Pharmacokinetic herb-drug interactions between Aidi injection and doxorubicin in rats with diethylnitrosamine-induced hepatocellular carcinoma.

BACKGROUND: Aidi Injection (ADI), a Chinese herbal preparation with anti-cancer activity, is used for the treatment of hepatocellular carcinoma (HCC). Several clinical studies have shown that co-administration of ADI with doxorubicin (DOX) is associated with reduced toxicity of chemotherapy, enhanced clinical efficacy and improved quality of life for patients. However, limited information is available about the herb-drug interactions between ADI and DOX. The study aimed to investigate the pharmacokinetic mechanism of herb-drug interactions between ADI and DOX in a rat model of HCC. METHODS: Experimental HCC was induced in rats by oral administration of diethylnitrosamine. The HCC rats were pretreated with ADI (10 mL/kg, intraperitoneal injection) for 14 consecutive days prior to administration of DOX (7 mg/kg, intravenous injection) to investigate pharmacokinetic interactions. Plasma concentrations of DOX and its major metabolite, doxorubicinol (DOXol), were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). RESULTS: Preadministration of ADI significantly altered the pharmacokinetics of DOX in HCC rats, leading to increased plasma concentrations of both DOX and DOXol. The area under the plasma drug concentration-time curve (AUCs) of DOX and DOXol in rats pretreated with ADI were 3.79-fold and 2.92-fold higher, respectively, than those in control rats that did not receive ADI. CONCLUSIONS: Increased levels of DOX and DOXol were found in the plasma of HCC rats pretreated with ADI.

A Novel Long-circulating DOX Liposome: Formulation and Pharmacokinetics Studies.

BACKGROUND: Doxorubicin (DOX) is a leading chemotherapeutic in cancer treatment because of its high potency and broad spectrum. Liposomal doxorubicin (Doxil®) is the first FDA-approved PEG-liposomes of DOX for the treatment of over 600,000 cancer patients, and it can overcome doxorubicin-induced cardiomyopathy and other side effects and prolong life span. The addition of MPEG2000-DSPE could elevate the total cost of cancer treatment. OBJECTIVE: We intended to prepare a novel DOX liposome that was prepared with inexpensive materials egg yolk lecithin and Kolliphor HS15, thus allowing it to be much cheaper for clinical application. METHODS: DOX liposomes were prepared using the combination of thin-film dispersion ultrasonic method and ammonium sulfate gradient method and the factors that influenced formulation quality were optimized. After formulation, particle size, entrapment efficiency, drug loading, stability, and pharmacokinetics were determined. RESULTS: DOX liposomes were near-spherical morphology with the average size of 90 nm and polydispersity index (PDI) of less than 0.30. The drug loading was up to 7.5%, and the entrapment efficiency was over 80%. The pharmacokinetic studies showed that free DOX could be easily removed and the blood concentration of free DOX group was significantly lower than that of DOX liposomes, which indicated that the novel DOX liposome had a certain sustainedrelease effect. CONCLUSION: In summary, DOX liposome is economical and easy-prepared with prolonged circulation time. Lay Summary: Doxorubicin (DOX) is a leading chemotherapeutic in cancer treatment because of its high potency and broad spectrum. Liposomal doxorubicin (Doxil®) is the first FDAapproved PEG-liposomes of DOX to treat over 600.000 cancer patients, overcoming doxorubicin- induced cardiomyopathy and other side effects and prolonging life span. The addition of MPEG2000-DSPE could elevate the total cost of cancer treatment. We intend to prepare a novel DOX liposome prepared with inexpensive materials egg yolk lecithin and Kolliphor HS15, thus allowing it to be much cheaper for clinical use. The novel DOX liposome is economical and easy-prepared with prolonged circulation time.

Use of a Glass Membrane Pumping Emulsification Device Improves Systemic and Tumor Pharmacokinetics in Rabbit VX2 Liver Tumor in Transarterial Chemoembolization.

PURPOSE: To evaluate the phamacokinetics of epirubicin in conventional transarterial chemoembolization using a developed pumping emulsification device with a microporous glass membrane in VX2 rabbits. MATERIALS AND METHODS: Epirubicin solution (10 mg/mL) was mixed with ethiodized oil (1:2 ratio) using the device or 3-way stopcock. Forty-eight rabbits with VX2 liver tumor implanted 2 weeks prior to transarterial chemoembolization were divided into 2 groups: a device group (n = 24) and a 3-way-stopcock group (n = 24). Next, 0.5 mL of emulsion was injected into the hepatic artery, followed by embolization using 100-300-µm microspheres. The serum epirubicin concentrations (immediately after, 5 minutes after, and 10 minutes after) and the tumor epirubicin concentrations (20 minutes after and 48 hours after) were measured after transarterial chemoembolization. Histopathologic evaluation was performed with a fluorescence microscope. RESULTS: The area under the curve and maximum concentrations of epirubicin in plasma were 0.45 ± 0.18 µg min/mL and 0.13 ± 0.06 µg/mL, respectively, in the device group and 0.71 ± 0.45 µg min/mL and 0.22 ± 0.17 µg/mL, respectively, in the 3-way-stopcock group (P = .013 and P = .021, respectively). The mean epirubicin concentrations in VX2 tumors at 48 hours in the device group and the 3-way-stopcock group were 13.7 ± 6.71 and 7.72 ± 3.26 µg/g tissue, respectively (P = .013). The tumor necrosis ratios at 48 hours were 62 ± 11% in the device group and 51 ± 13% in the 3-way-stopcock group (P = .039). CONCLUSIONS: Conventional transarterial chemoembolization using the pumping emulsification device significantly improved the pharmacokinetics of epirubicin compared to the current standard technique using a 3-way stopcock.

Development of a high-precision bladder hyperthermic intracavitary chemotherapy device for bladder cancer and pharmacokinetic study.

BACKGROUND: Bladder hyperthermic intracavitary chemotherapy (HIVEC) has good effectiveness for bladder cancer, but conventional HIVEC systems lack precision and convenient application. To test the safety of a new HIVEC device (BR-TRG-II-type) in pigs and to perform a preliminary clinical trial in patients with bladder cancer. METHODS: This device was tested on six pigs to optimize the temperature and time parameters. Then, 165 patients (HIVEC after transurethral resection (TUR), n = 128; or HIVEC, n = 37) treated between December 2006 and December 2016 were recruited. Mitomycin C (MMC) was the chemotherapeutic agent. A serum pharmacokinetic study was performed. The primary endpoints were tumor recurrence, disease-free survival (DFS), and cumulative incidence rate (CIR) during follow-up. The adverse effects were graded. RESULTS: The animal experiment showed that 45 °C for 1 h was optimal. HIVEC was successful, with the infusion tube temperature stably controlled at about 45 °C, and outlet tube temperature of about 43 °C in all patients, for three sessions. Serum MMC levels gradually increased during HIVEC and decreased thereafter. The mean DFS was 39 ± 3.21 months (ranging from 8 to 78 months), and the DFS rate was 89.1% during follow-up. No adverse events occurred. CONCLUSION: The use of the BR-TRG-II-type HIVEC device is feasible for the treatment of bladder cancer. Future clinical trials in patients with different stages of bladder cancer will further confirm the clinical usefulness of this device. TRIAL REGISTRATION: chictr.org.cn: ChiCTR1900022099 (registered on Mar. 252,019). Retrospectively registered.

Real-time fluorescence imaging for visualization and drug uptake prediction during drug delivery by thermosensitive liposomes.

Objective: Thermosensitive liposomal doxorubicin (TSL-Dox) is a promising stimuli-responsive nanoparticle drug delivery system that rapidly releases the contained drug in response to hyperthermia (HT) (>40 °C). Combined with localized heating, TSL-Dox allows highly localized delivery. The goals of this study were to demonstrate that real-time fluorescence imaging can visualize drug uptake during delivery, and can predict tumor drug uptake. Methods: Nude mice carrying subcutaneous tumors (Lewis lung carcinoma) were anesthetized and injected with TSL-Dox (5 mg/kg dose). Localized HT was induced by heating tumors for 15, 30 or 60 min via a custom-designed HT probe placed superficially at the tumor location. In vivo fluorescence imaging (excitation 523 nm, emission 610 nm) was performed before, during, and for 5 min following HT. After imaging, tumors were extracted, drug uptake was quantified by high-performance liquid chromatography, and correlated with in vivo fluorescence. Plasma samples were obtained before and after HT to measure TSL-Dox pharmacokinetics. Results: Local drug uptake could be visualized in real-time during HT. Compared to unheated control tumors, fluorescence of heated tumors increased by 4.6-fold (15 min HT), 9.3-fold (30 min HT), and 13.2-fold (60 min HT). HT duration predicted tumor drug uptake (p = .02), with tumor drug concentrations of 4.2 ± 1.3 µg/g (no HT), 7.1 ± 5.9 µg/g (15 min HT), 14.1 ± 6.7 µg/g (30 min HT) and 21.4 ± 12.6 µg/g (60 min HT). There was good correlation (R2 = 0.67) between fluorescence of the tumor region and tumor drug uptake. Conclusions: Real-time in vivo fluorescence imaging can visualize drug uptake during delivery, and can predict tumor drug uptake.

Intra-arterial idarubicin_lipiodol without embolisation in hepatocellular carcinoma: The LIDA-B phase I trial.

BACKGROUND & AIMS: Idarubicin shows high cytotoxicity against hepatocellular carcinoma (HCC) cells, a high hepatic extraction ratio, and high lipophilicity leading to stable emulsions with lipiodol. A dose-escalation phase I trial of idarubicin_lipiodol (without embolisation) was conducted in patients with cirrhotic HCC to estimate the maximum-tolerated dose (MTD) and to assess the safety, efficacy, and pharmacokinetics of the drug, and the health-related quality of life achieved by patients. METHODS: Patients underwent two sessions of treatment with a transarterial idarubicin_lipiodol emulsion without embolisation. The idarubicin dose was escalated according to a modified continuous reassessment method. The MTD was defined as the dose closest to that causing dose-limiting toxicity (DLT) in 20% of patients. RESULTS: A group of 15 patients were enrolled, including one patient at 10 mg, four patients at 15 mg, seven patients at 20 mg, and three patients at 25 mg. Only two patients experienced DLT: oedematous ascitic decompensation and abdominal pain at 20 and 25 mg, respectively. The calculated MTD of idarubicin was 20 mg. The most frequent grade ≥3 adverse events were biological. One month after the second session, the objective response rate was 29% (complete response, 0%; partial response, 29%) based on modified Response Evaluation Criteria In Solid Tumours. The median time to progression was 5.4 months [95% confidence limit (CI) 3.0-14.6 months] and median overall survival was 20.6 months (95% CI 5.7-28.7 months). Pharmacokinetic analysis of idarubicin showed that the mean Cmax of idarubicin after intra-arterial injection of the idarubicin-lipiodol emulsion is approximately half the Cmax after intravenous administration. Health-related quality of life results confirmed the good safety results associated with use of the drug. CONCLUSIONS: The MTD of idarubicin was 20 mg after two chemolipiodolisation sessions. Encouraging safety results, and patient responses and survival were observed. A phase II trial has been scheduled. LAY SUMMARY: There is a need for transarterial regimens that improve the responses and survival of patients with unresectable HCC. In this phase I trial, we showed that two sessions of treatment with a transarterial idarubicin_lipiodol emulsion without embolisation was well tolerated and gave promising efficacy in terms of tumour control and patient survival.

Method of hyperthermia and tumor size influence effectiveness of doxorubicin release from thermosensitive liposomes in experimental tumors.

Systemic chemotherapy of solid tumors could be enhanced by local hyperthermia (HT) in combination with thermosensitive liposomes (TSL) as drug carriers. In such an approach, effective HT of the tumor is considered essential for successful triggering local drug release and targeting of the drug to the tumor. To investigate the effect of HT method on the effectiveness of drug delivery, a novel laser-based HT device designed for the use in magnetic resonance imaging (MRI) was compared systematically with the frequently used cold light lamp and water bath HT. Long circulating phosphatidyldiglycerol-based TSL (DPPG2-TSL) with encapsulated doxorubicin (DOX) were used as drug carrier enabling intravascular drug release. Experiments were performed in male Brown Norway rats with a syngeneic soft tissue sarcoma (BN 175) located on both hind legs. One tumor was heated while the second tumor remained unheated as a reference. Six animals were investigated per HT method. DPPG2-TSL were injected i.v. at a stable tumor temperature above 40°C. Thereafter, temperature was maintained for 60min. Total DOX concentration in plasma, tumor tissue and muscle was determined post therapy by HPLC. Finally, the new laser-based device was tested in a MRI environment at 3T using DPPG2-TSL with encapsulated Gd-based contrast agent. All methods showed effective DOX delivery by TSL with 4.5-23.1ng/mg found in the heated tumors. In contrast, DOX concentration in the non-heated tumors was 0.5±0.1ng/mg. Independent of used HT methods, higher DOX levels were found in the smaller tumors. In comparison water bath induced lowest DOX delivery but still showing fourfold higher DOX concentrations compared to the non-heated tumors. With the laser-based applicator, a 13 fold higher DOX deposition was possible for large tumors and a 15 fold higher for the small tumors, respectively. Temperature gradients in the tumor tissue were higher with the laser and cold light lamp (-0.3°C/mm to -0.5°C/mm) compared to the water bath (-0.1°C/mm and -0.2°C/mm). Visualization of HT in the MRI demonstrated successful localized heating throughout the entire tumor volume by contrast agent release from DPPG2-TSL. In conclusion, HT triggered drug delivery by using DPPG2-TSL is a promising tool in chemotherapy but effectiveness markedly depended on the method of heating and also on tumor size. Local HT using a cold light lamp or the new laser applicator allowed more efficient drug delivery than using a regional water bath heating. MR-compatibility of the new applicator gives the opportunity for future experiments investing drug delivery in more detail by MRI at low technical efforts.

Refilling drug delivery depots through the blood.

Local drug delivery depots have significant clinical utility, but there is currently no noninvasive technique to refill these systems once their payload is exhausted. Inspired by the ability of nanotherapeutics to target specific tissues, we hypothesized that blood-borne drug payloads could be modified to home to and refill hydrogel drug delivery systems. To address this possibility, hydrogels were modified with oligodeoxynucleotides (ODNs) that provide a target for drug payloads in the form of free alginate strands carrying complementary ODNs. Coupling ODNs to alginate strands led to specific binding to complementary-ODN-carrying alginate gels in vitro and to injected gels in vivo. When coupled to a drug payload, sequence-targeted refilling of a delivery depot consisting of intratumor hydrogels completely abrogated tumor growth. These results suggest a new paradigm for nanotherapeutic drug delivery, and this concept is expected to have applications in refilling drug depots in cancer therapy, wound healing, and drug-eluting vascular grafts and stents.

Two phase I dose-escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (LTLD) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer.

PURPOSE: Unresectable chest wall recurrences of breast cancer (CWR) in heavily pretreated patients are especially difficult to treat. We hypothesised that thermally enhanced drug delivery using low temperature liposomal doxorubicin (LTLD), given with mild local hyperthermia (MLHT), will be safe and effective in this population. PATIENTS AND METHODS: This paper combines the results of two similarly designed phase I trials. Eligible CWR patients had progressed on the chest wall after prior hormone therapy, chemotherapy, and radiotherapy. Patients were to get six cycles of LTLD every 21-35 days, followed immediately by chest wall MLHT for 1 hour at 40-42 °C. In the first trial 18 subjects received LTLD at 20, 30, or 40 mg/m2; in the second trial, 11 subjects received LTLD at 40 or 50 mg/m2. RESULTS: The median age of all 29 patients enrolled was 57 years. Thirteen patients (45%) had distant metastases on enrolment. Patients had received a median dose of 256 mg/m2 of prior anthracyclines and a median dose of 61 Gy of prior radiation. The median number of study treatments that subjects completed was four. The maximum tolerated dose was 50 mg/m2, with seven subjects (24%) developing reversible grade 3-4 neutropenia and four (14%) reversible grade 3-4 leucopenia. The rate of overall local response was 48% (14/29, 95% CI: 30-66%), with. five patients (17%) achieving complete local responses and nine patients (31%) having partial local responses. CONCLUSION: LTLD at 50 mg/m2 and MLHT is safe. This combined therapy produces objective responses in heavily pretreated CWR patients. Future work should test thermally enhanced LTLD delivery in a less advanced patient population.

Comparison of drug release and pharmacokinetics after transarterial chemoembolization using diverse lipiodol emulsions and drug-eluting beads.

In many studies for chemoembolization of hepatocellular carcinoma, the Lipiodol emulsion preparation protocols, especially the mixing steps, were unclear or even unrevealed at all. However, doxorubicin (DOX) release may depend on the composition and volume ratio (Lipiodol to DOX solution) of a Lipiodol emulsion. Therefore, we conducted a preclinical study to compare in-vitro drug release and in-vivo pharmacokinetics of DOX from diverse Lipiodol emulsions and drug-eluting beads (DEBs) and to compare the tumor response in a rabbit VX2 carcinoma model. DOX release profiles of four types of Lipiodol emulsions with different media (normal saline or Pamiray as an iodinated contrast medium), volume ratio (Lipiodol to DOX solution), and DEBs were investigated in-vitro. For the in-vivo study, 15 rabbits bearing VX2 carcinoma in the liver were treated with 4∶1 volume ratio Lipiodol emulsion (group A), 1∶1 volume ratio Lipiodol emulsion (group B), and DEBs (group C) chemoembolization. Blood and tissue sampling was conducted to evaluate DOX concentration in plasma and tissues, histological changes, and liver toxicity. The most stable emulsion was formed with Pamiray (including DOX) at a 4∶1 volume ratio. The AUC value of group A was significantly lower than that of group B (p = 0.003) but comparable to that of group C (p = 0.071). The Cmax value of group A was significantly different compared with those of group B (p = 0.004) and C (p = 0.015). The tissue drug concentration in group A was comparable to that in group C (p = 0.251). No viable tumor was detected in rabbits of group A and B. In group C, viable tumor less than 10% was seen in two of the five rabbits. There were no significant differences in liver enzyme levels after the procedure. In conclusion, DOX release and pharmacokinetics of presented emulsion systems depend substantially on their composition. Therefore, Lipiodol emulsion type should be considered when interpreting data and designing new studies dealing with chemoembolization.

Enhanced solubility and oral absorption of sirolimus using D-α-tocopheryl polyethylene glycol succinate micelles.

The objective of this study was to develop an oral formulation that would improve the solubility and oral absorption of sirolimus using a TPGS micellar solution. The effect of TPGS on the solubility and stability of sirolimus was evaluated. The sirolimus-loaded TPGS micelles were prepared using the thin-film hydration method. The average size of the sirolimus-loaded TPGS micelles was 11 nm. The concentration of sirolimus in a 50 mg/mL TPGS micellar solution was 0.97 ± 0.12 mg/mL, which demonstrates an enhancement of approximately 400-fold from the solubility of sirolimus in water. Furthermore, pharmacokinetic studies in rats indicated that the TPGS micellar solution significantly improved the oral absorption of sirolimus. Therefore, the preliminary results from this study suggest that a TPGS micellar solution has great potential for clinical applications.

Risk factors for the leakage of chemotherapeutic agents into systemic circulation after transcatheter arterial chemoembolization of hepatocellular carcinoma.

This prospective study was to investigate the possible risk factors for the leakage of chemotherapeutic agent into the systemic circulation after transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). Peripheral plasma concentrations of chemotherapeutic agents were determined at 1 hour and 72 hours after TACE by high-performance liquid chromatography in 53 patients. HCC were divided into three types namely single nodule (<5cm), multiple nodules (all <5cm), and main nodule measuring 5cm or more. Forty-four patients (83%) showed detectable chemotherapeutic concentrations within 72 hours after TACE. Patients with single nodular-type HCC had lower incidence of detectable plasma chemotherapeutic agents after TACE than the other two groups (all p<0.05). The injected doses of lipiodol, epirubicin, and mitomycin C were lower in patients without detection than in patients with detectable chemotherapeutic agents (all p<0.05). Multivariate logistic regression showed that tumor type and injected dose of lipiodol were two independent risk factors for the leakage of mitomycin C at 1 hour after TACE (all p<0.05), and the injected dose of mitomycin C was the risk factor for the leakage of epirubicin at 1 hour after TACE (p<0.05). In conclusion, multiple nodular type and large nodule measuring 5cm or more have a risk of leakage of mitomycin C after TACE. Injected dose of lipiodol and mitomycin C as risk factor for the leakage of mitomycin C and epirubicin respectively may be because of competition of their injected volume within the limited space of target.

Changes induced by surgical and clinical factors in the pharmacology of intraperitoneal mitomycin C in 145 patients with peritoneal carcinomatosis.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are a combined treatment modality considered for selected patients with peritoneal carcinomatosis from colorectal and appendiceal cancer. Mitomycin C is a drug often used in this clinical setting. The surgical and clinical factors that may influence the pharmacokinetics of hyperthermic intraperitoneal chemotherapy should be further elucidated. MATERIALS AND METHODS: The patients included were 145 who had colorectal or appendiceal carcinomatosis resected using cytoreductive surgery prior to treatment with hyperthermic intraperitoneal chemotherapy with mitomycin C as part of a multidrug regimen. The effect of clinical and surgical factors on drug distribution after single intraperitoneal bolus administration with mitomycin C was determined. RESULTS: The pharmacokinetics of 145 patients treated with intraperitoneal mitomycin C showed a 27 times greater exposure to peritoneal surfaces when compared to plasma. At 90 min, 29% of the drug remained in the chemotherapy solution, 62% was retained in the body, and 9% was excreted in the urine. The extent of peritonectomy increased the clearance of mitomycin C from the peritoneal space (p = 0.051). A major resection of visceral peritoneal surface and a contracted peritoneal space reduced drug clearance. A contracted peritoneal space significantly reduced (p = 0.0001) drug concentrations in the plasma. CONCLUSIONS: Surgical and clinical factors may require modifications of drug dose or timing of chemotherapy administration. A large visceral resection and a contracted peritoneal space caused a reduced mitomycin C clearance. Total diffusion surface is an important determinant of mitomycin C pharmacokinetics.

Determination and pharmacokinetic study of indirubin in rat plasma by high-performance liquid chromatography.

A specific, simple and sensitive HPLC method with UV detection was developed and validated for the pharmacokinetic studies of indirubin in rat plasma for the first time. Indirubin, with osthole as the internal standard, was extracted from plasma samples by liquid-liquid extraction. Chromatographic separation was conducted on a reverse-phase ODS column (200 mm x 4.6 mm, i.d., 5 microm), using a mixture of methanol-water (75:25, v/v) as the mobile phase at a flow rate of 1.0 ml/min with UV detection at 289 nm. The calibration curve of indirubin was linear over the range of 6.5-1950 ng/ml in rat plasma. The lower limit of quantification (LLOQ) was found to be 6.5 ng/ml. The present method was successfully applied for estimating the pharmacokinetic parameters of indirubin following intravenous and intraperitoneal administration of indirubin to rats.

Combined radiofrequency ablation and adjuvant liposomal chemotherapy: effect of chemotherapeutic agent, nanoparticle size, and circulation time.

PURPOSE: To evaluate the effects of liposomal chemotherapeutic agent, nanoparticle size, and liposome circulation time on tissue coagulation and intratumoral drug uptake when radiofrequency (RF) ablation is combined with adjuvant intravenous liposomal chemotherapy in an animal breast tumor model. MATERIALS AND METHODS: Ninety-one R3230 mammary adenocarcinoma nodules were implanted in 48 Fischer rats. First, standardized RF ablation was combined with intravenous liposomal doxorubicin, cisplatin, or 5-fluorouracil (35 tumors each). Second, three different-sized doxorubicin-containing nanoparticle preparations were combined with standardized RF ablation. Last, two doxorubicin-containing liposome preparations with different blood elimination half-lives were combined with RF ablation. Coagulation diameter and interstitial doxorubicin concentration were measured 48 hours after treatment and compared with use of statistical analysis. RESULTS: All combinations of RF with liposomal chemotherapy caused significantly greater tumor necrosis than RF alone (P<.05). Significantly increased necrosis was observed with intravenous liposomal RF/doxorubicin and RF/cisplatin compared with intravenous liposomal RF/5-fluorouracil (P<.01). Greater coagulation was observed with RF combined with 100-nm nanoparticles compared with 20-nm or 250-nm nanoparticles (P=.01 and P=.04, respectively). Additionally, greater intratumoral doxorubicin uptake was observed in the group treated with 20-nm nanoparticles compared with those treated with other sizes of nanoparticles (P<.05). RF plus liposomal doxorubicin produced greater coagulation and intratumoral doxorubicin uptake than RF plus 1,2-dipalmitoyl-sn-glycero-3-phosphatidic acid (P<.05). CONCLUSION: When combined with RF ablation, modification of adjuvant intravenous liposomal chemotherapy, including nanoparticle size, circulation time, and chemotherapeutic agent, can influence intratumoral drug accumulation and tissue coagulation.

Extent of parietal peritonectomy does not change intraperitoneal chemotherapy pharmacokinetics.

PURPOSE: To measure the clearance intraperitoneal mitomycin C and doxorubicin in patients having peritonectomy and analyze the impact of the extent of peritoneal resection on pharmacokinetics. METHODS: A group of 15 patients with peritoneal carcinomatosis were submitted to cytoreductive surgery and heated intraperitoneal chemotherapy. Ten patients received mitomycin C and five, doxorubicin. Six patients underwent total parietal peritonectomy and nine had less-extensive peritonectomy. Pharmacokinetics were determined by sampling peritoneal fluid and blood. Drug concentrations over time, area under the curve ratios and the amount of drug recovered from the peritoneal cavity were calculated and compared between the groups. RESULTS: The concentrations of mitomycin C over time in the peritoneal fluid and plasma were similar in five patients with total parietal peritonectomy as compared to five patients with less-extensive peritonectomy ( P=0.5350 and 0.6991; Mann-Whitney test). Mitomycin C area under the curve ratio in total peritonectomy patients was 20.5 and 25.7 in patients with less-extensive peritonectomy. The difference in total amount of drug recovered from the peritoneal cavity was not significant (30.6+/-6.188% versus 22.6+/-3.84%, P=0.095). In the studies with doxorubicin, one patient underwent total parietal peritonectomy with similar pharmacokinetics to four patients submitted to partial peritonectomy. CONCLUSIONS: The extent of parietal peritoneal resection did not affect the pharmacokinetics of intraoperative intraperitoneal chemotherapy. The pharmacological barrier between the abdominopelvic cavity and plasma is not directly related to an intact peritoneum.

Studies on hyperthermia combined with arterial therapeutic blockade for treatment of tumors: (Part III) effectiveness of hyperthermia combined with arterial chemoembolization using degradable starch microspheres on advanced liver cancer.

Arterial chemoembolization using degradable starch microspheres and adriamycin was combined with hyperthermia to treat advanced liver cancer. The prolonged peak adriamycin level in hepatic venous blood suggested that the drug persisted for longer in the liver after injection containing microspheres. Heating efficiency was increased more in tumor tissue than in normal liver tissue after embolization. This combined therapy was performed in eight patients with advanced liver cancer and was effective in three (complete or partial remission). The mean survival time was 25 weeks and there were no severe side effects. This combined therapy may be useful for liver cancer.

Plasma mitomycin C concentrations determined by HPLC coupled to solid-phase extraction.

The aim of this study was to set up a method for quantification of plasma mitomycin C (MMC) concentrations during intravesical chemotherapy delivered in the presence of local bladder hyperthermia (HT). In comparison with existing methods, this assay, characterized by relative simplicity and efficiency, resulted in the facilitation of performance with nondedicated instrumentation or nonspecialized staff. Purification from plasma matrix was carried out by solid-phase extraction under vaccuum. The purified drug was then collected directly into the vials of the HPLC autosampler. Chromatographic analysis was performed on a reversed-phase C18 column with water:acetonitrile (85:15 by vol) as the mobile phase and the UV detector set at 365 nm. The use of porfiromycin as internal standard provided a method with good within-day precision (CV 6.0% at 5 micrograms/L, n = 6), linearity (0.5-50 micrograms/L), and specificity. The lower limit of detection (< or = 0.5 microgram/L) proved to be suitable for plasma pharmacokinetics monitoring in two tested patients treated with MMC + HT for superficial bladder cancer.

Disposition of epirubicin after intraarterial administration in Lipiodol to patients with hepatocellular carcinoma.

Delivering emulsions of anthracycline drugs in Lipiodol, an iodinated poppy-seed oil, via the hepatic artery for the treatment of hepatocellular carcinoma (HCC) has become increasingly popular. However, investigations to determine the extent to which the Lipiodol sequesters the anthracycline in the liver have been limited. Concern has been expressed that such emulsions are not stable and that the anthracycline is, therefore, released rapidly into the circulation. We studied the pharmacokinetics of epirubicin (50 mg m-2) in five patients with nonresectable primary hepatocellular carcinoma after infusion of an epirubicin/Lipiodol emulsion via the hepatic artery. We used a reliable and specific high-performance liquid chromatography assay that allows quantitation of plasma concentrations of epirubicin, epirubicinol, epirubicin glucuronide, and epirubicin aglycone. Although a large interpatient variability in pharmacokinetics was observed, our results were similar to historical data after epirubicin intravenous therapy. Only the results from one patient provided evidence of significant retention of the drug in the liver. It would appear that more stable formulations of epirubicin/Lipiodol are required to increase the efficacy of this form of treatment. We suggest that pharmacokinetic studies should accompany clinical evaluation of emulsions of epirubicin/Lipiodol for the treatment of HCC.