The protective effect of co-administration of platelet-rich plasma (PRP) and pentoxifylline (PTX) on cyclophosphamide-induced premature ovarian failure in mature and immature rats.

Cyclophosphamide (CP), as an antineoplastic agent, causes premature ovarian failure (POF) due to ovarian toxicity and subsequent infertility in women. Platelet-rich plasma (PRP) has accumulated significant attention in regenerative medicine. Pentoxifylline (PTX) as a methylxanthine derivative has been shown to have antioxidant and antiapoptotic properties. The aim of this study was to evaluate the protective effect of PRP and PTX on CP-induced POF. Fifty mature and immature female rats were assigned into five groups: control, CP (75 mg/kg, intraperitoneal [ip] on days 1 and 10 to induce POF), CP + PRP (200 µl, ip, half an hour after CP injection on day 1 and 10), CP + PTX (50 mg/kg, orally, half an hour after CP injection daily for 21 day), and CP + PRP + PTX. At the end of experiments on day 21, measurement of body weight, ovarian parameters (ovarian volume, follicular granulosa cell layers diameter, oocyte diameter, and the number of granulosa cells), measurement of ovarian hormone in sera for estradiol (E2), and anti-Mullerian hormone (AMH), as well as biochemical assessment were performed.The results showed that CP significantly reduced the ovarian parameters, E2, AMH, superoxide dismutase (SOD) activity and increased Malondialdehyde (MDA) levels compared to the control group (p < 0.001). Our results also indicated that all histomorphometric parameters and biochemical markers in CP-induced POF, were preserved close to normal by PRP and PTX treatments in both mature and immature rats (p < 0.001). Therefore, it is concluded that the co-administration of PRP and PTX can protect the ovary from CP-induced POF.

Microfluidic assemblies designed for assessment of drug effects on deformability of human erythrocytes.

Extreme deformability of human erythrocytes is a prerequisite for their ability to squeeze through narrow capillaries of the blood microcirculation system. Various drugs can modify this deformability and consequently provoke circulation problems. We demonstrate that microfluidic assemblies are very convenient platforms for in vitro study of the associated processes. Two types of microfluidic channels were designed to quantitatively investigate modifications of erythrocyte deformability induced by hydrogen peroxide, ethanol and pentoxifylline based on transit velocity measurements. With a high sensitivity our microfluidic assemblies show that hydrogen peroxide decreases erythrocyte deformability in a dose-dependent manner. Then, results on ethanol resolve a biphasic nature of this reactant on the deformability of single erythrocyte cells. Results on pentoxifylline provide evidence that, similar to ethanol, also this medical drug has a double-sided effect on the erythrocyte deformability, i.e. increasing the deformability at low concentrations, while decreasing it at higher ones. Taken together, our microfluidic designs propose a potent measurement method for the erythrocyte deformability, as well as providing a perspective to evaluate effects of drugs on it.

Is there any way to protect from tacrolimus-induced renal and pancreas injury?

BACKGROUND: The aim of this study was to explore effects of erythropoietin and pentoxifylline in tacrolimus-induced pancreatic beta cell and renal injury in rats. METHODS: Rats in group I were given saline; rats in group II were injected with tacrolimus; rats in group III were received erythropoietin (Epo) and tacrolimus; while rats in group IV were injected pentoxifylline (Ptx) plus tacrolimus for nine d. On 10th day, blood and tissue samples were taken for biochemical and pathological evaluations. RESULTS: Tacrolimus-injected animals exhibited significant elevation in blood urea nitrogen (BUN), and serum BUN levels were improved in rats pretreated with Ptx. Significantly more apoptotic nuclei were observed in kidneys of tacrolimus group. In rats subjected to tacrolimus and pretreated with Epo, there was significant decrease in apoptotic nuclei staining than those in tacrolimus group. Blood trough levels of tacrolimus were significantly higher in erythropoietin-pretreated group, although same amount of tacrolimus was injected with other groups. CONCLUSION: Results of our study demonstrated significant antiapoptotic effects of erythropoietin on renal tubules, increasing effect of erythropoietin on tacrolimus blood levels, and insignificant antioxidant effects of both erythropoietin and pentoxifylline on renal and pancreas tissues. Study with clinically greater tacrolimus levels may be useful to confirm these findings.

Potentiation of anticancer drugs: effects of pentoxifylline on neoplastic cells.

The drug efflux activity of P-glycoprotein (P-gp, a product of the mdr1 gene, ABCB1 member of ABC transporter family) represents a mechanism by which tumor cells escape death induced by chemotherapeutics. In this study, we investigated the mechanisms involved in the effects of pentoxifylline (PTX) on P-gp-mediated multidrug resistance (MDR) in mouse leukemia L1210/VCR cells. Parental sensitive mouse leukemia cells L1210, and multidrug-resistant cells, L1210/VCR, which are characterized by the overexpression of P-gp, were used as experimental models. The cells were exposed to 100 µmol/L PTX in the presence or absence of 1.2 µmol/L vincristine (VCR). Western blot analysis indicated a downregulation of P-gp protein expression when multidrug-resistant L1210/VCR cells were exposed to PTX. The effects of PTX on the sensitization of L1210/VCR cells to VCR correlate with the stimulation of apoptosis detected by Annexin V/propidium iodide apoptosis necrosis kit and proteolytic activation of both caspase-3 and caspase-9 monitored by Western blot analysis. Higher release of matrix metalloproteinases (MMPs), especially MMP-2, which could be attenuated by PTX, was found in L1210/VCR than in L1210 cells by gelatin zymography in electrophoretic gel. Exposure of resistant cells to PTX increased the content of phosphorylated Akt kinase. In contrast, the presence of VCR eliminated the effects of PTX on Akt kinase phosphorylation. Taken together, we conclude that PTX induces the sensitization of multidrug-resistant cells to VCR via downregulation of P-gp, stimulation of apoptosis and reduction of MMPs released from drug-resistant L1210/VCR cells. These facts bring new insights into the mechanisms of PTX action on cancer cells.

Phase I trial of escalating pentoxifylline dose with constant dose thiotepa.

Pentoxifylline, a methylxanthine, is an effective modulator of alkylating agents in tissue culture and in human tumor explants in mice. In this Phase I trial, escalating dose controlled release pentoxifylline was administered p.o. 3 times daily for 5 days (15 doses) with a constant dose of thiotepa, 40 mg/m2 i.v. on day 2. Forty-four courses of escalating doses of pentoxifylline varying from 400 to 2400 mg were administered to 22 patients with refractory malignancies. Gastrointestinal toxicity, consisting mainly of nausea and vomiting, was dose limiting at 2400 mg pentoxifylline and subsided completely within 24 h of cessation of the drug. Nongastrointestinal toxicity of this thiotepa/pentoxifylline combination was infrequent and included bone marrow depression and supraventricular tachycardia. Increasing the dose of pentoxifylline did not increase the frequency of these rare toxic effects. Plasma concentrations of pentoxifylline and its major metabolites were determined by gas chromatography. Drug accumulation was noted within a cycle (i.e., by day 5) in only two patients and between cycles in no patient. The recommended Phase II dose of p.o. pentoxifylline is 1600 mg (four 400-mg tablets) when given 3 times daily for 5 days (15 doses) with 40 mg/m2 i.v. thiotepa. Based on an interspecies comparison, this dose exceeds that predicted from mouse models to enhance chemotherapy. This regimen can be safely administered on an outpatient basis, with adequate control of gastrointestinal symptoms achieved by standard antiemetics and intermittent dosing with meals. Phase II trials are required to determine the activity of alkylator/modulator combinations.

Influence of pentoxifylline, A-802710, propentofylline and A-802715 (Hoechst) on the expression of cell cycle blocks and S-phase content after irradiation damage.

The toxicity of the five methylxanthine derivatives, caffeine, pentoxifylline, A802710, propentofylline and A802715, was determined against the two human melanoma lines, Be11 and MeWo, and against the two human squamous cell carcinoma lines, 4197 and 4451, by vital dye staining assay. Pentoxifylline and A802710 emerge as the least toxic showing TD(50) (toxic dose of 50%) levels of 3.0-4.0 mM. Propentofylline and caffeine take an intermediate position. A802715 has a TD(50) of 0.9-1.1 mM and is the most toxic. Subtoxic concentrations (

Pentoxifylline: its pharmacokinetics and ability to improve tumour perfusion and radiosensitivity in mice.

The pharmacokinetics of pentoxifylline and its three major metabolites were measured after intraperitoneal administration of 10 mg/g or 100 mg/kg of drug in C3H mice. Peak concentrations of pentoxifylline were approximately 10 and 100 micrograms/ml, respectively, with elimination half-lives (+/- 2 SE) of 4.6 (4.2-5.1) and 7.5 (7.2-7.9) min, respectively. Plasma concentrations of the pharmacologically active hydroxy metabolite were approximately one-tenth those of the parent compound. In vitro evidence of the ability of pentoxifylline to increase blood cell deformability indicates that concentrations of up to 30 micrograms/ml can increase deformability of both red and white blood cells; doses between 5 mg/kg and 100 mg/kg were therefore tested 15 min after administration to test the effect of the drug on tumour and normal tissue perfusion, tumour radiosensitivity and renal function immediately after exposure to appropriate drug concentrations. Using 86Rb extraction, doses of 10-100 mg/kg pentoxifylline were shown to increase relative tumour perfusion of the RIF-1 tumour to 140-170% of control, with no effect in skin, muscle, kidney, liver or lung, but with similar increases in spleen perfusion; there was no significant effect in any tissue after 5 mg/kg. Using a clonogenic assay, this increased tumour perfusion was shown to be reflected in increased tumour radiosensitivity to 25 Gy 15 min after pentoxifylline, with the same dose threshold of 10 mg/kg, and similar lack of dose-dependence at higher doses; the response indicated reduction in hypoxic fraction by a factor of 2-3. Renal function, measured by [51Cr]EDTA and [125I]iodohippurate clearance was unaffected at doses up to 50 mg/kg, with a slight effect at 100 mg/kg. The data indicate that pentoxifylline is effective at increasing relative tumour perfusion, with minimal effects on other tissues, and this increase is reflected in improved radiosensitivity. The doses at which the drug is effective are compatible with the mechanism being modification of blood cell deformability. Pentoxifylline shows promise as a clinical radiosensitiser acting by direct increase in tumour oxygenation.

Effects of pentoxifylline on inflammatory cytokine expression and acute pleuropneumonia in swine.

Pentoxifylline, a methylxanthine derivative and nonspecific type 4 phosphodiesterase inhibitor, has been used to improve survival of animals with sepsis and to attenuate lung injury in acute lung inflammation. The purpose of this study was to examine whether pentoxifylline would inhibit the expression of inflammatory cytokines, particularly tumor necrosis factor alpha (TNF), and thereby decrease the pathophysiology of acute porcine pleuropneumonia. E. coli lipopolysaccharide (LPS) and bacterial extracts of A. pleuropneumoniae--induced elevations in TNF mRNA which were fully abrogated by addition of pentoxifylline in both alveolar macrophage and neutrophil cultures. A 30% reduction in the level of LPS-induced interleukin (IL)-1beta mRNA levels also was achieved in macrophages. Pentoxifylline did not affect either IL-1alpha or IL-8 expression in vitro. Pentoxifylline therapy in vivo significantly reduced the number of band neutrophils in swine but did not reduce the pathology associated with pleuropneumonia, including changes in serum zinc, iron, or haptoglobin. Neither did it alter TNF, IL-1, IL-6, or IL-8 expression. Measurement of pentoxifylline and its metabolites in pig sera suggested that efficacious doses of pentoxifylline were probably not achieved in vivo. However, subcutaneous doses of pentoxifylline higher than 25 mg/kg produced transient diarrhea, vomiting, and tremors. These results suggest that pentoxifylline is an effective pharmacological tool for the dissection of cytokine regulation in vitro, but inhibitory concentrations may not be achievable for in vivo pharmacological use in swine.

A randomized placebo-controlled trial of lisofylline in HLA-identical, sibling-donor, allogeneic bone marrow transplant recipients. The Lisofylline Marrow Transplant Study Group.

The purpose of the study was to evaluate the effect of lisofylline (LSF) on engraftment, regimen-related toxicities (RRT), and mortality in patients undergoing allogeneic bone marrow transplantation (BMT). We performed a multicenter, randomized placebo-controlled trial in 60 patients with hematologic malignancies receiving BMT from HLA-identical sibling donors. Patients were randomized to receive either placebo, 2 mg/kg LSF or 3 mg/kg LSF every 6 h, beginning before conditioning and continuing to day 21 or hospital discharge. Treatment groups were balanced with respect to conditioning regimen and disease stage. However, significantly more patients in the 2 mg/kg LSF group were at high risk for RRT due to performance status >/=1, age >/=40 years, and prior exposure to CMV. Nausea and vomiting were the only adverse events observed in a higher proportion of LSF-treated patients that led to study withdrawal in six of 42 patients (14%). The times to neutrophil recovery to >/=500/microl and platelet recovery (>20 000/microl) were not improved by LSF treatment. Nevertheless, no patient who received treatment with 3 mg/kg LSF developed a documented infection between day 0 and 35 or had a serious or fatal infection between day 0 and 100 (P = 0.003 vs placebo for both). The day-100 survival rate was also significantly improved in the 3 mg/kg LSF group (89%), compared with either the 2 mg/kg LSF (48%) or placebo (61%) groups (log-rank test, 3 mg/kg LSF vs placebo, P = 0. 026). We conclude that treatment with LSF 3 mg/kg reduced the incidence of infections and improved 100-day survival in patients receiving related-donor allogeneic bone marrow transplantation. Bone Marrow Transplantation (2000) 25, 283-291.

Fluosol-DA/carbogen with lonidamine or pentoxifylline as modulators of alkylating agents in the FSaIIC fibrosarcoma.

In an effort to increase the efficacy of several antineoplastic alkylating agents (CDDP, L-PAM, CTX, or BCNU), we examined the effect of the modulator Fluosol-DA/carbogen in combination with a second modulator, either lonidamine or pentoxifylline, on the survival of FSaIIC tumor cells and of bone marrow CFU-GM from tumor-bearing C3H mice. Fluosol-DA/carbogen increased the tumor-cell killing activity of each alkylating agent by about 10 times. In contrast, lonidamine alone did not significantly increase the cytocidal activity of any of the alkylating agents tested. However, in combination with Fluosol-DA/carbogen, the use of lonidamine produced about a 100-fold increase in the tumor cell kill achieved with CDDP as compared with CDDP alone. No increase in tumor cell kill over that produced with the single modulator Fluosol-DA/carbogen was seen following the addition of lonidamine to the combination treatment with L-PAM, CTX, or BCNU. Unfortunately, although neither lonidamine nor Fluosol-DA/carbogen alone significantly increased alkylator toxicity to bone marrow CFU-GM, the combination of modulators increased the toxicity of each alkylating agent to bone marrow by about 10 times. Pentoxifylline caused an increase in alkylator activity against the FSaIIC fibrosarcoma only when used with BCNU; this effect was further augmented by the addition of Fluosol-DA/carbogen. The combination of modulators pentoxifylline plus Fluosol-DA/carbogen was more effective than Fluosol-DA/carbogen alone only when the former was used with BCNU, whereas only minimal increases in tumor-cell killing activity were obtained with this modulator combination and CDDP, L-PAM, or CTX. Pentoxifylline increased the bone marrow CFU-GM toxicity of L-PAM by about 10 times. The bone marrow CFU-GM toxicity was further increased by Fluosol-DA/carbogen, as was the toxicity of each of the other alkylating agents. Lonidamine plus Fluosol-DA/carbogen may be useful in increasing the therapeutic efficacy of CDDP, and the combination of pentoxifylline plus Fluosol-DA/carbogen might improve the antitumor activity of BCNU.

Differential responses of human sperm to varying concentrations of pentoxyfylline with demonstration of toxicity.

Pentoxyfylline (PF), a methylxanthine derivative, is an inhibitor of the cAMP-phosphodiesterase enzyme, and is known to stimulate the motility of fresh and post-thaw human sperm. The purpose of this study was to examine the effects of different concentrations of PF on motility (MOT), path (curvilinear) velocity (PV), and hyperactivation (HA) of fresh sperm from patients (n = 24) and donors (n = 6) and post-thaw donor sperm (n = 5). For cryopreservation, the donor semen was frozen in liquid nitrogen using test-yolk-glycerol cryopreservative, stored for a minimum of 48 hours, then thawed at room temperature prior to assay. Aliquots of all samples to equal 10 x 10(6)/ml were diluted in 1 ml of the following: medium (human tubal fluid) only (control), or 2.5, 5, 10, or 20 mg/ml PF in medium. Specimens were incubated at 37 degrees C, and all were assessed by computer-assisted motion analysis at 0, 0.5, 1, and 2 hours. The patient specimens were divided into two groups: group 1, mean percent (standard deviation [SD]) MOT < 20% (12.8 +/- 5.8); group 2, mean percent (SD) MOT > 20% (37.8 +/- 14). For fresh donor sperm, 2.5 mg/ml PF significantly stimulated PV and HA at 0, 1, and 2 hours, and MOT at 0, 0.5, and 2 hours. PF at 5 mg/ml resulted in a decreased PV and HA, whereas MOT was decreased by 10 mg/ml. In the < 20% MOT group, 2.5 mg/ml PF significantly stimulated MOT at 0.5, 1, and 2 hours, and HA at 0 and 2 hours. There was no effect on PV.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of pentoxifylline as a modulator of alkylating agent activity in vitro and in vivo.

Pentoxifylline, a methylxanthine that is used to treat veno-occlusive disease, can increase perfusion in undervascularized tissues. Addition of high concentrations, like caffeine, causes progression through radiation or drug induced G2 phase blocks, thereby limiting time for repair of DNA breaks and crosslinks. We have examined the potential of pentoxifylline to augment the effects of antitumor alkylating agents in vitro and in vivo. In MCF-7 human breast cancer cells in vitro, pentoxifylline (2 mM) present for 24 h was only slightly cytotoxic (approximately 10% cell kill at 2 mM), but when present prior to and during AA it increased the cytotoxicity of CDDP by 2 logs at 250 microM. With L-PAM in vitro, pentoxifylline was much less effective and only at a concentration of 250 microM L-PAM did 2 mM pentoxifylline increase cytotoxicity (approximately 0.3 logs). In the FSaIIC murine fibrosarcoma system, 100 mg/kg of pentoxifylline i.p. immediately prior to the alkylating agent or 50 mg/kg x 5 of pentoxifylline over 24 h with the alkylating agent given immediately after the third dose increased the tumor cell kill achieved by CDDP, carboplatin, cyclophosphamide, and thiotepa. The increase in tumor cell killing was modest (2.9-fold). Pentoxifylline in the multiple dose regimen (50 mg/kg x 5 over 24 h) was more effective than in the single dose (100 mg/kg) protocol. In the EMT6 mouse mammary adenocarcinoma, pentoxifylline (100 mg/kg daily x 5) improved the tumor growth delay produced by CDDP (3.3 mg/kg alternate days x 3), carboplatin (25 mg/kg daily x 5), cyclophosphamide (100 mg/kg alternate days x 3) and thiotepa 5 mg/kg (daily x 5). Only with cyclophosphamide, however, did the interaction appear to be large, as a 2.4-fold increase was observed.

Assessment of toxicity, clastogenicity, mutagenicity and transforming activity of pentoxifylline in mammalian cells cultured in vitro.

We tested the possible cytotoxic, clastogenic and genotoxic effects of pentoxifylline on different lines of mammalian cells cultured in vitro. This study was part of the developmental research of agapurin, since pentoxifylline represents an effective compound of this drug. Cells treated for a short time manifested a relatively high resistance to the toxic effects of pentoxifylline. Generally, only cells treated for a long time (18 h) or a short time (2 h) with high concentrations of drug manifested sensitivity to the toxic effects of pentoxifylline. Although the tested drug induced DNA synthesis inhibition in V79 and EUE cells and clastogenic effects in V79 cells, it was not able to induce either 6-TGr mutations in the HGPRT locus of V79 cells or morphological transformation of Syrian hamster embryo cells. Adding of microsomal fraction S9 to the treated cells did not markedly change the effects of pentoxifylline on different studied endpoints. We suggest that pentoxifylline has no genotoxic effects, and that the cytotoxicity and induction of chromosomal aberrations were induced by inhibition of cellular DNA replication.

Chromosomal aberrations, sister chromatid exchanges and micronuclei induced by pentoxifylline in in vitro cultivated Chinese hamster cells (V79) and human blood lymphocytes.

Pentoxifylline (PTX) is a methylxanthine widely used in clinical practice. The mechanism of PTX effects on cellular and molecular level have not been fully explained yet. The present study was carried out to investigate the cytogenetic effect of this drug using cultured Chinese hamster V79 cells and human blood lymphocytes in vitro. The occurrence of chromosomal aberrations (CA), sister chromatid exchanges (SCE) and micronuclei (MN) was observed after the treatment of cells by different concentrations (0.002-2.0mg/ml) of PTX. In exposed V79 cells and lymphocytes as well, the dose-dependent increases of the above mentioned cytogenetic endpoints were found. The statistically significant increase has appeared at lower PTX concentrations in human lymphocytes than in V79 cells in all the investigated parameters. Our results show that, the applied concentrations of PTX has the clastogenic effect on in vitro cultured V79 cells and human lymphocytes. These findings are notable because of the frequent use of this drug and may serve as preliminary data to the further detailed examination of PTX action on molecular level.

Toxicity of pentoxifylline on monolayers of highly proliferative cells of epithelial origin.

Interest in pentoxifylline has been recently reawakened owing to its suppressive effect on cell cytokine production. In this capacity, it may be of value as a routine supplement for culture media containing donor corneas. The purpose of the present study was to evaluate the toxic effects of pentoxifylline on two standardized cell lines of epithelial origin. Vero and Chang cells were incubated with various concentrations of pentoxifylline. Acute toxicity (4 hr) was assessed by monitoring the permeability of cells to propidium iodide; chronic toxicity (7 days) was determined by monitoring the effect of pentoxifylline on esterase activity and cell proliferation. The viability of cells was also assessed by microscopic inspection. Signs of acute toxicity became manifest at a pentoxifylline concentration of 100 mg/l in both Chang and Vero cells. Indications of chronic toxicity were observed at a drug concentration of 10 mg/l in Chang cells but at 1 mg/l in Vero ones. Proliferation was suppressed at pentoxifylline concentrations of 100 mg/l and 10 mg/l in Chang and Vero cells, respectively. Degenerative morphological changes were observed at a drug concentration of 100 mg/l in both cell types. At a concentration of 0.1 mg/l, pentoxifylline elicited no signs of acute or chronic toxicity in either Chang or Vero cells. At this dose, the drug is therefore unlikely to have deleterious effects on cultured donor corneas.

[Effect of pentoxifylline on the vascular toxicity secondary to cyclosporine in rats]. / Influence de la pentoxifylline sur la toxicité vasculaire secondaire à la cyclosporine chez le rat.

Chronic administration of cyclosporine (CyA) has been shown to affect local vascular tone. Pentoxifylline (PTX), a xanthine-derived vasoactive agent, has been reported to prevent CyA toxicity but its effect on CyA-related increased vascular tone remains uncertain. In vitro experiments were designed to study the effects of PTX on endothelium-dependent and independent vasorelaxation of the rat thoracic aorta. Three groups of rats (n = 10) were respectively treated for 4 weeks with CyA (30 mg/kg/day), CyA and PTX (40 mg/kg/day), and CyA and PTX (80 mg/kg/day). At the end of the period, rings (4-5 mm) of aorta were harvested and suspended in organ chambers containing Krebs Ringer solution (37 degrees C, 95% O2, 5% CO2) for assessment of endothelial and smooth muscle reactivity. Endothelium-dependent relaxation to acetylcholine was significantly enhanced in animals treated with CyA and PTX (40 mg/kg/day) compared to those exposed to CyA alone (p < 0.05). Response to histamine and adenosine diphosphate was not affected. However, the use of PTX (80 mg/kg/day) significantly deteriorated the endothelial response to the same drugs (p < 0.05) suggesting a detrimental effect of PTX at this concentration. Endothelial-independent relaxation to sodium nitroprusside was comparable in all groups. The results suggest the clinical benefit reported with the use of PTX on patients chronically exposed to CyA may partly be due to an improvement of the vascular endothelial function. However, the toxicity encountered at high dose should cautioned its use in clinical setup.

Distribution and metabolism of pentoxifylline in non-tumor-bearing mice.

Pentoxifylline increases tissue oxygen delivery in patients with atherosclerotic arterial disease by several mechanisms, including lowering blood viscosity and increasing erythrocyte flexibility. Since tumor neo-vessels are also abnormal and associated with intra-tumoral hypoxia and, thus, with radiation failure, pentoxifylline might also be useful as a radiation sensitizer. The mouse is frequently used to study such drugs, but the pharmacokinetics of pentoxifylline in the mouse have not been determined. We investigated this in three separate experiments by administering pentoxifylline intraperitoneally, subcutaneously, or orally. Plasma was assayed for the parent drug and its metabolites by capillary gas chromatography. High plasma levels of pentoxifylline and both major derivatives occurred within several minutes after intraperitoneal or subcutaneous injection, but plasma levels were low after oral administration.

[Experimental research on the toxicity of pharmapentoxifylline (II)]. / Eksperimentalni prouchvaniia vurkhu toksichnostta na farmapentoksifilin (II suobshtenie).

The results from morphological studies on liver, lung, heart, spleen, intestine, brain, skin, testes (ovaries), obtained in the end of the first and third month of animals, treated with pharmapentoxiphyline (PP), are described. The experiments were carried out on 312 white rats (male and female), divided into 2 series: I series--oral usage of the preparation in doses of 100, 300 and 6 mg/kg, II series--intraperitoneal administration in doses of 30, 75 and 150 mg/kg. It was established that PP, administered for a period of 3 months orally in a dose of 100 mg/kg and intraperitoneally in a dose of 30 mg/kg did not induced changes in the structure of all examined organs. Slight dystrophic changes in liver, lung and spleen occurred in the end of the third month under the influence of an oral dose of 300 mg/kg and an intraperitoneal dose of 75 mg/kg. The obtained results are discussed in connection with the pharmacological action of drug-peripheral vasodilatator.

[Effects of pentoxifylline on 5-hydroxytryptamine in the mouse brain].

Effects of combined administration of pentoxifylline (PTX) and precursors of 5-hydroxytryptamine (5-HT) on behavior and cerebral contents of 5-hydroxytryptophan (5-HTP), 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were examined in mice. The intraperitoneal administration of PTX at 100 mg/kg to mice pretreated with pargyline (100 mg/kg, i.p.) significantly increased the frequency of head twitches induced by 5-HTP (25 mg/kg, i.p.), and the effect of PTX was approximately 2 times more potent than that of other methylxanthines. In these mice, the cerebral contents of 5-HTP, 5-HT and 5-HIAA were also elevated significantly. However, PTX itself had no effect to induce head twitch response or to increase the contents of the indoles in mice. When administered in combination with tryptophan (100 mg/kg, i.v.) to pargyline-pretreated mice, PTX (100 mg/kg, i.p.) did not affect the contents of the indoles in the brain. These results suggest that PTX may have an effect to promote transport of exogenous 5-HTP into the neurons, besides the 5-HT turnover-increasing effect common to methylxanthine derivatives.

[Experimental research on the toxicity of pharmapentoxifylline (I)]. / Eksperimentalni prouchvaniia vurkhu toksichnostta na farmapentoksifilin (I suobshtenie).

Results from the study on acute, subacute and chronic toxicity of the therapeutic preparation pharmapentoxiphyline (PP), produced by Pharmachem, are described. The experiments were carried out on 312 male and female white rats. According to the limiting index of LD50 with, Oral dose of (1220 mg/kg of body mass for male rats and 1050 mg/kg for female rats) and intraperitoneal PP dose of PP (230 mg/kg for female rats and 235 mg/kg for female rats) it was included into IV class of slightly toxic compounds. Doses of 100, 300 and 600 mg/kg/oral administration) and 30, 75 and 150 mg/kg (intraperitoneal administration) were used in subacute and chronic experiments. Integral, hematological and biochemical methods and parameters were applied for evaluation of the toxic effect. There was no hemato-, hepato- and nephrotoxicity after oral and intraperitoneal administration of PP in doses of 10 and 30 mg/kg for a period of 3 months. Some recommendations, which should be taken into consideration during continuous treatment with PP, are given on the basis of a complex evaluation of the results from the hematological parameters.