A comprehensive safety evaluation of trabectedin and drug-drug interactions of trabectedin-based combinations.

Trabectedin (Yondelis(®)) is a potent marine-derived antineoplastic drug with high activity against various soft tissue sarcoma (STS) subtypes as monotherapy, and in combination with pegylated liposomal doxorubicin (PLD) for the treatment of patients with relapsed platinum-sensitive ovarian cancer. This article reviews the safety and pharmacokinetic profiles of trabectedin. Records were identified using predefined search criteria using electronic databases (e.g. PubMed, Cochrane Library Database of Systematic Reviews). Primary peer-reviewed articles published between 1 January 2006 and 1 April 2014 were included. The current safety and tolerability profile of trabectedin, based on the evaluation in clinical trials of patients treated with the recommended treatment regimens for STS and recurrent ovarian cancer, was reviewed. Trabectedin as monotherapy or in combination with PLD, was not associated with cumulative and/or irreversible toxicities, such as cardiac, pulmonary, renal, or oto-toxicities, often observed with other common chemotherapeutic agents. The most common adverse drug reactions (ADRs) were myelosuppression and transient hepatic transaminase increases that were usually not clinically relevant. However, trabectedin administration should be avoided in patients with severe hepatic impairment. Serious and fatal ADRs were likely to be related to pre-existing conditions. Doxorubicin or PLD, carboplatin, gemcitabine, or paclitaxel when administered before trabectedin, did not seem to influence its pharmacokinetics. Cytochrome P450 (CYP) 3A4 has an important role in the metabolism of trabectedin, suggesting a risk of drug-drug interactions with trabectedin used in combination with other CYP3A4 substrates. Trabectedin has a favorable risk/efficacy profile, even during extended treatment in pretreated patients.

Farmacovigilancia y medicina interna / Pharmacovigilance and internal medicine

En Medicina Interna es indispensable conocer y reportar las Reacciones Adversas a los Medicamentos (RAM). Se presentan cuatro (4) situaciones de este tipo, provenientes del Servicio de Medicina Interna del Hospital General del Oeste, Caracas, Venezuela. Caso 1: paciente con SIDA y toxoplasmosis cerebral, en tratamiento con antiretrovirales, trimetoprim-sulfa y pirimetamina. Consulta a la emergencia por presentar lesiones cutáneas. Caso 2: paciente de 24 años, síndrome de Down, con comunicación interventricular corregida, hipotiroidismo controlado y Hepatitis C en tratamientocon ribavirina – tegainterferon, con abscesoinguinal. Se encuentra pancitopenia severa y progresiva. Caso 3: Mujer de 70 años en preoperatori de facotomía en quien se diagnóstica trombosis venosa profunda poplítea izquierda. Se prescribe enoxaparina – warfarina y se aprecia un hematoma del recto anterior del abdomen. Se identifica el uso previo y simultáneo de productos herbarios. Caso 4: paciente que ingiere un producto sin registro sanitario y prohibido por las autoridades regulatorias del país; contiene compuestos no declarados: diclofenac sódico y esteroides. La farmacovigilancia es indispensable en un servicio de medicina interna.

Pharmacovigilanceis essential in the practice of Internal Medicine. Four situations from an Internal Medicine Department of the Hospital General del Oeste, Caracas, Venezuela, are analyzed. Case 1: patient with AIDS and cerebral toxoplasmosis, trated with antiretroviral drugs, trimetoprim-sulfimetoxasol and pyrimethamine. This patient consultedbecause of with cutaneous. Case 2: 24 year-old patient with Down syndrome, corrected congenital cardiac disease, treated hypothyroidism and hepatitis C treated with ribavirin - tegainterferon had an inguinal abscess. A severe and progressive pancytopenia is found and It analyzed the high suspicion causality of RAM. Case 3: A 70 year-old woman, was examined for a preoperative evaluation and a left popliteal deep vein thrombosis is found. Enoxaparin - warfarin were prescribed and in the next 24 hours a hematoma of abdominal rectus was found. The oriented anamnesis identifies the use of herbal products. Drug interaction is discussed. Case 4: regulatory authorities prohibit an unregistered health product that has not reported compounds: diclofenac and steroids. Pharmacovigilance is essential in a department of internal medicine.

Renograma con mercaptoacetiltriglicina para el diagnóstico diferencial de necrosis tubular aguda y nefritis intersticial asociada a vancomicina / Mercaptoacetyltriglycine renal scan for the differential diagnosis of acute tubular necrosis and interstitial nephritis associated to vancomycin

El diagnóstico diferencial de toxicidad renal asociada a la vancomicina incluye la necrosis tubular aguda y la nefritis intersticial. Se presenta un caso de toxicidad renal inducida por vancomicina, demostrada en el renograma con 99mTc-MAG3. La nefrotoxicidad se desarrolló secundariamente a vancomicina utilizada en el tratamiento de un paciente con meningitis. El renograma con 99mTc-MAG3 puede desempeñar un papel en el diagnóstico diferencial entre necrosis tubular aguda y nefritis tubulointersticial en caso de toxicidad renal asociada a vancomicina y puede facilitar la toma de decisiones clínicas(AU)

The differential diagnosis of vancomycin associated renal toxicity includes acute tubular necrosis and interstitial nephritis. We report a case of vancomycin induced renal toxicity shown by Tc-99m mercaptoacetyltriglycine renal scan. Nephrotoxicity was evolved secondary to vancomycin used for treating a patient with meningitis. Tc-99m mercaptoacetyltriglycine renal scan may play a role in differentiation between acute tubular necrosis and tubulointerstitial nephritis of vancomycin associated renal toxicity and can facilitate the clinical decision making(AU)

Serotonin delays habituation of leech swim response to touch.

Serotonin, acting through a cAMP-signaling pathway, delayed habituation to criterion of the leech's swim response to touch. This delay was reversed by crushing the connective between serotonin-exposed and serotonin-naive ganglia, and correlated with an increase in spontaneous impulse activity in this connective. We suggest that increased activity in intersegmental interneurons may play a role in maintaining swim responsiveness when concentrations of serotonin are elevated.

Behavioral and electrophysiological evidence for opioid tolerance in adolescent rats.

Morphine and other opiates are successful treatments for pain, but their usefulness is limited by the development of tolerance. Given that recent studies have observed differential sensitivity to drugs of abuse in adolescents, the aim of this study was to assess antinociceptive tolerance to morphine in adolescent rats using both behavioral and cellular measures. Early (28-35 days postnatal) and late (50-59 days) adolescent and adult (73-75 days) male rats were injected with morphine (5 mg/kg, s.c.) or saline twice a day for two consecutive days. On Day 3, tolerance to morphine was evident in morphine-pretreated rats when tested on the hot plate test. Although baseline latencies for the early compared to late adolescent rats were faster, the magnitude of the shift in ED(50) for morphine was similar for the two adolescent groups. However, the shift in ED(50) tended to be greater in adolescent compared to adult rats. Subsequent to behavioral testing, whole cell patch-clamp recordings were made from ventrolateral PAG neurons. The opioid agonist, met-enkephalin (ME), activated similar outward currents in PAG neurons of early and late adolescent rats. However, reversal potentials of ME-induced currents were shifted to more hyperpolarized potentials in cells from morphine-pretreated rats. In addition, ME induced larger currents in morphine-pretreated rats with faster hot plate latencies compared to the mean (more tolerant) than in rats with slower latencies. These results indicate that repeated intermittent administration of morphine produces tolerance in adolescent rats that is associated with novel changes in opioid-sensitive ventrolateral PAG neurons.

The evaluation of radiolabeled artesunate on tissue distribution in rats and protein binding in humans.

The present study reports the tissue distribution, pharmacokinetics, mass balance, and elimination of [(14)C] artesunate (AS) following single intravenous administration in rats. Protein binding was performed with rat and human plasma. Radioactivity and drug levels in blood, plasma, tissues, urine, and feces up to 192 hours were collected and measured. The mean terminal half-life of plasma (76 h) and blood (105 h) radioactivity was prolonged compared with that of unchanged AS (0.43 h) and dihydroartemisinin (0.75 h), an active metabolite of AS. Drug was widely distributed after 1 hour in select tissues. After 24 hours, the radioactivity rapidly declined in all tissues except spleen until 96 hours. Only 1% of total radioactivity was detected in brain tissue. AS revealed a higher binding capacity with human and rat plasma proteins (73-81%). The radioactivity in whole blood was higher (two to fourfold) than that in plasma throughout the period of the treatment, suggesting that AS binding to RBCs may relate to its powerful antimalarial activity.

Physiological changes in glucose differentially modulate the excitability of hypothalamic melanin-concentrating hormone and orexin neurons in situ.

The physiological signaling mechanisms that link normal variations in body energy status to the activity of arousal- and metabolism-regulating brain centers are not well understood. The melanin-concentrating hormone (MCH) and orexin/hypocretin types of neurons of the lateral hypothalamus (LH) exert opposing effects on arousal and metabolism. We examined whether shifts in brain extracellular glucose that correspond to physiological changes in blood glucose can alter the electrical output of neurochemically and biophysically defined LH cells in mouse brain slices. Here, we show that physiologically relevant concentrations of glucose dose-dependently enhance the electrical excitability of MCH neurons by inducing depolarization and increasing membrane resistance. We also demonstrate that the same physiological shifts in glucose have the opposite effects on the electrical activity of orexin neurons. We propose that these direct actions of glucose on the arousal- and metabolism-regulating LH neurons play a key role in the translation of normal variations in body energy resources into appropriate changes in arousal and metabolism.

Modulation of the phototoxic effect of hypericin in human leukemia CEM cell line by N-ethylmaleimide, amiloride and omeprazole.

Hypericin is a photosensitizing plant pigment from Hypericum perforatum with multiple modes of light-induced biological activities due to production of singlet oxygen and/or excited-state proton transfer with consequent pH drop in the hypericin environment. In the present work, we studied the effects of three inhibitors of crucial mechanisms responsible for intracellular pH (pHi) regulation on hypericin phototoxicity: N-ethylmaleimide (NEM), an inhibitor of H+-ATPase, 5'-(N,N-dimethyl)-amiloride (DMA), an inhibitor of Na+/H+ exchanger, and omeprazole (OME), an inhibitor of H+K+-ATPase. Our experiments show that the effect of hypericin at 1 x 10(-5) and 1 x 10(-6) mol x l(-1) was significantly potentiated by NEM (1 x 10(-7)-1 x 10(--9) mol x l(-1)) and DMA (1 x 10(-6) and 1 x 10(-7) mol x l(-1)) in leukemic CEM cell line. On the other hand, OME had no significant effect on hypericin cytotoxicity. Our results support the hypothesis that the excited-state proton transfer and the consequent acidification of hypericin environment could play a role in the biological activity of hypericin.

Soil solution dynamics of Cu and Zn in a Cu- and Zn-polluted soil as influenced by gamma-irradiation and Cu-Zn interaction.

A pot experiment was conducted to study soil solution dynamics of Cu and Zn in a Cu/Zn-polluted soil as influenced by gamma-irradiation and Cu-Zn interaction. A slightly acid sandy loam was amended with Cu and Zn (as nitrates) either singly or in combination (100 mg Cu and 150 mg Zn kg(-1) soil) and was then gamma-irradiated (10 kGy). Unamended and unirradiated controls were included, and spring barley (Hordeum vulgare L. cv. Forrester) was grown for 50 days. Soil solution samples obtained using soil moisture samplers immediately before transplantation and every ten days thereafter were used directly for determination of Cu, Zn, pH and absorbance at 360 nm (A360). Cu and Zn concentrations in the solution of metal-polluted soil changed with time and were affected by gamma-irradiation and metal interaction. gamma-Irradiation raised soil solution Cu substantially but generally decreased soil solution Zn. These trends were consistent with increased dissolved organic matter (A360) and solution pH after gamma-irradiation. Combined addition of Cu and Zn usually gave higher soil solution concentrations of Cu or Zn compared with single addition of Cu or Zn in gamma-irradiated and non-irradiated soils, indicating an interaction between Cu and Zn. Cu would have been organically complexed and consequently maintained a relatively high concentration in the soil solution under higher pH conditions. Zn tends to occur mainly as free ion forms in the soil solution and is therefore sensitive to changes in pH. The extent to which gamma-irradiation and metal interaction affected solubility and bioavailability of Cu and Zn was a function of time during plant growth. Studies on soil solution metal dynamics provide very useful information for understanding metal mobility and bioavailability.

The riboflavin-mediated photooxidation of doxorubicin.

PURPOSE: Previously, it was shown that exposing doxorubicin (ADR) to 365 nm light resulted in the loss of its cytotoxic activity as well as its absorbance at 480 nm. These processes were much enhanced when mediated by riboflavin. In the present study we investigated the quantitative and qualitative aspects of riboflavin-mediated photodegradation of ADR. METHODS: ADR solutions containing variable concentrations of riboflavin and other agents were exposed to 365 nm light for variable time periods and then the absorbance spectrum of ADR was measured by a double beam spectrophotometer. These measurements were used to calculate the half-time of the ADR degradation process. The degraded ADR solutions were analyzed by chromatography and mass spectrometry. RESULTS: Analysis of the riboflavin effect indicated that a maximal rate of photolytic degradation of ADR was obtained only after most of the ADR molecules had formed bimolecular complexes with riboflavin. The retardation of lumichrome formation by ADR and the inhibition of ADR bleaching by excess of ascorbic acid suggested that ADR was degraded by a photooxidation process. Similar spectral changes occurred when ADR was exposed to strong oxidizers such as sodium hypochlorite and dipotassium hexachloroiridate. Cyclic voltammetry revealed that the oxidation-reduction process of ADR was not electrochemically reversible and therefore the oxidation potential could not be determined accurately; however its value should be between 0.23 and 0.78 V. Analysis of the photooxidative process revealed that it was not mediated by the formation of singlet oxygen, superoxide anion radicals, hydrogen peroxide or hydroxyl radicals, and it is suggested that ADR was oxidized directly by the excited triplet riboflavin. The mass spectrograms and the HPLC chromatograms of photooxidized ADR indicate that the central ring of ADR was opened and that 3-methoxysalicylic acid was produced by this cleavage. CONCLUSIONS: The riboflavin-mediated photodegradation of ADR is an oxidative process resulting in the cleavage of the anthraquinone moiety. 3-Methoxysalicylic acid was identified as one of the resulting fragments. It is possible that some of the large fractions of the ADR metabolites that are non-fluorescent are the result of an in vivo oxidation of ADR and that 3-methoxysalicylic acid may play a role in the different biological activities of ADR.

The interaction of hydroxyurea and ionizing radiation in human cervical carcinoma cells.

PURPOSE: The results from prior in vitro and in vivo studies and recent phase 3 clinical trials suggest a significant potential role for hydroxyurea (HU) as a clinical radiosensitizer for cervix cancer. However, a detailed study of possible cellular mechanisms of radiosensitization in human cervix cancer cells as a consequence of dose and timing of HU and ionizing radiation (IR) has not been performed. This in vitro study analyses the interactions of HU and IR in a human cervical carcinoma cell line, Caski. MATERIALS AND METHODS: Exponentially growing Caski cells were continuously exposed to clinically achievable but minimally cytotoxic concentrations of HU (0.3-3.0 mM) for various time intervals (6, 12, 18, 24, and 30 hours) up to one population doubling time either prior to or immediately following IR (2-8 Gy). The radiation survival data were analyzed using our modification of the linear-quadratic model to test for an interaction (greater than additive). The effects of HU alone, IR alone, and the combination on cell cycle progression and on apoptotic cell death in exponentially growing Caski cells were measured. RESULTS: We report a significant HU-IR interaction (radiosensitization) based on the sequence of HU exposure (post- > pre-IR) and with increasing concentrations of HU (0.3-3.0 mM), but no effect on radiosensitization with the duration of exposure to HU for up to one cell population doubling (6-30 hours). HU concentration has a significant effect on both alpha and beta linear-quadratic values in the post-IR sequences. Exposures of exponentially growing Caski cells to 1 mM and 3 mM HU alone result in a complete block in early S phase throughout the 30-hour exposure, while 0.3 mM HU causes a transient early S-phase block over the initial 12 to 18 hours of exposure. HU alone has no effect on cell cycle progression in G1 or G2/M populations but results in a large apoptotic population (31% following 1 mM HU x 30 hours), which appears to be the principal mechanism of drug cytotoxicity in these cells. IR alone (4 or 6 Gy) results in a significant G2 delay for 6 to 18 hours following IR but no G1 delay and a small apoptotic population at 30 hours post-IR (5.4% vs 2.1% in non-IR controls). The use of HU (0.3 or 1.0 mM) following IR (4 or 6 Gy) results in a significantly larger G2 delay compared with IR alone, but with only an additive effect on the apoptotic population. CONCLUSIONS: These in vitro data demonstrate that radiosensitization of Caski cells is more significant with post-IR exposures to clinically achievable concentrations of HU. This HU-IR interaction is associated with an increased G2 delay, suggesting a reduction in IR damage repair. However, this interaction appears to be independent of the cytotoxicity (principally by apoptosis) from HU alone.

[The action of benzimidazole derivative preparations on the formation of DNA-protein cross-links in the UV irradiation of chromatin]. / Deistvie preparatov proizvodnykh benzimidazola na obrazovanie sshivok DNK--belok pri UF-obluchenii khromatina.

Effect of benzimidazole-derivatives on the DNA-protein binding formation was studied after UV-radiation of chromatin. These derivatives were shown to protect chromatin from UV-induced DNA-protein binding formation. Structural analog contained two aminomethyl residuals sensibilized additional binding formation in chromatin. Results suggested, that benzimidazole interacted with DNA, while aminomethyl groups interacted with protein and sensibilized binding of DNA with histone H1.

[Interaction of different N-nitroso compounds with DNA in vitro]. / Vzaimodeistvie razlichnykh N-nitrozosoedinenii s DNK in vitro.

The interaction of 11 N-nitroso compounds of different structure and carcinogenic activity with DNA in vitro under the influence of UV light was studied by the method of melting. UV light is shown to induce the DNA damage by N-nitroso compounds irrespective of their carcinogenic activity.

Gamma-radiation-induced interactions between amino acids and glucagon.

The interaction of glucagon and phenylalanine mediated by the OH . radical causes formation of higher molecular weight products of glucagon and phenylalanine, loss of amino acid residues in glucagon, and formation of adducts of glucagon and phenylalanine. The relative yields of these products depend upon the molar ratio of phenylalanine to glucagon in solution. At low ratios, glucagon aggregation and loss of amino acid residues predominate; at high ratios, the formation of phenylalanine dimers (and possible trimers and tetramers) predominates. The formation of adducts reaches a maximum at a phenylalanine:glucagon molar ratio of 3-4, and then decreases gradually, as the molar ratio increases, but is still discernible even at high molar ratios. Mechanisms for the formation of adducts are suggested. The influence of the primary aqueous radical intermediates, OH., H., and e-aq, on adduct formation has been evaluated for several different amino acids by irradiating in the presence of specific radical scavengers. For the aromatic amino acids (phenylalanine, tryptophan, and tyrosine), OH. is considerably more effective than e-aq for mediating adduct formation, whereas for histidine and methionine, these primary radicals are equally effective.

[Modifying effect of alcohols on the radiation transformations of serum albumin]. / O modifitsiruiushchem vliianii spirtov na radiatsionnye prevrashcheniia syvorotochnogo al'bumina.

The method of roentgenochemoluminescence was used to study the reactions of alcohol radicals with tryptophanyl residues of protein. These radicals exhibited a high reactivity. In a series of alcohol radicals and 3-oxy-pyridine derivatives, a positive correlation was revealed between the rate of the reaction of radicals with the macromolecule and the hydrophobic character of free radicals.

[Metabolic disorder of various protein fractions in the thymocytes of irradiated rats (an electrophoretic analysis and proteins interacting with DNA]. / Narushenie metabolizma razlichnykh belkovykh fraktsii v timotsitakh obluchennykh krys (élektroforeticheskii analiz i belki, vzaimodeistvu-iushchie s DNK).

Using PAAG-electrophoresis and subsequent fluorography no essential disorders were detected in the biosynthesis of some protein fractions of the cytoplasm and nuclear sap of thymocytes during the first 2 h following irradiation of rats with a dose of 8 Gy. There was a decrease, progressing in time, in the rate of the synthesis of certain polypeptides. Inhibition of the biosynthesis of the proteins reacting with DNA was demonstrated by the chromatography, on DNA-containing columns, of labeled proteins of different fractions. The most pronounced changes were observed in the group of firmly bound proteins.

Pulse radiolytic study of the interaction of thiols and ascorbate with OH adducts of dGMP and dG: implications for DNA repair processes.

Using the technique of pulse radiolysis, the interaction of .OH radicals with 2'-deoxyguanosine (dG) and dG-5'-monophosphate (dGMP) has been shown to result in the production of intermediates with different redox properties as demonstrated by their reactions with tetranitromethane (TNM) and N,N,N',N'-tetramethyl-p-phenylenediamine. The ratio of the yields of oxidizing to reducing-type .OH radical adducts of dGMP was determined to be about 1:1 and independent of pH (6-11). The nature of the intermediates produced on reaction of .OH with dGMP are discussed. The thiols, cysteine, glutathione, mercaptoacetic acid, and ascorbate have been shown to interact with those .OH adducts of dGMP and dG with oxidizing properties preferentially via an electron transfer process (k approximately 3 X 10(7)-1.4 X 10(9) dm3 mole-1 sec-1) as implied from the pH dependence of the rate constants. It is further demonstrated that oxygen and TNM do not interact with those .OH adducts of the purines with oxidizing properties. The implications of these findings are discussed with reference to the mechanistic aspects of radioprotection and especially of radiosensitization.

[RNA-protein interactions in influenza virus A ribonucleoprotein detected by UV radiation]. / RNK-belkovye vzaimodeistviia v ribonukleoproteide virusa grippa A, vyiavliaemye pri UF-obluchenii.

RNA and protein interaction in the structure of influenza virus ribonucleoprotein (RNP) was studied by ultraviolet (UV) irradiation. After UV-irradiation of virion RNP for 1 hour only 6% of 3H-uridine-labeled RNA was found to go into the aqueous phase upon phenol-detergent extraction. Pretreatment of RNP with small doses of pancreatic RNase before RNA extraction slightly increased (up to 18%) the amount of RNA going into the aqueous phase. About 90% RNA was found after extraction in the aqueous phase in the nonirradiated material. As a result of UV-irradiation of RNP, RNA in RNP became more resistant to RNase: the residual acid-insoluble radioactivity was 21% whereas with nonirradiated RNP it was 3.2%. The results of the analysis of RNP labeled for protein in polyacrylamide gel and SDS-sucrose gradient after UV-irradiation and ribonuclease treatment indicate the formation of UV-induced linkages between RNA and NP protein.