoring. Adherence was measured by capsule counting, electronic registration of pill-box openings and by measuring serum bromide concentrations. Potassium bromide was added to each TV capsule.
RESULTS Thirty patients participated in the study. Treatment with TV significantly lowered office BP and ambulatory BP.
Results for electronic monitoring and adherence based on bromide measurements were comparable. Adherence was slightly higher when assessed by capsule counting.
CONCLUSIONS Measuring serum bromide concentrations may be suitable for assessment of adherence to drug therapy giving comparable results to electronic monitoring. Using capsule counting, electronic monitoring and measurement of bromide concentrations, nonadherent patients were identified.