Effect of lacosamide on ethanol induced conditioned place preference and withdrawal associated behavior in mice: Possible contribution of hippocampal CRMP-2

BackgroundExcessive consumption of ethanol is known to activate the mTORC1 pathway and to enhance the Collapsin Response Mediator Protein-2 (CRMP-2) levels in the limbic region of brain. The latter helps in forming microtubule assembly that is linked to drug taking or addiction-like behavior in rodents. Therefore, in this study, we investigated the effect of lacosamide, an antiepileptic drug and a known CRMP-2 inhibitor, which binds to CRMP-2 and inhibits the formation of microtubule assembly, on ethanol-induced conditioned place preference (CPP) in mice.MethodsThe behavior of mice following ethanol addiction and withdrawal was assessed by performing different behavioral paradigms. Mice underwent ethanol-induced CPP training with alternate dose of ethanol (2 g/kg, po) and saline (10 ml/kg, po). The effect of lacosamide on the expression of ethanol-induced CPP and on ethanol withdrawal associated anxiety and depression-like behavior was evaluated. The effect of drug on locomotor activity was also assessed and hippocampal CRMP-2 levels were measured.ResultsEthanol-induced CPP was associated with enhanced CRMP-2 levels in the hippocampus. Lacosamide significantly reduced the expression of ethanol-induced CPP and alleviated the levels of hippocampal CRMP-2 but aggravated withdrawal-associated anxiety and depression in mice.ConclusionThe present study demonstrated the beneficial effect of lacosamide in attenuation of expression of ethanol induced conditioned place preference via reduction of hippocampal CRMP-2 level. These findings suggest that lacosamide may be investigated further for ethanol addiction but not for managing withdrawal.     

Xanthogranulomatous orchitis: Review of the published work and report of one case

Xanthogranulomatous orchitis is an extremely rare inflammatory non-neoplastic destructive lesion of the testis. We report a 44-year-old man who presented with right scrotal swelling and two discharging sinuses. Testicular tumor markers were normal. Scrotal ultrasound showed heterogeneous testicular areas and irregular margin of the tunica. Surgical exploration revealed infected, unhealthy testicular tissue with necrosis and tumor-like lesion. Orchidectomy was done and histopathology showed xanthogranulomatous orchitis.     

Schwannoma of submandibular region

Tumours of the nerve sheath origin in the head and neck are not common. Schwannomas are rare. Only a few cases have been reported so far. We report a rare case of Schwannoma of Submandibular region arising from the lingual nerve.     

Lipophilic platinum complexes entrapped in liposomes: improved stability and preserved antitumor activity with complexes containing linear alkyl carboxylato leaving groups

Lipophilic diaminocyclohexane (DACH) platinum complexes have shown significant promise in preclinical studies. One of these compounds,cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum(II) (NDDP), which contains two branched leaving groups of 10 carbons, showed a favorable toxicity profile in a liposomal formulation in early clinical trials. However, like many other DACH platinum compounds with branched leaving groups, it is unstable within the liposomes, thus preventing its widespread clinical evaluation. We studied the effect of the configuration of leaving groups on intraliposomal complex stability by studying a series of DACH platinum complexes containing linear alkyl carboxylato leaving groups of 5–18 carbons. The entrapment efficiency was greater than 90% for all liposomal preparations of the complexes and was independent of lipid composition and length of the leaving group. The drug leakage from the liposomes was minimal, but was directly related to the length of the leaving group. Intraliposomal stability was inversely related to the length of the leaving group and the content of DMPG (dimyristoyl phosphatidylglycerol) in the liposomes. The effect of length of leaving group on intraliposomal stability was minimal in compounds with leaving groups smaller than 10 carbons, but very pronounced in compounds with longer leaving groups. Stable liposomal formulations of selected compounds with leaving groups of 6 and 10 carbons had significant in vivo antitumor activity against both L1210/S and L1210/PDD leukemias. The results indicate (1) that compounds with linear leaving groups are much more stable within DMPG-containing liposomes than compounds with branched leaving groups and (2) that DMPG is required for in vivo antitumor activity. Stable and active liposomal formulations of selected compounds with linear leaving groups have been identified. These formulations are candidates for clinical development.Abbreviations DMPC dimyristoyl phosphatidylcholine - DMPG dimyristoyl phosphatidylglycerol - L-NDDP liposomalcis-bis-neodecanoato-trans-1,2-diaminocyclohexaneplatinum(II) The work reported in this paper was supported in part by NIH grants CA 41581, 45423, 50270, and 58342     

Loading anticancer drugs into HDL as well as LDL has little affect on properties of complexes and enhances cytotoxicity to human carcinoma cells

Low density lipoprotein (LDL) has been found to represent a suitable carrier for cytotoxic drugs that may target them to cancer. This study investigated whether very low density lipoprotein (VLDL), LDL and high density lipoprotein (HDL) can be used to effectively incorporate four cytotoxic drugs, 5-fluorouracil (5-FU), 5-iododeoxyuridine (IUdR), doxorubicin (Dox) and vindesine; characterized the complexes; and examined the effect of incorporation on drug cytotoxicity against HeLa cervical and MCF-7 breast carcinoma cells. Significant drug loading was achieved into all three classes of lipoproteins, consistent with the sizes and hydrophobicity of the drugs. The relative loading efficiency was found to be vindesine>IUdR>Dox>5-FU for all three classes of lipoproteins. As shown by electron microscopy (EM), drug incorporation did not affect the size or morphology of the lipoproteins. Differential scanning calorimetry (DSC) showed that drug loading did not significantly change the thermal transition temperature of core lipids in the lipoproteins. The transition enthalpy was changed only for LDL–Dox and LDL–vindesine. The drugs remained stable in the lipoproteins as determined by high performance liquid chromatography (HPLC). EM, DSC and HPLC data suggest that drugs were incorporated into lipoproteins without disrupting their integrity and drugs remained in their stable forms inside lipoproteins. Compared with free drugs in cytotoxicity assays, the IC₅₀ values of LDL– and HDL–drug complexes were significantly lower (2.4- to 8.6-fold for LDL complexes and 2.5- to 23-fold for HDL complexes). All free or lipoprotein-bound drug formulations were comparably more cytotoxic against MCF-7 than HeLa cells. Upregulating the lipoprotein receptors enhanced, and downregulating them inhibited, the cytotoxicity, indicating the mechanistic involvement of lipoprotein receptor pathways. Complexes of all four drugs with VLDL, in contrast to LDL and HDL, had the same cytotoxicity as the four corresponding free drugs. Our results suggest that further studies are required of the potential of HDL to be a cancer targeting drug carrier.