Pharmacogenetics of irinotecan toxicity

Irinotecan is an anticancer drug approved in combination therapy for advanced colorectal cancer. Severe, life-threatening toxicities can occur from irinotecan treatment. Although multiple genes may play a role in irinotecan activity, the UDP glycuronosyltransferase 1 family, polypeptide A1 (UGT1A1) enzyme has been strongly associated with toxicity. A common dinucleotide repeat polymorphism in the UGT1A1 promoter region (UGT1A1*28) has been correlated with severe toxicity in cancer patients receiving irinotecan-containing therapy. Prospective screening of patients prior to chemotherapy selection may reduce the frequency of severe toxicities by allowing alternate therapy selections for patients carrying the UGT1A1*28 polymorphism.     

Patient satisfaction with doctor–patient interaction in a radiotherapy centre during the severe acute respiratory syndrome outbreak

An outpatient radiotherapy department assessed how precautions implemented during the severe acute respiratory syndrome (SARS) outbreak affected patient satisfaction with doctor–patient interaction and explored variables potentially influencing satisfaction. The information obtained would help prepare us for future infectious disease outbreaks. Outpatients seen during the outbreak completed a validated questionnaire assessing satisfaction with doctor–patient interaction. Additional items assessed included patients’ perception of SARS measures and patient demographics. Of 149 patients, 97% had heard of SARS, 92% believed SARS precautions necessary, and 54% believed contracting SARS was possible despite the precautions. Patients were satisfied with doctors wearing masks (97%), temperature checks (97%), and patients wearing masks (96%). Despite the high satisfaction levels with SARS precautions, 24% believed it had adversely affected doctor–patient interaction. With regards to doctor–patient interaction, 94% of patients were satisfied. Patients were most satisfied with the ‘information exchange’ domain (mean score 3.23 out of 4) compared to other domains (P < 0.0001, 100.00% confidence) and were less satisfied with the ‘empathy’ domain compared to other domains (P < 0.0001, 100.00% confidence). Patients were most satisfied with understanding their treatment plan (100%), doctor being honest (97%) and being understood (96%). Patients were least satisfied with information about caring for their illness (61%), that the visit could be better (59%), and the doctor showing more interest (58%). On multivariate analysis, patients who were less satisfied with SARS measures were significantly less satisfied with doctor–patient interaction (P = 0.0001). Dissatisfaction with SARS measures was associated with significant dissatisfaction for questions in all domains. Older age and non‐breast cancer patients were also less satisfied with doctor–patient interaction. Most (94%) of patients were satisfied with doctor–patient interaction, despite implementation of infectious disease prevention measures. However, patients who were dissatisfied with the SARS precautions had poorer satisfaction. In particular, physician empathy appeared to be most adversely affected. The results have relevance to any radiotherapy department preparing contingency plans in the event of infectious disease outbreaks.     

The heterogeneity of central benzodiazepine receptor subtypes in the human hippocampal formation,frontal cortex and cerebellum using [3H]flumazenil and zolpidem

The ability of clonazepam and zolpidem to displace [3H]flumazenil binding was measured in the human hippocampal formation, frontal cortex (BA9) and the cerebellum using in situ radioligand binding and autoradiography. The use of high resolution phosphorimaging in all regions indicated the displacement of [3H]flumazenil by clonazepam was monophasic with K(i) values ranging from 2.73+/-0.17 to 6.49+/-0.21 nM. [3H]flumazenil binding that was not displaced by clonazepam ranged from 3.39+/-0.86 to 7.15+/-1.11%. The ability of zolpidem to displace [3H]flumazenil was also monophasic in the frontal cortex and cerebellum with K(i) values of 37.53+/-1.79 and 31.80+/-1.68 nM, respectively. In contrast, within all hippocampal regions, zolpidem displacement of [3H]flumazenil was biphasic, with K(i) values for the high affinity site ranging from 0.13+/-0.04 to 0.54+/-0.03 nM, whereas the low affinity site was between 84.98+/-1.58 and 98.84+/-1.89 nM. In addition, zolpidem insensitive [3H]flumazenil binding was observed to vary markedly between brain regions, ranging between 37.85+/-1.60 and 6.13+/-0.83%. In conclusion, the present results indicate that in situ radioligand binding and high-resolution phosphorimaging techniques can be utilized to measure the differential displacement of [3H]flumazenil by zolpidem and clonazepam. Moreover, our data suggests that the differential distribution of the zolpidem insensitive component of [3H]flumazenil binding is an indicator of GABA/BZ receptors assembled by different subunits within the human brain.     

Mutation spectrum in Australian pedigrees with hereditary hyperferritinaemia-cataract syndrome reveals novel and de novo mutations

Hereditary hyperferritinaemia-cataract syndrome (HHCS) (OMIM #600886) is a rare autosomal dominant condition identified by high serum ferritin levels with normal iron saturation and distinctive bilateral cataract. It may be misdiagnosed as haemochromatosis and such patients become anaemic as a result of inappropriate venesection. The elevated serum ferritin is due to a mutation in the iron-responsive element (IRE) of the l-ferritin gene, resulting in excessive l-ferritin production. We report the identification of three Australian pedigrees; one with a previously described mutation at position 40, a pedigree with a novel mutation at position 39 and an individual with a de novo mutation at position 32 of the l-ferritin IRE.     

(3)H]Flumazenil binding in the human hippocampal formation, frontal cortex and cerebellum detected by high-resolution phosphorimaging

The pharmacological characterisation of the benzodiazepine binding site associated with the gamma-aminobutyric acid (GABA(A)) receptor in human brain has been demonstrated using in situ radioligand binding and autoradiography. The use of high-resolution phosphorimaging has allowed both the affinity (K(d)) and density (B(max)) of [(3)H]flumazenil binding to be measured within regions of the hippocampal formation as well as the cerebellum and frontal cortex. The Scatchard plots of data from all brain regions were linear with Hill coefficients close to unity consistent with the presence of a single binding site for [(3)H]flumazenil. The affinities of [(3)H]flumazenil binding within all the brain regions were similar (K(d) 1.57+/-0.20-3.08+/-0.01 nM), while the density of [(3)H]flumazenil binding varied significantly between the brain regions analysed (B(max) 182.7+/-7.3-596.7+/-34.0 fmol/mg ETE; P<0.0001). In conclusion, the present results indicate that in situ radioligand binding and high-resolution phosphorimaging techniques can be utilized to measure the distribution, density and affinity of [(3)H]flumazenil to the GABA(A) receptor within the human frontal cortex, cerebellum and hippocampal formation.     

Factors associated with adverse perinatal outcome in the Term Breech Trial

BACKGROUND: In the Term Breech Trial, the risk of adverse perinatal outcome was lower with planned cesarean section versus planned vaginal birth. We undertook secondary analyses to determine factors associated with adverse perinatal outcome. STUDY DESIGN: By using multiple logistic regression analyses, we determined the effect of prelabor cesarean section, cesarean section during early labor, cesarean section during active labor versus vaginal birth, and other factors, on adverse perinatal outcome. For 1384 fetuses delivered after labor, we determined the effect of variables associated with labor on adverse perinatal outcome. RESULTS: The risk of adverse perinatal outcome was lowest with prelabor cesarean section (odds ratio [OR]=0.13) and highest with vaginal birth. For those delivered after labor, labor augmentation (P=.007), birth weight less than 2.8 kg (P=.003), and longer time between pushing and delivery (P<.001) increased the risk, whereas the presence of an experienced clinician at delivery (P=.004) reduced the risk of adverse perinatal outcome. CONCLUSION: Breech infants at term are best delivered by prelabor cesarean section.     

Lessons learned from the irinotecan metabolic pathway

Irinotecan, a camptothecin analogue, is a prodrug which requires bioactivation to form the active metabolite SN-38. SN-38 acts as a DNA topoisomerase I poison. Irinotecan has been widely used in the treatment of metastatic colorectal cancer, small cell lung cancer and several other solid tumors. However, large inter-patient variability in irinotecan and SN-38 disposition, as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan. Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy. Irinotecan is subjected to be shunted between CYP3A4 mediated oxidative metabolism to form two inactive metabolites APC or NPC and tissue carboxylesterase mediated hydrolysis to form SN-38 which is eventually detoxified via glucuronidation by UGT1A1 to form SN-38G. The pharmacology of this compound is further complicated by the existence of genetic inter-individual differences in activation and deactivation enzymes of irinotecan (e.g., CYP3A4, CYP3A5, UGT1A1) and sharing competitive elimination pathways with many concomitant medications, such as anticonvulsants, St. John's Wort, and ketoconazole. Efflux of the parent compound and metabolites out of cells by several drug transporters (e.g., Pgp, BCRP, MRP1, MRP2) also occurs. This review highlights the latest findings in drug activation, transport mechanisms, glucuronidation, and CYP3A-mediated drug-drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent.     

Pharmacological characterization of the novel histamine H3-receptor antagonist N-(3,5-dichlorophenyl)-N'-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687)

We present the pharmacological and pharmacokinetic profiles of a novel histamine H3 receptor antagonist, N-(3,5-dichlorophenyl)-N'-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687). The H3-receptor binding Ki values for SCH 79687 were 1.9 and 13 nM in the rat and guinea pig (GP), respectively. The Ki values for SCH 79687 at histamine H1 and H2 receptors were greater than 1 microM. SCH 79687 showed a 41- and 82-fold binding selectivity for the H3 receptor over alpha 2A-adrenoceptors and imidazoline I2, and >500-fold H3 selectivity compared with over 60 additional receptors. The pA2 value for SCH 79687 in the GP ileum electrical field-stimulated (EFS) contraction was 9.6 +/- 0.3. Similar H3 antagonist activity was observed in the EFS cryopreserved and fresh tissue isolated human saphenous vein (HSV) assays (pKb = 9.4 +/- 0.3 and 10.1 +/- 0.4). SCH 79687 (30 nM) did not block clonidine-induced inhibition of EFS-induced contractions in HSV. SCH 79687 (ED50 = 0.3 mg/kg i.v.) attenuated (R)-alpha-methylhistamine inhibition of sympathetic hypertensive responses in the GP. At the time of activity evaluation, the GP plasma SCH 79687 concentration was 25 ng/ml at the dose of 0.3 mg/kg i.v. In feline nasal studies, combined administration of SCH 79687 (3 mg/kg i.v.) and the H1-antagonist loratadine (3 mg/kg i.v.), at individual doses that do not produce decongestion, inhibited the compound 48/80-induced congestion by 47%. The alpha-adrenergic agonist phenylpropanolamine (PPA; 1 mg/kg i.v.) also attenuated compound 48/80 nasal responses by 42%. Unlike the H3/H1 combination that did not affect blood pressure (BP), PPA (1 mg/kg i.v.) significantly increased BP compared with control animals by a maximum of 31 mm Hg. Orally, SCH 79687 (10 mg/kg) plus loratadine (10 mg/kg) also produced decongestion without effects on BP. In pharmacokinetic studies, oral dosing with SCH 79687 in the rat (10 mg/kg) and monkey (3 mg/kg) achieved plasma Cmax and area under the curve values greater than 1.5 and 12.1 microg. h/ml, respectively. SCH 79687 is an orally active H3 antagonist with a good pharmacokinetic profile that, in combination with an H1 antagonist, demonstrates decongestant efficacy comparable with oral sympathomimetic decongestants but without hypertensive liabilities.