Biological Evaluation of Dinuclear Platinum(II) Complexes with Aromatic N-Heterocycles as Bridging Ligands.

The history of effective anti-cancer medications begins with the discovery of cisplatin's anti-cancer properties. Second-generation analogue, carboplatin, with a similar range of effectiveness, made progress in improving these drugs with fewer side effects and better solubility. Renewed interest in platinum-based drugs has been increasing in the past several years. These developments highlight a revitalized enthusiasm and ongoing exploration in platinum chemotherapy based on the series of dinuclear platinum(II) complexes, [{Pt(L)Cl}2(µ-bridging ligand)]2+, which have been synthesized and evaluated for their biological activities. These complexes are designed to target various cancerous conditions, exhibiting promising antitumor, antiproliferative, and apoptosis-inducing activities. The current work aims to shed light on the potential of these complexes as next-generation platinum-based therapies, highlighting their enhanced efficacy and reduced side effects, which could revolutionize the approach to chemotherapy.

Characterization, modes of interactions with DNA/BSA biomolecules and anti-tumor activity of newly synthesized dinuclear platinum(II) complexes with pyridazine bridging ligand.

Platinum-based drugs are widely recognized efficient anti-tumor agents, but faced with multiple undesirable effects. Here, four dinuclear platinum(II) complexes, [{Pt(1,2-pn)Cl}2(µ-pydz)]Cl2 (C1), [{Pt(ibn)Cl}2(µ-pydz)]Cl2 (C2), [{Pt(1,3-pn)Cl}2(µ-pydz)]Cl2 (C3) and [{Pt(1,3-pnd)Cl}2(µ-pydz)]Cl2 (C4), were designed (pydz is pyridazine, 1,2-pn is ( ±)-1,2-propylenediamine, ibn is 1,2-diamino-2-methylpropane, 1,3-pn is 1,3-propylenediamine, and 1,3-pnd is 1,3-pentanediamine). Interactions and binding ability of C1-C4 complexes with calf thymus DNA (CT-DNA) has been monitored by viscosity measurements, UV-Vis, fluorescence emission spectroscopy and molecular docking. Binding affinities of C1-C4 complexes to the bovine serum albumin (BSA) has been monitored by fluorescence emission spectroscopy. The tested complexes exhibit variable cytotoxicity toward different mouse and human tumor cell lines. C2 shows the most potent cytotoxicity, especially against mouse (4T1) and human (MDA-MD468) breast cancer cells in the dose- and time-dependent manner. C2 induces 4T1 and MDA-MD468 cells apoptosis, further documented by the accumulation of cells at sub-G1 phase of cell cycle and increase of executive caspase 3 and caspase 9 levels in 4T1 cells. C2 exhibits anti-proliferative effect through the reduction of cyclin D3 and cyclin E expression and elevation of inhibitor p27 level. Also, C2 downregulates c-Myc and phosphorylated AKT, oncogenes involved in the control of tumor cell proliferation and death. In order to measure the amount of platinum(II) complexes taken up by the cells, the cellular platinum content were quantified. However, C2 failed to inhibit mouse breast cancer growth in vivo. Chemical modifications of tested platinum(II) complexes might be a valuable approach for the improvement of their anti-tumor activity, especially effects in vivo.

Platinum(II) complexes with malonic acids: Synthesis, characterization, in vitro and in vivo antitumor activity and interactions with biomolecules.

Four Pt(II) complexes of the general formula [Pt(L)(5,6-epoxy-1,10-phen)], where L is an anion of either malonic acid (mal, Pt1), 2-methylmalonic acid (Me-mal, Pt2), 2,2-dimethylmalonic acid (Me2-mal, Pt3) or 1,1-cyclobutanedicarboxylic acid (CBDCA, Pt4) and 5,6-epoxy-1,10-phen is 5,6-epoxy-5,6-dihydro-1,10-phenanthroline, were synthesized and characterized by elemental microanalysis and different spectroscopic techniques. The crystal structure of anhydrous Pt3 complex was determined by single crystal X-ray diffraction. The in vitro anticancer activity of the platinum(II) complexes was investigated in human and murine cancer cell lines as well as in a normal murine cell line by MTT assay. The results show that the investigated platinum(II) complexes exhibit potent cytotoxic activity against murine breast carcinoma cells (4T1), human (HCT116) and murine (CT26) colorectal carcinoma cells. The Pt3 complex shows stronger selectivity against cancer cells compared to other platinum(II) complexes tested and thus exhibits beneficial antitumor activity, mainly by inducing apoptosis and inhibiting cell proliferation and migration. The Pt3 complex also exhibits significant in vivo antitumor activity in the orthotopical 4T1 tumor model without detected liver, kidney, lung, and heart toxicity. All the results indicate that these novel platinum(II) complexes have good antitumor activity on breast and colorectal cancer and have the potential to become possible candidates for cancer treatment.

Cytotoxic activity and influence on acetylcholinesterase of series dinuclear platinum(II) complexes with aromatic nitrogen-containing heterocyclic bridging ligands: Insights in the mechanisms of action.

Herein, the stability, lipophilicity, in vitro cytotoxicity, and influence on acetylcholinesterase of five dinuclear platinum(II) complexes with the general formula [{Pt(en)Cl}2(µ-L)]2+ (L is a different aromatic nitrogen-containing heterocyclic bridging ligands pyrazine (pz, Pt1), pyridazine (pydz, Pt2), quinoxaline (qx, Pt3), phthalazine (phtz, Pt4) and quinazoline (qz, Pt5), while en is bidentate coordinated ethylenediamine) were evaluated. The most active analyzed platinum complexes induced time-dependent growth inhibition of A375, HeLa, PANC-1, and MRC-5 cells. The best efficiency was achieved on HeLa and PANC-1 cells for Pt1, Pt2, and Pt3 at the highest concentration, while Pt1 was significantly more potent than cisplatin at a lower concentration. Additionally, a lower effect on normal cells was observed compared to cisplatin, which may indicate potentially fewer side effects of these complexes. Selected complexes induce reactive oxygen species and apoptosis on tumor cell lines. The most potent reversible acetylcholinesterase (AChE) inhibitors were Pt2, Pt4, and Pt5. Pt1 showed similar inhibitory potential toward AChE as cisplatin, but a different type of inhibition, which could contribute to lower neurotoxicity. Docking studies revealed that Pt2 and Pt4 were bound to the active gorge above the catalytic triad. In contrast, the other complexes were bound to the edge of the active gorge without impeding the approach to the catalytic triad. According to this, Pt1 represents a promising compound with potent anticancer properties, high selectivity, and low neurotoxicity.

Dinuclear platinum(II) complexes as the pattern for phosphate backbone binding: a new perspective for recognition of binding modes to DNA.

The mechanism of action of most approved drugs in use today is based on their binding to specific proteins or DNA. One of the achievements of this research is a new perspective for recognition of binding modes to DNA by monitoring of changes in measured and stoichiometric values of absorbance at 260 nm. UV-Vis and IR spectroscopy, gel electrophoresis and docking study were used for investigation of binding properties of three dinuclear platinum(II) complexes containing different pyridine-based bridging ligands, [{Pt(en)Cl}2(µ-4,4'-bipy)]Cl2·2H2O (Pt1), [{Pt(en)Cl}2(µ-bpa)]Cl2·4H2O (Pt2) and [{Pt(en)Cl}2(µ-bpe)]Cl2·4H2O (Pt3) to DNA (4,4'-bipy, bpa and bpe are 4,4'-bipyridine, 1,2-bis(4-pyridyl)ethane and 1,2-bis(4-pyridyl)ethene, respectively). In contrast to the system with well-known intercalated ligand (EtBr), covalently bound ligand (cis-Pt) and with minor groove binder (Hoechst 33258), which do not have significant differences in measured and stoichiometric values, the most pronounced deviations are recorded for two dinuclear platinum(II) complexes (Pt1 and Pt2), as a consequence of complex binding to the phosphate backbone and bending of DNA helix. The hydrolysis of complexes and changes in DNA conformation were also analysed as phenomena that may have an impact on the changes in absorbance.

In vitro and in vivoactivity of series of cationic dinuclearPt(II) complexes.

The antitumour potential of nine dinuclear platinum(II) complexes of the type [{Pt(L)Cl}2(µ-X)]2+(where L represents two NH3 or different bidentantly coordinated diamine ligand - ethylenediamine, en; (±)-1,2-propylenediamine, 1,2-pn; isobutylenediamine, ibn; trans-(±)-1,2-diaminocyclohexane, dach; 1,3-propylenediamine, 1,3-pd; 2,2-dimethyl-1,3-propylenediamine, 2,2-diMe-1,3-pd; (±)-1,3-pentanediamine,1,3-pnd, and X is a bridging pyrazine (pz) or pyridazine (pydz) ligand) were determined by in vitro and in vivo assays using the CT26 cell line and a murine model of heterotopic colon cancer tumour induced in immunocompetent BALB/c mice. This study concludes that complexes Pt1, Pt2 and Pt7 possess significant in vitro cytotoxic activity against mouse colon carcinoma CT26 cells, while all these complexes show moderate apoptotic effect. Complexes Pt1 and Pt7 arrested CT26 cells in G2/M phase of cell cycle, while, evaluated by detection of Ki67 expressing cells, complexes Pt5 and Pt6 exerted the highest antiproliferative effect. Complexes Pt1 and Pt2 exerted significant in vivo antitumour effects. These complexes reduced the growth of primary tumour and the incidence of lung and liver metastases without causing the significant hepato- and nephro- toxicity. Our data indicate considerable antitumour activity of platinum(II) complexes against CT26 cells in vitro and in vivo and imply possible further investigations on their role as potential chemotherapeutic agents.

In vitro cytotoxic activities, DNA- and BSA-binding studies of dinuclear palladium(II) complexes with different pyridine-based bridging ligands.

Three new dinuclear palladium(II) complexes with general formula [{Pd(en)Cl}2(µ-L)]2+ (L is pyridine-based bridging ligand 4,4'-bipyridine (4,4'-bipy, 1), 1,2-bis(4-pyridyl)ethane (bpa, 2), 1,2-bis(4-pyridyl)ethylene (bpe, 3) and en is bidentate coordinated ethylenediamine) were synthesized and characterized by elemental microanalyses, NMR (1H and 13C), IR and UV-Vis spectroscopy. In vitro cytotoxic activity of these complexes against human A549 and murine LLC1 lung cancer cells, as well as two human HCT116 and SW480 and one murine CT26 colon cancer cells was investigated using MTT assay (MTT is 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). The potential of complexes 1-3 to induce apoptosis was tested by flow cytometric analysis of Annexin V and propidium iodide stained treated cells, while their antiproliferative activity was analyzed by detection of Ki67 expression in treated cancer cells. The DNA binding affinity of complexes 1-3 was evaluated by UV-Vis, fluorescence emission spectroscopy and by viscosity measurements in aqueous phosphate buffer solution at pH 7.40. Furthermore, interaction of these complexes with bovine serum albumin was investigated by fluorescence spectrometry. The present study showed that the nature of pyridine-based bridging ligand (L) in dinuclear [{Pd(en)Cl}2(µ-L)]2+ complex has an influence on the complex preference for the cytotoxic activity and CT-DNA/BSA (CT-DNA is calf thymus DNA and BSA is bovine serum albumin) binding affinity.

New minor groove covering DNA binding mode of dinuclear Pt(II) complexes with various pyridine-linked bridging ligands and dual anticancer-antiangiogenic activities.

New anticancer platinum(II) compounds simultaneously targeting tumor cells and tumor-derived neoangiogenesis, with new DNA interacting mode and large therapeutic window are appealing alternative to improve efficacy of clinical platinum chemotherapeutics. Herein, we describe three novel dinuclear [{Pt(en)Cl}2(µ-L)]2+ complexes with different pyridine-like bridging ligands (L), 4,4'-bipyridine (Pt1), 1,2-bis(4-pyridyl)ethane (Pt2) and 1,2-bis(4-pyridyl)ethene (Pt3), which highly, positively charged aqua derivatives, [{Pt(en)(H2O)}2(µ-L)]4+, interact with the phosphate backbone forming DNA-Pt adducts with an unique and previously undescribed binding mode, called a minor groove covering. The results of this study suggested that the new binding mode of the aqua-Pt(II) complexes with DNA could be attributed to the higher anticancer activities of their chloride analogues. All three compounds, particularly complex [{Pt(en)Cl}2(µ-4,4'-bipy)]Cl2·2H2O (4,4'-bipy is 4,4'-bipyridine) (Pt1), overcame cisplatin resistance in vivo in the zebrafish-mouse melanoma xenograft model, showed much higher therapeutic potential than antiangiogenic drug sunitinib malate, while effectively blocking tumor neovascularization and melanoma cell metastasis. Overall therapeutic profile showed new dinuclear Pt(II) complexes could be novel, effective and safe anticancer agents. Finally, the correlation with the structural characteristics of these complexes can serve as a useful tool for developing new and more effective anticancer drugs.

New dinuclear palladium(II) complexes with benzodiazines as bridging ligands: interactions with CT-DNA and BSA, and cytotoxic activity.

Three new dinuclear Pd(II) complexes with general formula [{Pd(en)Cl}2(µ-L)](NO3)2 [L is bridging ligand quinoxaline (Pd1), quinazoline (Pd2) and phthalazine (Pd3)] were synthesized and characterized by elemental microanalyses, UV-Vis, IR and NMR (1H and 13C) spectroscopy. The interaction of dinuclear Pd1-Pd3 complexes with calf thymus DNA (CT-DNA) has been monitored by viscosity measurements, UV-Vis and fluorescence emission spectroscopy in aqueous phosphate buffer solution (PBS) at pH 7.40 and 37 °C. In addition, these experimental conditions have been applied to investigate the binding affinities of Pd1-Pd3 complexes to the bovine serum albumin (BSA) by fluorescence emission spectroscopy. In vitro antiproliferative and apoptotic activities of the dinuclear Pd(II) complexes have been tested on colorectal and lung cancer cell lines. All tested Pd(II) complexes had lower cytotoxic effect than cisplatin against colorectal cancer cells, but also had similar or even higher cytotoxicity than cisplatin against lung cancer cells. All complexes induced apoptosis of colorectal and lung cancer cells, while the highest antiproliferative effect exerted Pd2 complex.

Synthesis, cytotoxic activity and DNA interaction studies of new dinuclear platinum(ii) complexes with an aromatic 1,5-naphthyridine bridging ligand: DNA binding mode of polynuclear platinum(ii) complexes in relation to the complex structure.

The synthesis, spectroscopic characterization, cytotoxic activity and DNA binding evaluation of seven new dinuclear platinum(ii) complexes Pt1-Pt7, with the general formula [{Pt(L)Cl}2(µ-1,5-nphe)](ClO4)2 (1,5-nphe is 1,5-naphthyridine; while L is two ammines (Pt1) or one bidentate coordinated diamine: ethylenediamine (Pt2), (±)-1,2-propylenediamine (Pt3), trans-(±)-1,2-diaminocyclohexane (Pt4), 1,3-propylenediamine (Pt5), 2,2-dimethyl-1,3-propylenediamine (Pt6), and 1,3-pentanediamine (Pt7)), were reported. In vitro cytotoxic activity of these complexes was evaluated against three tumor cell lines, murine colon carcinoma (CT26), murine mammary carcinoma (4T1) and murine lung cancer (LLC1) and two normal cell lines, murine mesenchymal stem cells (MSC) and human fibroblast (MRC-5) cells. The results of the MTT assay indicate that all investigated complexes have almost no cytotoxic effects on 4T1 and very low cytotoxicity toward LLC1 cell lines. In contrast to the effects on LLC1 and 4T1 cells, complexes Pt1 and Pt2 had significant cytotoxic activity toward CT26 cells. Complex Pt1 had a much lower IC50 value for activity on CT26 cells compared with cisplatin. In comparison with cisplatin, all dinuclear Pt1-Pt7 complexes showed lower cytotoxicity toward normal MSC and MRC-5 cells. In order to measure the amount of platinum(ii) complexes taken up by the cells, we quantified the cellular platinum content using inductively coupled plasma mass spectrometry (ICP-QMS). Molecular docking studies performed to evaluate the potential binding mode of dinuclear platinum(ii) complexes Pt1-Pt7 and their aqua derivatives W1-W7, respectively, at the double stranded DNA showed that groove spanning and backbone tracking are the most stable binding modes.

Irritable bowel syndrome - from etiopathogenesis to therapy.

Irritable bowel syndrome (IBS) is a chronic and relapsing functional gastrointestinal disorder that affects 9-23% of the population across the world. Patients with IBS are often referred to gastroenterology, undergo various investigations, take various medicines, take time off work and have a poor quality of life. The pathophysiology of IBS is not yet completely understood and seems to be multifactorial. Many pathogenetic factors, in various combinations, and not all necessarily present in each patient, can play an important role. Discomfort or abdominal pain relieived by defacation, asociated with a change in stool form, is a typical clinical manifestation of IBS. Many factors, such as emotional stress and eating, may exacerbate the symptoms. A timely diagnosis of IBS is important so that treatment which will provide adequate symptomatic relief (diarrhoea, constipation, pain and boaring) can be introduced. The diagnosis of IBS is not confirmed by a specific test or structural abnormality. It is made using criteria based on clinical symptoms such as Rome criteria, unless the symptoms are thought to be atypical. Today the Rome Criteria IV is the current gold-standard for the diagnoses of IBS. Treatment of patients with IBS requires a multidisciplinary approach. Some patients respond well to non-pharmacological treatment, while others also require pharmacological treatment. This review will provide a summary of pathophysiology, diagnostic criteria and therapies for IBS.

Boerhaave syndrome - case report / Síndrome de Boerhaave - relato de caso

ABSTRACT CONTEXT: Boerhaave syndrome consists of spontaneous longitudinal transmural rupture of the esophagus, usually in its distal part. It generally develops during or after persistent vomiting as a consequence of a sudden increase in intraluminal pressure in the esophagus. It is extremely rare in clinical practice. In 50% of the cases, it is manifested by Mackler's triad: vomiting, lower thoracic pain and subcutaneous emphysema. Hematemesis is an uncommon yet challenging presentation of Boerhaave's syndrome. Compared with ruptures of other parts of the digestive tract, spontaneous rupture is characterized by a higher mortality rate. CASE REPORT: This paper presents a 64-year-old female patient whose vomit was black four days before examination and became bloody on the day of the examination. Her symptoms included epigastric pain and suffocation. Physical examination showed hypotension, tachycardia, dyspnea and a swollen and painful abdomen. Auscultation showed lateral crackling sounds on inspiration. Ultrasound examination showed a distended stomach filled with fluid. Over 1000 ml of fresh blood was extracted by means of nasogastric suction. Esophagogastroduodenoscopy was discontinued immediately upon entering the proximal esophagus, where a large amount of fresh blood was observed. The patient was sent for emergency abdominal surgery, during which she died. An autopsy established a diagnosis of Boerhaave syndrome and ulceration in the duodenal bulb. CONCLUSION: Boerhaave syndrome should be considered in all cases with a combination of gastrointestinal symptoms (especially epigastric pain and vomiting) and pulmonary signs and symptoms (especially suffocation).

RESUMO CONTEXTO: A síndrome de Boerhaave é uma ruptura longitudinal transmural espontânea do esôfago, normalmente da parte distal. Ela geralmente se desenvolve durante ou após vômitos persistentes como consequência do aumento repentino da pressão intraluminal no esôfago. É extremamente rara na prática clínica. Em 50% dos casos, manifesta-se pela tríade de Mackler: vômitos, dor torácica inferior, enfisema subcutâneo. Hematêmese é uma apresentação incomum porém desafiadora da síndrome de Boerhaave. Em comparação com rupturas de outras partes do tubo digestivo, a ruptura espontânea é caracterizada pela taxa de mortalidade mais elevada. RELATO DO CASO: O artigo apresenta uma paciente do sexo feminino de 64 anos de idade, cujo vômito era preto, quatro dias antes do exame, e continha sangue no dia do exame. Os sintomas incluíam dor epigástrica e sufocação. No exame físico, foi verificada hipotensão, taquicardia, dispneia e abdômen inchado e doloroso. Ausculta revelou estertores laterais na inspiração. A ultrassonografia mostrou estômago dilatado, preenchido com conteúdo líquido. Sucção nasogástrica evacuou mais de 1.000 ml de sangue fresco. Esofagogastroduodenoscopia foi abortada imediatamente ao se entrar no esôfago proximal, onde foi observada grande quantidade de sangue fresco. A paciente foi encaminhada com urgência para cirurgia abdominal, durante a qual faleceu. Autópsia estabeleceu diagnóstico de síndrome de Boerhaave e úlcera no bulbo-duodenal. CONCLUSÃO: A síndrome Boerhaave deve ser considerada em todos os casos com uma combinação de sintomas gastrointestinais (especialmente dor epigástrica e vómitos) e sintomas e sinais pulmonares (especialmente sufocação).

Boerhaave syndrome - case report.

CONTEXT:: Boerhaave syndrome consists of spontaneous longitudinal transmural rupture of the esophagus, usually in its distal part. It generally develops during or after persistent vomiting as a consequence of a sudden increase in intraluminal pressure in the esophagus. It is extremely rare in clinical practice. In 50% of the cases, it is manifested by Mackler's triad: vomiting, lower thoracic pain and subcutaneous emphysema. Hematemesis is an uncommon yet challenging presentation of Boerhaave's syndrome. Compared with ruptures of other parts of the digestive tract, spontaneous rupture is characterized by a higher mortality rate. CASE REPORT:: This paper presents a 64-year-old female patient whose vomit was black four days before examination and became bloody on the day of the examination. Her symptoms included epigastric pain and suffocation. Physical examination showed hypotension, tachycardia, dyspnea and a swollen and painful abdomen. Auscultation showed lateral crackling sounds on inspiration. Ultrasound examination showed a distended stomach filled with fluid. Over 1000 ml of fresh blood was extracted by means of nasogastric suction. Esophagogastroduodenoscopy was discontinued immediately upon entering the proximal esophagus, where a large amount of fresh blood was observed. The patient was sent for emergency abdominal surgery, during which she died. An autopsy established a diagnosis of Boerhaave syndrome and ulceration in the duodenal bulb. CONCLUSION:: Boerhaave syndrome should be considered in all cases with a combination of gastrointestinal symptoms (especially epigastric pain and vomiting) and pulmonary signs and symptoms (especially suffocation).

Reactions of Dinuclear Platinum(II) Complexes with Peptides.

The present review article highlights recent findings in the reactions between different dinuclear Pt(II) complexes with peptides containing cysteine, methionine and histidine residues. The reactions of {trans-[Pt(NH3)2Cl]2(µ-X)}(2+) and {trans-[Pt(NH3)2(H2O)]2(µ-X)}(4+) type complexes with different bridging ligands (X) (X = pyrazine, 4,4'-bipyridyl and 1,2-bis(4-pyridyl)ethane) with the tripeptide glutathione proceeded in two steps. In the first step, one water or chlorido ligand of the dinuclear Pt(II) complex was substituted by the sulfhydryl group of GSH, while in the second step, the remaining water or chlorido ligand from the dinuclear Pt(II)-peptide complex was replaced by the second molecule of glutathione, finally leading to the formation of the {trans-[Pt(NH3)2(GS)]2(µ-X)}(2+) complex. It was shown that the bridging ligand had an important influence on the reactivity of these complexes with glutathione. No hydrolytic cleavage of any amide bond was observed in the reactions between these complexes and glutathione. However, in reactions performed in acidic media (2.0 < pH < 2.5) between dinuclear Pt(II) complexes with the general formulae {[Pt(L)(H2O)]2(µ-diazine)}(4+) (L is different bidentate coordinated diamine ligands and diazine is a pyrazine- or pyridazine-bridging ligand) and Nacetylated peptides containing L-methionine and L-histidine amino acids in the side chains (Ac-L-Met-Gly, Ac-L-His-Gly and Ac-L-Met-Gly-L-His-GlyNH2), regioselective cleavage of these peptides occurred. The mechanism of these hydrolytic reactions was discussed in relation to the structure of the diazine-bridged Pt(II) complex and the investigated peptides. A systematic summary of these results could contribute to the future design of new dinuclear Pt(II) complexes as potential reagents for regioselective cleavage of peptides and proteins.

Hyperparathyroidism as a cause of recurrent acute pancreatitis: A case report.

Introduction: One of the more uncommon etiological factors responsible for the development of acute pancreatitis (AP) is hypercalcemia. Hyperparathyroidism (HPT), as a cause of hypercalcemia, is responsible for 1.5­13% of AP according to a number of studies. A mechanism of the development of AP in hyperparathyroidism is still unclear. Case report: We presented a 47-year-old female patient, who had five episodes of AP in total before the etiological factors were finally determined. The patient had certain comorbidities which were considered to be potential causes of AP. She had chronic renal insufficiency (she was on a regular hemodialysis program), systemic lupus erythematosus and mioma uteri. She used to regularly take an antiepileptic drug (combination of sodium valproate and valproic acid). During the fifth episode of AP, the serum calcium level was for the first time elevated to twice the normal value. Level of parathyroid hormone was several times higher. A static scintigraphy found hyperplasia or hyperfunctional adenoma of the right inferior and superior parathyroid glands. Abdominal multislice computed tomography (MSCT) scan verified the enlargement of the entire pancreas, as well as the presence of heterogeneous structures with diffuse amorphous calcifications. The lytic lesions in the pelvic bones could be seen in both sides. Parathyroidectomy was being postponed by an endocrine surgeon because of the poor overall condition of the patient. In the next period the patient had five more episodes of AP. The condition was significantly contributed by increasingly more frequent and longer episodes of metrorrhagia. Despite all therapeutic measures that were taken, systemic inflammatory response syndrome (SIRS) developed, and fatal outcome occurred. Conclusion: In case of recurrent pancreatitis, hyperparathyroidism is to be considered even if a significant elevation of serum calcium is not present. This is especially the case for patients with chronic renal insufficiency or impaired vitamin D metabolism, who have a higher risk of secondary hyperthyroidism.

Synthesis and evaluation of series of diazine-bridged dinuclear platinum(II) complexes through in vitro toxicity and molecular modeling: correlation between structure and activity of Pt(II) complexes.

Polynuclear Pt(II) complexes are a novel class of promising anticancer agents with potential clinical significance. A series of pyrazine (pz) bridged dinuclear Pt(II) complexes with general formulas {[Pt(L)Cl]2(µ-pz)}(2+) (L, ethylenediamine, en; (±)-1,2-propylenediamine, 1,2-pn; isobutylenediamine, ibn; trans-(±)-1,2-diaminocyclohexane, dach; 1,3-propylenediamine, 1,3-pd; 2,2-dimethyl-1,3-propylenediamine, 2,2-diMe-1,3-pd) and one pyridazine (pydz) bridged {[Pt(en)Cl]2(µ-pydz)}(2+) complex were prepared. The anticancer potential of these complexes were determined through in vitro cytotoxicity assay in human fibroblasts (MRC5) and two carcinoma cell lines (A375 and HCT116), interaction with double stranded DNA through in vitro assay, and molecular docking study. All complexes inhibited cell proliferation with inhibitory concentrations in the 0.5-120 µM range. While {[Pt(1,3-pd)Cl]2(µ-pz)}(2+) showed improved activity and {[Pt(en)Cl]2(µ-pydz)}(2+) showed comparable activity to that of clinically relevant cisplatin, {[Pt(en)Cl]2(µ-pydz)}(2+) was less toxic in an assay with zebrafish (Danio rerio) embryos, causing no adverse developmental effects. The in vitro cytotoxicity of all diazine-bridged dinuclear Pt(II) complexes is discussed in correlation to their structural characteristics.

[The role and importance of biochemical markers in diagnosis of alcoholic acute pancreatitis].

INTRODUCTION: Alcoholic acute pancreatitis occurs in 10% of alcoholics, who take more than 80 g alcohol daily. Different biochemical markers are used to diagnose acute pancreatitis, and some of them may help in establishing etiology of acute pancreatitis. MATERIAL AND METHODS: This study is a prospective review of 21 patients. All patients were hospitalized at the Department for Gastroenterology and Hepatology or at the Department for Surgery of the Clinical Centre of Nif in the period from August 1st 2009 to March 1st 2010 with diagnosis of acute alcoholic pancreatitis. Detailed anamnesis, clinical examination, biochemical analyses and ultrasonography of the upper abdomen were done in all patients. All patients provided data on alcohol abuse. RESULTS: The analysis of the corresponding biochemical parameters revealed a statistically significant correlation between the following values: serum amylase and serum lipase (R = 0.964674; p < 0.001), cholesterol and triglycerides (R = 0.93789; p < 0.001), total and direct bilirubin (R = 0.857899; p < 0.001) and between aspartate aminotransferase and alanine aminotransferase (R = 0.824461, p < 0.001) in patients with alcoholic acute pancreatitis. In addition, there was a statistically significant correlation between the values of serum amylase and urinary amylase (R = 0.582742, p < 0.001). DISCUSSION: The analysis of biochemical markers showed that some of them were significant for beforehand diagnosis of alcoholic acute pancreatitis, which is in accordance with other studies. CONCLUSION: Some biochemical parameters can be potential predictors of alcoholic acute pancreatitis (lipase/amylase ratio > 2, greater ratio of aspartate aminotransferase/alanine aminotransferase, enhanced triglycerides and values of mean corpuscular volume.

A study of the reactions of a methionine- and histidine-containing tetrapeptide with different Pd(II) and Pt(II) complexes: selective cleavage of the amide bond by platination of the peptide and steric modification of the catalyst.

(1)H NMR spectroscopy was applied to the study of the reactions of [M(en)(H(2)O)(2)](2+) complexes (M = Pd(ii) and Pt(ii)) with the N-acetylated methionyl-glycyl-histidyl-glycineamide, MeCOMet-Gly-His-GlyNH(2). All reactions were performed in the pH range 1.5-2.0 with equimolar amounts of the [M(en)(H(2)O)(2)](2+) complex and the tetrapeptide at 60 degrees C. In all these reactions, a metal(ii) complex bound to a methionine residue affects the regioselective cleavage of the amide bond involving the carboxylic group of methionine. The priority in the cleavage of the Met-Gly amide bond in relation to the other amide bonds in this peptide is due to the high affinity of Pt(ii) and Pd(ii) ions for the sulfur donor atom. The mechanism of these hydrolytic reactions is discussed and, for its clarification, the reaction of the [Pd(en)(H(2)O)(2)](2+) complex with MeCOMet-Gly-His-GlyNH(2) was additionally investigated by potentiometric titration. The steric effects of the various palladium(ii) complexes of the type [Pd(L)(H(2)O)(2)](2+), in which L is a chelating diamine (ethylenediamine, en, 2-picolylamine, pic, or 2,2-dipyridylamine, dpa) on the hydrolytic cleavage of the amide bond involving the carboxylic group of histidine in the MeCOMet-Gly-His-GlyNH(2) tetrapeptide were also studied by (1)H NMR spectroscopy. All reactions were performed under the above-mentioned conditions and in the initial stage of these reactions, the MeCOMet-Gly-His-GlyNH(2) was reacted with an equimolar amount of the [Pt(dien)Cl](+) complex (dien is diethylenetriamine) and then the monoplatinated [Pt(dien)(MeCOMet-Gly-His-GlyNH(2)-S)](2+) complex was treated with an equimolar amount of [Pd(L)(H(2)O)(2)](2+). It was found that the rate of hydrolysis of the His-GlyNH(2) amide bond in [Pt(dien)(MeCOMet-Gly-His-GlyNH(2)-S)](2+) decreased from the en to the pic complex, with finally a total inhibition of this reaction with [Pd(dpa)(H(2)O)(2)](2+). These results are an important step in the study of the regioselective cleavage of peptides and proteins and in the development of new palladium(ii) complexes as artificial metallopeptidases.

Hydrolysis of the amide bond in methionine-containing peptides catalyzed by various palladium(II) complexes: dependence of the hydrolysis rate on the steric bulk of the catalyst.

(1)H NMR spectroscopy was applied to study the reactions of cis-[Pd(L)(H(2)O)(2)](2+) complexes (L is en, pic and dpa) with the N-acetylated tripeptides L-methionylglycylglycine, MeCOMet-Gly-Gly, and glycyl-L-methionyl-glycine, MeCOGly-Met-Gly. All reactions were performed in the pH range 2.0-2.5 with equimolar amounts of the cis-[Pd(L)(H(2)O)(2)](2+) complex and the tripeptide at 60 degrees C. The hydrolytic reactions of the cis-[Pd(en)(H(2)O)(2)](2+), cis-[Pd(pic)(H(2)O)(2)](2+) and cis-[Pd(dpa)(H(2)O)(2)](2+) complexes with MeCOMet-Gly-Gly were regioselective and only the amide bond involving the carboxylic group of methionine was cleaved. However, in the reactions of these three Pd(II) complexes with MeCOGly-Met-Gly, two amide bonds, Met-Gly and MeCO-Gly, were cleaved. From UV-Vis spectrophotometry studies, it was found that the rate-determining step of these hydrolytic reactions is the monodentate coordination of the corresponding Pd(II) complex to the sulfur atom of the methionine side chain. The rate of the cleavage of these amide bonds is dependent on the nature of the bidentate coordinated diamine ligand L (en>pic>dpa). The hydrolytic reaction of cis-[Pd(L)(H(2)O)(2)](2+)-type complexes with MeCOMet-Gly-Gly, containing the methionine side chain in the terminal position of the peptide, is regioselective while in the reaction of these Pd(II) complexes with MeCOGly-Met-Gly, none selective cleavage of the peptide occurs. This study contributes to a better understanding of the selective cleavage of methionine-containing peptides employing palladium(II) complexes as catalysts.