The aim of this study was to investigate the effect that recombinant interleukin-2 (rIL-2) (0.16 MUI/injection) had on the pharmacokinetics of imatinib (IM) in plasma. In this study, IM was given orally to mice at a dose of 150 mg/kg once a day for 11 days (from day 1 to 11) either alone or in combination with intraperitoneal injections of rIL-2 twice a day from day 8 to 11. Pharmacokinetic parameters were determined using WinNonLin software. Areas under the curve were compared using Bailer's method. The repeated administration of the rIL-2+IM combination was shown to have two pharmacokinetic advantages compared with repeated IM doses alone. In addition to the pharmacodynamic interest of this treatment, we found that the combined treatment significantly increased the IM Cmax (P<0.05) and significantly increased the IM trough concentration (C(24 h)) (P<0.01), which was always above the minimum therapeutic IM concentration (1 mumol/l) in plasma. Those pharmacokinetic modifications may be explained, in part, by a decrease in the P-glycoprotein expression in the three intestinal segments of the mice (duodenum, P<0.01; jejunum, P<0.05; and ileum, P<0.05) and a decrease in BCRP expression in the duodenum segment (P<0.05) due to rIL-2. In another experiment, we found a significant induction of intestinal P-glycoprotein expression in mice that had been given IM orally (150 mg/kg) twice a day for 11 days. It would be interesting to further investigate the IM disposition associated with rIL-2 treatment for clinical applications.
Introduction Nivolumab, the monoclonal antibody inhibitor of programmed cell death protein 1, enhances the T-cell response, including anti-tumour responses, by blocking the attachment of programmed death-ligand 1 and programmed death-ligand 2 ligands to the programmed cell death protein 1 receptor, which in turn leads to a reduction in tumour growth. Nivolumab has been approved in relapsed or refractory classic Hodgkin's lymphoma after autologous transplantation of haematopoietic stem cell and treatment with brentuximab as monotherapy. Case report We herewith report a case of 65-year-old woman who developed an interstitial pneumonitis and a global cardiac hypokinesis following a treatment with Nivolumab for a refractory Hodgkin's Lymphoma. Nivolumab was administered as the fifth line of therapy. Some concomitant patient treatments include drug with known autoimmune toxicities. Although the patient had a persistent complete remission following the sixth infusion, it was discontinued as she developed dyspnea of NYHA stage IV and orthopnea. The chest tomography revealed a bilateral micronodular pattern of organizing pneumonia with bilateral pleural effusion. The forced expiratory volume was decreased to 50%. In parallel her transthoracic echocardiography revealed a global hypokinesis with a left ventricular ejection fraction of 20%. Management and outcome The patient was treated with empiric antibiotics although the microbial assessments were negative. She was also treated with beta-blocker and angiotensin-converting enzyme inhibitors. The cardiac magnetic resonance imaging performed after 4 months confirmed the hypokinetic cardiopathy with an ejection fraction of 48%. The patient had a significant clinical improvement. The tomography emission positron scan conducted 8 months after interruption of Nivolumab showed complete remission with some moderate activation of residual lesion basal posterior lobe of left lung field. Discussion Early and effective diagnosis of immune-related adverse events through the search for predictive biomarkers like drug factors and individual risk factors will allow targeted surveillance leading to a better tolerance.
Objectives. A main goal of neoadjuvant chemotherapy (CT) in locally advanced breast carcinomas (clinical size >3 cm) is to decrease the tumour volume to permit conservative surgery. In about 10% of the cases, the tumour nodule is not clinically palpable after CT and it is necessary to tattoo the initial site in order to guide the surgeon for the resection of any residual tumour. We have developed a charcoal suspension for injection into human breast tumours. The aim is to enable the pathologist to guide the surgeon during excision of the residual tumour, which is not otherwise visible, after CT. Pharmacological and toxicological studies in animals have indicated that the suspension is well tolerated. Methods. We investigated the efficacy and tolerability of a charcoal suspension in a group of eight patients with a palpable breast tumour of clinical size 1.5-4 cm, which was removed 24 hours to 4 days after the injection of 1 mL of 4% charcoal suspension into the tumour. Results. This preliminary clinical study shows that the injection of charcoal is well tolerated by patients and is a good method of tattooing tumour. The charcoal was seen in or at the periphery of the nodule in the surgical specimen. No inflammatory reaction or diffusion was observed. Conclusions. Based on these results, this suspension appears suitable for tattooing breast carcinomas over a period of 3 months for patients programmed to receive preoperative CT.
20748 Background: Cetuximab (Cetux) is an anti-EGFR monoclonal IgG1 antibody with proven activity both as a single agent or in combination with chemotherapy against metastatic colorectal cancer (MCC). Approximately 3% of severe IRR occur, especially during the first minutes of the first infusion, despite the only recommended antihistamine premedication, preventing further administration. We sought 1/ to reduce the occurrence of severe IRR through improved premedication and 2/ to decrease drug wasting costs through an original pharmaceutical preparation. Methods: 344 patients (pts) entered consecutively in our institution, 134 women and 210 men, with a median age of 60 y (range, 19–88) and a Karnovsky PS >70% treated for advanced gastrointestinal malignancies received a first Cetux infusion (400 or 500 mg/m2 over 2 h) from March 2004 to November 2007. Premedication consisted of dexchlorpheniramine (5 mg) for the first 44 pts (group A) and dexchlorpheniramine (5 mg), methylprednisolone (60 mg) and ranitidine (50 mg) for the subsequent 300 pts (group B). Cetux (2 mg/ml) was prepared in 2 bags, a test one (100 mg) and a second one containing the remaining dose. In case of severe IRR, this second bag kept in the pharmacy ward at 4–8°C was reused within the next 24 h. Results: Grade 3–4 IRRs occurred in 3/44 pts of group A (6.8%) and 4/300 pts of group B (1.7%) (Exact Fisher test, p=0.047). As a result, the hospital costs related to the management of severe IRR were markedly reduced. The second Cetux bag, that was not infused in these 7 pts and 2 patients with Grade 1–2 IRR, was administered to subsequent pts. This pharmaceutical preparation further allowed to avoid the waste of 63 100-mg vials of Cetux, and a subsequent economy of 14 600 euros. Conclusions: This overall medico-pharmaceutical approach minimized Cetux costs through improved prevention of severe IRR at our institution. Its widespread application could contribute both to a better quality of patient care and a better control of cancer treatment-related costs. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Merck Serono France
Solutions of bupivacaine precipitate when bicarbonate is added. This limits the clinical use of pH-adjustment in optimizing bupivacaine activity. In this study four different bupivacaine solutions were studied with the addition of sodium bicarbonate at 4 degrees C or 20 degrees C. Bupivacaine concentrations remained unchanged after pH-adjustment. Least crystallization was observed with bupivacaine solutions containing a small amount of sodium bicarbonate and stored at 4 degrees C.
