Population pharmacokinetics of cyclophosphamide and its metabolites 4-hydroxycyclophosphamide, 2-dechloroethylcyclophosphamide, and phosphoramide mustard in a high-dose combination with Thiotepa and Carboplatin

The anticancer prodrug cyclophosphamide (CP) is activated by the formation of 4-hydroxycyclophosphamide (4OHCP), which decomposes into phosphoramide mustard (PM). This activation pathway is inhibited by thiotepa. CP is inactivated by formation of 2-dechloroethylcyclophosphamide (2DCECP). The aim of this study was to develop a population pharmacokinetic model describing the complex pharmacokinetics of CP, 4OHCP, 2DCECP, and PM when CP is administered in a high-dose combination with thiotepa and carboplatin. Patients received a combination of CP (1000-1500 mg/m/d), carboplatin (265-400 mg/m/d), and thiotepa (80-120 mg/m/d) administered in short infusions over 4 days. Twenty blood samples were collected per patient per course. Concentrations of CP, 4OHCP, 2DCECP, PM, thiotepa, and tepa were determined in plasma. Using NONMEM, an integrated population pharmacokinetic model was used to describe the pharmacokinetics of CP, 4OHCP, 2DCECP, and PM, including the already described processes of autoinduction of CP and the interaction with thiotepa. Data were available on 35 patients (70 courses). The pharmacokinetics of CP were described with a 2-compartment model, and those of 4OHCP, 2DCECP, and PM with 1-compartment models. Before onset of autoinduction, it was assumed that CP is eliminated through a noninducible pathway accounting for 20% of total CP clearance, whereas 2 inducible pathways resulted in formation of 4OHCP (75%) and 2DCECP (5%). It was assumed that 4OHCP was fully converted to PM. Induction of CP metabolism was mediated by 2 hypothetical amounts of enzyme whose quantities increased in time in the presence of CP (kenz=0.0223 and 0.0198 hours). Induction resulted in an increased formation of 4OHCP (approximately 50%), PM (approximately 50%), and 2DCECP (approximately 35%) during the 4-day course, and concomitant decreased exposure to CP (approximately 50%). The formation of 2DCECP was not inhibited by thiotepa. Apparent volumes of distribution of CP, PM, and 2DCECP could be estimated being 43.7, 55.5, and 18.5 L, respectively. Exposure to metabolites varied up to 9-fold. The complex population pharmacokinetics of CP, 4OHCP, 2DCECP, and PM in combination with thiotepa and carboplatin has been established and may form the basis for further treatment optimization with this combination.     

Postoperative functional outcome and stability in recurrent traumatic anteroinferior glenohumeral instability: comparison of two different surgical capsular reconstruction techniques

INTRODUCTION: Patients (n=62) with recurrent traumatic anterior or anteroinferior glenohumeral instability were prospectively evaluated with reference to the surgical reconstruction technique performed. MATERIALS AND METHODS: Neer's T-plasty procedure was performed in group I (n=31) while a modified, anatomically orientated, anteroinferior capsular shift was performed in group II (n=31). All patients underwent an additional Bankart repair. After 18.1 (group II) and 22.2 (group I) months, patients were assessed in terms of subjective satisfaction, objective stability, range of motion, and functional outcome. RESULTS: No significant differences (91.5% group II, 87.8% group I) were noted between the study groups regarding the patient's subjective evaluation (p=0.17106). Results of Rowe's (93.1% group II, 87.9% group I; p=0.14419) and Constant's Score (96.5% group II, 93.8% group I; p=0.16582) showed no significant differences for both collectives. Postoperative lack of external rotation remained significantly smaller in group II (5.6 degrees +/-2.5 degrees ) compared with group I (9.8 degrees +/-2.5; p=0.00028). Although no significant differences (p=0.612) were found, the rate of recurrence was obviously smaller in group II (group II vs group I: 6 patients). CONCLUSIONS: Our results demonstrate no significant differences between the two capsular reconstruction techniques regarding patient's satisfaction, Rowe and Constant Scores. However, the anatomically orientated anteroinferior capsular shift leads to a significantly smaller external rotation deficit and seems to offer a more reliable postoperative stability.     

Influence of tidal volume on left ventricular stroke volume variation measured by pulse contour analysis in mechanically ventilated patients

OBJECTIVE: Real-time measurement of stroke volume variation by arterial pulse contour analysis (SVV) is useful in predicting volume responsiveness and monitoring volume therapy in mechanically ventilated patients. This study investigated the influence of the depth of tidal volume (V(t)) on SVV both during the state of fluid responsiveness and after fluid loading in mechanically ventilated patients. DESIGN AND SETTING: Prospective study in a university hospital, adult cardiac surgery intensive care unit. PATIENTS AND PARTICIPANTS: 20 hemodynamically stable patients immediately after cardiac surgery. INTERVENTIONS: Stepwise fluid loading using colloids until stroke volume index (SVI) did not increase by more than 10%. Before and after fluid loading V(t) was varied (5, 10, and 15 ml/kg body weight) in random order. MEASUREMENTS AND RESULTS: Pulse contour SVV was measured before and after volume loading at the respective V(t) values. Thirteen patients responded to fluid loading with an increase in SVI greater than 10%, which confirmed volume responsiveness at baseline measurements. These were included in further analysis. During volume responsiveness SVV at V(t) of 5 ml/kg (7+/-0.7%) and SVV at V(t) of 15 ml/kg (21+/-2.5%) differed significantly from that at V(t) of 10 ml/kg (15+/-2.1%). SVV was correlated significantly with the magnitude of V(t). After volume resuscitation SVV at the respective V(t) was significantly reduced; further, SVV at V(t) of 5 ml/kg(-1) (5.3+/-0.6%) and 15 ml/kg (16.2+/-2.0%) differed significantly from that at V(t) of 10 ml/kg (10.2+/-1.0%). SVV and depth of V(t) were significantly related. CONCLUSIONS: In addition to intravascular volume status SVV is affected by the depth of tidal volume under mechanical ventilation. This influence must be regarded when using SVV for functional preload monitoring.     

Impact of vitamin A supplementation through different dosages of red palm oil and retinol palmitate on preschool children

Red palm oil (5 ml and 10 ml), ground nut oil fortified with 400 and 800 retinol equivalent retinol palmitate, and ground nut oil (5 and 10 ml), were administered to six groups of preschool children (four experimental and two control groups) in randomly assigned balwadis of Ramanathapuram District of Tamil Nadu for a period of 7 months, to monitor the difference in the efficacy of the mode of supplementation and the optimum dose for improving vitamin A status. Results show that red palm oil groups recorded more gain in retinol and beta-carotene levels compared to other dosage groups, and that administration of 10 ml did not offer any substantial improvement over the 5-ml daily dose.     

Mid-term results and quantitative comparison of postoperative shoulder function in traumatic and non-traumatic rotator cuff tears

Introduction The objective of this study was to compare the postoperative range of motion (ROM) and patient satisfaction after surgical reconstruction of traumatic and non-traumatic rotator cuff tears.Materials and methods The cases of 46 consecutive patients who underwent the same standardised surgical reconstruction and postoperative rehabilitation protocol between 1993 and 1998 were reviewed. Traumatic (group I, n=20, average age 34.2 years, range 15–49 years) and non-traumatic tears (group II, n=26, average age 54.1 years, range 50–68 years) formed the two study groups. Mean follow-up lasted 47.1 months (range 13–105 months) in group I and 41.4 months (range 11–94 months) in group II. Assessment included postoperative shoulder function with Constant and Murley's score and visual analogue scale (VAS).Results Significantly (p=0.0019) better results were observed in group I with an average of 94.1 points for Constant's score, compared with 75.3 points in group II. Postoperative shoulder function was not affected regarding full-thickness or partial tears (p=0.239) in group I. VAS revealed an excellent or good result in all patients of group I (n=20) and 50% of group II (n=13/26). Quantitative comparison of postoperative ROM demonstrated significantly better results in forward flexion (p=0.013), abduction (p=0.0019) and external rotation (p=0.0042) for group I. The remaining postoperative external rotation deficit for group II with a loss of 31% compared with group I (38.9° vs 56.6°) was statistically and clinically relevant.Conclusion The results demonstrate that surgical reconstruction of traumatic and non-traumatic rotator cuff tears is a successful procedure. Comparison of both groups revealed significantly better postoperative results in the younger, traumatic collective.     

Centrosomal aberrations in primary invasive breast cancer are associated with nodal status and hormone receptor expression

Our purpose was to assess the presence of centrosomal aberrations as measured by immunohistochemistry in primary invasive breast cancer and their association with established and proposed prognostic factors. Tissue sections of 103 primary invasive breast cancers were examined using centrosome-specific antibodies to pericentrin and gamma-tubulin. At least 3 different tumor regions per case were examined to determine maximum centrosomal aberration levels, which represent the proportion of cells with abnormal centrosomes in the region with the highest percentage of cells with centrosomal aberrations. The chi(2) test was performed to evaluate the association of maximum centrosomal aberration levels with patient age; tumor size; nodal status; nuclear grade; hormone receptor and Her2/neu expression; proportion of Ki67-, p53- and Bcl-2-positive tumor cells; DNA index; S-phase fraction; and proliferation index. With pericentrin immunohistochemistry, maximum centrosomal aberration levels >35% were detectable in 92 of the 103 breast carcinomas (89%). We found a highly significant correlation of maximum centrosomal aberration levels above 35% with axillary nodal tumor involvement (p < 0.0001) and the absence of hormone receptors (p < 0.0001). In addition, there was a borderline significant relationship with age <50 years (p = 0.050) and Her2/neu overexpression (p = 0.050). Among node-negative patients, maximum centrosomal aberration levels >35% were also associated with an increased DNA index (p = 0.006). In a subset of patients, additional staining of centrosomes with a monoclonal anti-gamma-tubulin antibody essentially confirmed these results. In primary invasive breast cancer, centrosomal aberrations are associated with those factors predicting a more aggressive course of disease. This might indicate a fundamental role of centrosomal dysfunction in disease evolution, possibly as a result of chromosome missegregation during mitosis.     

Urinary excretion of thioTEPA and its metabolites in patients treated with high-dose cyclophosphamide, thioTEPA and carboplatin.

The urinary excretion of N,N',N"-triethylenethiophosphoramide (thioTEPA), and its metabolites N,N',N"-triethylenephosphoramide (TEPA), N,N'-diethylene,N"-2-chloroethylphosphoramide (monochloroTEPA) and thioTEPA--mercapturate was determined in patients receiving thioTEPA as part of a high-dose combination chemotherapy regimen with cyclophosphamide and carboplatin. The thioTEPA dose was 40 or 60 mg/m(2) in short infusions, twice daily, during 4 days. Urine samples were collected after each voiding on each day of drug administration until 24--48 h after the last thioTEPA infusion. ThioTEPA, TEPA and monochloroTEPA concentrations were determined with gas chromatography and thioTEPA--mercapturate with liquid chromatography--mass spectrometry with direct sample injection. ThioTEPA was present in urine 30 min after infusion and was still excreted 18 h after the last infusion. All metabolites were detected in urine 1 h after infusion. Patients with a creatinine clearance above 140 ml/minl showed higher excretion of TEPA than patients with a creatinine clearance below 140 ml/min (12.8 versus 4.9%, p=0.01). The excretion of monochloroTEPA relative to the excreted amount of TEPA increased at lower pH values of the urine. The excretion of thioTEPA--mercapturate relative to the dose was higher in patients treated with 60 mg/m(2). Excretion of thioTEPA and monochloroTEPA both accounted for only 0.5% of the dose, while TEPA and thioTEPA--mercapturate both accounted for 11.1%.     

Neurons of the rat suprachiasmatic nucleus show a circadian rhythm in membrane properties that is lost during prolonged whole-cell recording

The suprachiasmatic nucleus is commonly considered to contain the main pacemaker of behavioral and hormonal circadian rhythms. Using whole-cell patch-clamp recordings, the membrane properties of suprachiasmatic nucleus neurons were investigated in order to get more insight in membrane physiological mechanisms underlying the circadian rhythm in firing activity. Circadian rhythmicity could not be detected either in spontaneous firing rate or in other membrane properties when whole-cell measurements were made following an initial phase shortly after membrane rupture. However, this apparent lack of rhythmicity was not due to an unhealthy slice preparation or to seal formation, as a clear day/night difference in firing rate was found in cell-attached recordings. Furthermore, in a subsequent series of whole-cell recordings, membrane properties were assessed directly after membrane rupture, and in this series we did find a significant day/night difference in spontaneous firing rate, input resistance and frequency adaptation. As concerns the participation of different subpopulations of suprachiasmatic nucleus neurons expressing circadian rhythmicity, cluster I neurons exhibited strong rhythmicity, whereas no day/night differences were found in cluster II neurons. Vasopressin-containing cells form a subpopulation of cluster I neurons and showed a more pronounced circadian rhythmicity than the total population of cluster I neurons. In addition to their strong rhythm in spontaneous firing rate they also displayed a day/night difference in membrane potential.