Spectrofluorometric Method Development and Validation for the Determination of Curcumin in Nanoliposomes and Plasma.

In this paper, we have reported a rapid, simple, sensitive, straightforward, and validated method for the concentration determination of curcumin (CUR) in nanoliposomes and plasma using the spectrofluorimetry. For both nanoliposomal formulation and plasma, methanol was used as a solvent to extract the CUR. The excitation and emission wavelengths were set at 423 nm and 527 nm, respectively. The method validation was performed based on International Council for Harmonization (ICH) guidelines, Q2, in which parameters; such as, linearity, precision, accuracy and etc., were determined. The results showed that the calibration curve was linear for CUR concentrations of 0.05 to 0.5 µg /mL with a correlation coefficient of 0.9996. The limit of detection (LOD) and limit of quantification (LOQ) were 0.03 and 0.10 µg/mL, respectively. Liposomal CUR (15 mg/kg) was injected intravenously to mice, and at certain time intervals (1, 3, 6, and 24 h), blood samples were collected. The samples were extracted by methanol and CUR concentrations were detected using a fluorescence spectrophotometer. Results indicated the rate of liposomal formulation decline was slower than free CUR. The results of this study indicated that the validation method based on fluorimetry which was developed here is reliable for the detection of CUR in liposomal formulations and plasma.

Preparation, characterization, and biodistribution of glutathione PEGylated nanoliposomal doxorubicin for brain drug delivery with a post-insertion approach.

Objectives: Brain cancer treatments have mainly failed due to their inability to cross the blood-brain barrier. Several studies have confirmed the presence of glutathione (GSH) receptors on BBB's surface, as a result, products like 2B3-101, which contain over 5% pre-inserted GSH PEGylated liposomal doxorubicin, are being tested in clinical trials. Here we conducted the PEGylated nanoliposomal doxorubicin particles that are covalently attached to the glutathione using the post-insertion technique. Compared with the pre-insertion approach, the post-insertion method is notably simpler, faster, and more cost-effective, making it ideal for large-scale pharmaceutical manufacturing. Materials and Methods: The ligands of the DSPE PEG(2000) Maleimide-GSH were introduced in the amounts of 25, 50, 100, 200, and 400 on the available Caelyx. Following physicochemical evaluations, animal experiments such as biodistribution, fluorescence microscopy, and pharmacokinetics were done. Results: In comparison with Caelyx, the 200L and 400L treatment arms were the most promising formulations. We showed that nanocarriers containing 40 times fewer GSH micelles than 2B3-101 significantly increased blood-brain barrier penetrance. Due to the expressed GSH receptors on tissues as an endogenous antioxidant, doxorubicin will likely concentrate in the liver, spleen, heart, and lung in comparison with Caelyx, according to other tissue analyses. Conclusion: The post-insertion technique was found a successful approach with more pharmaceutical aspects for large-scale production. Moreover, further investigations are highly recommended to determine the efficacy of 5% post-inserted GSH targeted nanoliposomes versus 2B3-101 as a similar formulation with a different preparation method.

Development of a stable and high loaded liposomal formulation of lapatinib with enhanced therapeutic effects for breast cancer in combination with Caelyx®: In vitro and in vivo evaluations.

Lapatinib, a dual tyrosine kinase inhibitor, has poor water solubility, which results in poor and incomplete absorption from the gastrointestinal tract. To overcome this obstacle, we designed a stable and high-loaded liposomal formulation encapsulating lapatinib and examined its therapeutic efficacy in vitro and in vivo on TUBO and 4T1 cell lines. We also assessed the impact of liposomal lapatinib on the extent of the tumor and spleen-infiltrating lymphocytes and the autophagy and apoptosis gene expression within the tumor site. Our results showed that liposomal lapatinib inhibits cell proliferation and significantly induces autophagy and apoptosis compared to control groups. Moreover, when it used in combination with liposomal doxorubicin, it extended the time to end from 22.4 ± 3.5 in the control group to 40 days in the TUBO cell line and from 29.2 ± 1.7 to 38.6 ± 2.2 days in 4T1 triple-negative breast cancer cell line, which reveals its promising effects on the survival of tumor-bearing mice. Our results indicated the need for further evaluations to understand liposomal lapatinib's potential effects on autophagy, apoptosis, and particularly on immune system cells.

Tramadol half life is dose dependent in overdose.

BACKGROUND: Tramalol overdose is disproportionately more common in Iran. In recent years, Tramadol overdose has become one of the most common causes of poisoning admissions to emergency departments in this country. To the best of our knowledge, there is little or no information regarding the toxicokinetic properties of Tramadol such as its half life. Given the fact that poisoning management should be based on the toxicokinetic of substances, we aimed at investigating the half life of Tramadol in man as a critical toxicokinetic variable in overdose. METHODS: Blood samples of each patient were collected on admission and repeated later. Plasma was harvested after separation from blood cells by centrifugation and quantified using HPLC method. Calculations were performed on Tramadol blood concentration quantities. FINDINGS: Demographic: Most of cases were men (81.81%). Mean (Standard Deviation (SD), min-max) age was 23 (8.142, 17-40). Serum Tramadol levels: Mean (SD, min-max) first Tramadol concentration was 786.91 (394.53, 391-1495). Mean (SD, min-max) second Tramadol concentration was 433.09 (269.63, 148-950). Mean (SD, min-max) of Tramadol half life was calculated as 9.24 hour (2.310, 4.99-13.45) Associations: Half life was associated with higher concentrations (r=0.708 Sig=0.015). CONCLUSION: We report the mean half life of tramadol in overdose to be 9.24 hours which is remarkably higher than that measured in previous pharmacokinetic studies. We also concluded that Tramadol half life is dose dependent in overdose which may explain the further consequences of severe overdoses.