Population pharmacokinetics of peritoneal, plasma ultrafiltrated and protein-bound oxaliplatin concentrations in patients with disseminated peritoneal cancer after intraperitoneal hyperthermic chemoperfusion of oxaliplatin following cytoreductive surgery: correlation between oxaliplatin exposure and thrombocytopenia.

PURPOSE: First, to evaluate the peritoneal (IP), plasma ultrafiltrated (UF) and protein-bound (B) pharmacokinetics (PK) of oxaliplatin after intraperitoneal hyperthermic chemoperfusion (HIPEC) following cytoreductive surgery. Second, to evaluate the relationship between oxaliplatin exposure and observed toxicity. METHODS: IP, UF, and B concentrations from 75 patients treated by 30-min oxaliplatin-based HIPEC procedures were analysed according to a pharmacokinetic modelling approach using NONMEM. Oxaliplatin was administered in a 5 % dextrose solution (2 L/m(2)) at 360 (n = 58) or 460 mg/m(2) (n = 17). The most frequently observed toxicities were related to the peritoneal, systemic exposures and to the parameters corresponding to the oxaliplatin absorption from peritoneal cavity into plasma. RESULTS: IP (n = 536), UF (n = 669) and B (n = 661) concentrations were simultaneously described according to a five-compartment PK model with irreversible nonlinear binding from UF to B according to a Michaelis-Menten equation. The mean (±SD) maximum fraction of dose absorbed and elimination half-life from the peritoneum was 53.7 % (±8.5) and 0.49 h (±0.1), respectively. The mean (±SD) ratio AUC(IP)/AUC(UF) was 5.3 (±2) confirming the pharmacokinetic advantage of the procedure. Haemoperitoneum (22.7 %), neuropathy (18.7 %), grade 3/4 thrombocytopenia (13.3 %) were the most frequently reported toxicities. AUC(UF) accounts for approximately 12 % of the variation in the maximum percentage of platelet decrease (r = 0.35, p = 0.002). Thrombocytopenia was correlated with higher AUCUF, partly dependent on the extent and rate of oxaliplatin absorption. CONCLUSIONS: Despite a common dose administered, variability in peritoneal and systemic oxaliplatin exposures are observed, leading to differences in haematological toxicity between patients.

[Morbidity and mortality of hyperthermic intraperitoneal chemoperfusion]. / Morbidität und Letalität der hyperthermen intraperitonealen Chemoperfusion.

Cytoreductive surgery (CRS) combined with perioperative intraperitoneal chemotherapy (PIC) is a treatment option for peritoneal surface malignancy. Despite the survival benefits, this treatment was previously associated with a high morbidity and mortality rates, and the perception of the poor perioperative outcomes associated with this regimen remains. Careful patient selection with an optimal level of postoperative care must be advocated to avoid undesirable complications of this treatment.However, for this treatment to be accepted as standard of care, teams undertaking this treatment strategy must aim to minimize morbidity and mortality by learning from the experience of established centers and using the "global learning curve". The HIPEC Registry and accreditation of centers will improve the quality of the treatment.

Hyperthermic intraperitoneal chemotherapy: methodology and safety considerations.

Several methods of delivering hyperthermic intraperitoneal chemotherapy (HIPEC) during the course of cytoreductive surgery have been described, but no significant differences in treatment results have been found among them. HIPEC is a safe treatment for the patient and for healthcare workers involved in the procedure provided standard protective and environmental measures are used. This article describes the different techniques in use and the technology available for the administration of HIPEC. Also reviewed are the safety features that must be taken into consideration when performing this procedure. Recommended guidelines to prevent associated occupational hazards are provided.

Continuous intraventricular infusion of pentosan polysulfate: clinical trial against prion diseases.

Prion diseases are progressive neurological disorders due to abnormal prion protein (PrP(Sc)) deposition in the central nervous system. At present, there is no effective treatment available for any form of prion disease. Pentosan polysulfate (PPS) has been shown to prolong significantly the incubation period in mice with PrP(Sc) infection when administered to the cerebral ventricles in preclinical trials. In human studies conducted in European countries and Japan, intraventricular PPS was administered to patients with different forms of prion disease and was well tolerated. We report 11 patients with prion disease treated with intraventricular PPS at Fukuoka University from 2004. Cases included three familial CJD (two with V180I mutation, one GSS with P102L mutation), two iatrogenic CJD, and six sporadic CJD cases. At present, average survival period after treatment was 24.2 months (range, 4-49). Seven cases died of sepsis and pneumonia. Subdural effusion with various degrees was seen on CT scan in most cases. Except for these, adverse effects did not occur in the treatment period. Although our preliminary study of the new treatment with PPS by continuous intraventricular infusion showed no apparent improvement of clinical features in patients with prion disease, the possibility of extended survival in some patients receiving long-term PPS was suggested.

Design and evaluation of microemulsions for improved parenteral delivery of propofol.

The objective of this investigation was to evaluate the potential of the microemulsions to improve the parenteral delivery of propofol. Pseudo-ternary phase diagrams were plotted to identify microemulsification region of propofol. The propofol microemulsions were evaluated for globule size, physical and chemical stability, osmolarity, in vitro hemolysis, pain caused by injection using rat paw-lick test and in vivo anesthetic activity. The microemulsions exhibited globule size less than 25 nm and demonstrated good physical and chemical stability. Propofol microemulsions were slightly hypertonic and resulted in less than 1% hemolysis after 2 h of storage with human blood at 37 degrees C. Rat paw-lick test indicated that propofol microemulsions were significantly less painful as compared to the marketed propofol formulation. The anesthetic activity of the microemulsions was similar to the marketed propofol formulation indicating that they do not compromise the pharmacological action of propofol. The stability studies indicated that the microemulsions were stable for 3 months when stored at 5 +/- 3 degrees C. Thus, microemulsions appeared to be an interesting alternative to the current propofol formulations.

Severe hyponatremia, hyperglycemia, and hyperlactatemia are associated with intraoperative hyperthermic intraperitoneal chemoperfusion with oxaliplatin.

BACKGROUND: Since the introduction of surgical debulking in combination with intraoperative hyperthermic intraperitoneal chemoperfusion (HIPEC) with oxaliplatin in our institution, severe hyponatremia (sodium: 126.5 +/- 3.8 mmol/L), hyperglycemia (glucose: 22.37 +/- 4.89 mmol/L), and hyperlactatemia (lactate: 3.17 +/- 1.09 mmol/L) have been observed post HIPEC. This metabolic disorder was not observed in patients in whom cisplatin or mitomycin C was used as a chemotherapeutic drug. METHODS: In order to understand the pathophysiology of this finding, an analysis of our data was made. In a first analysis, plasma sodium was corrected for hyperglycemia based on the formula of Hillier. In a second analysis, the influence of total exchangeable sodium, total exchangeable potassium, and total body water on plasma sodium concentration was modeled. RESULTS: Analysis of our data revealed a double mechanism for the observed metabolic disorder: hyperglycemia caused by dextrose 5%, which is used as a carrier for the oxaliplatin, and major loss of sodium into the dialysate (256.7 +/- 68.7 mmol). CONCLUSION: Better control of hyperglycemia and intravenous compensation of sodium loss into the dialysate can attenuate the reported biochemical disturbance.

Comparison of subcutaneous infusion needles for transfusion-dependent thalassemia patients by the intrapersonal cross-over assessment model.

Needle-induced trauma is one of the major contributing factors for poor compliance in patients with thalassaemia major on iron chelation therapy. A new generation of needles is currently available on the market, but their theoretical advantages have not been tested clinically. We performed a study to compare the pros and cons of the representative prototypes from each of the new (Thalaset needle) and old (butterfly scalp vein needle) generations of needles. Patients with thalassemia major who had been receiving subcutaneous iron chelation therapy for at least 2 years were recruited. Patients using butterfly needles were instructed to switch to the newer form of needle (Thalaset) for 2.5 months and then to change back to butterfly needles for another 2.5 months. Comparison was done by the intrapersonal cross-over model using three identical sets of questionnaires collected at the beginning of the study and after the use of Thalaset and butterfly needles, respectively. Fifty-four (22 females; 32 males) patients were included in the statistical analysis. The median age was 24.1 years (range = 7.6-47.2 years). Local reactions such as pain, itchiness, tenderness, and swelling were significantly different among the three evaluation periods and were all in favor of the Thalaset needle (all with P < 0.001), even after adjusting for the intention-to-treat calculation. The Thalaset needle is significantly better than the butterfly needle in reducing needle-related trauma. It induced fewer local skin reactions such as pain, itchiness, tenderness, and swelling. However, recommendations for its routine clinical use require further cost-effectiveness analysis.

Prediction of precipitation-induced phlebitis: a statistical validation of an in vitro model.

To avoid phlebitis, new intravenous (IV) parenterals are often screened by injection into animals. This method is not only expensive and time consuming, it is also detrimental to the animals. An alternate method, focusing on precipitation as the cause, uses an in vitro dynamic injection model that requires less money and time and reduces the need for live models. Validation of the dynamic injection apparatus, for predicting mechanical phlebitis, is established. Twenty-one currently marketed IV products were injected into isotonic Sorenson's phosphate buffer flowing at 5 mL/min. The resulting opacities, produced by precipitation, are measured in an ultraviolet flow cell. These opacity data, coupled with literature reports on phlebitis occurrence, were used to generate a logistic regression that indicates the probability of phlebitis given an opacity value measured by the apparatus. Regression results are supported by a receiver operator characteristic curve that establishes the most ideal cut-off opacity value. This opacity value provides the highest combined sensitivity (statistical power) and specificity while minimizing false-positive and false-negative results. Both analyses show that an opacity value of 0.003 best delineates phlebitic and nonphlebitic products. Measures of sensitivity (0.83), specificity (0.93), positive predictive value (0.93), and negative predictive value (0.78) indicate the model's predictive accuracy and reliability. These results support the use of the dynamic model in place of animals for preliminary phlebitis testing of new IV injectables.

Intra-abdominal fibrosis after systemic and intraperitoneal therapy containing fluoropyrimidines.

BACKGROUND: Intra-abdominal and retroperitoneal fibrosis has been described as secondary to intraperitoneal (IP) administration of several chemotherapeutic agents, including carboplatin, mitoxantrone, and the combination of 5-fluorouracil and cisplatin. The IP administration of floxuridine (FUDR) is an effective and minimally toxic treatment for patients with metastases to the peritoneum. An increasing number of patients with colorectal, gastric, or ovarian carcinoma are treated with IP chemotherapy. METHODS: The authors report two patients with metastatic colon carcinoma who experienced severe intra-abdominal fibrosis presenting as an intra-abdominal mass mimicking recurrence in one patient and diffuse encasement of the bowel in the other, after the administration of IP FUDR and leucovorin. RESULTS: Two patients with Stage III colon adenocarcinoma received postoperative adjuvant 5-fluorouracil and levamisole. They subsequently presented with a rise in carcinoembryonic antigen level and isolated liver metastasis. They underwent hepatic lobectomy with postoperative intra-arterial hepatic FUDR and systemic 5-fluorouracil and leucovorin. They each had an intra-abdominal recurrence, which was resected and treated with postoperative IP FUDR and leucovorin. They then presented with a diffuse pattern of IP fibrosis with no tumor identified. CONCLUSIONS: IP FUDR and leucovorin therapy can be associated with diffuse IP fibrosis, which in this study caused an intra-abdominal mass that was indistinguishable from recurrent malignancy in one patient and encasement of the bowel in the other.

Intraosseous infusion: an alternative route of pediatric intravascular access.

Substantial difficulties can be encountered when establishing rapid intravascular access in critically ill children. The historic technique of tibial intraosseous infusion is presented as an alternate intravenous route in children less than 3 years old. Review of the literature reveals this technique to be a rapid, reliable method with an acceptably low complication rate. Substances absorbed through the marrow, flow rates, technical difficulties, and complications are discussed.

Coagulase-negative staphylococcal bacteremia in patients receiving immunosuppressive therapy.

From January 1977 to June 1980, coagulase-negative staphylococci caused bacteremia in 22 (17%) of 130 patients receiving immunosuppressive therapy and were the most common cause of all bacteremias. Sixteen (73%) of the 22 patients had granulocytopenia, and eight were isolated in a laminar air-flow room. A Broviac or Hickman central intravenous (IV) catheter was present in 20 (91%) of 22 patients, and soft-tissue inflammation at the catheter exit site was a significant risk factor for bacteremia. Except for debilitating fevers and local mucocutaneous infections, there were no distinguishing clinical features in patients with bacteremia. Most infections responded to cefazolin sodium or vancomycin hydrochloride therapy; catheter removal was necessary in only seven patients. These data show that coagulase-negative staphylococci can be important pathogens in patients receiving immunosuppressive therapy, even when the patients are isolated in a laminar air-flow room, if normal mucocutaneous, host-defence barriers are interrupted by IV catheter-insertion or chemotherapy.