ABSTRACT
The DNA interstrand cross-links of the antitumor drug {[cis-Pt(NH3)2Cl]2(4,4'-methylenedianiline)}2+ (1) play a prevalent role in its antitumor effects. Complex 1 forms DNA long-range interstrand cross-links uniquely in the 3'-3' direction. Conformational distortions induced by these interstrand cross-links in DNA represent a potential structural motif for recognition by high-mobility-group proteins.
Subject(s)
DNA Adducts/chemistry , Intercalating Agents/chemistry , Intercalating Agents/pharmacology , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Base Sequence , Cross-Linking Reagents/chemistry , Cross-Linking Reagents/pharmacology , DNA/chemistry , Humans , Molecular Docking Simulation , Nucleic Acid Conformation/drug effectsABSTRACT
NAMI-A is a ruthenium-based drug endowed with the unique property of selectively targeting solid tumour metastases. Although two clinical studies had already been completed, limited information exists on the behavior of NAMI-A after injection into the bloodstream. PK data in humans informs us of a rather low free drug concentration, of a relatively high half-life time of elimination and of a linear relationship between the administered dose and the corresponding AUC for up to toxic doses. In the present study, we examined the chemical kinetics of albumin binding with or without the presence of reducing agents, and we evaluated how these chemical aspects might influence the in vivo PK and the in vitro ability of NAMI-A to inhibit cell migration, which is a bona fide, rapid and easy way to suggest anti-metastatic properties. The experimental data support the binding of NAMI-A to serum albumin. The reaction is facilitated when the drug is in its reduced form and, in agreement with already reported data, the adduct formed with albumin maintains the biological activity of the ruthenium drug. The formation of the adduct is favored by low ratios of NAMI-A : HSA and by the reduction of the drug with ascorbic acid. The difference in in vivo PK and the faster binding to albumin of the reduced NAMI-A seem to suggest that the drug is not rapidly reduced immediately upon injection, even at low doses. Most probably, cell and protein binding prevail over the reduction of the drug. This observation supports the thesis that the reduction of the drug before injection must be considered relevant for the pharmacological activity of NAMI-A against tumour metastases.
Subject(s)
Antineoplastic Agents , Dimethyl Sulfoxide/analogs & derivatives , Organometallic Compounds , Serum Albumin/chemistry , Serum Albumin/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Ascorbic Acid/chemistry , Cell Adhesion/drug effects , Cell Line, Tumor , Dimethyl Sulfoxide/chemistry , Dimethyl Sulfoxide/pharmacokinetics , Dimethyl Sulfoxide/pharmacology , Humans , Kidney/metabolism , Liver/metabolism , Lung/metabolism , Male , Mice, Inbred ICR , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacokinetics , Organometallic Compounds/pharmacology , Oxidation-Reduction , Rhodamines/metabolism , Ruthenium/blood , Ruthenium/metabolism , Ruthenium CompoundsABSTRACT
The case-history occupies of a case of acute cardiac insufficiency in a patient at early postoperative period, who underwent a small surgical operation. Apparently the banal operation became the starting mechanism of life threatening cardiopulmonary insufficiency. Transthoracic echocardiografic diagnostic process not gave us the unambiguous response about a cause of that distressed state. The primary clinical consideration of the pulmonary embolization was not ambiguously acknowledged, though nor excluded. The clinical had to decided, whether the heparinization or the thrombolysing treatment was justified.
Subject(s)
Cardiac Output, Low/therapy , Postoperative Complications/therapy , Pulmonary Embolism/diagnosis , Respiratory Insufficiency/therapy , Cardiac Output, Low/etiology , Diagnosis, Differential , Echocardiography , Humans , Male , Middle Aged , Pulmonary Embolism/drug therapy , Respiratory Insufficiency/etiology , Thrombolytic TherapyABSTRACT
The case-history presents a case of unexpected pulmonary embolization manifestated in a middle-aged patient closely before operation (classical cholecystectomy). The severe respiratory insufficiency was the consequence, which proceeded to a metabolic dysbalance and the state of disseminated intravascular coagulation. The prognosis was very serious, but the patient recovered after 4 weeks of complete resuscitative care. The authors would like to initiate the discussion about the way and timing of antithrombic preoperative preparation in elderly patients and in those with a high risk of thromboembolic complications.
