Adenoid hypertrophy affects screening for primary ciliary dyskinesia using nasal nitric oxide.

AIM: In patients with primary ciliary dyskinesia (PCD), the release of nitric oxide (NO) is extremely low by epithelia of the nasopharynx and sinuses. Measurement of nasal NO (nNO) is recommended as a screening test for PCD. The study aimed to evaluate if adenoids affects nNO and may deteriorate the performance of the test. METHODS: In 48 nonallergic patients between 5 and 18 years of age with chronic symptoms of nasal obstruction and indications for adenoidectomy, the measurements of nNO by chemiluminescence analyser and nasal patency by active anterior rhinomanometry were performed both before and after adenoidectomy. Adenoidal tissue size was graded during surgery under general anaesthesia using transoral endoscopy. RESULTS: Patients were stratified into groups with adenoids grades 1, 2 and 3 (<1/3, 1/3-2/3 and > 2/3 of the choana and post-nasal space covered by adenoids). Before adenoidectomy, the median of nNO decreased with the increasing grade of adenoids (920, 663, and 491 ppb, P < 0.05). The rhinomanometry results were comparable and showed no correlation with nNO. Seven patients (14.6%) were incorrectly classified to have PCD based on a subthreshold value of the volume flow of nNO (FnNO < 77 nL/min). Following adenoidectomy, nNO of the grade 3 patients increased by 107 ppb (P < 0.05) and no differences were found between groups (P = 0.40). All patients had the postadenoidectomy FnNO >77 nL/min. CONCLUSIONS: nNO and FnNO are reduced in nonallergic children with obstructive adenoids. Adenoid hypertrophy can potentially cause a false positive result of the test for PCD.

A comparative study of pharmacokinetics, urinary excretion and tissue distribution of platinum in rats following a single-dose oral administration of two platinum(IV) complexes LA-12 (OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) and satraplatin (OC-6-43)-bis(acetato)amminedichloro(cyclohexylamine)platinum(IV).

PURPOSE: This study compared the pharmacokinetics, tissue distribution, and urinary excretion of platinum in rats after single oral doses of LA-12 and satraplatin. METHODS: Both platinum derivatives were administered to male Wistar rats as suspensions in methylcellulose at four equimolar doses within the range of 37.5-300 mg LA-12/kg body weight. Blood sampling was performed until 72 h, and plasma and plasma ultrafiltrate were separated. Moreover, urine was collected until 72 h, and kidney and liver tissue samples were obtained at several times after administration. Platinum was measured by atomic absorption spectrometry. The pharmacokinetics of platinum was analyzed by population modelling and post hoc Bayesian estimation as well as using non-compartmental pharmacokinetic analysis of the mean concentration-time curves. RESULTS: Platinum was detected in all plasma and ultrafiltrate samples 15 min after oral administration of both compounds and peaked between 3-4 h and 1-3 h, respectively. Similar for LA-12 and satraplatin, the C (max) and AUC values of plasma and ultrafiltrate platinum increased less than in proportion to dose. The mean C (max) and AUC values of plasma platinum observed after administration of LA-12 were from 0.84 to 2.5 mg/l and from 20.2 to 75.9 mg h/l. For ultrafiltrate platinum, the corresponding ranges were 0.16-0.78 mg/l and 0.63-1.8 mg h/l, respectively. The AUC of plasma platinum was higher after satraplatin (P < 0.001). However, administration of LA-12 resulted in significantly higher AUC values of ultrafiltrate platinum after the doses of 150 mg and 300 mg/kg (P < 0.01), respectively, and the C (max) values were significantly higher starting from the dose of 75 mg/kg LA-12 and upward (P < 0.01). Cumulative 72-h urinary recovery of platinum dose was below 5% for both compounds, and it decreased with the dose of satraplatin (P < 0.01), while a numerical decrease was observed after administration of LA-12 that did not reach statistical significance (P = 0.41). The renal clearance of free platinum was similar regardless of the dose and compound administered. Platinum concentrations in the liver homogenate exceeded those in the kidney. Distribution of platinum to tissues was higher after LA-12 compared to satraplatin. The difference in kidney platinum increased with dose and was twofold after 350 mg/kg LA-12. Liver platinum was twofold higher after LA-12 across all four doses. CONCLUSIONS: In conclusion, this first comparative pharmacokinetic study with LA-12 and satraplatin shows that characteristics of platinum exposure evaluated in the plasma, plasma ultrafiltrate and kidney and liver tissues increase less than in proportion to dose following a single-dose administration of 37.5-300 mg/kg to Wistar rats. These findings together with the dose-related elevation in the pharmacokinetic characteristics V/F and CL/F of platinum and ultrafiltrate platinum as well as a drop in platinum urinary recovery are consistent with a dose-related decrease in the extent of oral bioavailability most likely due to saturable intestinal absorption.

Nitrite in exhaled breath condensate as a marker of nitrossative stress in the airways of patients with asthma, COPD, and idiopathic pulmonary fibrosis.

BACKGROUND: Nitrite and nitrate are exhaled in droplets of an aerosol during breathing and can be assayed in the exhaled breath condensate (EBC) as markers of nitrossative stress in the airways of patients with asthma, COPD, and idiopathic pulmonary fibrosis (IPF). SUBJECTS AND METHODS: Using HPLC with fluorescence detection, nitrite and nitrate were assayed in EBC of 14 atopic patients with mild-to-moderate stable asthma, 18 atopic asthmatics with exacerbation, 14 COPD patients without exacerbation, 18 patients with exacerbated COPD, 13 patients with active IPF, and in 29 healthy subjects. RESULTS: The geometric mean [exp(mean±SD)] EBC concentrations of nitrite (micromol/l) in patients with asthma [5.1(2.1-12.3)], exacerbation of asthma [5.1(2.8-9.6)], exacerbation of COPD [5.3(3.2-8.7)], and with IPF [5.5(2.9-10.2)] were higher (P<0.05) compared with those of healthy subjects [2.9(1.6-5.3)] and patients with stable COPD [3.0(1.3-6.7)]. Nitrite concentration increased with decreased lung function of patients with asthma (r(s)=-0.31, P<0.02). Presumably owing to the contamination of the EBC sample with nitrate during collection, nitrate levels were highly variable among healthy subjects and higher compared with all groups of patients. CONCLUSION: EBC nitrite is a suitable marker of nitrossative stress in adult patients with lung diseases but cannot differentiate controlled and exacerbated asthma. Further improvements to the methods of EBC collection and sample handling are warranted.

High-dose methotrexate in children with acute lymphoblastic leukemia: 7-hydroxymethotrexate systemic exposure and urinary concentrations at the steady state correlate well with those of methotrexate.

The present study evaluated the pharmacokinetics of methotrexate (MTX, CAS 59-05-2) and 7-hydroxymethotrexate (7-OHMTX, CAS 5939-37-7) in children with acute lymphoblastic leukemia (ALL) with particular interest devoted to the renal excretion at the steady-state and to the relationships between total (CL) and renal clearances (CL(R)) of both compounds. Ten children (seven girls) aged 8.5 years (2.9-16) years with standard or medium-risk ALL received four 24-h i.v. infusions of high-dose MTX (HDMTX, 5 g/m2) with leucovorin (CAS 58-05-9) rescue according to the ALL-BFM-95 protocol. MTX and 7-OHMTX were assayed in plasma and urine by high-performance liquid chromatography. At the steady-state, the clearance (CL) of MTX (6.28 +/- 2.79 l h(-1)) was correlated with its CL(R) (r(s) = 0.79, p < 0.0001) which accounted for 61% (SD 26%) of the former. There were weak correlations between pretreatment values of creatinine clearance calculated using Schwartz's formula and the drug's CL (r(s) = 0.30, p < 0.05) or CLR (r(s) = 0.41, p < 0.02). In contrast, the CL(R) accounted for only 26% (SD 15%) of the metabolite's CL which was estimated assuming 10% conversion of MTX to 7-OHMTX. The CL values of both compounds were highly correlated (r(s) = 0.86, p < 0.0001). The CL(R) of the parent compound was on the average 9-fold higher (range: 3.5- to 17-fold) and was strongly correlated with the CL(R) of the metabolite (r(s) = 0.87, p < 0.0001). The ratio 7-OHMTX/MTX of urinary concentrations was between 2.4 and 9.8% with the mean value of 4.1%. This study suggests that during the 24-h i.v. infusions of HDMTX to children with ALL, the exposure of patients to 7-OHMTX can be reasonably well predicted from the knowledge of MTX concentrations. The steady-state renal CLs, total CLs as well as urinary concentrations of the parent compound and metabolite are highly correlated and the correlation of plasma concentrations is moderate. Therefore, it is unlikely that simultaneous evaluation of 7-OHMTX and MTX steady-state concentrations could improve the predictive performance of the latter towards the response or the risk of complications, although future larger studies should verify this conclusion.