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PubMed2006

Suppression of angioplasty-related inflammation by pre-procedural treatment with trimetazidine.

Percutaneous transluminal coronary angioplasty (PTCA) has been recognized as a reliable treatment procedure for acute reversible ischemia and reperfusion. Ischemic reperfusion cycle in PTCA leads to the systemic inflammation and extensive tissue injury by the production of reactive oxygen species including nitric oxide (NO) radicals. In patients with coronary artery disease, undergoing PTCA, the effects of trimetazidine (TMZ), a piperazine-derivative anti-anginal drug, were studied on several indirect markers of systemic inflammatory response: tumor necrosis factor-alpha (TNF-alpha), C-reactive protein (CRP) and NO products (nitrite and nitrate). Patients (n = 11 each group) were untreated or pre-treated with TMZ (20 mg per orally three times a day), begun three days prior to PTCA, and marker levels were measured before the start of TMZ therapy (baseline), just before PTCA (0 hr), and 4, 24, and 48 hrs after PTCA. The baseline levels of markers were not significantly different between the untreated and pre-treated patients. In contrast, all parameters were lower in the TMZ-treated group than those in the matched control group in the pre- and post-angioplasty periods. Interestingly, in the TMZ group, CRP and nitrite levels were significantly lower than in the control group at each time point of the pre- and post-angioplasty periods, but the TNF-alpha levels were significantly decreased only in the post-angioplasty period. Pre-procedural treatment with oral TMZ for three days significantly suppressed the elevation of inflammatory markers before and shortly after PTCA. We suggest the usefulness of TMZ in preventing inflammatory cardiovascular events after PTCA.

Aged↗
PubMed2000

Temozolomide, a novel alkylating agent with activity in the central nervous system, may improve the treatment of advanced metastatic melanoma.

Temozolomide (TMZ) is the first new chemotherapy agent to be approved for the treatment of high-grade malignant gliomas in more than 20 years. This novel oral alkylating agent has demonstrated promising activity not only in brain tumors, but in a variety of solid tumors, including malignant melanoma. TMZ is 100% bioavailable when taken orally and, because of its small size and lipophilic properties, it is able to cross the blood-brain barrier. Concentrations in the central nervous system are approximately 30% of plasma concentrations. Once it has entered the central nervous system, TMZ can be spontaneously converted to the active metabolite. These pharmacologic properties make it an ideal agent for treating central nervous system malignancies. In patients with advanced metastatic melanoma, brain metastases are a major cause of treatment failure. In this setting, TMZ has been shown to be as effective as dacarbazine, with a similar safety profile. More importantly, there is evidence to suggest that TMZ-treated patients have a lower incidence of central nervous system relapse compared with dacarbazine-treated patients. Therefore, TMZ is actively being investigated for the treatment and prevention of brain metastases in melanoma patients. TMZ may become an important part of treatment regimens for advanced metastatic melanoma.

Administration, Oral↗
PubMed2026

ERP44 Is Associated With Poor Prognosis and Promotes Proliferation and Temozolomide Resistance in Lower-grade Glioma.

BACKGROUND/AIM: Endoplasmic reticulum resident protein 44 (ERP44), a protein disulfide isomerase family member, has been implicated in tumor biology, but its role in lower-grade glioma (LGG) remains unclear. This study investigated the prognostic significance and biological function of ERP44 in LGG, focusing on proliferation and temozolomide (TMZ) resistance. MATERIALS AND METHODS: ERP44 expression, clinicopathological associations, and prognostic value were analyzed using The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Chinese Glioma Genome Atlas (CGGA) datasets. Time-dependent receiver operating characteristic (ROC) curves, Cox regression, and a prognostic nomogram were constructed. Differential expression, Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO) enrichment, immune infiltration, and drug sensitivity analyses were performed. Functional validation was conducted in SW1088 and SW1783 cells using shRNA-mediated ERP44 knockdown, followed by RT-qPCR, western blotting, CCK-8, colony formation, and TMZ IC50 assays. Subcutaneous xenograft models with or without TMZ treatment were used for in vivo validation. RESULTS: ERP44 was markedly upregulated in LGG and associated with higher WHO grade, IDH wildtype status, 1p/19q non-codeletion, and poor survival in TCGA and CGGA cohorts. ERP44 showed strong prognostic performance and improved risk stratification in a multivariable nomogram. Enrichment analyses linked high ERP44 expression to immune/inflammatory pathways and reduced neuronal functional signatures. ERP44 positively correlated with immune infiltration, proliferation/stemness markers, and predicted TMZ resistance, while its knockdown inhibited proliferation and colony formation, reduced TMZ IC50, suppressed xenograft growth, enhanced TMZ efficacy, and decreased Ki67 positivity. CONCLUSION: ERP44 is a prognostic biomarker that promotes LGG proliferation and TMZ resistance, suggesting its potential as a therapeutic target.

Humans↗
PubMed2002

Base excision repair as a therapeutic target in colon cancer.

Base excision repair (BER) is a fundamental cellular process used to reduce the cytotoxicity of alkylating agent chemotherapy. Heretofore, no therapeutic agents have targeted this DNA repair pathway. Methoxyamine (MX), which binds abasic sites, acting as an inhibitor of BER, was evaluated in combination with the methylating agent temozolomide (TMZ). Three human colon cancer cell lines were used, SW480 cells, which are wild-type for mismatch repair genes and have mutated p53, HCT116 cells, which are mutant in hMLH1 and wild-type for p53, and HCT15 cells, which are mutant in hMSH6 and mutant in p53 as well. Nude mice carrying these tumors received TMZ alone or in combination with MX or O(6)-benzylguanine (BG), an inhibitor of O(6)-alkylguanine DNA-alkyltransferase, daily i.p. for 5 consecutive days. At the highest tolerable dose of TMZ (120 mg/kg), a tumor growth delay of approximately 9.3 +/- 1.2 days was noted in SW480. Addition of BG resulted in a tumor growth delay of 25 +/- 2.4 days accompanied by significant weight loss (23%) and severe myelosuppression. In contrast, SW480 tumor-bearing mice treated with MX + TMZ had cessation of tumor growth for 50 +/- 13 days and very slow regrowth, yielding tumor growth delays of >70 +/- 14 days (P < 0.002) without additive systemic toxicity. HCT116 and HCT15 xenografts were completely resistant to treatment with TMZ alone or in combination with BG. However, treatment with MX + TMZ induced significant tumor growth delays (20 +/- 1.4 days in HCT116 and 14 +/- 3.1 days in HCT15 xenografts, P < 0.05). These studies demonstrate that a significant enhancement of the antitumor effect of TMZ by MX was observed in human colon cancer xenografts with mismatch repair proficiency and deficiency. DNA BER may be a useful pharmacological target through which tumor cells can be sensitized to alkylating therapeutic agents.

Animals↗
PubMed2005

Mitochondrial changes induced by trimetazidine in the myocardium.

BACKGROUND: The aim was to assess the effect of trimetazidine (TMZ) on mitochondrial alterations induced in a canine model of brief, repeated episodes of ischemia. MATERIAL/METHODS: Twelve crossbred dogs were analyzed, after double-blind randomization, to a 7-day treatment with either TMZ or placebo. Twenty brief, complete occlusions of the left anterior descending coronary artery were performed. Mitochondrial analysis entailed a qualitative (percentage of mitochondrial damage, merging, pairing, vacuoles, and lipofucsin granules) and a quantitative size analysis (major and minor axes, perimeter, and area) of the mitochondria in the ischemic and control zones. RESULTS: Comparative study of the control zones revealed an increase in lipofucsin granules in the TMZ series and a greater percentage of damaged mitochondria and vacuoles. The control-zone mitochondria treated with TMZ presented a significant increase in the perimeter and major axis and a decrease in the minor axis (p<0.005). No significant differences were found between the series in the qualitative analysis of mitochondrial damage in the ischemic zone. The mitochondria in the TMZ series presented a greater major axis and perimeter than those in the placebo series (p<0.05), which presented a smaller minor axis. CONCLUSIONS: TMZ made the mitochondria adopt an elongated, "rod-like" morphology in both the control and ischemic zones. This is interpreted as an increase in the membrane surface. In the non-ischemic zone, TMZ produced an increase in mitochondrial turnover. There were no differences in the myocardium subjected to ischemia in both series in terms of observable mitochondrial damage.

Animals↗
PubMed1976

The actions of trimetazidine on nerve and muscle cells in frogs.

The effect of trimetazidine (TMZ) on cardiac, skeletal muscle fibres and sympathetic ganglion cells in frogs were studied. In cardiac muscles, the contraction was depressed and the duration of action potentials were shortened by 1.5 mM TMZ. In skeletal muscles, the contraction induced by motor nerve stimulations was depressed by 0.3 mM TMZ, and the amplitude of end-plate potentials was decreased under this condition. The nicotinic transmission in sympathetic ganglia was inhibited by 0.003 mM TMZ, but the muscarinic transmission was not affected by 1.5 mM TMZ. In a Na-free TEA solution, prolonged action potentials (TEA potentials) of sympathetic ganglion cell, which appeared to be produced by an inward Ca movement across the membrane, were shortened by 1.5 mM TMZ. These results suggest that TMZ has a dual action, namely 1) a blocking action of nicotinic transmissions and 2) a blocking action of Ca movement during the generation of action potentials.

Action Potentials↗
PubMed1997

Pharmacokinetics of 3-methyl-(triazen-1-yl)imidazole-4-carboximide following administration of temozolomide to patients with advanced cancer.

The antitumor activity of temozolomide (TMZ) is believed to arise via formation of the reactive, alkylating metabolite 3-methyl-(triazen-1-yl)imidazole-4-carboximide (MTIC), which is produced by chemical hydrolysis of the parent drug. MTIC has not been quantitated in plasma or urine following administration of TMZ to patients. We developed a sensitive, specific method for the determination of MTIC levels in plasma, based on reverse-phase high-pressure liquid chromatography of the supernatant that is obtained by methanol precipitation of plasma proteins. Due to poor stability under physiological conditions, determination of MTIC required rapid specimen processing, precipitation of plasma proteins with methanol, and storage of the methanolic supernatant at -70 degreesC. The pharmacokinetics of MTIC were studied in 15 patients who received 125-250 mg/m2 TMZ. Peak plasma concentrations of 0.07-0.61 microgram/ml MTIC were observed approximately 1 h after a p.o. dose of TMZ. Appearance and disappearance (t1/2, 88 min) of the reactive metabolite paralleled the appearance and disappearance of TMZ in plasma. The mean values of the metabolite peak plasma concentration and AUC were 2.6% (range, 1.6-4.6%) and 2.2% (range, 0.8-3.6%), respectively, of the values for TMZ. MTIC did not accumulate in plasma following five consecutive daily doses of TMZ.

Adult↗
PubMed1984

Prophylaxis of fever and infection in adult cancer patients. A placebo-controlled trial of oral trimethoprim-sulfamethoxazole plus erythromycin.

Oral trimethoprim-sulfamethoxazole (Bactrim) plus erythromycin (TMZ-E) was tested versus placebo (P) as prophylaxis for bacterial infection in a randomized, double-blind trial in adult cancer patients receiving cytotoxic chemotherapy expected to result in significant neutropenia. The incidence of adverse reactions attributable to TMZ and/or E was higher in drug-treated episodes (18 of 28 vs 3 of 29 for P, P less than 0.0005) resulting in poorer compliance. The incidence of fever was not significantly different between episodes treated with TMZ-E (18/27) and those treated with P (17/29), nor was there a significant difference in the median interval between the onset of neutropenia and the onset of fever. However, 14 of 18 fevers in TMZ-E recipients were without a documented infectious source compared with only 6 of 17 in P recipients (P less than 0.05). The same patterns were apparent even when episodes in which compliance with the regimen was either excellent or good were considered separately. There was no significant difference in the number of deaths from infection between TMZ-E and P recipients (3/27 vs 1/29). It is concluded that TMZ-E prophylaxis is of no practical benefit, may mask the cause of infection in febrile neutropenic cancer patients, and is associated with substantial toxicity.

Adolescent↗
PubMed1994

Hydrolysis of temazepam in simulated gastric fluid and its pharmacological consequence.

Temazepam (TMZ), a hypnotic and anxiolytic drug, underwent hydrolysis in simulated gastric fluid (SGF; pH 1.2). The hydrolysis reaction of TMZ in acetonitrile:SGF (1:19 v/v) at 37 degrees C was an apparent first-order reaction, with a half-life of 5.47 +/- 0.17 h (i.e., approximately 12% of the remaining TMZ was hydrolyzed per hour). The predominant hydrolysis product (2'-benzoyl-4'-chloro-N-methyl-2-amino-2-hydroxyacetanilide) and a minor hydrolysis product [2-(methylamino)-5-chlorobenzophenone], derived from acid-catalyzed reaction of TMZ in an aqueous solution, were characterized by ultraviolet-visible absorption mass, infrared, and proton nuclear magnetic resonance spectra analyses. The kinetics of the hydrolysis reaction were studied as a function of acid concentration, temperature, and ionic strength and in deuterated solvent. Results indicated that the predominant hydrolysis reaction at pH approximately pKa (1.46) was caused by protonation at N4, followed by a nucleophilic attack by water at C5 of the C5-N4 iminium ion and a subsequent ring-opening reaction. Pharmacological activity tests in mice indicated that the predominant hydrolysis product of TMZ was inactive. The results suggest that a fraction of an orally taken TMZ may be inactivated by hydrolysis in the highly acidic gastric fluid.

Animals↗
PubMed1999

Cytoprotective effect of trimetazidine on 60 minutes of intestinal ischemia-reperfusion injury in rats.

Trimetazidine (TMZ), a potent antioxidant agent, has been used to protect the myocardium, liver and kidney from ischemia reperfusion (IR) injury. We investigated the effect of TMZ, a cellular anti-ischemic agent and a free radical scavenger, on 60 min of warm intestinal IR injury in rats. Sprague-Dawley rats were divided into three groups: a sham-operated group (no IR injury, n = 8), an ischemic control group (control, n = 8), and a TMZ-treated group (3 mg/kg, n = 8). Malondialdehyde (MDA) levels, myeloperoxidase (MPO) activity, and mucosal damage were investigated after 120 min of reperfusion. MDA levels and MPO activity were more elevated and histopathological damage more severe in the control group than in the sham group (P < 0.05). MDA levels and MPO activity were lower and there was less histopathological damage in the TMZ group than in the control group (P < 0.05). Accumulation of lipid peroxidation products and neutrophils in mucosal tissues were significantly inhibited by TMZ treatment. We conclude that pretreatment of rats with TMZ before intestinal ischemia attenuates but does not prevent, histological damage.

Animals↗
PubMed2006

Role of temozolomide in pediatric brain tumors.

FEATURES OF TEMOZOLOMIDE: Temozolomide (TMZ) belongs to the imidazotetrazine class and it is a DNA-methylating agent that has a good antitumor activity. Despite of dacarbazine, TMZ is spontaneously converted into its active metabolite 5-(3-methyltriazen-l-yl)imidazole-4-carboxamide at physiologic pH, so it is not required in enzymatic demethylation in the liver. TMZ is able to cross the blood brain barrier and is stable at gastric acid pH so it has almost 100% oral bioavailability and is rapidly absorbed after it is taken orally. TEMOZOLOMIDE IN CANCER PATIENTS: On the basis of the relatively safe toxicity and the findings achieved in adult malignant gliomas, phase I and II clinical trials were set up to evaluate the opportunity of using this novel drug in pediatric cancer, too. In this review, we evaluate the antitumor activity of TMZ against high-grade gliomas, low-grade-gliomas, and medulloblastoma/primitive neuroectodermal tumors analyzing several phases I and II clinical trials in children. CONCLUSIONS: In spite of the poor activity of TMZ against pediatric brain tumors, the use of the drug in combination with other compounds should be evaluated in phases I and II clinical trials. Moreover, the evaluation of the methylation status of the O6-methylguanine DNA methyltransferase promoter in glioblastoma biopsy specimens could be assayed as a predictive factor of TMZ efficacy.

Antineoplastic Agents, Alkylating↗
PubMed2002

Temozolomide and whole brain irradiation in melanoma metastatic to the brain: a phase II trial of the Cytokine Working Group.

PURPOSE: To evaluate the antitumor effects and toxicities of whole brain irradiation (WBI) with temozolomide (TMZ) administered by prolonged oral dosing in patients with melanoma metastatic to the brain. BACKGROUND: Patients with melanoma metastatic to the central nervous system (CNS) have an extremely poor prognosis and appear to benefit little from WBI. TMZ is an alkylating agent chemically similar to dacarbazine (DTIC) with good oral bioavailability and CNS penetration. TMZ has broad preclinical antitumor activity which in melanoma is comparable to that of DTIC. The combination of TMZ and WBI may provide enhanced antitumor activity against CNS metastasis from melanoma. PATIENTS AND METHODS: Patients with measurable CNS metastases with or without systemic disease were treated with WBI, 30 Gray over ten fractions (days 1-5 and 8-12). TMZ, 75 mg small middle dotm(2 small middle dot)day, was started on day 1, continued daily for 6 weeks and repeated every 10 weeks. RESULTS: Thirty-one patients were treated. There was one CNS complete response of 4.5 months and two CNS partial responses of 2 months and 7 months duration; the latter patient also had a 4-month complete remission of systemic metastases. Toxicities were limited to a single episode of grade 3 transaminase elevation and two episodes of grade 3 neutropenia, one complicated by fatal sepsis. The median progression-free interval for both CNS and extracranial sites was 2 months (range 1 week-11 months), and median survival 6 months (range 2-12 months). CONCLUSIONS: WBI has lower than expected activity in CNS metastasis of malignant melanoma. Although TMZ can be safely administered with WBI, the combination has limited anti-tumor activity.

Administration, Oral↗
PubMed2006

Temozolomide treatment for newly diagnosed anaplastic oligodendrogliomas: a clinical efficacy trial.

PURPOSE: Chemotherapy with alkylating agents is of proven efficacy in recurrent anaplastic oligodendroglioma (AO) with reported response rates ranging between 50% and 70%. The response of newly diagnosed AO to initial treatment with temozolomide (TMZ) has not yet been reported. This study evaluated the response and time to tumor progression of newly diagnosed AO initially treated with TMZ. PATIENTS AND METHODS: Twenty patients with a median age of 47 (range: 26-65) received a median of 14 (range: 3-24) cycles of TMZ as their first modality of therapy following diagnosis of AO. Treatment was given every 28 days for 5 days at a starting dose of 200 mg/m2/d and was continued for 24 cycles unless toxicity or tumor progression required withdrawal of TMZ. MRI evaluations were repeated every 8 weeks and scales of Karnofsky performance status (KPS) and of neurological function were used to assess clinical response. RESULTS: Clinical improvement was observed in 60% of the patients with statistically significant gain measured by KPS and the neurologic function scales. The objective response rate was 75%, and median time to tumor progression was 24 months. Maximal objective response was reached within a median of 6 months (range: 3-12). Tumors with 1p loss had longer progression free survival compared to tumors without deletions (PFS at 24 months: 1p LOH = 100%, 1p intact = 20%; P = 0.057). TMZ was well tolerated with only two events of grade 3/4 hematological toxicity. CONCLUSIONS: Newly diagnosed AO demonstrates a high rate of response to initial therapy with TMZ, similar to the response reported for PCV combination therapy. Further studies are needed to determine the optimal duration of treatment and whether radiotherapy should immediately follow chemotherapy.

Adult↗
PubMed2004

Temozolomide is a novel regional infusion agent for the treatment of advanced extremity melanoma.

BACKGROUND: Regional infusion therapy with melphalan (LPAM) is an accepted treatment for advanced extremity melanoma. However, much room exists for improving the therapeutic index of this type of therapy. METHODS: Isolated limb infusion (ILI) with temozolomide (TMZ), a novel methylating agent, was performed using a nude rat bearing human melanoma xenograft. Additional rats were treated systemically with TMZ, or regionally with LPAM or 10% dimethyl sulfoxide (DMSO; control) using ILI. RESULTS: Rats that received systemic TMZ showed a poor tumor response and no tumor regression. In contrast, intra-arterial TMZ demonstrated a prolongation of tumor growth delay in a dose-responsive manner. In comparison with LPAM of equitoxic dose, TMZ provided both longer tumor growth delay and a greater number of tumor regressions. CONCLUSIONS: These data suggest that ILI with TMZ is an effective treatment for advanced extremity melanoma and may be better than LPAM in this setting.

Analysis of Variance↗
PubMed2006

Effect of trimetazidine on the nucleotide profile in rat kidney with ischemia-reperfusion injury.

Ischemia-reperfusion injury is often responsible for delayed graft function after transplantation. Trimetazidine (TMZ) is an antioxidant agent used to protect grafts from ischemia-reperfusion injury. The aim of the study was to examine the effect of TMZ on nucleotide profile in rat kidney with ischemia-reperfusion injury. The study was carried out on Wistar rats divided into two groups: animals treated with TMZ and control group receiving placebo. TMZ 10mg/kg/day was administrated for 30 days. Concentrations of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), adenosine (Ado), guanosine triphosphate (GTP), guanosine diphosphate (GDP), guanosine monophosphate (GMP), guanosine (Guo), inosine monophosphate (IMP), inosine (Ino), hypoxanthine (Hyp), xanthine (Xan), uric acid (UA), uridine (Urd), nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) were determined in kidney tissues after ischemia-reperfusion using HPLC. The total adenine nucleotide concentration (TAN) and adenylate energy charge (AEC) were also determined. Moreover the kidneys were evaluated histologically. Tissue concentrations of ATP, ADP, AMP, TAN and AEC were significantly increased in kidneys from rats treated with TMZ in comparison with rats receiving placebo. Concentrations of products of nucleotide degradation: inosine (Ino), guanosine (Guo) and uridine (Urd), as well as oxypurines: Hyp and Xan, were significantly decreased in rats treated with trimetazidine. Moreover, significantly less pronounced acute tubular necrosis was observed in kidneys of rats treated with TMZ. These results suggest that trimetazidine protects against dephosphorylation of nucleotides and ischemic damage.

Adenine Nucleotides↗
PubMed2004

[Temozolomide in patients with melanoma brain metastases treated with whole brain irradiation].

BACKGROUND AND OBJECTIVE: Whole brain irradiation (WBRT) remains a recommended treatment for patients with brain metastases from malignant melanoma. Temozolomide (TMZ) displays efficacy for the treatment of metastatic melanoma. Our objective was to evaluate the potential benefit of TMZ administered along with WBRT. PATIENTS AND METHOD: We have conducted a retrospective study in a group of 26 patients comparing WBRT (n = 10) (20 Gy/5 fr) with WBRT+TMZ (n = 16) administered as a single chemotherapeutic agent (200 mg/m2) or in combination with chemoimmunotherapy (150 mg/m2). RESULTS: The median survival of the total group (n = 26) was 3 months (CI 95%, 2-4 months). The median survival of the WBRT+TMZ group was 6 months (CI 95%, 0-12 months), while the median survival of the WBRT group was 1 month (CI 95%, 1-2 months) (p < 0.0001). The analysis of survival at different time intervals (90, 180 and 270 days) showed a clear benefit for the group treated with WBRT + TMZ (p = 0.016). CONCLUSIONS: These results suggests a benefit of TMZ added to WBRT in terms of long-term survival for patients with melanoma brain metastases.

Adult↗
PubMed2001

Does trimetazidine exert cytoprotective activity on astrocytes subjected to hypoxia in vitro?

The aim of the present study was to establish whether trimetazidine (TMZ) is capable of protecting astrocytes against hypoxic injury. Using the model of astrocyte cell culture we tried to observe the cells treated with TMZ before, during and after hypoxia simulated in vitro. Cell viability was determined by Live/Dead (viability/cytotoxicity) Assay Kit and MTT conversion test. Apoptotic cell death was distinguished by a method using fluorescence microscopy with Hoechst 33342. The effect of the drug on the DNA synthesis was evaluated by measuring the incorporation of [3H]thymidine into DNA of astrocytes. TMZ stimulates the proliferation of astrocytes most significant one when the astrocytes are exposed to the drug in normoxia, hypoxia and/or re-oxygenation. Adding TMZ into cultures during re-oxygenation and hypoxial re-oxygenation significantly decreases the number of dead and apoptotic cells. Our experiment has proved that TMZ exerts the most significantly cytoprotective effect on astrocytes in vitro when added during hypoxia and/or re-oxygenation. We may conclude that the protective effect of TMZ depends on the sequence of drug adding and hypoxia/ re-oxygenation onset.

Animals↗
PubMed2001

Recipient treatment with trimetazidine improves graft function and protects energy status after lung transplantation.

BACKGROUND: Ischemia-reperfusion injury remains an important obstacle to successful lung transplantation. Trimetazidine is an anti-ischemic drug that restores the ability of ischemic cells to produce energy and reduces the generation of oxygen-derived free radicals. The aim of this study was to assess the protective effect of trimetazidine after prolonged ischemia in lung transplantation. METHODS: Rat single-lung transplantation was performed in 4 experimental groups (n = 5 each). In all groups, transplantation was performed after 18 hours of cold (4 degrees C) ischemia. All donor lungs were flushed with low-potassium dextran-glucose (LPDG) solution that also contained 500 microg/liter prostaglandin estradiol (E(1)). Groups studied included: Group I: flush solution was administered containing 10(-6) mol/liter trimetazidine (TMZ), neither donor nor recipient treatment given; Group II: donors were treated with 5 mg/kg intravenous TMZ 10 minutes prior to harvest, but the flush solution did not contain TMZ; Group III: recipients treated with 5 mg/kg intravenous TMZ 10 minutes before reperfusion, and flush solution contained 10(-6) mol/liter trimetazidine; Group IV: ischemic control group. After 2 hours of reperfusion, oxygenation was measured and lung tissue was frozen and assessed for adenosine triphosphate (ATP) content, myeloperoxidase (MPO) activity and thiobarbituric acid-reactive substances (TBARS). Peak airway pressure (PawP) was recorded throughout the reperfusion period. RESULTS: Group III showed significantly higher levels of ATP content (11.1 +/- 5.01 pmol vs Group I, 3.36 +/- 1.8 pmol, p = 0.008; vs Group II, 4.7 +/- 1.9 pmol, p = 0.03; vs Group IV, 0.7 +/- 0.2 pmol, p = 0.008), better oxygenation (442.5 +/- 26.5 mm Hg, vs Group I, 161.06 +/- 54.5 mm Hg; vs Group II, 266.02 +/- 76.9 mm Hg; vs Group IV, 89.4 +/- 14.7 mm Hg, p = 0.008) and reduced lipid peroxidation (TBARS) (0.15 +/- 0.03 nmol/g; vs Group I, 1.04 +/- 0.76 nmol/g; vs Group II, 0.69 +/- 0.4 nmol/g; vs Group IV, 2.29 +/- 0.4 nmol/g, p = 0.008). PawP and MPO activity were comparable in the 4 study groups. CONCLUSION: Recipient treatment with TMZ provided significant protection of energy status, better oxygenation and reduced lipid peroxidation. Our data suggest that TMZ may be an important adjunct in the prevention of post-transplant lung ischemia-reperfusion injury.

Animals↗