Avner Ramu

Reduced UV-Induced Degradation of Doxorubicin Encapsulated in Polyethyleneglycol-Coated Liposomes

AbstractPurpose. The aim of this study was to investigate the stability of doxorubicin encapsulated in polyethyleneglycol-coated liposomes (Doxil™) under UV-A light. Methods. High performance liquid chromatography and a fluorimetric method were used to quantify doxorubicin in bulk solution and doxorubicin in Doxil formulation. Results. The photodegradation of Doxil was significantly lower in comparison to the photodegradation of the free drug and showed no concentration dependency at the measured concentration range of 5−50 μg/ml. During and after UV-A irradiation, there was no leakage of the drug from liposomes to the medium. After induced leakage of doxorubicin from the liposomes by the ionophore nigericin, the degradation kinetics of Doxil were identical to that of free doxorubicin. Conclusions. High intraliposomal doxorubicin concentration and intraliposomal acidic pH are the two critical factors that protect DXR in Doxil from UV-A degradation.

Anthraquinone intercalators as carrier molecules for second-generation platinum anticancer drugs

Summary A series of complexes PtAm2L [where Am2 = (NH3)2, ethylenediamine(en), 1,2-diaminocyclohexane (DACH) or (NH3)(c-C6H11NH2) and where L is a bidentate 1,1-dicarboxylate ligand tethered to 1-aminoanthraquinone by various spacers] was prepared and screened in vitro against P388 leukemia cells. The free ligands displayed moderate activity and the corresponding platinum complexes were tenfold more active. The nature of the linker chain does not seem to affect the potency of the complexes. The potency depends on the nature of the inert amine ligand [NH3 > DACH > en]. The low aqueous solubility of these complexes prevented any in vivo studies and the preparation of water soluble analogs is currently under way.

Synthesis of aminoanthraquinone derivatives and their in vitro evaluation as potential anti-cancer drugs

Abstract Anthraquinones, monosubstituted by aminoalkylamino side chains at positions 1, 2 or disubstituted at positions 1, 5 or 1, 8 were prepared. Their in vitro cytotoxic activity ( ED 50 ) was evaluated using: 1) P388 murine leukemia cells and 2) a subline of these cells resistant to doxorubicin (P388/ADR). The results of the structure—activity relationship analysis indicated that monosubstitution in position 1 or 2 showed a decrease of the activity when compared to adryamicin. Disubstitution in positions 1, 5 by N,N -dimethyl ethylenediamine side chain led to optimal activity, whereas the presence of cyclic dialkylamino substituents in the same positions resulted in a corresponding decrease in the anti-tumor activity. Disubstitution in positions 1,8 did not show any improvement in the cytotoxic activity.

Central hyperglycemic effect of carbachol in rats

Intraventricular injection of carbachol produces hyperglycemia in rats at doses which are ineffective when given subcutaneously. This effect is suppressed by intraventricular administration of small amounts of atropine, further supporting the suggestion that the effect of carbachol is due to its action on central cholinergic receptors. Carbachol-induced hyperglycemia is not abolished by adrenalectomy and hypophysectomy, or pretreatment with reserpine.

Preparation, characterization and antileukemic properties of diaminemalonatoplatinum(II) complexes tethered to ferrocene

Abstract In search for new antitumor agents with target specificity we have prepared four new complexes in which diaminemalonatoplatinum(II) moieties are covalently tethered to ferrocene — and organ specific biological carrier. The four PtAm2[(ferrocenemethyl)propanedioic acid] complexes (where Am2(NH3)2, bis(aminocyclobutane), cis- and trans-1,2-diaminocyclohexane) were characterized by 195pt NMR spectroscopy and by elemental analysis. Their activity was assessed in vitro against P388 leukemia cells. They showed considerable activity (ED50 in the 5–45 μM range) though to a smaller extent than cis-diamminedichloroplatinum(II). They are, however, more active than the previously reported complexes in which a bis(phosphinecatecholato)platinum(II) moiety was tethered to ferrocene or to ruthenocene.

Preparation, characterization and the anticancer activity of a novel series of triaminemonochloroplatinum(II) cations linked to anthraquinone intercalators

Abstract A new series of complexes of the type [PtAm2LCl]+ (where Am = NH3 or Am2 = ethylenediamine and L is a monodentate AQ-Y-(CH2)n-NH2, AQ = anthraquinone, Y = NH, O) was prepared and screened in vitro against P388 leukemia. These complexes displayed higher activities than the corresponding neutral PtAm2L2 1:2 Pt:anthraquinone complexes but lower than the neutral diaminedichloro 1:1 complexes. The [Pt(en)LCl]+ complexes were significantly less active than the cis- and trans-[Pt(NH3)2LCl]+ complexes. The cis and trans isomers displayed similar activities. The complexes bearing the shorter linker chains were more active than those with longer chains. In vivo toxicity studies indicate that they are significantly less toxic than cis-DDP.

Evidence of central influences on blood glucose level: malathion hyperglycemia.

To suppress the hyperglycemic effect of malathion in rats, a smaller amount of atropine was required when the drug was injected by intraventricular (i. vent.) than s.c. Pentobarbital, but not diazepam, blocked the hyperglycemic response. The results suggest that central accumulation of acetylcholine was the mediator of the response. Since hyperglycemia was not abolished by adrenalectomy and/or hypophysectomy, a hypothesis is presented to explain how central accumulation of acetylcholine might cause hyperglycemia.

Design, Characterization and Anti-Tumor Activity of Adriamycin-Containing Phospholipid Vesicles

In this report we describe the design of adriamycin (ADM)-containing liposome preparations aiming at optimization of various pre-established parameters. Regarding liposome composition phosphatidylserine (PS) and phosphatidylglycerol (PG) appear to be suitable negatively charged phospholipids which combined with phosphatidylcholine (PC) and cholesterol (CHOL), confer to liposomes high loading capacity for ADM and reasonable stability in plasma. Intravenous administration of these negatively-charged liposomes resulted in a favorable tissue distribution of ADM in both normal and tumor-bearing mice, characterized by decreased cardiac uptake of drug, and increased and sustained drug levels in the liver. Moreover, enhanced accumulation of drug also occurred in metastatic tumor cells isolated from the liver when ADM was injected in the liposome-associated form. This passive drug targeting resulted in an improved therapeutic efficiency of liposome-associated ADM in a tumor model of liver metastases. Liposome delivery of ADM was also shown to increase significantly its cytoreductive effect on spleen-infiltrating leukemia cells and to maintain the same cytoreductive efficiency on bone marrow residing leukemia cells with an overall favorable effect on survival in the BCL1 leukemia model. The reduction of ADM toxicity by liposome association together with the anti-tumor results indicate that liposomes represent a useful drug-delivery system for the treatment of major neoplastic conditions.

Effect of intraventricular phentolamine on hyper- and hypotensive vasomotor reflexes.

Abstract Injection of small amounts of phentolamine into the lateral ventricle of the cat abolishes the blood pressure fall, evoked by vagal stimulation, and finally converts it into a pressure rise; all other vasomotor responses tested remain unchanged. In contrast, intraventricular pentobarbitone blocks both the pressor and depressor reactions following sciatic stimulation, although the vagal hypotension is again affected first. It appears probable that the depressor neurons, reached by afferent vagus fibers, are situated at the surface of the floor of the fourth ventricle and are thus accessible to intraventricular phentolamine. These neurons are activated by a -adrenergic transmission.

The effects of pentobarbitone and cerebellectomy on blood-pressure changes evoked by stimulation of the central end of the cut vagus of the rabbit.

Abstract Electrical stimulation of the central end of the cut vagus of the rabbit produced 2 types of blood-pressure response, depending on the frequency used: stimulation at low frequencies ( 100/sec) lowered blood pressure, whereas intermediate frequencies (50–100/sec) raised blood pressure. Small doses of pentobarbitone converted the high-frequency depressor response into a pressure rise, but did not alter qualitatively the effects of stimulation at low or intermediate frequencies. Cerebellectomy reduced the amplitude of all blood-pressure changes, evoked by stimulation of the central end of the cut vagus, but did not change their direction. Thus, blood-pressure changes evoked by stimulation of the central end of the cut vagus of the rabbit behave differently from those evoked by sciatic stimulation. The central pathways involved in these blood-pressure changes are discussed in the light of the present observations.