Atypical pharmacokinetics and excretion of new platinum analogues in rodents

PURPOSE: Two new series of platinum complexes with cytotoxic activity in vivo are [Pt(NRCH2)2L2], (R=polyfluorophenyl, L=pyridine or substituted pyridine) and [Pt(NRCH2CH2NR'2)2L(X)], (R, L as before; R'=Me or Et, X=halogen). The aim of this study was to determine the pharmacokinetics and excretion in mice and in isolated perfused rat livers of a representative compound from each class, respectively: Pt103 (R=p-HC6F4, L=pyridine) and Pt109 (R, L as for Pt103, R'=Et, X=I). METHODS: Mice were given intraperitoneal injections of active doses of Pt103, Pt109, or cisplatin in a variety of vehicles. Blood was sampled at several times to 48 h. Some mice were placed in metabolic cages where urine and feces were collected. In isolated, perfused rat livers, perfusate and bile were collected following a dose of Pt103, cisplatin or carboplatin. Platinum was measured in blood, urine, feces, or perfusate by atomic absorption spectroscopy. Three vehicles used were peanut oil, dimethyl sulphoxide, and saline/Tween 20. RESULTS: In contrast to renal excretion of over 70% for cisplatin in saline, urinary excretion of platinum was less than 24% of a dose of Pt109 in peanut oil, less than 21% of P103 in DMSO, and only 4% for Pt103 in peanut oil. Over 60% of Pt103 was eliminated in mouse feces, and 57% was excreted in bile from rat liver. Plasma protein binding of Pt109 was greater than 90% at 6 h following administration in mice. CONCLUSION: In contrast to cisplatin and carboplatin, representatives of two new classes of platinum anticancer agents undergo minimal renal elimination, but are excreted mainly in the bile and feces. If a platinum complex with a similar excretion profile was introduced into the clinic, there might be a therapeutic advantage in terms of drug toxicity and combination therapy with other cytotoxics.     

Reflex seizures induced by defecation,with an ictal EEG focus in the left frontotemporal region

We report a 9-year-old boy with seizures induced by defecation. The episodes occurred 1-2 min after passing a bowel action and consisted of initial staring, gagging, and drooling followed by a secondarily generalized tonic-clonic seizure. The interictal EEGs were normal, but an ictal EEG with concurrent video monitoring demonstrated a polyspike wave discharge in the left frontotemporal region. There was no evidence of syncope, and the seizures did not occur while straining to empty his bowels or immediately on standing afterward. His magnetic resonance imaging scan was normal. This is the first reported case in which ictal EEG monitoring has demonstrated reflex seizures induced by defecation.     

Does uric acid have a pathogenetic role in graft dysfunction and hypertension in renal transplant recipients?

BACKGROUND: Uric acid (UA) may play a pathogenetic role in hypertension and kidney disease. We explored the prevalence of hyperuricemia and the relationship of UA to graft function and hypertension in prevalent renal transplant recipients (RTR). METHODS: Baseline and follow-up data were collected on 90 RTR (mean age 51 yrs, 53% male, median transplant duration 7 years). Graft function was estimated using MDRD Study Equation 7. RESULTS: At baseline, 70% RTR had hyperuricemia (UA >7.0 mg/dl (0.42 mmol/L) in men and >6.0 mg/dl (0.36 mmol/L) in women) compared to 80% after 2.2 years (P=0.06). UA was not associated with blood pressure (BP) level but was higher in RTR with a history of hypertension compared to those without (8.6+/-1.8 vs. 7.3+/-2.2 mg/dl, [0.51+/-0.11 vs. 0.43+/-0.13 mmol/L], P=0.003) and in RTR on > or =3 antihypertensive medications compared to those taking less (9.1+/-1.6 vs. 7.6+/-1.8 mg/dL, [0.54+/-0.1 vs. 0.45+/-0.11 mmol/L], P<0.001). A history of hypertension was independently predictive of UA (beta 0.06, [95% CI 0.02 to 0.10], P=0.007) in addition to sex, cyclosporine dose, prednisolone dose, estimated glomerular filtration rate (eGFRMDRD) and beta-blocker therapy. UA was independently predictive of follow-up eGFRMDRD (beta -22.2 [95% CI -41.2 to -3.2], P=0.02) but did not predict change in eGFRMDRD over time. UA was independently associated with requirement for antihypertensive therapy (beta 0.34, [95% CI 1.05 to 1.90], P=0.02). CONCLUSIONS: Hyperuricemia is common in RTR and is associated with need for antihypertensive therapy and level of graft function.     

Free fatty acids are associated with obesity, insulin resistance, and atherosclerosis in renal transplant recipients

BACKGROUND: Insulin resistance (IR) may be implicated in the pathogenesis of atherosclerosis in renal transplant recipients (RTRs) and be contributed to, in part, by free fatty acids (FFAs), produced in excess in centrally obese individuals. The aim of this study was to determine the prevalence of IR and the relationships between FFAs, central obesity, and atherosclerosis in a cohort of prevalent RTRs. METHODS: Observational data were collected on 85 RTRs (mean age 54 years; 49% male, 87% Caucasian). Fasting serum was analyzed for FFAs, glucose, and insulin; IR was calculated using the homeostasis model assessment (HOMA-IR) score. Vascular structure was assessed by carotid intima-media thickness (IMT) measurement. Linear regression analyses were performed to determine the factors associated with IR and atherosclerosis. RESULTS: IR occurred in 75% of RTRs, and FFA levels were independently associated with its occurrence (beta: -0.55, 95% CI: -1.02 to -0.07, P = 0.02). Other variables independently associated with IR were male sex, body mass index, central obesity, diabetes, systolic blood pressure and corticosteroid use. There was a significant correlation between FFA levels and IMT (r = 0.3, P=0.01). On multivariate analysis, IMT correlated with elevated FFA (beta: 0.07, 95% CI: 0.02-0.12, P = 0.007), diabetes mellitus (P = 0.05), older age (P < 0.002), and a body mass index >25 kg/m (P = 0.002). CONCLUSIONS: FFAs are associated with the development of IR and may be involved in the pathogenesis of atherosclerosis in RTRs. Additional studies are required to explore these associations further before considering whether an interventional trial aimed at lowering FFA would be a worthwhile undertaking.     

Assessment of left ventricular function by breath-hold cine MR imaging: Comparison of different steady-state free precession sequences

PURPOSE: To compare steady-state free precession (SSFP) sequence protocols with different acquisition times (TA) and temporal resolutions (tRes) due to the implementation of a view sharing technique called shared phases for the assessment of left ventricular (LV) function by breath-hold cine magnetic resonance (MR) imaging. MATERIALS AND METHODS: End-diastolic and end-systolic volumes (EDV, ESV) were measured in contiguous short-axis slices with a thickness of 8 mm acquired in 10 healthy male volunteers. The following true fast imaging with steady-state precession (TrueFISP) sequence protocols were compared: protocol A) internal standard of reference, segmented: tRes 34.5 msec, TA 18 beats per slice; protocol B) segmented, shared phases: tRes 34.1 msec, TA 10 beats per slice; and protocol C) real-time, shared phases, parallel acquisition technique: tRes 47.3 msec, TA 24 beats for 12 slices covering the entire left ventricle. RESULTS: Phase sharing leads to a significant decrease in EDV, stroke volume (SV), and ejection fraction (EF) (median difference -7.0 mL [*], -9.6 mL, and -3.4%, respectively, for protocol B; -15.3 mL, -13.3 mL, and -2.4% for protocol C; P = 0.002, *P = 0.021). The observed median difference of real-time EDV and SV estimates is of clinical relevance. Real-time cine MR imaging shows a greater variability of EDV and SV. No relevant differences in ESV were observed. CONCLUSION: The true cine frame duration of both shared phases sequence protocols exceeds the period of isovolumetric contraction (IVCT) of the left ventricle resulting in a systematic and significant underestimation of EDV and consequently SV and EF. SSFP sequence protocol parameters, particularly tRes and use of view sharing techniques, should therefore be known at follow-up examinations in order to be able to assess LV remodeling in patients with heart failure.     

Elevated white cell count at commencement of peritoneal dialysis predicts overall and cardiac mortality

BACKGROUND: Higher total white blood cell counts (WCC) have been shown in the general population to be strongly and independently predictive of coronary heart disease and all-cause mortality. The aim of the present study was to evaluate the prognostic value of WCC in patients commencing peritoneal dialysis (PD). METHODS: A cohort of 323 patients (mean age 55.1 +/- 17.7 years, 54% male, 81% Caucasian) commencing PD at the Princess Alexandra Hospital between January 1, 1998 and March 31, 2003 were prospectively followed until death, completion of PD therapy, or otherwise to the end of the study (January 2, 2004), at which point data were censored. Individuals with failed renal transplants (N= 17) and those with acute infections at the time of PD onset (N= 12) were not included. A multivariate Cox's proportional hazards model was applied to calculate hazard ratios and adjusted survival curves for time to death or cardiac death, adjusting for baseline demographic, clinical, and laboratory characteristics. RESULTS: Median actuarial patient survival was 3.9 years [95% confidence interval (CI) 3.2-4.7 years]. The highest quartile of WCC (>9.4 x 10(9)/L) was significantly and independently associated with increased risks of both death from all causes [adjusted hazard ratio (HR) 2.27, 95% CI 1.09-4.74, P < 0.05] and cardiac death (HR 3.75, 95% CI 1.2-11.8, P < 0.05). Other adverse risk factors included older age, lower serum albumin, and the presence of coronary artery disease. Similar associations were found between mortality and PMN count, but not lymphocyte count. CONCLUSION: Elevated baseline WCC or PMN count at the commencement of PD (in the absence of acute infection) strongly predicts all-cause and cardiovascular mortality. These data suggest that new PD patients with higher WCC may warrant closer monitoring and extra attention to modifiable cardiovascular risk factors.     

An assessment of the interval between booster doses of Japanese encephalitis vaccine in the Torres Strait

OBJECTIVE: Japanese encephalitis (JE) emerged for the first time in the Torres Strait, north Australia, in 1995. The inactivated mouse-brain derived JE vaccine was offered to all residents of the outer Torres Strait Islands prior to the 1996 wet season. This study was undertaken to determine the appropriateness of the recommended three-year interval between booster doses of the vaccine. METHODS: JE neutralising antibody was measured in residents of Badu Island for whom 30-36 months had passed since either a previous booster or the completion of the primary immunisation series. RESULTS: Only 70 (32%) of 219 eligible individuals had protective antibodies; 50 (37%) of the adults were immune, compared with 20 (24%) of the children (odds ratio (OR) 1.93; 95% confidence interval (CI) 1.01-3.74). CONCLUSIONS: This low level of immunity suggests that there is little in the way of natural boosting from either JE or other closely related viruses. Given the apparent low level of risk of exposure to the JE virus in the Torres Strait, and the logistical complexities involved in delivering the booster doses, the current recommendation of a three-year interval is not inappropriate. IMPLICATIONS: It would be advantageous to have a JE vaccine that is not only safer but also more immunogenic, so that it might be possible to further increase the booster dose interval.     

Influence of cobalamin deficiency compared with that of cobalamin absorption on serum holo-transcobalamin II

BACKGROUND: Cobalamin attached to transcobalamin II (TC II), known as holo-TC II, is the active cobalamin fraction taken up by tissues. Holo-TC II is also the form in which absorbed cobalamin enters the circulation from the ileum. Therefore, holo-TC II has been proposed variously as a marker of cobalamin adequacy, cobalamin absorption, or both, including even its advocacy as a surrogate Schilling test. Such claims carry conflicting diagnostic implications because metabolic adequacy and absorption are not identical. OBJECTIVE: The objective was to examine metabolic and absorptive influences on holo-TC II. DESIGN: Treated patients with pernicious anemia (PA), who have abnormal absorption but a normal metabolic status, were chosen as the model to differentiate between the effects of the 2 cobalamin-related characteristics. Serum holo-TC II and indexes of cobalamin metabolism in 23 treated patients were compared with those of 6 untreated PA patients (abnormal absorption and metabolic status) and 33 control subjects (normal absorption and metabolic status). RESULTS: Holo-TC II, which correlated directly with cobalamin and inversely with homocysteine, was significantly higher in treated PA patients in metabolic remission than in untreated PA patients (74 +/- 59 compared with 9 +/- 6 pmol/L) and was significantly lower than in control subjects (105 +/- 58 pmol/L), although the latter difference was small and the values overlapped greatly. CONCLUSIONS: Metabolic cobalamin status is a major determinant of serum holo-TC II. Absorption status may have mild influence as well, although other explanations remain possible. Serum holo-TC II cannot be used clinically to diagnose cobalamin malabsorption because of overlap with normal values. The influences on holo-TC II are complex and require careful analysis.