Renal excretion kinetics of high-dose cis-dichlorodiammineplatinum(II) administered with hydration and mannitol diuresis.

The effect of hydration and mannitol diuresis on the nephrotoxicity and renal excretion kinetics of high-dose cis-dichlorodiammineplatinum(II) was examined in seven men undergoing treatment for testicular or bladder carcinoma. The elimination half-life averaged 26.8 hours, shorter than values previously reported from studies not employing hydration and diuresis. In addition, no signs of nephrotoxicity were observed. The results suggest that hydration and mannitol diuresis decrease the nephrotoxicity of cis-dichlorodiammineplatinum(II) by increasing its rate of elimination.     

Pharmacokinetics of high-dose chemotherapy

There is considerable variation in the severity of preparative regimen-related toxicity (RRT) in hematopoietic stem-cell transplantation (HSCT). This variation has been recognized to be due, in part, to the wide variation in the pharmacokinetics (PK) of high-dose chemotherapy (HDC). Consequently, therapeutic drug modeling and pharmacokinetic-directed therapy (PKDT) represents an attractive strategy in this setting. Advances in our understanding of drug metabolism, the nature of the active metabolites, and the ability to measure drug concentrations have led to the point where for some agents it is now possible to treat to a given PK end point with a great deal of reliability. In-depth knowledge of the PK and pharmacodynamics (PD) associations of the agents employed in the high-dose setting will make possible more efficient research into preparative regimen dosing intensity and comparisons of different preparative regimens as well as safer HSCT overall. In this review, we discuss PK and PD studies of high-dose cyclosphamide, melphalan, thiotepa, carmustine, cisplatin, carboplatin, paclitaxel, docetaxel, and busulfan.     

Pharmacokinetics of high-dose teniposide

This paper describes the pharmacokinetics of teniposide (VM-26) after being administered iv in high doses to eight cancer patients (maximum dose, 1.0 g/m2). VM-26 levels in plasma, urine, saliva, duodenal fluid, and cerebrospinal fluid were determined using high-performance liquid chromatography in combination with electrochemical detection. The plasma concentration-time curve of VM-26 showed a triphasic decay with a slow third phase in five patients, whereas in two patients the plasma concentration decay was biphasic. The plasma pharmacokinetics of VM-26 proved to be linear and could be fitted to a three-compartment model (five patients) and to a two-compartment model (two). The steady-state volume of distribution varied from 13.2 to 24.7 L/m2. The total-body clearance ranged from 5.84 to 10.18 ml/minute/m2. Low concentrations of VM-26 were found in saliva, duodenal fluid, cerebrospinal fluid, and urine. Excretion of unchanged VM-26 into the urine varied from 8.8% to 13.9% of the administered dose. No glucuronide of VM-26 could be detected in plasma or other biological fluid.     

Encephalopathy complicating high-dose melphalan

High-dose melphalan (HDM) with peripheral blood stem cell transplant (PBSCT) is a common treatment for patients with multiple myeloma (MM) and more recently also with AL amyloidosis (ALA). We report two female patients with severe renal failure who underwent treatment with HDM for MM (patient 1) and ALA (patient 2). Both patients developed severe encephalopathy with generalised tonic-clonic seizures and a Glasgow Coma Scale (GCS) of 3/15. Causes for coma such as infections, metabolic disturbances, cerebral ischaemia or haemorrhage were excluded. Patient 1 died on day 25 post transplant while comatose. Patient 2 recovered from her comatose state 18 days after transplantation. To our knowledge this is the first report on a possible role of high-dose melphalan in the development of encephalopathy.     

Pharmacokinetics of continuous-infusion high-dose thiotepa

The pharmacokinetics of thiotepa administered as a continuous infusion over 4 days have been studied in 18 patients receiving high-dose thiotepa, cyclophosphamide, and autologous bone marrow reinfusion as treatment for advanced neoplasms. Patients received cyclophosphamide at a total dose of 6 g/m2 and thiotepa at a total dose of 180-900 mg/m2 over the 4-day infusion. Samples of plasma were obtained during and following infusion, and the plasma concentration of thiotepa was determined by the method of Egorin et al. For many patients (72%), peak concentrations of plasma thiotepa were achieved during the initial 24 hours of infusion and then declined an average of 29% by the end of the 96-hour infusion. The average total systemic clearance of thiotepa was 16.7 +/- 7.4 (SD) L/m2/hour [or 420 +/- 162 (SD) ml/kg/hr]. An inverse correlation between the average total systemic clearance and the dose of thiotepa was observed (P less than 0.01).     

Cardiac toxicity of high-dose chemotherapy

Cardiac toxicity is an uncommon but potentially serious complication of high-dose (HD) chemotherapy and little is known about incidence, severity and underlying mechanisms. We have systematically reviewed the literature of the last 30 years to summarize and appraise the published evidence on cardiac toxicity associated with HD chemotherapy. HD cyclophosphamide-containing regimens have been most commonly associated with cardiac toxicity, with a progressively decreasing incidence over time. Dosage, application regimens and coadministration of other chemotherapeutic agents emerged as risk factors. While cardiac toxicity has been rarely associated with other cytotoxic drugs, an unexpected incidence of severe cardiotoxicity resulted from reduced-intensity conditioning regimens containing melphalan and fludarabine. Predictive value of cardiologic examination of patients is limited, and patients with a slight depression of cardiac performance could tolerate HD chemotherapy. Clinical examination, resting electrocardiography and dosage adjustment in overweight patients remain the mainstay of prevention, with bidimensional echocardiography (2D echo) for patients with a history of anthracycline exposure. Strategies to decrease the long-term negative impact of anthracycline administration on cardiac performance are being investigated. New 2D echo-based techniques and circulating markers of cardiac function hold promise for allowing identification of patients at high risk for and early diagnosis of cardiac toxicity.     

Effects of hydration on blood rheology

This study investigated the impact of oral fluid intake on blood rheology of 17 healthy adults following a 12-14 hour overnight fast from food and drink. An oral fluid load of 500 ml was consumed every 30 minutes for 2 hours. Blood viscosity values at shear rates of 1, 10 and 100 s(-1) were reduced (p<0.05 to p<0.01) at 30 and 120 minutes following hydration; however, these differences were not significant after hematocrit correction. With fluid intake, both uncorrected and corrected viscous component of blood viscoelasticity at oscillatory shear rate of 1 s(-1) and at a constant frequency of 2 Hz were reduced (p<0.05 to p<0.001) at all time points as compared to fasting values. The corrected elastic component of blood viscoelasticity increased 90 minutes after hydration (p<0.05). An overnight fast is accompanied by rheological abnormalities that are altered by fluid intake.     

Retreatment of high-dose interferon (5 MU daily) nonresponders with high-dose IFN + ribavirin

The treatment of chronic hepatitis C infection continues to evolve. Interferon (IFN) and ribavirin (RIBA) have become the mainstays of current therapy. The ideal dose and form of treatment of these two agents remains to be determined. An open label prospective trial of 5 MU of interferon daily plus ribavirin dosed according to weight was performed utilizing 40 patients, who were identified as being IFN nonresponders to 1 year or more of continuous IFN administered at a dose of 5 MU/day. Nineteen of the 40 subjects (47.5%) became HCV-RNA negative with normal serum ALT level when treated with the combination of IFN + RIBA. Thirteen of the 40 were sustained responders when reexamined after 6–12 months off active therapy. These results were achieved in a predominantly genotype 1 population (75%). This study suggests that the addition of RIBA to high-dose (5 MU daily) IFN can result in an increase in the number of cases experiencing both a short and sustained response to combination therapy.     

Estimating hydration changes upon biomolecular reactions from osmotic stress, high pressure, and preferential hydration experiments

How do we estimate, from thermodynamic measurements, the number of water molecules adsorbed or released from biomolecules as a result of a biochemical process such as binding and allosteric effects? Volumetric and osmotic stress analyses are established methods for estimating water numbers; however, these techniques often yield conflicting results. In contrast, Kirkwood–Buff theory offers a novel way to calculate excess hydration number from volumetric data, provides a quantitative condition to gauge the accuracy of osmotic stress analysis, and clarifies the relationship between osmotic and volumetric analyses. I have applied Kirkwood–Buff theory to calculate water numbers for two processes: (i) the allosteric transition of hemoglobin and (ii) the binding of camphor to cytochrome P450. I show that osmotic stress analysis may overestimate hydration number changes for these processes.     

Bacterial overgrowth after high-dose corticosteroid treatment

A 63-year-old man with systemic lupus erythematosus and selective IgA deficiency developed intractable diarrhoea the day after treatment with prednisone, 50 mg daily, was started. The diarrhoea was considered to be caused by bacterial overgrowth and was later successfully treated with doxycycline. Although IgA deficiency is a risk factor for bacterial overgrowth, a further predisposing condition is necessary for development of this disorder but was not present in this case. We therefore suppose that high-dose treatment with corticosteroids might be a hitherto undescribed risk factor for bacterial overgrowth in vulnerable patients.     

Acquired pseudocholinesterase deficiency after high-dose cyclophosphamide

Succinylcholine, a depolarizing neuromuscular blocking agent used in anesthesia is hydrolyzed in the plasma by the enzyme pseudocholinesterase (PSC). Conditions associated with reduced PSC activity lead to sustained action of succinylcholine and result in prolonged apnea. Cyclophosphamide is an inhibitor of PSC and its suppressive effect may be dose-dependent. We report a case of severe PSC deficiency after high-dose cyclophosphamide at 7 g/m2. The patient received succinylcholine during anesthesia 9 h after chemotherapy and developed prolonged apnea. This case highlights the potential risk of drug-induced PSC deficiency and cautions the use of depolarizing muscular relaxants soon after high-dose cyclophosphamide.