Main effects and mechanisms of action of sehydrin

Main effects and mechanisms of action of sehydrin

WITH

ehydrin, the main ingredient of which is
hydrazine sulfate
, does not have a direct cytotoxic effect, but is a very biologically active substance (V. Ya. Rusin). Moreover, its toxicity is relatively low (for example, LD50 for mice when administered orally is 740 mg/kg).

We studied sehydrin in an experiment for antitumor activity. Solid (sarcoma 37, Ehrlich carcinoma, squamous cell skin cancer, sarcoma 180, Walker carcinosarcoma) and ascitic (sarcoma 37, Ehrlich carcinoma, Seidel hepatoma, NK/Ly lymphocytic leukemia) variants of allogeneic tumors were used (V.A. Filov et al., 1983 ). In the case of solid tumors, the effect of tumor growth inhibition was obtained only on Walker carcinosarcoma. In the treatment of ascites tumors, a moderate but significant effect of tumor growth inhibition was achieved on sarcoma 37 and NK/Ly lymphocytic leukemia (50–55%) and a significant effect on Seidel hepatoma – 85%.

The results obtained were sufficient to submit the drug to the Pharmacological Committee of the Ministry of Health to consider conducting clinical trials, although compared to conventional cytostatics they were more modest. However, the unusual nature of the substance, the clearly different mechanism of its possible action compared to other antitumor drugs, the absence of hematological and any other significant side effects indicated the feasibility of such a study. As a result of the first phase of the clinical study, a regimen for using the drug was developed: sehydrin in enteric-coated tablets was prescribed 3 times a day, 60 mg 1-2 hours after meals daily for 30-40 days. After a break of 2-3 weeks, the course can be repeated. In principle, the number of courses is not limited, provided that the intervals between them are gradually increased.

Clinical study in phase 2 was conducted in 5 clinics

(Moscow Institute of Oncology named after Herzen; Institute of Radiology and Oncology in Vilnius; Rostov Research Institute of Oncology; Kiev Institute of Oncology Problems named after R.E. Kavetsky and Research Institute of Oncology named after N.N. Petrov in St. Petersburg). Treatment was carried out for patients with common forms of solid malignant tumors, including relapses and metastases, malignant lymphomas in generalized stages and relapses of desmoids, subject only to symptomatic therapy, who did not take any treatment at least 2 months before the start of the course of sehydrin. The vast majority of these patients had previously been subjected to various types of special treatment (surgical, radiation, cytostatic, hormonal), the possibilities of which were exhausted by the time sehydrin was prescribed. Repeated courses were prescribed if the process stabilized; usually their number was 2–3, but in some cases reached 10, 20, 40 (in particular, with neuroblastoma). For patients who noted difficulty in taking tablets (for cancer of the esophagus, larynx, pharynx), sehydrin was prescribed in the form of a 0.4% solution, dosing it by volume (1 tablet is equivalent to 15 ml). Along with sehydrin, the intake of alcohol and barbiturates was prohibited and the consumption of cheese was limited.

The effect of sehydrin was assessed at the end of the treatment course. The objective effect was assessed using a scoring system: “3” – regression of lesions by more than 50% with a duration of effect of at least 1.5 months; “2” – tumor regression by 25–50% for at least 1 month; “1” – tumor reduction by less than 25% and/or stabilization of the process; “0” – no effect. The symptomatic effect of sehydrin was assessed as “pronounced”, “moderate” and “absent”. This action consisted of a decrease in fever (sometimes until the temperature completely normalized), a decrease or disappearance of hemoptysis, a decrease in respiratory failure and often edema, and normalization of laboratory parameters; this also included a significant improvement in general well-being, the appearance of appetite, a decrease or elimination of weakness, a decrease or complete relief of pain, which in some cases made it possible to give up drugs (V.A. Filov et al., 1990).

Cooperative results from a clinical study of sehydrin

are presented in Table 1. The results of the cooperative study were assessed on 740 patients with malignant tumors of various locations. Regression of tumors (primary, recurrent and metastatic) by more than 50% with a duration of effect of more than 1.5 months was observed in only 6 cases: 1 patient with lung cancer, 1 with neuroblastoma, 1 patient with lymphogranulomatosis, 1 with fibrosarcoma of the retroperitoneal space, 2 patients with relapse of desmoid of the anterior abdominal wall. The group with a score of “2” included 25 patients, which, together with a score of “3,” is 4.2%. Stabilization of the process with some reduction in some cases in the size of tumors was achieved in 263 patients, which is 35.5% and is a significant result. Most often, a stabilizing effect was observed in lymphogranulomatosis, breast cancer, lung cancer, colon, sigmoid and rectal cancer and, what is especially interesting, in renal cell cancer (in 5 out of 9 patients), cervical cancer (in 8 out of 22 patients ), uterine cancer (in 7 out of 9 patients), generalized skin melanoma (in 12 out of 31 patients). No effect was observed in 446 patients (60.3%). Assessing these results, it should be emphasized that we are talking about patients who were practically in the terminal phase of the disease.

Of particular interest from our point of view is the symptomatic effect of sehydrin
, which occurred in varying degrees of severity in 344 patients (46.5%). However, it was not possible to establish a correlation between objective and symptomatic effects.

In cases of symptomatic effect, usually an improvement in the patient's general condition occurred at 2–3 weeks of treatment, sometimes at the end and even during the 2nd course. The same applies to reducing pain even with metastases of bronchial cancer to the bones (spine, ribs, pelvis). In some patients with tumor metastases of this localization, with the help of sehydrin it was possible to achieve such a reduction in pain that they were in a state of satisfactory activity, up to self-care and walking. This effect could last up to 2 months even as the process progressed. A similar effect was observed in bone metastases of breast cancer, but in rarer cases and with less severity.

Among the characteristic manifestations of the symptomatic effect of sehydrin is its peculiar psychotropic effect. Already at 2-3 weeks of taking the drug, a significant part of the patients experienced an improvement in mood with a decrease in the critical assessment of their condition, up to an overestimation of the possibility of physical activity. A similar effect of sehydrin could persist during tumor progression. In some observations, patients expressed a desire to return to work. The overall frequency of described positive symptomatic effects, characterized as an improvement in quality of life, was 37% in terminal patients with lymphogranulomatosis, breast cancer - 53%, stomach cancer - 44%, laryngeal cancer - 57%, neuroblastoma - 71%, desmoids - 90% .

Of the side effects

very rarely – in 2–3% of cases – only dyspeptic symptoms in the form of nausea and vomiting were observed. However, it should be taken into account that the number of patients studied included those in whom these phenomena could be caused by intoxication accompanying an advanced tumor process. This is all the more likely since, to eliminate such a complication, the tablet is coated with an enteric coating. Nausea and vomiting could regress without special treatment, only if the dose of sehydrin was initially reduced from 180 mg/day to 120 mg.

For primary brain tumors

(glioblastoma, dedifferentiated astrocytoma, malignant meningioma, astrocytoma, ependymoma, meningioma, acoustic neuroma (giant)) sehydrin was tested in 4 clinics: the neurosurgical department of the Research Institute of Experimental Medicine (St. Petersburg), the Neurosurgical Institute named after. Polenov (St. Petersburg), the neurosurgical department of the Mariinsky Hospital (St. Petersburg) and the Institute of Radiology and Oncology in Vilnius (V.A. Filov and others). The subjects were patients after palliative operations and in cases of inoperable tumors with exhausted treatment options (52 people, of which 46 with malignant tumors). In all patients, the tumors were characterized by an extremely rapid rate of recurrence, even with the visible radicality of the operation. The usual lifespan of such patients from the date of diagnosis (craniotomy) does not exceed 6 months. Partial tumor removal before treatment with sehydrin was performed in 38 patients with glioblastoma and undifferentiated astrocytoma. In all cases, there were pronounced symptoms of continued tumor growth in the form of toxic and neurological disorders (signs of increased intracranial pressure, epileptic seizures, headaches, sensory and motor disorders, etc.). The same symptoms were observed during relapses in 5 of 6 previously operated patients with benign tumors. Treatment was carried out in the previously described courses.

The pronounced therapeutic effect in the entire combined group of patients with brain tumors is very high (63.5%), and in combination with partial regression of general cerebral and focal neurological symptoms - even higher (73.1%). In the case of malignant tumors only (46 patients), these figures are 60.8% and 71.7%, respectively. The results obtained exceed the effectiveness of treating brain tumors using nitrosourea derivatives.

The use of sehydrin in a group of patients with glioblastomas led to stabilization with partial regression of symptoms in 27 out of 38 people (71%) and was accompanied by a significant improvement in quality of life. The lifespan in this group averaged 13.0 ± 0.6 months, i.e. turned out to be 2 times greater than after conventional surgery. Of these 27 people, 8 (30%) remained alive for more than 19 months (including 1 for more than 30 months). In the absence of effect in 11 patients, their survival period after surgery was the usually observed period of 4–5 months. Analysis of the medical histories of other patients with malignant tumors leads to similar results. In a group of 6 patients with benign tumors, a positive clinical and rehabilitation effect lasting 5 years (they were then lost from follow-up for domestic reasons) was noted in 5 cases as a result of 8 courses of sehydrin, conducted at intervals of 5 to 7 months.

Initial signs of positive changes in treatment usually became noticeable in the second week of taking sehydrin (a clearly expressed improvement in general condition with varying degrees of regression of symptoms).

Compared to the nitrosoureas currently used for the treatment of brain tumors, not only the therapeutic effects of sehydrin compare favorably, but also its virtual absence of side effects (with the exception of nausea in 3% of cases).

Sehydrin is a pharmacopoeial drug, its registration number in the form of tablets is 94/229/3.

Mechanisms of action of sehydrin

1. In multiple experiments in in vitro

and the inhibitory effect of sehydrin on the metabolism of xenobiotics was shown in animals (V.A. Filov et al.).
The inhibitory effect is responsible for the sehydrin-modified action of xenobiotics. In particular, a sharp increase in the toxicity of ethanol and barbiturates by sehydrin was noticed (A.N. Stukov et al.). The anti-microsomal oxidation effect of sehydrin prevents the normal metabolism of these compounds, which leads to a sharp increase in their toxicity. However, inhibition of metabolism does not necessarily increase the toxicity of the xenobiotic. Here everything depends on the nature of the toxic effect of the xenobiotic and its metabolites, on the ratio of doses of sehydrin and xenobiotic, on the sequence and time relationships of their administration, etc. 1
Thus, the effects of sehydrin and thiophosphamide were studied separately and in various combinations. Sehydrin was administered intraperitoneally 30–45 minutes before the administration of the cytostatic. In the case of Walker carcinosarcoma, the combination of drugs increases the antitumor effect, while thiophosphamide is combined in an ineffective dose (the same with Seidel ascites hepatoma). In other words, the use of sehydrin allows, by reducing the dose of thiophosphamide, to obtain an antitumor effect that is superior to that of the full therapeutic dose of the alkylating drug. In the case of the remaining strains used, the effect, and a considerable one, is manifested only when combined, while each drug individually in the doses used turns out to be ineffective.

Another example is the combination of sehydrin with cyclophosphamide. On sarcoma 180, sehydrin at a dose of 60 mg/kg is absolutely ineffective. Cyclophosphamide on this strain at a dose of 50 mg/kg leads to a 70% delay in tumor growth. The combination of these drugs reduces the degree of growth retardation by up to 40%.

The results are explained by the inhibitory effect of sehydrin. The metabolism of thiophosphamide, when used after sehydrin, slows down and it exhibits its antitumor properties for a longer period of time. In the case of cyclophosphamide, the manifestation of its antitumor properties requires the metabolism of the latter, which is inhibited by sehydrin with a corresponding decrease in the antitumor effect. It is very interesting and important to transfer these results to the clinic.

2

.
Sehydrin has a strong effect on the activity and isoenzyme composition of mitochondrial monoamine oxidase (MAO) in tumors (V.A. Filov et al.). In vitro
experiments showed a pronounced inhibition of MAO activity. As a result of treating rats with Walker carcinosarcoma using electrophoresis, it was found that the activity of MAO isoforms with Rst = 0.63 and 0.78–0.94 decreases to 40–60%. Similar results were obtained in a study of the isoenzyme composition of mitochondrial MAO of Zajdela ascitic hepatoma at its maximum growth 24 hours after a single intravenous injection of 100 mg/kg sehydrin. Experiments on intact rabbits also established the inhibitory effect of sehydrin on MAO activity.

It is known that hydrazines are competitive inhibitors of MAO due to binding to the active centers of the enzyme. As you can see, sehydrin is no exception in this regard. In this case, an additional option for the action of sehydrin is possible - its specific effect on the biosynthesis of the enzyme. This assumption is supported by both a change in the fractional composition of proteins in the mitochondrial membranes of Walker carcinosarcoma after exposure to sehydrin, and, in particular, a decrease in the number of protein fractions.

MAO inhibition leads to the accumulation of biogenic amines (serotonin, adrenaline, etc.). Also from L.F. Larionov there are indications of the antitumor activity of biogenic amines. Later, this was confirmed more than once, and there were even unsuccessful attempts to find antitumor activity in adrenalone derivatives (L.L. Malyugina and others). It is very likely that sehydrin has an antitumor effect indirectly, through the accumulation of biogenic amines in the body. Let us give two more considerations in favor of this. First, we have shown that benzylamine (MAO substrate) at a dose of 15 mg/kg eliminates the antitumor effect of sehydrin. Secondly, the clinical picture of the symptomatic effect of sehydrin on patients can be explained by the influence of biogenic amines.

3

. A comparative study of Walker carcinosarcoma before treatment and after exposure to sehydrin at a dose of 60 mg/kg x 10 shows that the drug causes a significant decrease in mitotic activity. As a result of treatment, the mitotic index decreases by 2 times. Analysis of the ratio of mitotic phases indicates that the decrease in the number of dividing cells occurs mainly due to a decrease in the number of prophases (9.3 in the experiment versus 29.9 in the control). This suggests that sehydrin acts on tumor cells in interphase, slowing down their progression through the cell cycle and delaying their entry into mitosis.

It also cannot be ruled out that the drug can damage the mitotic apparatus of tumor cells. This is supported by the appearance of a significant number of pathological mitotic figures, the number of which reaches 27.6% in the experiment versus 5.7% in the control. The most frequently observed forms of pathological figures of mitosis were scattering of chromosomes and lag of chromosomes or chromatids in metakinesis and during divergence to the poles in anaphase.

4

. Sehydrin is a cytomembrane stabilizer. Moreover, this applies to both the cell membrane and the membranes of cellular organelles (V.A. Filov, etc.). At the same time, sehydrin does not affect artificial membranes.

Sehydrin is an inhibitor of vitamin B6, as shown in the following experiments. Sehydrin was used at a dose of 60 mg/kg, vitamin B6 at a dose of 4 mg/kg. B6 was administered to animals in the morning, sehydrin - in the afternoon. In this experimental setting, a weakening of the antitumor effect of sehydrin was observed. Thus, if sehydrin at a dose of 60 mg/kg inhibits the growth of Walker carcinosarcoma by an average of 50%, then when used together with B6, growth inhibition is 20–25% (P < 0.05). These results indicate the possibility of linking the antitumor effect of sehydrin with the B6 deficiency it causes. An additional argument is the complications (polyneuritis) characteristic of hypovitaminosis B6, which occurred when trying to treat patients continuously for 6 months (without interruption) in phase 1 of the drug trial.

Sehydrin affects the activity of a number of enzymes and interferes with a number of biochemical processes (V.A. Filov).

5

. PD Ray et al. showed that hydrazine sulfate in toxic doses inhibits gluconeogenesis by inhibiting the key enzyme in this process, phosphoenolpyruvate carboxykinase (PEK). On this basis, J. Gold developed the concept of the mechanism of cancer cachexia. It is known that in tumors glucose is broken down by glycolysis to lactate. This process is energetically unfavorable, since the breakdown of 1 molecule of glucose produces only 2 molecules of ATP. The excess of lactate formed, together with other under-oxidized products, stimulates gluconeogenesis occurring in the liver and renal cortex. The latter, in the presence of a malignant tumor in the body, is very intense (V.S. Shapot and others). Gluconeogenesis requires energy expenditure: 6 molecules of ATP are consumed for 1 molecule of glucose formed. Next, the newly formed glucose undergoes glycolysis, etc. In this case, energy consumption per cycle is 4 ATP molecules per glucose molecule. The source of this energy is the patient’s body, the irreversible loss of which leads to the development of cachexia. According to Gold, cachexia can be prevented by breaking this vicious circle by inhibiting FEPC. In this case, one can expect stimulation of the body’s fight against the tumor. However, experimental testing did not confirm this hypothesis. Thus, in various tumor models of mice and rats exposed to hydrazine sulfate, it was not possible to establish increased activity of PEPC in the liver, kidneys and tumors (V.S. Misheneva et al.). In other experiments (V.A. Filov, T.M. Burova) it was found that when treated with sehydrin, the level of newly formed glucose in the liver is reduced by approximately half, and in the kidneys it increases by the same amount; the balance for the body remains zero, and for mice, in which the rate of gluconeogenesis is genetically high, it is even somewhat positive. There were also no significant changes in the glucose content in the liver, kidneys and blood in tumor animals treated with sehydrin.

The mechanism of action of sehydrin on tumor growth, in our opinion, consists of several links;
the main ones are listed above. Inhibition of gluconeogenesis may also play a role. However, the main link is MAO inhibition. In this case, the mechanism can develop as a result of influences on a number of biochemical links. Literature:
1. L. F. Larionov. Chemotherapy of malignant tumors. M. 1962. P. 106.

2. L. L. Malyugina, R. I. Polkina, A. L. Remizov. Antitumor effect of some adrenalone derivatives. // Chem.-Pharm. Magazine. 1979. No. 7. P. 56–58.

3. V. S. Misheneva, T. M. Burova, T. A. Goryukhina. Effect of hydrazine sulfate on the activity of phosphoenolpyruvate carboxykinase and the growth of experimental tumors. // Issues of oncology. 1980. No. 2. P. 71–73.

4. V. Ya. Rusin. Hydrazinium sulfate. // Harmful chemicals. Inorganic compounds of elements of groups V–VIII. Ed. V. A. Filov. L.: Chemistry. 1989. pp. 18–23.

5. A. N. Stukov, O. B. Razumeiko, V. A. Filov. On the incompatibility of hydrazine sulfate with ethanol and barbiturates. // Dep. VINITI No. 1706–75 Dep. 1975.

6. V. A. Filov. Sehydrin is a new type of antitumor drug. // Issues of oncology. 1994. T. 40, no. 1–3. pp. 3–14.

7. V. A. Filov, T. M. Burova. Gluconeogenesis in the treatment of animals with experimental tumors with hydrazine sulfate. // Experimental Bulletin. biol. honey. 1984. No. 1. P. 73–74.

8. V. A. Filov, M. L. Gershanovich, B. A. Ivin, et al. Treatment of primary brain tumors with sehydrin. // Issues of oncology. 1994. T. 40, no. 7–12. pp. 332–336.

9. V. A. Filov, L. A. Danova, M. L. Gershanovich et al. Hydrazine sulfate: experimental and clinical data, mechanisms of action. // Drug therapy of tumors in experiment and clinic. Ed. N. P. Napalkov, V. A. Filov, etc. L.: Research Institute of Oncology. 1983. pp. 91–139.

10. V. A. Filov, L. A. Danova, M. L. Gershanovich, et al. Results of a clinical study of the drug hydrazine sulfate. // Issues of oncology. 1990. T. 36, no. 6. pp. 721–726.

11. V. A. Filov, A. V. Tretyakov, A. E. Grinfeldt. Hydrazine sulfate as a cytomembrane stabilizer. // Experimental Bulletin. biol. honey. 1986. No. 5. P. 610–611.

12. V. S. Shapot, V. P. Shelepov, V. A. Ushakov. Gluconeogenesis and homeostasis disorders in the tumor organism. // Bulletin of the USSR Academy of Medical Sciences. 1982. No. 9. pp. 29–34.

13. V. A. Filov et al. Experience of the treatment with Sehydrin in the advanced cancer patients. // Investigational New Drugs. 1995. V. 13. P. 89–97.

14. J. Gold. Hydrazine sulfate and cancer cachexia. // Nutrition and Cancer. 1979. V. 1, n 4. P. 4–9.

15. PD Ray, RL Hanson, HA Lardy. Inhibition by Hydrazine of gluconeogenesis in the rat. // J. biol. Chem. 1970. V. 245. P. 690–696.

Introduction

In the clinical practice of every oncologist, there are patients with generalized processes for whom we are forced to refuse further antitumor treatment due to its ineffectiveness.
However, many patients insist on continuing therapy and want to continue fighting the disease, despite the prevalence of the tumor and its resistance to treatment. These people prefer to continue antitumor treatment as long as possible; in this they see the principle of “living until the end of life.” There are few drugs in our arsenal that can be used to improve the quality of life of palliative patients with inoperable progressive forms of local and disseminated forms of malignant neoplasms (MNT). One of them is hydrazine sulfate (HS), or Sehydrin, which has been used in clinical practice since 1994, registered for the treatment of patients with common forms of lung cancer, primary brain tumors (glioblastoma, astrocytomas, etc.), neuroblastoma, lymphogranuloma, lymphosarcoma, cancer of the stomach and other organs of the gastrointestinal tract, as well as soft tissue desmoids with infiltrative growth and tumors of other localizations, with chemotherapy-induced and post-radiation cytopenia.

According to previous studies, it has been proven that GS (trade name Sehydrin) is able to suppress tumor growth and inhibit monoamine oxidase activity [1–3]. It reduces the permeability of cell membranes and biomembranes of subcellular structures, is an inhibitor of xenobiotic metabolism and is used in the form of oral tablets for symptomatic treatment of common tumor processes [4–6]. The drug does not have myelosuppressive and other side effects characteristic of many other anticancer drugs.

These and some other properties of GS lead to the fact that it improves the quality of life, daily activity of cancer patients, and reduces the severity of pain [4, 6, 7–8].

Since currently there is only scattered information about the effect of GS on the intensity of pain in patients receiving opioid analgesics, the purpose of our study was to find out to what extent the domestic antitumor drug GS (Sehydrin) is able to influence pain relief in palliative cancer patients. For this purpose, an open multicenter randomized study was carried out in the form of a research work “Experience with the use of the drug Sehydrin in cancer patients receiving opioid analgesics.” This study examined the effect of long-term use of the drug Sehydrin at a dose of 120–180 mg per day for two cycles (28 days each) on the quality of life, severity of pain and the need for opioid analgesics in cancer patients receiving palliative care.

To achieve the goal of the study, we set the following main tasks:

• to evaluate the effect of a course of use of the drug Sehydrin on the intensity of pain in cancer patients by assessing the dynamics of pain intensity (PI) using a numerological rating scale (NRS), to evaluate the clinical (analgesic) response to a course of treatment with the drug and the patient’s daily need for analgesics;
• to evaluate the effect of the drug Sehydrin on the quality of life of patients, assessed by the modified SF-36 questionnaire, the Leeds Sleep Questionnaire and the Beck Depression Inventory;
• evaluate patient satisfaction with Sehydrin therapy at the study stages.

Methods

GS was prescribed at a dose of 120 mg/day (1 tablet twice a day) to patients with underweight; patients with normal body weight took GS at a dose of 180 mg/day (1 tablet three times a day). The first course lasted 28 days, followed by a break of 14 days, and the second course of therapy was carried out for 28 days.

According to the protocol, the schedule of visits was as follows:

• visit 0 – screening;
• visit 1 – randomization, start of therapy;
• visit 2 after 14 days (3rd week) from the start of therapy;
• visit 3 after 28 days (5th week) from the start of therapy.

Break – 14 days (2 weeks).

• visit 4 after 42 days (7 weeks) from the start of therapy;
• visit 5 after 56 days (9 weeks) from the start of therapy;
• Visit 6 70 days (11 weeks) from the start of therapy.

The study was conducted in two research centers, 60 patients took part, 57 patients completed the study, 3 patients dropped out of the study at their own request due to progression of the tumor process and/or inability to take the drug orally (switching to parenteral forms of painkillers).

The study population consisted of cancer patients with cancer of various locations, who were included according to the protocol in one study group. All patients had stage 3 or 4 cancer, their physical activity was 2–3 points according to ECOG, and the pain syndrome was at the level of “moderate pain” and “severe pain.” For pain treatment, patients received opioid analgesics (tramadol, morphine sulfate, TTC fentanyl, propionylphenylethoxyethylpiperidine - Prosidol), as well as accompanying therapy: non-steroidal anti-inflammatory drugs, adjuvant drugs (pregabalin, tolperisone). About 40% of patients had cancer of the digestive organs, 9% of the female genital organs, 6% of the urinary tract, the remaining localizations ranged from 1 to 4%.

results

1. Assessment of the effect of course use of GS on the intensity of pain.

When assessing the change in IB according to the NOR (from 0 to 100%), it was revealed that at the initial stage of the study (visit 1), on average for the group it was 58.08±10.82%, at visit 3 it decreased to 48.25±12, 24% (p<0.05). The obtained result, taking into account the characteristics of the studied population of patients with cancer, can be regarded as good. Visit 4 (after a 14-day break in taking GS) was characterized by IB at the level of 52.08±10.10%, which practically did not change after 4 weeks at visit 6 (52.88±11.54%). The presented data allow us to conclude that IB decreased at the stages of the study, however, to fully assess the dynamics of IB at individual stages, a pairwise comparison analysis of the average NOS indicators on visits 3, 4 and 6 was carried out relative to the initial value on visit 1 and between individual visits (Table 1 ).

The analysis showed that, in general, there was a significant decrease in IB at the study stages (visits 3, 4, 6) relative to the initial visit 1. The best result was observed after 28 days of therapy at visit 3.

In accordance with the generally accepted methodology, we assessed the clinical response to a course of HS use based on changes in IB indicators according to the NOS (increased, stable level, weakened; Table 2).

A one-sample test showed that the proportion (16%) of patients whose pain increased was significantly lower than that of patients whose pain weakened or did not change (84%; p<0.01).

After 28 days of taking the drug, at visit 3, a weakening of pain was detected in 42 (70%) patients (in the range from 5 to 35% according to NOR), pain increased in 6 (10%) patients (by 10–15%) and remained without changes in 12 (20%) patients.

Among the patients who noted one or another decrease in FI, 15 (25%) patients who responded to treatment were identified (decrease in FI by 20% or more) and 8 (13%) patients with a clinically significant response to treatment (decrease in FI by 20% or more). 30% or more). There were no patients who reported a 50% or more reduction in pain at visit 3.

2. Assessing the dynamics of patients' needs for opioid analgesics.

To assess the dynamics of patients' daily need for opioid analgesics, all these drugs were reduced to a single tramadol equivalent. This made it possible to track the dynamics of patient use of opioids at all stages of the study.

By the end of the study (visit 6), the following indicators were identified:

• 16 (26.7%) patients received a stable dose of opioid analgesics (200–300 mg tramadol);
• in 10 (16.7%) patients, the dose of opioids was increased, of which 5 patients were transferred to stronger drugs (oral morphine - 2 patients, TTC fentanyl - 2 patients, oral morphine and Prosidol - 1 patient);
• 3 (5%) patients left the study due to active progression of the tumor process, the appearance of severe weakness, and worsening IB (two were transferred to TTC fentanyl, one patient continued to take tramadol at a dose of 50 mg/day);
• In 31 (51.7%) patients, the dose of tramadol was reduced by the end of the study, including:
• tramadol was discontinued in 5 patients (from visits 4–5);
• in 2 patients the dose was reduced from 100–200 to 50 mg/day;
• in 15 patients the dose was reduced from 200 to 100 mg/day;
• in 3 patients the dose was reduced from 200 to 150 mg/day;
• in 5 patients the dose was reduced from 300 to 200 mg/day;
• In 1 patient who received morphine sulfate 40 mg/day (orally) at visit 1, the pain decreased significantly, morphine was discontinued, and the patient took tramadol starting at visit 3, 200 mg/day.

Thus, we can conclude that about half of the patients taking Sehydrin reduced the dose of tramadol by the end of the study, with 25% reducing its use by 2 times, 12% completely stopped using it.

3. Assessing the impact of HS on the quality of life of patients (according to the SF-36 questionnaires, the Leeds Sleep Inventory and the Beck Depression Inventory).

Eight scales of the SF-36 questionnaire were assessed, as well as the resulting indicators “physical component of health” and “psychological component of health” (Table 3).

Analysis of the integrative indicator “Physical health component” (PH) showed that, despite positive changes in individual items of the questionnaire, in general it had negative dynamics (Table 4). This indicates an increase in the effectiveness of pain therapy, but only at rest, without active physical activity, when patients can take care of themselves, but are not able to fully carry out professional activities.

The integrative indicator “psychological component of health” (Mental Health - MH) throughout the study was stable relative to the initial state, without significant changes relative to the beginning of the study.

Analysis of the average values ​​of the level of depression on the Beck Depression Inventory did not reveal significant changes, however, a pairwise comparison of the average values ​​between visits showed a significant difference between visits 3, 4 and 6 relative to the initial visit 1 and non-significant differences in other variants (Table 5).

Overall, more than half (54%) of patients reported a decrease in general depression, 23% showed no change, and 13% of patients showed an increase in depression. These indicators correlate with changes in information security according to the NOS.

Changes in the indicators of the Leda Sleep Questionnaire showed that by visit 4 there was a significant increase in the number of positive subjective assessments of sleep quality; relative to other visits, these changes were not long-lasting and by the 6th visit the number of positive assessments decreased to the initial level. Thus, we can conclude that there is a temporary improvement in sleep quality in patients receiving HS after 3–5 weeks from the start of treatment.

4. Changes in indicators of satisfaction with treatment during the stages of the study.

Satisfaction with therapy at the stages of the study was assessed on a 4-point scale from 1 to 4: bad - 1 point, satisfactory - 2 points, good - 3 points, excellent - 4 points.

During the stages of the study, these indicators underwent significant changes both in the average values ​​and in the percentage distribution of patient ratings. Starting from visit 5, the mean score on the treatment satisfaction scale was significantly different from the baseline level. By visit 5 it increased by 0.40 to 2.67 points (p<0.05), by visit 6 – by 0.56 and amounted to 2.82 points (p<0.01), which is presented in table. 6.

The proportion of patients who rated the treatment as “good” increased significantly both for the first (to 46.7%) and for the second course of treatment with Sehydrin (61.4%). However, when Holm's correction for multiple comparisons is included in the statistical analysis, statistical significance is retained only in the paired analysis of the indicators “visit 1–visit 6” (p = 0.00098), and the remaining pairs of visits do not demonstrate significant differences.

The integrative indicator of positive ratings (“good” and “excellent”) for satisfaction with treatment at the end of the study was 71.9%.

Conclusion

The study noted a significant decrease in PI in cancer patients 28 days after starting Sehydrin, which correlated with improvements in individual domains of the SF36 questionnaire: “role functioning,” “social functioning,” “general health,” and “pain intensity.” About half of the patients taking GS (Sehydrin) reduced the dose of the main opioid analgesic tramadol by the end of the study (25% reduced it by half, 12% stopped taking it completely). Adequate pain control while reducing the dose of opioid analgesics did not have the expected positive effect on the final integrative indicators “physical component of health” and “psychological component of health” according to the SF 36 questionnaire, but was reflected in positive changes in indicators of the level of depression on the Beck Depression Scale, as well as indicators “subjective quality of sleep” according to the Lida Sleep Questionnaire. The dynamics of positive assessments of patient satisfaction with treatment (“good” and “excellent”) demonstrated a significant increase in their number only towards the end of the study (between visits 1 and 6).

It should be noted that the objectives of the study did not include assessing the adverse effects of GS and its drug interactions. We can only indirectly judge them by the dynamics of quality of life indicators. In general, the drug was well tolerated by patients, and the fact that more than half of the patients assessed its effect positively indicates the advisability of using Sehydrin in cancer patients who, for various reasons, are denied antitumor therapy. The drug will not replace the use of opioid analgesics, if they are indicated, but may delay their use and prolong the period between tumor progression and the terminal stage of the process. Our experience with Sehydrin suggests that it should not be prescribed to terminally ill patients with minimal physical activity. We observed the best results with the use of Sehydrin in patients receiving small doses of opioids, leading a relatively active lifestyle, spending 50% of the daytime in bed, although some successful clinical cases were observed in patients with physical activity ECOG points of 3–4. In subsequent publications, it is advisable to systematize and describe this clinical experience.

Sehydrin

Release form, composition and packaging

Tablets, enteric-coated, red-brown in color; white tablet core; On a cross section, two layers are visible.

Excipients: disubstituted calcium phosphate, polyvinylpyrrolidone, magnesium stearate, highly dispersed silicon dioxide, dimethicone, talc, polymethacrylate, polyethylene glycol 600, red iron oxide (E172), titanium dioxide.

10 pieces. — contour cell packaging (5) — cardboard packs.

50 pcs. — polymer jars (1) — cardboard packs.

Clinical and pharmacological group: Antitumor drug

Registration No.:

• tab., cover enteric coated, 60 mg: 50 pcs. — R No. 003061/01, 12/17/03 PPR

pharmachologic effect

Antitumor drug. Suppresses the growth of tumors, affects a number of biochemical parameters: inhibits monoamine oxidase activity, reduces the permeability of cell membranes and biomembranes of subcellular structures, and is an inhibitor of xenobiotic metabolism.

It has a symptomatic therapeutic effect for malignant neoplasms in advanced stages. Does not have a myelosuppressive effect.

In the treatment of locally advanced and disseminated forms of malignant neoplasms, the drug has a pronounced symptomatic effect: there is a decrease or elimination of pain (up to the cessation of opioid analgesics), feelings of weakness, symptoms of respiratory failure (shortness of breath, cough), fever, causes improved appetite, increased motor activity.

Pharmacokinetics

After taking the drug orally at a dose of 60 mg (1 tablet), the Cmax of the active substance in the blood serum is achieved after 2 hours; after 24 hours, small amounts of it are still detectable in the serum. When blood is collected 9 hours after the end of a 30-day course of treatment, from 0 to 89 ng/ml of hydrazine sulfate is detected in different patients.

Experimental studies on intact rats and animals with sarcoma 45 showed that hydrazine sulfate is rapidly absorbed from the gastrointestinal tract, complete elimination from the blood is completed by 25-28 hours after intragastric administration at a dose of 100 mg/kg. Cmax in the blood of intact animals is reached approximately 50 minutes after administration, in tumor carriers (sarcoma 45) - after 3 hours.

A 3-5 times increased accumulation of the active substance in the liver, kidneys, and lungs compared to the blood, but not in the tumor, was registered; cleansing of intact organs of healthy animals and tumor carriers ends by the end of 4 days. Excretion in urine in healthy animals lasts up to 3 days and is approximately 50% of the administered amount; in tumor carriers, excretion ends between the first and second days, and only 25% of the drug is excreted. Vd in intact rats is 14 ml, in the presence of a tumor - 29.4 ml. Tumor carriers are prone to accumulation of hydrazine.

Hydrazine sulfate is oxidized in the body, and its undegraded part is excreted in the urine, partly in acetylated form (in rats and rabbits).

Indications

• symptomatic treatment of locally advanced and disseminated forms of malignant neoplasms
• malignant neoplasms in advanced stages (including in the preterminal phase of the process) - in order to obtain a positive psychotropic effect, improve general well-being, improve mood

Dosage regimen

Sehydrin is prescribed orally 1-2 hours before or 1-2 hours after meals or taking other medications.

For adults, the drug is prescribed 1 tablet. 3 times/day. The course dose is 100 tablets. If tolerance is unsatisfactory, the daily dose is reduced to 2 tablets. The dose for the course of treatment may not change.

A repeated course of treatment is carried out at intervals of at least 14 days. The number of courses is not limited, and the intervals between courses are increased by 1-2 weeks.

Side effect

From the digestive system: dyspeptic symptoms are possible (nausea, vomiting, belching), which quickly disappear with a dose reduction or a short-term (2-3-day) break in treatment.

From the central nervous system and peripheral nervous system: rarely - insomnia, general agitation, mild and transient symptoms of polyneuritis.

Contraindications

• hypersensitivity to hydrazine sulfate and other components of the drug

Use with caution in cases of severe dysfunction of the liver and kidneys.

Use during pregnancy and breastfeeding

The possibility of using the drug during pregnancy and lactation has not been studied.

Use for liver dysfunction

Use with caution in cases of severe liver dysfunction.

Use for renal impairment

Use with caution in cases of severe renal dysfunction.

special instructions

Prescribing the drug for jaundice caused by liver metastases (especially obstructive) is not contraindicated.

For dyspeptic symptoms, astringents and anti-inflammatory drugs (infusion of chamomile, romazulon, vikalin), antispasmodics and antiemetics (including pyridoxine, cerucal) are prescribed internally.

For neurotoxic effects, it is advisable to use pyridoxine (in a 5% solution, 1 ml IM 1-2 times a day), thiamine (vitamin B1), oral multivitamin preparations, and intravenous administration of a 20-40% glucose solution.

During the treatment period, drinking all types of alcohol and taking barbiturates is contraindicated due to a sharp increase in the toxicity of treatment.

Due to the complete absence of myelotoxicity, Sehydrin is used in patients with cytopenia resulting from specific treatment - radiation and chemotherapy.

Use in pediatrics

The possibility of using the drug in children has not been studied.

Overdose

Data on overdose of the drug Sehydrin are not provided.

Drug interactions

When Sehydrin with barbiturates, toxic effects develop.

In experimental studies on animals, in the case of preliminary administration of Sehydrin, the effectiveness of treatment with many antitumor drugs increases (excluding cyclophosphamide).

Conditions for dispensing from pharmacies

The drug is available with a prescription.

Storage conditions and periods

List B. The drug should be stored out of the reach of children, in a dry place, protected from light. Shelf life: 3 years.