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Nanoparticles are the solid particles which are colloidal in nature and their size ranges from 10 to 400nm. They are made up of macromolecular materials where the active ingredient (drug) is entrapped, encapsulated or incorporated or onto which it is adsorbed or attached. For drugs, large and broad antigenic sequences and immunomodulatory factors liposomes can be used for encapsulation and these serve as potent delivery vehicles. Liposomes are used to target the drugs to tumors and thus representing an attractive therapeutic strategy. Thus liposomal drug delivery system is a better way to administer drugs so as to avoid any complications and side effects and also to provide better availability of the drug.
One important characteristic of liposomal formulation is that it can avoid reticuloendothelial system (RES) uptake. The reduction in RES uptake leads to increased pharmacokinetic and biological benefits to the chemotherapy under process. It imparts better specificity and selectivity and plasma half life is increased with decrease in toxic effects.
Liposomal drugs flowing in the blood cannot exude/extravasate from the blood vessels that are intact, instead these drug molecules accumulate in the areas where there are discontinuous capillaries like those in tumor tissues. It is known that Kaposi's Sarcoma is a highly vascularised tumour with capillary leakage thus the property of liposomal drug discussed here proves to be helpful in this case. Liposomes however also target the RES and while circulating in the blood these liposomes bind to the immunoglobulins and plasma proteins which leads to RES uptake which is can be useful in case of immunomodulatory therapy but in most anti-cancer therapies this is not desirable.
History and Development of DaunoXome:
Daunoxome (liposomal daunorubicin) is a product originally developed by NeXstar pharmaceuticals and launched in the year 1996. The company was then owned by Gilead Sciences in March 1999. DaunoXome was then acquired from Gilead Sciences by 'Galen' which is a Northern Ireland Pharmaceutical company. DaunoXome is used for the treatment of Kaposi's Sarcoma. Kaposi's Sarcoma was identified in the year 1872 by Moritz Kaposi, a Hungarian dermatologist. Kaposi's Sarcoma is characterized by mesenchymal tumor which involves blood and lymph vessels. There are many variants of this disease. Kaposi's Sarcoma is commonly seen in patients with HIV infection. It is becoming one of the fast growing cancer among AIDS patients worldwide. DaunoXome demonstrated higher levels of in vivo stability and specificity due to which the patients suffering from Kaposi's Sarcoma could benefit at higher doses without any significant cardiotoxicity. Daunorubicin is an anthracycline antibiotic which induces programmed apoptosis in cells and it is cell specific.
Phase IV Preclinical studies were performed using DaunoXome (liposomal daunorubicin) which is used for treating the patients with AIDS related Kaposi's sarcoma. The subjects which were chosen for this study were eligible if they were HIV positive, had Kaposi sarcoma and were subjected to at least one daunorubicin treatment. From thirteen university hospitals 94 subject files were studied out of which 80% received cytostatic treatment prior to the first daunorubicin treatment cycle. The mean CD4 lymphocyte count was found to be 114/µl and to the 70% of patients the drug daunorubicin was given as single chemotherapy. The partial response rate and the complete response rate was found to be 26.5% and 11.5% respectively in accordance with ACTG (Aids Clinical Trials Group Oncology Committee). In 29% of the treatment cycles the hematopoietic growth factor was prescribed and after the final evaluation 71% out of the total number of subjects were alive and even after administering high doses of the drug there was no cardiotoxicity observed. Following table illustrates the main characteristics of the 94 subjects with AIDS related Kaposi's Sarcoma prior to the first daunorubicin treatment cycle:
A phase II study was conducted on 18 subjects and out of these 18 , 8 were subjected to higher doses of DaunoXome and 10 were subjected to low doses of the same drug and it was seen that the drug could resistant and relapsed lymphoma without showing any cardiotoxicity.
56 (60%) of the subjects were suffering from at least one opportunistic disease prior to the first daunorubicin treatment cycle and at baseline the mean HIV plasma loads (in 54 [57%] of subjects) and the mean CD4 count was found to be 5.38 ± 5.58 and 5.16 ± 5.09 and 114± 20 /µl respectively.
80% of the subjects received cytostatic treatment prior to daunorubicin administraion along with administration of doxorubicin in 27% (26) of subjects. The mean period was of 1 year counted from starting of diagnosis of Kaposi's Sarcoma to the first treatment cycle of daunorubicin.
In 66 out of the total (94) subjects Daunorubicin was administered as a single therapy. In 28 subjects daunorubicin was given initially to 3/28 primarily and to 25/28 secondarily with other cytostatic treatment. The mean daunorubicin dose intensity was 77%. Due to the progression Kaposi Sarcoma the dose in 14 subjects was increased from 40 to 60 mg/m² and in 6 of the subjects the dose was decreased due to intolerance or toxicity. The mean cumulative dose and the mean treatment duration for daunorubicin were 674 mg/m² and 258 ± 25 days respectively.
Final Evaluation and Analysis:
The CD4 count was done and it was found that the mean CD4 cells were higher than those found at the baseline. In 33 out of the total number of subjects the plasma viral load was evaluated and the mean values were not different from the baseline. 67 subjects were found to be alive during the final evaluation.
A randomized , open-label clinical study was conducted at 13 centres. The study took place in Canada and USA and was performed on subjects having advanced HIV-related Kaposi's sarcoma which is characterized by the presence of 25 or more mucocutaneous lesions, 10 or more within a month etc. For this purpose a regimen making use of two drugs was applied as first line cytotoxic therapy. The drugs DaunXome 40mg/m2 and ABV (doxorubicin [adriamycin] 10mg/m2, bleomycin 15U and vincristine 1mg) were administered every 2 weeks intravenously. Adriamycin is a registered trademark of Pharmacia and Upjohn Co. For the responses to be recorded and assessed the ACTG (Aids Clinical Trials Group Oncology Committee) criteria was used . The efficacy results were summarized as follows:
Out of 33 ABV, twenty responders responded by shrinkage and/or decrease in number of lesions which is a more stringent criteria than flattening of lesions.
Out of 27 DaunoXome , 11 responders did not respond by the criteria of flattening of the lesions but by different criteria. The tumor response to both , Daunoxome and ABV was easily compared with respect to the anatomical sites such as feet, oral cavity, face, trunk, legs etc. using photographic evidence.
In the year 1996 NeXstar Pharmaceuticals Inc. announced that the final marketing authorisation for DaunoXome which is a drug used for treatment of Aids related Kaposi's Sarcoma will be issued by the 10 member states of the EUROPEAN COMMUNITY which include: Germany, Denmark, Greece , Ireland, Sweden, Portugal , Luxembourg, Belgium, Austria , Netherland. The company acquired the approval from the United States FOOD AND DRUG (FDA) to sell the drug in April 1996 and thus they launched the drug DaunoXome on May 1st 1996. DaunoXome has been approved in CANADA as a rescue therapy for the treatment of Kaposi's Sarcoma. To broaden or expand the clinical use of DaunoXome , Nexstar pharmaceuticals decided to conduct phase II trials on DaunoXome in U.S and Europe for treatment of several other oncological conditions such as lung cancer, breast cancer , leukaemia , lymphoma etc.
In animal models it was found that liposomal drug DaunoXome was more effective than when administered as a free drug intravenously. A phase II trial was performed on 11 women with prior untreated metastatic breast cancer and it was found that DaunoXome is significantly tolerated and has shown anti-tumor activity for treating advanced breast cancer.
In few countries however, the drug DaunoXome can be prescribed by certain physicians who demand the product even if there is no regulatory approval for that product in that country. However, all the technical support , assistance and guidance is provided by the marketing professionals belonging to the company. NeXstar pharmaceuticals priced DaunoXome in few of its market in a currency with respect to that country where such pharmaceuticals are sold but the revenues were affected due to fluctuations in the currency.
In 4 subjects under trial during the initial phases the systolic blood pressure decreased by 20-30mm which gave rise to chest pain similar to angina pectoris. In 3 of 4 subjects under trial the symptoms decreased after stopping the drug infusion and the symptoms didn't occur again as the patient was given 100mg hydrocortisone prior the second cycle. In 1 of the 4 subjects the treatment had to be aborted due to the severe hypotension observed during the start of the second cycle. However, 1 hour before the treatment with DaunoXome all the subjects were given 100mg hydrocortisone so as to avoid any possibility of hypotension. Grade 4 wasn't seen in 15 subjects under study and in 5 subjects Grade 3 leucopoenia was seen and grade 1 thrombocytopenia was observed in not more than 1 subject. Toxic effects like nausea and vomiting were observed in 4 subjects for 2-3 days after the administration of DaunoXome. One of the subject developed mild alopecia.
In urothelial Transitional Cell Carcinoma (TCC) DaunoXome showed no significant activity and this effect was due to the fact that this drug could not treat tumour in this kind of malignancy. However in the case of advanced bladder cancer 100mg/m² dose of DaunoXome every third week is not found to be active. The liposomal DaunoXome is made up of three major components and these are : primary compound daunorubicin, cholesterol and distearoylphosphatidylcholine (DPC). Daunorubicin is prepared/formulated as a citrate salt so as to assist in drug encapsulation. The uptake in the reticuloendothelial system (RES) is minimal because of the smaller particle size and the neutral nature of DaunoXome which ultimately results in prolonged drug circulation. Efficiency of DaunoXome (liposomal daunorubicin) compared to the conventional daunorubicin was studied using mice with lymphosarcoma and it was found that daunorubicin levels in plasma were higher in mice treated with DaunoXome than those treated with conventional daunorubicin. The free daunorubicin was rapidly excreted than liposomal daunorubicin. However, the tumor drug accumulation rate was significantly higher in mice treated with conventional drug than in those treated with Daunoxome ; area under curve values were higher in the DaunoXome treatment than in free daunorubicin treatment.
After the clinical trial/studies were performed it was observed that the more prominent side effect/toxic effect caused by DaunoXome is leucopoenia which was seen in 11% - 17% of the treatment cycles. 85% of the subjects that were administered DaunoXome showed signs of grade 3/4 neutropenia. Statistics also showed that leucopoenia was observed more in DaunoXome treated subjects than in combination therapy which includes doxorubicin, bleomycin and vincristine (ABV). Although not much differences were found in the subjects treated with DaunoXome and other conventional drugs used for similar purpose, Daunoxome resulted in less alopecia and neuropathy than that caused by conventional chemotherapy.
The clinical trials performed till now included male HIV positive subjects. The efficacy of DaunoXome was thus observed with respect to male participants (subjects). It is necessary to study the effect of DaunoXome (liposomal daunorobucin) on female subjects as well since little or no data is available on female HIV positive related Kaposi's Sarcoma. Also very little information is available about the effect of DaunoXome on HIV negative subjects.
In the year 1995 the product DaunoXome was licensed first in the United Kingdom and then it was approved by the FDA.
DaunoXome is useful in treatment of Kaposi's Sarcoma. However, it has several side effects. Daunoxome causes mild alopecia and nausea in patients suffering from Kaposi's Sarcoma. Since these toxic effects are not much significant , DaunoXome is still considered as a treatment for Kaposi's Sarcoma caused primarily due to HIV infection.