No abstract

1. The metabolism of 1-bromopropane in the rat has been re-investigated. The previously known metabolites have been isolated and confirmed as the three mercapturic acids N-acetyl-S-propyl cysteine, N-acetyl-S-propyl cysteine-S-oxide and N-acetyl-S-(2-hydroxypropyl)cysteine. 2. Three further metabolites have been isolated from the urine of rats treated with 4-bromopropane. These have been identified as 3-bromopropionic acid and the mercapturic acids N-acetyl-S-(3-hydroxypropyl)cysteine and N-acetyl-S-(2-carboxyethyl)cysteine. 3. The metabolites of 3-bromopropanol and 3-chloropropanol in the rat have been shown to be the mercapturic acids N-acetyl-S-(3-hydroxypropyl)cysteine and N-acetyl-S-(2-carboxyethyl)cysteine and the corresponding 2-carboxyethyl halide. 4. Studies with 1-bromopropane and the 3-halopropanols in vitro indicate that oxidation of C3 and C2 of 1-bromopropane occurs before conjugation of the alkyl group with glutathione. The implications of these studies are discussed in relation to the mechanism of the biosynthesis of the S-(2-hydroxyalkyl)mercapturic acid metabolites derived from the alkyl halides.

We study a q-deformation for the semi-direct product of the symmetric group S n with the Clifford algebra on n anticommuting generators. We obtain a q-version of the projective analogue for the classical Young symmetrizer introduced by the second author. Our main tool is an analogue of the Hecke algebra of complex valued functions on the group GL n over a p-adic field relative to the Iwahori subgroup.

We have studied the hyperglycaemic effect of the carbohydrate of glucose, sucrose, and honey equivalent to 20 g in twelve normal volunteers, eight patients with insulin-dependent diabetes mellitus (IDDM), and six patients with non-insulin-dependent diabetes mellitus (NIDDM). Honey produced an attenuated postprandial glycaemic response in normal volunteers (vs glucose p less than 0.005; vs sucrose p less than 0.05) and IDDMs (vs glucose p less than 0.005; vs sucrose p less than 0.05). The glycaemic index (GI) showed considerable variability within each subject group. Combined with a peak incremental index (PI), the two indices appear to be more valuable in predicting the glycaemic effects of carbohydrates rather than either one alone. We suggest that honey may prove to be a valuable sugar substitute in diabetics, and that both the GI and PI should be used in the analysis of food.

This study examined the clearance of gastric acid from the oesophagus in ambulant patients with gastrooesophageal reflux. Eighteen patients with proved reflux disease were studied, nine with (group 1) and nine without (group 2) endoscopic oesophagitis. Oesophageal pressure and pH were recorded over 24 hours. Pressures were measured by a probe with five sensors: a 5 cm long sensor in the lower oesophageal sphincter, three sensors in the body of the oesophagus, and one at the pharynx to detect swallowing. Oesophageal pH was monitored 5 cm above the lower oesophageal sphincter. Manometric activities were classified as either peristaltic or ineffective. The latter included simultaneous, non-transmitted, and low amplitude peristaltic contractions. A reflux episode was defined as starting when pH fell to less than 4 and ending when the pH rose to 5. When the rise to pH 5 took place in three or more discrete steps after motor responses to gastrooesophageal reflux, the pH steps were labelled as initial change (I), middle changes (M), and last change (L). A total of 595 episodes of gastro-oesophageal reflux and 1626 associated motor events were analysed. Of these, 1331 (81-9%) were classed as primary peristaltic activity, 174 (10-7%) as primary ineffective activity, 46 (2.8%) as secondary peristaltic activity, and 75 (4-6%) as secondary ineffective activity. There were no significant differences in initial change (p>O05), middle changes (p>005), and last change (p>005) between group 1 and group 2. In all patients, the successive changes of pH in response to motor activity were significantly different (p=0-0001) between initial, middle, and last changes. Last change was significantly higher when compared with initial (p=0001) and middle changes (p<0001). Primary oesophageal peristalsis was the most frequent motor response to gastrooesophageal reflux. The last motor activity during reflux showed the greatest change in pH.

No abstract

Iron accumulation and overload in beta thalassaemia patients are associated with significant morbidity and mortality. Iron chelators are used to manage iron accumulation but side effects and compliance issues restrict the use of available chelators. Deferitrin (Genzyme Corporation) is an orally available iron chelator intended for iron overload. Method: Patients were dosed in 4 cohorts, receiving 5, 10, 15 and 25 mg/kg/day of deferitrin. Deferitrin dosing in cohorts 1–3 was once daily for 12 weeks. Cohort 4 received deferitrin twice daily (BD) for 48 weeks (12.5mg/kg BD, 25 mg/kg/day). Pharmacokinetics (PK) were assessed in a subset of up to 5 patients in each cohort, pre-dose and 1, 2, 4 and 8 hours post dose. All patients had trough levels assessed at weeks 1, 6 and 12 (all Cohorts) and additionally at weeks 24, 36 and 48 for Cohort 4. PK parameters were determined by model independent (non-compartmental) analyses. Safety was assessed by collection of adverse events and laboratory assessments with renal parameters measured weekly due to observations of renal toxicity in preclinical testing. Efficacy (change in liver iron concentration (LIC)) was assessed by SQUID (superconducting quantum interference device) in Turin, Italy, between screening and end of study. Iron excretion and intake were estimated by calculation:Iron excretion due to deferitrin = Iron Intake (mg/kg/day) - TBI (mg/kg/day)Iron Intake (mg/kg/day) = [total mL pRBC (exclude last BT×) × 1.08] / [Weight (kg) × Days (Between 1st & last BT×)]TBI (mg/kg/day) = Change in LIC (mg Fe/g dry weight) × [10.6 (Angelucci Factor) / D (Days on deferitrin)] Key: pRBC = packed red blood cells, BT× = blood transfusion, TBI=Total Body Iron. Results: PK: PK for deferitrin dosed once daily was linear and dose proportional. The serum half-life was 1.3–1.8 hrs, clearance was 226–340 mL/min and mean residence time was 2.8–3.4 hrs for once daily dosing. PK data from BD dosing is not yet available. Safety: Deferitrin dosed once daily was generally well tolerated (Cohorts 1–3). Slight rises in transaminases were seen at 10 and 15 mg/kg/day. A large proportion of enrolled patients were hepatitis C positive (73%). When dosed BD (12.5 mg/kg BD in Cohort 4), 3 patients developed renal toxicity after 4–5 weeks of treatment. Two patients experienced increased proteinuria (max 3.73 g/L & 3.29 g/L) and one patient suffered acute renal failure (peak serum creatinine 4.1 mg/dL, lowest GFR 27 mmol/L). All patients recovered normal renal function after stopping treatment. No patients were re-challenged with deferitrin. Dosing was terminated in all patients because of safety concerns. Efficacy: Mean iron excretion in mg/kg/day (S.D) for Cohort 1 was 0.22 (0.22), Cohort 2 was 0.45 (0.14) and Cohort 3 was 0.33 (0.12). The reasons for the lack of dose proportionality in iron excretion are unclear. Efficacy could not be assessed in Cohort 4 due to early termination of the study. Conclusions: Deferitrin dosed once daily was generally well tolerated and associated with a mean iron excretion of 0.34 mg/kg/day. Deferitrin dosed BD (12.5mg/kg BD) was associated with unacceptable renal toxicity and led to study termination. Deferitrin does not appear to have an acceptable therapeutic margin to allow sufficient iron excretion for long-term administration.

1. The oxidative metabolism of [3-36C]chloropropan-1,2-diol (alpha-chlorohydrin, I) was studied in male rats. Two metabolites were isolated and identified as beta-chlorolactic acid (IV) and oxalic acid (V). 2. Neither alpha-chlorohydrin nor beta-chlorolactate was concentrated in any tissue. Traces of an intermediate metabolite, beta-chlorolactaldehyde (III) were detected in the urine within 4 h of administration. Studies in vitro indicated that the metabolic pathway is: alpha-chlorohydrin leads to beta-chlorolactaldehyde leads to beta-chlorolactic acid. 3. A comparative study of the metabolism of 36Cl- and 14C-beta-chlorolactate showed that oxalate was produced slowly and, as calcium oxalate, caused a type of renal glomerular nephritis. This pathological condition is responsible for the diuretic action of both alpha-chlorohydrin and beta-chlorolactate and, in higher doses, for their toxicities. 4. The role of oxalate, as a metabolite of alpha-chlorohydrin and of a number of related compounds, in inducing the formation of spermatocoeles in the male rat reproductive tract is discussed.