Artificial Cells, Blood Substitutes, and Biotechnology, 33: 3746, 2005 Copyright Q Taylor & Francis, Inc.

ISSN: 1073-1199 print/1532-4184 online DOI: 10.1081/BIO-200046654

Clinical Results of Perftoran Application: Present and Future

Eugene Maevsky, Genrih Ivanitsky, Ludmila Bogdanova, Olga Axenova, and Natalia Karmen
Institute of Theoretical and Experimental Biophysics of RAS, Moscow Region, Russia

Eugene Zhiburt
Center of Industrial Transfusiology of Russian Ministry of Health, Moscow, Russia

Raisa Senina, Sergey Pushkin, and Igor Maslennikov

OA Scientific-Productive Company Perftoran, Moscow Region, Russia

Andrey Orlov and Irina Marinicheva

Central Scientific-Research Institute of Stomatology, Moscow, Russia

Abstract: Clinical experience of Perftoran (commercial drug of low concentrated perfluorocheminal emulsion) applications is presented in some statistical data and in brief analysis of clinical trials and following clinical studies described in the Russian scientific literature. Observed data allow us to suppose that Perftoran facilitates oxygen delivery together with remaining red blood cells at blood replacements and will have more wider area for application than just a blood substitute. Its infusion alleviates symptoms of ischemia at different types of occlusion vessels disease, improves grafting in plastic surgery, diminishes inflammation and prevents rejection of transplants, activates detoxication functions of liver, inhibits retro-virus infection development. Local PF applications is able to accelerate wounds and ulcers healing.

We thank T. N. Kharybina and her colleagues in Pushchino Library, Professor G. A. Sofronov and his coworkers from the Military Medical Academy in SaintPetersburg for their help in looking for information about Perftoran applications. Address correspondence to Eugene Maevsky, Institute of Theoretical and Experimental Biophysics of RAS, 142290, Pushchino, Institutskaya, 3, Moscow Region, Russia. E-mail: emaevsky@iteb.ru 37

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Keywords: Perftoran, review clinical usage

1. GENERAL PICTURE OF PERFTORAN APPLICATION This paper presents a generalization of the widely used clinical application of Perftoran (PF). PF contains 10 vol.% perfluorochemicals (PFCs): perfluorodecalin and perfluoro-N-(4-methylcyclohexyl)piperidine in ratio 7:3 emulsified by non ionic surfactant Proxanol-268 in an isotonic electrolyte solution with average emulsion particle size of about 0.07 mm (Table 1). The whole composition of PF is packed in one bottle and has to be stored either frozen (at 18C to 4C for 3 years) or under refrigeration (at 4C for 2 weeks). PF is manufactured by Scientific-Productive Company Perftoran. PF was registered in Russia in 1996 as an oxygencarrying blood substitute. The various opportunities of PF applications (and not only for blood replacement) have already been revealed on the basis of analysis of patients distribution (Table 2) during preregistration clinical trials [14]. As is shown in Table 2, PF was administered in dosages from 4 to 30 ml=kg depending on the disease. The largest summary doses were from 1000 to 5300 ml for the treatment of severe anemia. In 1997, Scientific-Productive Company Perftoran began to sell PF to Central Regional Stations of Blood Transfusion and different hospitals. Judging the volume of the wholesale and assuming that a single patient received about 1000 ml, we deduced that PF had been administered to about 4500 patients. Information about PF use was collected

Table 1. Perftoran composition and its physical-chemical properties F-decalin and its satellites FN-(4-methylcyclohexyl)-piperidine and its satellites Proxanol-268 NaCl KCl MgCl2 NaHCO3 NaH2PO4 Glucose H2O [F ] Osmotic pressure pH Viscosity 7.0 ml 3.0 ml 4.0 g 0.6 g 0.039 g 0.019 g 0.065 g 0.02 g 0.2 g to 100 ml 10 mM 300 mOsM 7.3 2.3 cP

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Table 2. Distribution of patients according to indications during clinical trials Doses, Summary Patients % side ml per kg BW doses, L distributions reactions 630 412 48 46 30 28 1.05.0 0.41.2 0.41.0 0.40.8 1.02.0 1.02.0 0.11.0 23.5% 20% 12,7% 20,7% 11.1% 4,8% 8.2% 100% 2% 0% 0% 20% 0% 0% 25% 6,9%

Indications 1. Acute blood loss and hemorrhagic shock 2. Polytrauma, cranialcerebral trauma, shock 3. Toxic-infection shock 4. Occlusion of blood vessels and acute heart infarct 5. Cardioplegia 6. Transplantation 7. Burns, oncology & others Total 912 patients

with the help of questionnaires from 21 regions of Russia. The answers of respondents gave total evaluation of PF efficiency, which looked as follows: positive effects 88,3%, negative effects 3,3%, absence of any effect 8,3%; different side effects were listed in 4% of cases. Analysis of the Russian scientific literature from 1997 to 2002 let us find a listing of 1823 patients treated with PF in comparative studies with a total of 3332 patients (Table 3). The new fields of PF usage in clinical practice are much wider than was found out during clinical trials. Almost
Table 3. Indications and distribution of patients treated with Perftoran in comparative studies listed in Russia scientific literature for the period up to 2002 Total 3332= Perftoran treated 1823 862=401 490=292 269=163 375=170 197=152 184=134 123=53 206=87 165=72 461=299 Distribution of patients with Perftoran 22.0% 16.02 8.9% 9.3% 8.3% 7.3% 2.9% 4.8% 3.9% 16.2%

Indications 1. Blood losses, multiple organ failure 2. Disorders of perfusion and microcirculation (without blood loss) 3. Dysfunction of inflammatory response 4. Detoxication 5. Lung function damage, RDSA 6. Cranial-cerebral trauma 7. Burns, thermal shock 8. Transplantation 9. Cardioplegia, cardiopulmonary bypass 10. Local application: wound & ulcer of mucous, skin, spinal cord

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the complete reference list of PF applications for the period up to 2001 was published in Russian by G.A. Sofronov et al. [5].

2. THE PLACE OF PERFTORAN IN INFUSION-TRANSFUSION THERAPY OF BLOOD LOSSES According to the initial conception, PF was developed and manufactured as a blood substitute. Correspondingly, Perftoran should have been used in lieu of allogeneic blood and banked red blood cells (RBC) during the substitution of massive blood losses (about 10002500 ml). At massive blood replacement PF was used together with a combination of plasma expanders (dextran 60 or hydroxyethylstarch was infused into other veins or immediately after PF into the same vessel). Simultaneously it was necessary to provide the patients with breathing of air enriched with supplementary O2. In these cases PF was used without pure oxygen for breathing when the fraction of O2 in air did not exceed 0.40.6 [13, 69]. It enabled us to maintain venous pO2 at the level of 4565 mm Hg and did not block HbO2 desaturation in the remaining erythrocytes. Analysis of PF usage at massive, moderate and small blood losses has shown that PF was able to significantly improve tissue oxygenation due to oxygen delivery together with the remaining RBC and to facilitate blood rheology at early stages of infusion-transfusion therapy. PF turned out to be useful even if the level of circulating erythrocytes and hemoglobin was still sufficient (did not reach the trigger level of blood transfusion) and there was no need to use banked donor blood or RBCs [1012]. Consequently, a conclusion was made that PF should be administered at early stages of blood loss treatment immediately after crystalloid solutions (Table 4) when the symptoms of hypoxia, ischemia and microcirculation disorders appeared. The basic results of Perftoran application at blood replacement were an increase in efficiency of reanimation treatment and shortening of reanimation period, duration of lung artificial ventilation, an improvement of oxygen transport and its consumption, a decrease in the demand in banked blood and blood components more than 2-fold and even avoidance of donor blood infusion [13, 69]. Side reactions such as hypotension and pulmonary complications were observed at massive blood replacement with PF in about 1% of cases. The stomach-duodenal bleeding and operation blood losses are good examples when PF provided maintenance of arterial PO2 on the higher level than crystalloids or colloids [612]. In comparison with dextran 60 Perftoran decreased more efficiently heart rate, blood viscosity and erythrocytes rigidity, augmented the arterial pressure, cardiac output and central venous pressure, maintained vessel resistance

Table 4. The place of perftoran in infusion-transfusion therapy of blood losses

Blood loss volume % Circulat. Blood Volume <15 1530 3040 >40 Transfusion means and doses (ml) Fresh frozen plasma 10001500 15002000 Red blood cells & platelets on indications 26 units

ml < 750 7501500 15002000 >2000

Crystalloids 1500 15002000 10001500 8001000

Perftoran 200300 500700 8001000 10001500

Colloids 600800 800 1200 12001500

Albumin 10% 100200 200300

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and circulating blood volume. Thanks to that, Perftoran diminished acidosis. Here it is necessary to mention that in most cases the positive effect of PF was reached after its usage in small doses of 46 ml per kg body weight when the supplementary oxygen capacity of PFC emulsion was insignificant. These doses of PF accelerated patients resuscitation after cranial-cerebral trauma [12] and burns shock [9]. Significant antiacidosis effect and improvement of tissue oxygenation were obtained within cardiopulmonary bypass with PF during reconstruction operation on heart in more than 45 patients [13]. 3. PERFTORAN IMPROVES TISSUE OXYGENATION AT THE TREATMENT OF OCCLUSIVE VESSELS DAMAGES V. Moroz et al. [1,2] obtained 30% of skin PO2 augmentation measured with transcutaneal device after infusion of 400 ml of PF, while dextran 40 gave only 6% of tissue PO2 increase. Ultrasound dopplerometry and thermovision images demonstrated an improved resuscitation of the blood flow immediately after infusion of 200 ml PF. Summary effects received on 92 patients in the Rehabilitation Center of Government Medical Department are shown in Table 5. Treatment with repeated Perftoran infusion eliminated pain at rest and significantly enhanced painfree distances. L. V. Usenko et al. [14] and later a number of other researchers [15], described the diminishing of necrotic region after heart infarct treated with very small doses of PF: 100 ml per infusion. 4. IN TRANSPLANTOLOGY PF DECREASED KIDNEY GRAFTS REJECTION 2-FOLD Infusion of 10002000 ml of PF into kidney cadaver donors who had no heart function alleviated symptoms of kidney ischemia and decreased
TABLE 5. Results of Perftoran treatment at the occlusive vessels diseases of legs (Rehabilitation Center of Government Medical Department, 19992002) Quantity & average age of patients

Treatment before Perftoran

Painfree distances, m (% of patients)  180 (100%) 1200 (87%) 750 (9%) 200 (4%)

Pains Stages of at rest diseases 50% 0 23b 12a

N 92 68 years

Perftoran 200 ml 23 every 69 months

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graft reperfusion injury. Reperfusion damages and graft rejections diminished also after infusion of PF in dosage of 46 ml per kg body weight into recipients after transplantation [16,17].

5. UNEXPECTED PERFTORAN APPLICATIONS A. The first clinical experience of PF application for detoxication aim has been recently presented at the treatment of poisoning with carbofos and psyhotropic drugs [18]. PF usage was based on its capabilities to sorb lipophylic substances in blood stream and to induce the synthesis de novo of cytochrom P450 in liver [19]. B. Taking into account the fact that PF is able to inhibit functions of hyperactivated macrophages and primed neutrophils [20], which can produce viral particles and a lot of cytotoxic products, an attempt was made to treat 14 patients infected by human immunodeficiency virus (HIV) and suffered the last 23 years from secondary infections, weakness, tiredness, body weight loss, and in-ability to work [21]. After PF courses, which included several intravenous infusions, 12 patients felt much better, could return to work, stopped losing weight. Two patients did not undergo PF treatment because of side reactions. Within the year of treatment with PF, the secondary infections did not manifest. No significant changes in blood analysis were found except for some shifts in concentrations of HIV-1 and p24 protein in blood. C. An antiinflammatory effect of PF infusions applied at chronic uveitis of different etiology was obtained in the Center of Eye Microsurgery in Moscow [22]. A stable recovery was found after supplementary PF infusions (100 ml two times only) in 39 patients out of 40 in cases when previous traditional treatment did not produce any positive effect. PF infusion has been stopped in 1 case because of a side reaction after the first 5 drops of PF. Blood analysis revealed that concentrations of circulating immune complexes and CD-4 lymphacytes in this patients blood had an unusual response to PF. D. Original data were submitted by neurosurgeon Pavel Katunyan from Moscow Medical Academy [23]. He used oxygenated PF for local lavage of injured spinal cord at the decompression operation and simultaneously administered 200 ml of PF intravenously. Additionally, 56 intravenous infusions were made in the postoperation period. When PF was administered during the first days after trauma, the elastase activity of neutrophils in peripheric blood of patients dropped and this phenomenon was accompanied by the improvement of neorulogic state within 3 months. But delayed PF application or traditional therapy either slightly improved neurologic state or did not produce any improvement at all.

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E. Acceleration of healing was shown after PF lavage and local PF applications on the surface of stomach ulcer, skin wounds and even on leprosy chronic ulcers [24,25].

CONCLUSION The data described in the Russian scientific literature seem to show the place of PF among other blood substitutes as an antihypoxic and antiishemic drug that is worth administering on early stages of blood loss as it improves the functions of the remaining RBC, and thanks to that increases tissue oxygenation, delays usage of donor RBC and decreases demand in banked blood. Analyzed clinical experience enables us to suppose that, thanks to its various biophysical properties, PF will have a wider area of application than just as a blood substitute. Its infusion alleviates symptoms of ischemia in different types of occlusion vessels diseases, improves grafting in plastic surgery, diminishes inflammation and prevents rejection of transplan, activates detoxication functions of liver, and inhibits retrovirus infection development. Local PF application is able to accelerate wound and ulcer healing. REFERENCES
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