A novel treatment of bromelain and acetylcysteine (BromAc) in patients with peritoneal mucinous tumours: A phase I first in man study.

BACKGROUND: Bromelain (Brom) and Acetylcysteine (Ac) have synergistic activity resulting in dissolution of tumour-produced mucin both in vitro and in vivo. The aim of this study was to determine whether treatment of mucinous peritoneal tumour with BromAc can be performed with an acceptable safety profile and to conduct a preliminary assessment of efficacy in a clinical setting. METHODS: Under radiological guidance, a drain was inserted into the tumour mass or intraperitoneally. Each patient could have more than one tumour site treated. Brom 20-60 mg and Ac 1·5-2 g was administered in 5% glucose. At 24 h, the patient was assessed for symptoms including treatment-related adverse events (AEs) and the drain was aspirated. The volume of tumour removed was measured. A repeat dose via the drain was given in most patients. All patients that received at least one dose of BromAc were included in the safety and response analysis. FINDINGS: Between March 2018 and July 2019, 20 patients with mucinous tumours were treated with BromAc. Seventeen (85%) of patients had at least one treatment-emergent AE. The most frequent treatment-related AEs were CRP rise (n = 16, 80%), WCC rise (n = 11, 55%), fever (n = 7, 35%, grade I) and pain (n = 6, 30%, grade II/III). Serious treatment-related AEs accounted for 12·5% of all AEs. There were no anaphylactic reactions. There were no deaths due to treatment-related AEs. An objective response to treatment was seen in 73·2% of treated sites. CONCLUSION: Based on these preliminary results and our preclinical data, injection of BromAc into mucinous tumours had a manageable safety profile. Considerable mucolytic activity was seen by volume of mucin extracted and radiological appearance. These results support further investigation of BromAC for patients with inoperable mucinous tumours and may provide a new and minimally invasive treatment for these patients.

Production, characterization, in vitro and ex vivo studies of babchi oil-encapsulated nanostructured solid lipid carriers produced by a hot aqueous titration method.

An aqueous dispersion of solid fat nanoparticles of babchi oil (BOSLN) was prepared by means of the hot water titration method. Surface morphology was determined by HR-TEM which revealed a fairly spherical shape of the formulations. Further they were evaluated for in vitro drug release characteristics and ex vivo skin permeation profile, zeta potential and particle diameter, rheological measures and droplet size distribution. Highest values for steady state flux (Jss), permeability coefficient (Kp) and enhancement ratio (Er) were observed for formulation, BOSLN3 comprised of oil [10% v/v; BO (3.33%), CAT (6.67%)], Tween 80 (9.25% v/v), transcutol-P (28.75% v/v) and distilled water (53% v/v). These results suggest that the studied SLN might be promising vehicles for babchi oil in the management of psoriasis.

The use of lipiodol and medium chain triglyceride as delivery agents for hepatic arterial administration of 1, 25-dihydroxyvitamin D3--a potential new treatment for hepatocellular carcinoma.

It is well established that 1, 25 dihydroxyvitamin D3 is capable of inhibiting the proliferation of a number of human cancer cell lines, including hepatoma cell lines. However, clinical usage in the treatment of cancers has been limited by its hypercalaemic effects. We hypothesised that by delivering 1, 25 dihydroxyvitamin D3 dissolved in a lipid based carrier agent as a hepatic arterial infusion it would be possible to achieve high local concentrations within hepatomas for prolonged periods, whilst avoiding high systemic concentrations and hypercalcaemia. We examined this hypothesis by administering a hepatic arterial infusion of 1, 25 dihydroxyvitamin D3 in either Lipiodol, Medium Chain Triglyceride (MCT), or saline to hepatoma bearing rats. Assay of serum and tissue concentrations revealed that this approach using lipiodol or triglyceride results in selective distribution of 1, 25-dihydroxyvitamin D3 into, and retention within hepatoma tissue and low initial systemic serum levels. Lipiodol was more effective in these respects than MCT. This method of administration has potential in the treatment of hepatoma.

Hepatic intra-arterial injection of lipiodol-1,25-dihydroxyvitamin D3 for hepatocellular carcinoma in rats.

BACKGROUND: 1,25-(OH)2 D3 has an in vitro growth regulator effect on different cancers. Unfortunately, dose-limiting toxicity (hypercalcemia) limits its use in anticancer therapy. For primary liver tumors, loco-regional delivery of 1,25-(OH)2 D3 in lipiodol might avoid high systemic concentrations and development of hypercalcemia. MATERIALS AND METHODS: 1,25-(OH)2 D3 alone or mixed in lipiodol, was delivered at different concentrations into the hepatic artery of rats bearing a primary liver tumor. Calcium levels, tumor volume and proliferation index were assessed after treatment. RESULTS: Serum calcium values were significantly lower when the drug was mixed into lipiodol. Treatment with 10 micrograms of 1,25-(OH)2 D3 in ethanol resulted in a decrease in proliferation index within the tumor. CONCLUSIONS: The delivery of 1,25-(OH)2 D3 mixed in lipiodol reduces the subsequent elevation of serum calcium. Locoregional treatment with 1,25-(OH)2 D3 was shown for the first time to be effective on primary liver tumor growth in vivo.

1,25-dihydroxyvitamin D3 dissolved in lipiodol produces a sustained antiproliferative effect in the human hepatoblastoma cell line HepG2.

The steroid hormone 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] has potential to be used as an anti-tumor agent, but its clinical application has been restricted by the strong systemic calcemic activity. Regional administration of the drug dissolved in lipiodol, might be a way of selectively delivering high concentrations of the drug to lipiodol avid tumor cells without causing systemic side effects. In acute (1 day treatment) and chronic (5 days treatment) experiments, efficacy of the drug dissolved in ethanol (control) or lipiodol and subsequently diluted in the culture medium was tested in vitro against the hepatoblastoma cell line HepG2. Using [3H]thymidine incorporation and cell count, antiproliferative effects of 1,25-(OH)2D3 dissolved in the two different solvents was compared. Microscopic examination of cells exposed to the lipiodol containing media revealed intra-cellular presence of the oil in abundance. Chronic treatment of cells with either formulation of 1,25-(OH)2D3 resulted in profound inhibition of cell proliferation. However, exposure of cells to 1,25-(OH)2D3 in lipiodol was followed by significantly greater and lasting inhibition of cell proliferation in both acute and chronic studies. These results indicate that, 1,25-(OH)2D3 dissolved in lipiodol probably acts as a sustained release drug depot formulation, in which case it could have some potential for the regional treatment of liver tumors.

Vitamin D3 analog, EB1089, inhibits growth of subcutaneous xenografts of the human colon cancer cell line, LoVo, in a nude mouse model.

PURPOSE: In this study, we investigated the effect of the vitamin D3 analog, EB1089, on the growth of subcutaneous xenografts of the human colon cancer cell line, LoVo, in a nude mouse model. METHODS: BALB/c Nu/Nu nude mice were inoculated subcutaneously with 10(6) LoVo cells. EB1089 dissolved in isopropanol was administered intraperitoneally and orally on alternate days at doses of 0.1, 0.5, and 2.5 microg/kg/day. Control animals received isopropanol alone. Tumor volumes estimated using the formula 0.5 X length X (width)2. The tumor kinetic index was determined by immunohistochemical detection of proliferating cell nuclear antigen. RESULTS: Significant dose-dependent inhibition of tumor growth was seen. After 20 days of treatment with 0.1 microg/kg/day EB1089, mean tumor volume in treated mice was 41 to 49 percent less than that in control animals (P < 0.01). Significant inhibition of tumor growth was also seen with 0.5 microg/kg/day EB1089 after 22 days of treatment (51 percent of control P < 0.01). Treatment with 2.5 microg/kg/day resulted in weight loss that required termination of this group; these mice were subsequently found to be hypercalcemic. The tumor kinetic index was significantly lower in tumors treated with 0.1 microg/kg/day EB1089 compared with that for control tumors (8 vs. 30 percent in controls). CONCLUSION: These findings suggest that the vitamin D3 analog, EB1089, is a potent antiproliferative agent for some human colon cancers.