Paclitaxel

Paclitaxel is a drug that possesses anti-tumor properties, produced semi-synthetically on the basis of natural raw materials obtained from Taxus baccata, yew berry - mahogany from the yew family.

The main area of its application lies in the plane of those medications that are prescribed for chemotherapy for patients with cancer. This antitumor agent is included in treatment regimens for malignant lesions of the lungs, larynx, mucous membranes of the nasopharynx and oral cavity, in breast cancer, oncology of the ovaries, etc.

This drug, being a powerful mitotic inhibitor, produces a stimulating effect on the processes in which dimeric tubulin molecules are involved in the assembly of microtubules. The use of Paclitaxel also contributes to the stabilization of their structure and leads to a decrease in the rate of dynamic reorganization at the interphase stage, which causes a disturbance of the cellular myotonic function. Due to its use, the emergence of microtubule-generated anomalous clusters is induced throughout the life cycle of cells, and besides this, multiple star bundles of microtubules are formed during mitosis.

Further development of new regimens and combinatorial features of the administration of this drug is also underway, which is very promising in terms of ensuring high individualization of chemotherapy based on molecular genetic genotyping of tumor formations.

[1], [2], [3], [4], [5], [6], [7]

Indications Paclitaxel

Indications for the use of paclitaxel are due to the high degree of its effectiveness as a drug among those used to treat all kinds of oncologists.

So its use in ovarian cancer is advisable. In this case, the drug is included in first-line therapy with a common form of this malignant lesion, or with residual tumor formation not exceeding 1 centimeter. In addition, a combination of Paclitaxel and cisplatin is used after a laparotomy. Ovarian cancer with second-line therapy involves the use of the drug in the presence of metastases and the insufficient attained measure of therapeutic effect produced by standard therapeutic measures.

Indications for the use of paclitaxel may be the presence of breast cancer. Basically, when there are lesions of the lymph nodes after the end of adjuvant treatment, standard combination therapy; if the disease recurred in the semi-annual period from the moment when adjuvant therapy was started. As second-line therapy - with metastatic phenomena of breast cancer in the event that the accepted standard therapeutic measures have shown their inconsistency.

Further, the rationale for including this drug in the treatment regimen as second-line therapy is the lack of the proper effect of liposomal anthracycline therapy in connection with Kaposi's sarcoma in AIDS.

Paclitaxel has also been shown to be used for lung cancer in non-small cell form with first-line therapy. Here, in combination with it, cystoplatin is included. But the drug is prescribed only to those patients who are not supposed to be surgically treated and do not provide X-ray therapy.

Other cases where the use of Paclitaxel may be justified include the squamous type of neck and head cancer, bladder cancer in the transitional cell form, malignant formations in the esophagus, and leukemia.

Thus, on the basis of all the above, it becomes obvious that indications for the use of Paclitaxel cover a considerable number of cases of oncological diseases. In each of them, the drug exhibits this or that, but, as a rule, quite high, the degree of its effectiveness in the complex treatment of cancer.

[8], [9], [10], [11], [12], [13], [14]

Release form

The form of Paclitaxel is presented in the form of a concentrate, which is used in the preparation of the solution for its subsequent administration by the intravenous infusion method.

In the 1st milliliter of the drug contains paclitaxel 6 milligrams. In addition to this, the main active ingredient in the composition is the presence of various auxiliary substances: nitrogen, ethanol of anhydrous, macrogolglycerol ricinoleate purified.

The concentrate is contained in a vial made of transparent hydrolytic glass of class I. The capacity of the vial may be different and is 5 or 16.7 milliliters, respectively. The cork on the bottle is made of bromobutyl, an aluminum shell is formed over it, forming a cap, in which there is a polypropylene cover.

The bottle is located in a cardboard box, where together with the manufacturer is also placed a folded sheet containing instructions for the use of the drug Paclitaxel. As for the number of vials of such packaging, in this connection it should be noted that it also differs in a certain variety. So if you open the box there is found only a single 30-milligram bottle, in which 5 ml. Of the drug, or, in a larger package, there may be 10 bottles of a similar capacity. A variant is also proposed as 1 vial of 100 mg, correspondingly 16.7 milliliters. The treatment regimen in which Paclitaxel is used, the dosage to be administered, the frequency of application may be different and highly individual with respect to each individual patient, so that one or another form of release of the drug may be the most convenient.

[15], [16], [17], [18], [19], [20]

Pharmacodynamics

Pharmacodynamics Paclitaxel is manifested in the antitumor pharmacological action of the drug. Its use produces an effect of inhibiting the processes of mitosis, and also has a cytotoxic effect. Entering into specific relations with the beta-tubulin of microtubules, it causes disturbances in the depolymerization of this protein of key importance.

The effect of Paclitaxel is that the normal dynamic reorganization of the network formed by microtubules is suppressed. This is extremely important when the phase of the interphase comes, and without which the cells become incapable of performing functions during mitosis.

A characteristic feature of the pharmacology of the preparation is also the fact that in the phase of mitosis leads to the formation of several centrioles. Paclitaxel contributes to the fact that microtubules form abnormal beams throughout the entire period when the cell cycle lasts, and when mitotic, they form clusters of similar in appearance appearance stars - asters.

Pharmacodynamics Paclitaxel in addition is also characterized by oppression of the hematopoietic processes in the bone marrow. In addition, as is evident from the results of experimental studies, the drug has embryotoxic properties and can lead to a decrease in reproductive function.

[21], [22], [23], [24], [25], [26], [27], [28], [29], [30]

Pharmacokinetics

The essence of the processes that characterize the pharmacokinetics of Paclitaxel is as follows.

As a result of intravenous administration of the drug, its concentration in the blood plasma begins to decrease, thus, as it occurs, correspondingly, to two-phase kinetics.

To determine the specific pharmacokinetic features of Paclitaxel, studies were conducted of the processes taking place at 3, and also after 24 hours after it was introduced. The doses used were 135 and 175 milligrams, respectively, per square meter. On the basis of the results obtained, it became possible to ascertain that with increasing the dose in which the infusion was carried out, with the passage of more than 3 hours, the non-pharmacokinetics of the drug became non-linear. A 30 percent increase in dosage, that is, from 135 to 175 mg / m², resulted in an increase in Cmax of 75 percent and AUC in 81.

Carrying out several repeated courses of treatment, as was also revealed, does not cause a tendency to develop a cumulative effect due to taking the drug.

In addition, it was found that Paclitaxel binds to proteins by 89-98 percent.

The pharmacokinetics of paclitaxel to date have not been sufficiently studied. The information available justifies the assumption that it is biotransformed in the liver, as a result of which hydroxylated metabolites are formed. Leaves the body together with the elimination of bile.

[31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41]

Dosing and administration

The way of application and dose of Paclitaxel is regulated by a number of practical prescriptions, which must be followed when dealing with this drug.

It should be noted that the stage of treatment, when its immediate introduction begins, must be preceded by a specific preparatory period, during which, without exception, to anyone who has been prescribed Paclitaxel, it is necessary to undergo premedication. Its essence lies in the fact that in order to prevent a highly pronounced hypersensitivity reaction, antihistamine and glucocorticosteroid preparations of H2 antagonists of histamine receptors are used. An example of this is that from 12 to 6 hours before the infusion, dexamethasone is administered at a dose of 20 milligrams. An alternative to dexamethasone is diphenhydramine (50 mg), or another drug of similar effect. And also from 30 minutes to one hour - intravenously ranitidine 50 mg. Or cimetidine in a 300-milligram amount.

The solution for infusion is prepared before the actual onset of Paclitaxel administration.

To do this, the concentrate is combined with a 0.9% solution of sodium chloride. A dextrose solution of 5%, dextrose in solution with sodium chloride for injection, and in addition Ringer's solution with a 5% dextrose solution, whose final concentration should be 0.3-1.2 mg / ml, is also acceptable in combination with the drug.

Introduction Paclitaxel is carried out by intravenous infusion in which the drug in a single dose of 135-175 mg / m2 should enter the body over a period of 3 to 24 hours. Each course is separated from the previous break by at least 21 days. The drug is used until the neutrophil counts in the blood are at least 1500 / μl, and the platelets are 100,000 / μL, respectively.

The treatment with this drug Kaposi's sarcoma in AIDS occurs through the introduction of 100 mg / m 2 for 3 hours with 14-day intervals.

The method of administration and dose of this antineoplastic agent can be different based on the history, the nature of the disease, the stage and severity of each individual patient, the factors of individual tolerance to the components of Paclitaxel.

[45], [46], [47], [48], [49], [50]

Use Paclitaxel during pregnancy

The use of paclitaxel during pregnancy should cause concern at least due to the fact that, with all the proven effectiveness of the drug as a remedy to cure many forms of cancer, at the present time all its mechanisms in the human body are not fully understood. And for a woman in a situation where her body is particularly vulnerable, any threat from an externally exerted influence acquires a value elevated to a certain degree. The same statement applies to the future of the little man for whom she is responsible.

This drug, based on the existing criteria for assessing the possible effects on the child during the period of its intrauterine development (FDA), assigned category D. This indicates that, despite the confirmed existence of risk to the fetus, with a certain combination of factors and circumstances, Paclitaxel may be justified . A drug is prescribed only if the question is about the life and death of a woman waiting for a baby or if the likelihood is that the expected positive changes for her in what only possible least extent can have negative consequences for the fetus.

Since the preparation has experimentally confirmed fetotoxic and embryotoxic properties, the use of Paclitaxel during pregnancy is prescribed only in exceptional cases. A woman during the treatment with its use should use reliable methods of contraception, and during lactation it is necessary to stop breastfeeding the baby throughout the treatment course.

Contraindications

Contraindications to the use of paclitaxel may be caused, primarily, due to individual hypersensitivity, both to this drug, and to those medications in the dosage form of which there is the presence of macrogolglycerol ricinoleate.

Paclitaxel belongs to the list of those drugs that are to be excluded from the treatment regimen of Kaposi's sarcoma that can occur in AIDS, if the neutrophil counts recorded in the course of treatment are characterized by a value not exceeding 1000 / μL.

What else should be noted with respect to the initial amount in which neutrophils are present is that if they do not reach 1500 / μl in solid tumor formations, this fact classifies the drug as unacceptable for use in treatment.

Apply Paclitaxel with all possible precautions allowed for thrombocytopenia less than 100,000 / μL. If its quantitative index is below the lower limit of 1500 / μl, the drug is clearly contraindicated.

Under the ban, it is in the case of insufficient liver function, due to the severe course of cardiac ischemia, with arrhythmia and the presence in the patient's anamnesis of a myocardial infarction less than six months ago.

Refuse use of Paclitaxel is also recommended during pregnancy and during lactation and lactation.

There are also some cases that are not contraindicated directly, but require increased attention during the administration of Paclitaxel. This is chronic heart failure, angina, heart rhythm disturbances. This includes a number of infectious diseases.

Like any other medication, Paclitaxel has its strengths and weaknesses, exhibiting aggressive radical action, which is precisely what distinguishes many of the drugs used in anticancer therapy. But at the same time, the cost of the effectiveness achieved in this way often becomes all sorts of adverse side effects. Therefore, there are contraindications to the use of Paclitaxel and special regulations aimed at preventing and reducing the possibility of all accompanying negative phenomena.

[42], [43]

Side effects Paclitaxel

How often and with what degree of manifestation side effects of Paclitaxel are manifested, are significantly conditioned by the fact that they differ in a dose-dependent manner.

During the first hours after the drug was introduced, it is possible to develop an allergic reaction like bronchospasm, lowering blood pressure, flushing to the face, pain in the sternum, rash on the skin.

Those organs in the human body that take part in the processes associated with the execution of the hematopoietic function may display their specific reaction to the use of the drug in the form of developing anemia, thrombocytopenia and neutropenia. The main factor, by virtue of which it is necessary to limit the increase in dosage, is that the application of increased doses leads to inhibition of bone marrow function, that its granulocyte germ is particularly affected by its toxic effect. The level of neutrophil content reaches its extremely low level in the time interval from the 8th to the 11th day, followed by normalization after a three-week period.

The characteristic symptomatology during the course of treatment with the use of Paclitaxel is inherent in the cardiovascular system. Side effects are displayed as the appearance of unfavorable dynamics of changes occurring with arterial pressure, mainly with a tendency to decrease it. The increase in blood pressure is noted in fewer cases. The result of the administration of the drug is the occurrence of rapid heartbeat, bradycardia, the phenomenon of atrioventricular blockade, the development of vascular thrombosis and thrombophlebitis. Changes in cardiac rhythm are noted on the electrocardiogram.

Due to the active action of the drug in the body, the central nervous system is attacked from its side. This is mainly the case with paresthesia. Occasionally, seizures occur as grand mal, seizures of ataxia, encephalopathy, visual impairment, as well as vegetative neuropathy. The latter in turn often acts as a cause of paralytic intestinal obstruction and orthostatic hypotension.

Paclitaxel can adversely affect hepatic function, leading to the activation of transaminases of the liver (mainly AST), alkaline phosphatosis and bilirubin in the blood serum. Possible liver encephalopathy and hepatonecrosis.

The respiratory system responds to the action of the drug with pulmonary fibrosis, interstitial pneumonia, the appearance of pulmonary embolism. When Paclitaxel is used concomitantly with radiotherapy, there is an increased risk that radiation pneumonitis may develop.

The resulting dysfunction of the digestive system is reflected in the appearance of nausea, vomiting diarrhea, constipation, the development of anorexia.

Occurrence of side effects can be defeated and the musculoskeletal system, one hundred is manifested in myalgia and arthralgia.

Side effects Paclitaxel can affect various organs and systems of the body and have quite serious consequences. Therefore, it is very important that the use of the drug is carried out under medical supervision and with a carefully selected dosage, which will lead to the greatest possible positive result and at the same time negatively affect the patient's condition.

[44]

Overdose

To determine the optimal regimen and the required doses of Paclitaxel for each individual patient, the information contained in the special medical reference literature is used. The task of the medical specialist in this regard is to select the minimum possible dosage, which contributes to the achievement of positive progression of the cure and, at the same time, to prevent the appearance of negative consequences that may occur if the required optimal amount of the drug is exceeded.

In the case of the introduction of unreasonably high doses, an overdose is characterized by a certain list of symptomatic manifestations.

The drug, when it gets into the human body in excessive amounts, causes a significant decrease in the activity of processes associated with the hematopoietic function of the bone marrow.

The central nervous system is also affected, the answer being the development of peripheral neuropathy.

There is an occurrence of mucositis, in which inflammatory processes develop in the mucous membranes of various internal organs, and their ulceration takes place.

To avoid such negative consequences of an overdose throughout the treatment period in which Paclitaxel is used, continuous medical monitoring of the patient's condition should be carried out. Particular attention is required to the amount of neutrophils in the blood. If their values are less than 500 / mm3 for more than one week, or when peripheral neutropenia is severely affected, subsequent courses should be conducted with a 20 percent reduction in doses.

Overdose Paclitaxel does not provide for any specific treatment, the nature of all treatment measures is symptomatic. Antidote to the drug to date does not exist.

[51], [52], [53], [54], [55]

Interactions with other drugs

Based on studies of the interaction of Paclitaxel with other drugs, it can be argued that with the introduction of the following alone after the other Paclitaxel and cisplatin, the myelotoxic effect is more pronounced when the infusion was carried out in sequence-first cisplatin, followed by Paclitaxel. The overall clearance of the latter in this regard was approximately 20 percent lower in the mean.

When cimetidine was previously taken before infusion of the drug, the overall clearance of Paclitaxel in its mean values of changes did not undergo.

In vivo data, in vitro, may indicate that the metabolic processes of Paclitaxel are suppressed in a complex application together with drugs that inhibit microsomal oxidation, namely: verapamil, diazepam, ketoconazole, quinidine, cyclosporin, cimetidine, and the like.

In cases where the use of the drug is accompanied by the simultaneous inclusion of dexamethasone, ranitidine, and diphenhydramine into the treatment regimen, this in no way affects its binding to proteins in the blood plasma.

Interactions Paclitaxel with other drugs, depending on the combinations formed, can either enhance or even reduce the severity of certain aspects of its use. In some cases, this can help achieve a better therapeutic effect of the drug, while in others it can lead to a decrease in the effectiveness of its use. All these factors must be taken into account when drawing up a rational treatment plan.

[56], [57], [58], [59], [60], [61], [62]

Storage conditions

The drug is a potent drug, and therefore, in accordance with those criteria for the special conditions in which medicines should be stored, belongs to group B. This means that the storage conditions of Paclitaxel primarily require the observance of special precautions, as well as the fact that it must be kept separate from all other pharmacological products.

One can not ignore such a specific feature as the fact that some of the constituents of Paclitaxel can cause extraction of di-2-hexyl phthalate (DEGP) from plasticized containers made of PVC. And the longer the drug is stored in such a container, the more its concentration increases in the solution, and accordingly the DEHP is washed out with an ever-increasing degree. On this basis, how to store, and use for the introduction of the drug you need equipment in the manufacture of which was not used polyvinylchloride.

The storage conditions of Paclitaxel in the rest are basically not much different from the basic rules and principles that they need to be adhered to when dealing with many of the medicines. This concerns first of all the need to ensure the appropriate temperature regime (in this case it is 25 degrees Celsius) and to exclude light. Traditional is also a recommendation to keep medicines where they can not fall into the hands of children.

[63], [64], [65], [66], [67], [68]

Shelf life

Shelf life of the drug is 2 years from the date of manufacture indicated on the package. Do not use Paclitaxel after the expiration date indicated.