New Treatment Approaches for Dyslipidemia and its Management

The field of lipidology is evolving rapidly. Two novel medications have recently been approved for use in homozygous familial hypercholesterolemia (HoFH); the Apolipoprotein B (Apo B) mRNA antisense oligonucleotide (ASO), mipomersen (Kynamro®) and the microsomal triglyceride transfer protein (MTP) inhibitor, lomitapide (Juxtapid®). Equally important have been the disappointments in cholesterol research; the halting of further investigation into the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib, yet two others remain in development. The failure of the combination of extended release niacin and laropiprant to show benefit when combined with statin therapy has lead to the discontinuation of this product in Europe. Perhaps one of the most exciting avenues of future research is into the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9).     

Reduction of Cys–Cys and Cys–Cys disulfide bonds in recombinant human granulocyte colony stimulating factor

The Cys³⁶–Cys⁴² and Cys⁶⁴–Cys⁷⁴ disulfide bonds in recombinant methionyl human granulocyte colony-stimulating factor were reduced to sulfhydryls with dithiothreitol or mercury. Both reduction reactions are dependent on the pH. The reduction reaction with dithiothreitol increased in rate with increasing pH; between pH 7–9 and above pH 10.5 this increase was less than in other regions. These observations are explained by repulsive forces between dithiothreitol and regions in granulocyte colony-stimulating factor which intensify in these pH-regions. The hydroxyl catalysis causes the overall increase in k_obs in the pH-region studied. The reduction of the disulfides with mercury is, as could be expected from the Nernst equation for disulfide reduction, also pH dependent: the half-wave potential decreases with increasing pH as predicted by theory.     

Liposomes as carriers of the antiretroviral agent dideoxycytidine-5′-triphosphate

The presence and replication of the human immunodeficiency virus (HIV) in cells of the mononuclear phagocyte system (MPS) together with the preferential uptake of liposomes in macrophages suggest that liposomes can become a valuable carrier of anti-HIV agents. Moreover, liposomes reduce toxicity of encapsulated drugs and protect encapsulated drugs against rapid degradation in the blood circulation. To overcome problems associated with the administration of free nucleosides and to improve targeting to the MPS, dideoxycytidine-5′-triphosphate (ddCTP) was encapsulated in liposomes. Liposomes were stable with regard to retention of the entrapped drug, particle size and chemical stability of ddCTP. Results obtained with liposome encapsulated ddCTP in the murine acquired immunodeficiency syndrome (MAIDS) model indicate that ddCTP encapsulated in liposomes can reduce proviral DNA in cells of the mononuclear phagocyte system (MPS) in both spleen and bone marrow.     

The risks of handling cytotoxic drugs

Results of various biological and physical/chemical tests of the urines or blood of health-care personnel working with cytotoxic drugs are discussed. The outcomes of these tests are conflicting and inconclusive. The physical/chemical tests seem to be an alternative method. However, until now it has not been possible to establish the threshold concentration in urine or blood beneath which no effect has to be expected. Therefore, the interpretation of the concentration of cytotoxic drugs and/or the metabolites in the urine or blood is difficult. As long as one will not be able to provide conclusive data on the health hazards when working with cytotoxic drugs, protective measures have to be taken in order to lower the risk as much as possible.     

Quantitative aspects of the degradation of mitomycin C in alkaline solution

The alkaline hydrolysis of mitomycin C has been studied over a wide range of pH/H_(7-15). A stability-indicating high-performance liquid chromatographic (HPLC) method was used to separate the degradation products from the parent drug. The quantitative effects of temperature and buffers on the degradation of mitomycin C in alkali have been determined. A profile of log k(obs) against pH/H_ was constructed after corrections had been made for buffer effects and after extrapolation to 25 degrees C by application of the Arrhenius equation.     

Evaluating mobility for radiotherapy planning of lung tumors: a comparison of virtual fluoroscopy and 4DCT

PURPOSE: Fluoroscopy is widely used for evaluating tumor mobility in radiotherapy planning. Lung tumor mobility was scored using virtual fluoroscopy, and this was compared to mobility derived from contoured tumors in all phases of a respiration-correlated (or 4D) CT scan. METHODS AND MATERIALS: 4DCT datasets were reviewed and 29 patients were identified in whom tumors were visible on anterior-posterior fluoroscopy views. Mobility in all directions was estimated on fluoroscopy movie loops by four clinicians. These results were compared to mobility measured from contoured tumor volumes in all phases of the same 4DCT. Internal target volumes (ITV) were generated for both approaches. RESULTS: In eight patients, fluoroscopy did not allow for tumor mobility to be assessed in at least one direction. No significant inter-clinician variation was observed with respect to fluoroscopic assessment of mobility. Clinicians systematically overestimated mobility in all three directions (p<0.05). The mean ITVs derived using fluoroscopy were 52.2% larger than those derived using 4DCT contours, but the individual ITVs were smaller in three patients. CONCLUSION: Use of virtual fluoroscopy generally overestimates the mobility of visible lung tumors, and results in irradiation of unnecessarily large target volumes. In contrast, use of 4DCT minimizes the risk of normal tissue toxicity.