RU2225233C2 - Method for delivering photosensibilizer to tumor tissue in brain - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: method involves injecting 2-4 ml of 0.05% Photosense solution into cerebral liquor space twice with 24 h long pause. Electrophoresis session is carried out in tumor localization zone 2 h later. The negative electrode is set over the retained portion of the tumor and the other one on the opposite side. Electrophoresis session is administered for 20 min. EFFECT: enhanced effectiveness of delivery. 2 cl, 3 dwg

Description

 The invention relates to medicine, namely to neurosurgery, and can be used to improve the clinical results of the treatment of patients with malignant intracerebral brain tumors of various localization.

 The method of targeted delivery of certain drugs and, in particular, antibacterial drugs to the site of inflammation in the brain (meningoencephalitis) is widely known by slow continuous multi-day infusion of antibiotic solutions through a catheter implanted in the lumen of the internal carotid artery or its branch (N.S. Dralyuk / / To the substantiation of prolonged intracarotid infusion and regional perfusion in the treatment of severe inflammatory diseases of the brain and its membranes: Abstract of thesis, Doctor of Medical Sciences, L., 1971, - 34 c).

 Significant disadvantages of this method lie in the need to perform an additional technologically complex vascular operation that causes trauma to the carotid artery, prolonged spasm of its walls with the risk of developing neurological complications. In addition, the long-term location of the catheter in the lumen of the artery poses a threat to cerebral embolism and the development of fatal neurological complications. And finally, this method is provided only for the introduction of antibiotics, not a photosensitizer, and does not fully overcome the blood-brain barrier for the entire administered dose of the drug.

By analogy with the indicated method, some patients with malignant gliomas receiving radiation and chemotherapy courses were simultaneously injected with photosensitizers (Photofrin, Photosan) in the carotid artery at a dose of 1 mg / 1 cm ^{3 of the} remaining tumor mass, followed by photodynamic laser therapy at 40 J laser doses / cm ² , 80 J / cm ² , 120 J / cm ² (H. Kostron. Photodynamic treatment of malignant brain tumors. // Photodynamic therapy and biomedical lasers., Proceedings of the International Conference on Photodynamic Therapy and Medical Laser Applications, Milan 24-27 June 1992, Excerpta Medica, 1992, p. 386-390).

 The disadvantage of this method is, firstly, a rather pronounced phototoxic reaction on the part of the skin and retina, despite the insufficient dose, as well as the continued circulation of the less toxic drug Photosan in the systemic circulation with absorption by healthy tissues. Secondly, conducting photodynamic laser therapy based on this method of administering a photosensitizer has proven to be ineffective. The death of patients, according to the authors, occurred 6-14 months after the operation.

 Closest to the claimed is a method of direct administration of the HPD photosensitizer in the bed of a malignant tumor immediately after its surgical removal (H. Kostron Photodynamic treatment of malignant brain tumors // Photodynamic therapy and biomedical lasers., Proceedings of the International Conference on Photodynamic Therapy and Medical Laser Applications , Milan, 24-27 June 1992, Excerpta Medica, 1992, p. 386-390).

 A significant drawback of this method, firstly, is that due to the pronounced postoperative edema of the brain tissue, the photosensitizer is localized in the surface areas of the tumor and is not able to penetrate into all departments of the non-removed part of the brain tumor. In this regard, the conduct of photodynamic therapy based on this method of photosensitizer delivery will not be effective and will not give a lasting clinical effect.

 The objective of the proposed method is to create in the cerebrospinal fluid and tumor tissue such concentrations of photosensibility that would allow for clinically effective photodynamic laser therapy and prevent skin photothermal reactions during its implementation.

 The solution of this problem allows you to achieve a positive therapeutic effect - to save the patient’s life, reduce his stay in bed and significantly improve the postoperative results of treatment of this group of patients.

 The problem was solved due to the fact that 48 hours before the photodynamic laser therapy session, cerebrospinal fluid spaces of the brain are injected with a lumbar, ventricular, suboccipital puncture or directly into the peritumor cyst twice with an interval of 24 hours at a rate of 24 hours of a 0.05% solution photosens and 2 hours after each injection, an electrophoresis session is performed in the tumor localization zone for a duration of 20 minutes. The negative electrode was in the projection of the tumor.

 The method was carried out as follows.

 Upon histological confirmation of a malignant intracerebral brain tumor in a patient to conduct photodynamic laser therapy, a locoregional administration of a photosensitizer (photosensitivity) was performed to prevent continued tumor growth. To do this, after an operation aimed at the most radical removal of an intracerebral tumor, after relief of postoperative cerebral edema and wound healing (10-12 days after the intervention), the patient undergoes a local-local administration of photosens into the cerebrospinal fluid according to the technique developed by us.

 48 hours before the PDLT session under aseptic conditions (in the dressing or operating room) under local anesthesia of a 2% solution of novocaine 4-5 ml, cerebrospinal fluid spaces are punctured. For this, a lumbar, ventricular, suboccipital puncture is performed or a peritumor cyst is punctured. Measure cerebrospinal fluid pressure and evacuate for clinical analysis 2-4 ml of cerebrospinal fluid, and then inject 3-4 ml of 0.05% sterile photosensitivity solution. After that, the needle is removed and the puncture site is sealed with collodion. 2 hours after this, for the forced delivery of photosens into the tumor tissue, an electrophoresis session is carried out for 20 minutes. A period of 20 min during electrophoresis is the most optimal, since it is after 20 min that the maximum concentration of photosens is determined in the tumor tissue. For the same purposes (for the maximum accumulation of the photosensitizer in the tumor tissue), it is necessary that the negative electrode must be above the unremoved part of the tumor during electrophoresis. Positive - on the opposite side of it.

 A day after the first injection of photosens, a second similar introduction of it into the cerebrospinal fluid system is carried out in the same dosage. Before the introduction of photosens, 2-4 ml of CSF is also removed for spectroscopic and chromatographic control of photosens in CSF (based on these methods, qualitative and quantitative determination of photosens in CSF is performed). Two hours after the second administration of photosens, a similar electrophoresis session is performed.

 After each administration of photosens, the patient is in bed for the next several hours. He is under clinical observation with monitoring of blood pressure, pulse, respiratory rate and temperature. In dynamics, the neurological status is also controlled.

 An example of a specific implementation.

 Patient G., 17 years old, was admitted to the neurosurgery clinic of the Novosibirsk Research Institute of Nuclear Medicine with a diagnosis of cystic tumor of the right cerebellar hemisphere.

 From the anamnesis it was found that he fell ill about 4 years ago, when diffuse headaches first appeared, accompanied by dizziness. Subsequently, headaches began to be localized in the right occipital region, and the patient began to notice a decrease in visual acuity in the right eye and hearing in the right ear. Over time, tremor in the left hand joined, increasing in intensity with time. The letter began to suffer. Shakiness when walking appeared and began to progress. An MRI of the brain was performed on an outpatient basis, revealing a cystic tumor in the right hemisphere of the cerebellum. He was hospitalized in a neurosurgery clinic for surgical treatment.

 The patient underwent a comprehensive clinical and tomographic examination.

 In neurological status: horizontal mid-spread nystagmus when viewed from both sides. When looking down, a vertical component appears. The right nasolabial fold is smoothed. The strength in the right arm is 46, in the remaining muscle groups 56. Diffuse muscle hypotension. Plantar reflexes are sluggish. Permanent tremor of the left hand. Intension with a finger-nasal test on the right. In the Romberg position - a slight deviation back. Elements of chanted speech.

 The 2-projection R-grams of the skull showed a significant increase in finger impressions in the frontal region; the shape and size of the Turkish saddle were normal.

 EEE - moderate cerebral changes with signs of dysfunction of the median structures.

ECHOEG - a tendency to shift the M-echo from left to right in the middle sections by 1.5 mm. More echoes with 2 ^-x sides.

 Ophthalmologist examination: optic nerve discs pale pink, clear borders. Arteries of medium caliber. The veins are dilated, full-blooded, no edema.

 MRI of the brain: a cystic tumor in the right hemisphere of the cerebellum, causing deformation of the brain stem and fourth ventricle. Moderately pronounced internal occlusal hydrocephalus (figure 1).

 Based on a clinical and tomographic study, the patient was diagnosed with a cystic tumor of the right cerebellar hemisphere.

 On December 2, 1998, operations were performed: trepanation of the posterior cranial fossa, emptying of a tumorous cyst, subtotal removal of a tumor of the right hemisphere of the cerebellum. Due to the fact that the tumor grew into the brain stem, only a large part of the tumor located in the cerebellum was resected. Another part of the tumor growing in the brain stem, because of the high probability of a fatal outcome, was not removed. The histological diagnosis is anaplastic astrocytoma.

 The postoperative period was uneventful, wound healing by primary intention. Sutures were removed on the 7th day after the operation. A control MRI scan of the brain was performed 11 days after the operation, which revealed the presence of cerebrospinal fluid cysts at the site of the former tumor (Fig. 2).

 To prevent the procedure of that part of the tumor that was localized in the brain stem, it was decided to conduct photodynamic laser therapy based on the locoregional administration of photosens.

 To do this, 12 days after the operation (12/27/98 g), 48 hours before the photoplasty, the local-regional injection of photosens into the cerebrospinal fluid system was started: under local anesthesia Sol. Novocaini 2% - 4 ml; lumbar puncture was performed in the L3 / L4 interstitial interstitium. Liquor pressure was equal to 160 mm water column. After the evacuation of 2 ml of cerebrospinal fluid, sent for clinical analysis, 3 ml of a 0.05% photosensitizer solution (Photosens) was endolumbered. After that, the needle was removed and the puncture site was sealed with collodion.

 2 hours after this, an electrophoresis session was carried out for 20 min to force the photosens into the tumor tissue. In this case, to maximize the accumulation of photosensibility in the tumor tissue, electrophoresis was performed so that the negative electrode was located over the unremoved part of the tumor (right occipital region). Positive - on the opposite side of it (left occipital region).

 Then, a day after the first administration of photosens, a similar introduction was made into the cerebrospinal fluid system in the same dosage. Before introducing it into the cerebrospinal fluid system, 3 ml of cerebrospinal fluid were also evacuated for spectroscopic and chromatographic control of photosens in the cerebrospinal fluid. Spectrophotometry revealed the presence of photosens in the cerebrospinal fluid after 24 hours from the moment of its introduction - there was a characteristic peak in the absorption zone of photosens (wavelength 675 nm). The chromatographic method showed the presence of photosens in the cerebrospinal fluid in the amount of 1.9871 μg / ml. Two hours after the second administration of photosens, a similar electrophoresis session was conducted for 20 minutes.

 Both procedures of locoregional administration of photosens passed without complications. After each administration of photosens, the patient was in bed for the next 4 hours. Clinical and neurological follow-up was performed. Monitoring of blood pressure, heart rate, respiratory rate, body temperature and neurological status did not reveal their significant deviations from the baseline.

 Later, two hours after the electrophoresis session, the patient underwent a course of treatment with photodynamic laser therapy in the operating room.

 The patient was discharged from the clinic two days after the photodynamic laser therapy in satisfactory condition home. Subsequently, he underwent a standard course of radiation therapy on the tumor bed.

 At present (2 years and 3 months have passed since the moment of photodynamic laser therapy), the patient's condition is satisfactory: active, neurological symptoms do not increase. Regressed tremor in the hand, shakiness when walking, headaches. After a course of photodynamic laser therapy, he was twice on a follow-up examination with control MRI of the brain. The last time examined at the institute after discharge after 1 year and 8 months. However, clinically and by MRI (Fig. 3) data for continued tumor growth were not detected.

 Thus, conducting the local-area administration of photosens according to the technology developed by us, allowed us to conduct a full-fledged PDLT course. The effectiveness of the proposed method of photosens delivery to tumor tissue is evidenced by the fact that this technique contributed to the conduct of clinically significant PDLT, which allowed to stabilize the patient's condition and prevent the growth of a malignant tumor. This is evidenced by the good condition of the patient to date, stable neurological symptoms and the lack of data for filtering the tumor according to MRI images obtained 1 year and 8 months after the date of PDLT.

Claims (2)

1. A method of delivering a photosensitizer to the tumor tissue of the brain by introducing it into the body, characterized in that it is injected into the cerebrospinal fluid spaces with an interval of 24 hours twice 2-4 ml of a 0.05% solution of photosens, 2 hours after each injection conduct an electrophoresis session in the area of tumor localization, with a negative electrode placed over the unremoved part of the tumor, and a positive electrode on the opposite side. 2. The method according to claim 1, characterized in that the electrophoresis session is carried out for 20 minutes

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