Current Clinical Pharmacology - Volume 3, Issue 1, 2008

Bisphosphonates, like ibandronate (Bondronat®), represent the mainstay of treatment for metastatic bone disease. Ibandronate selectively binds to bone mineral and prevents osteoclast-mediated skeletal destruction. This review describes the preclinical and clinical profiles of ibandronate for treatment of cancer metastatic to bone. In preclinical studies ibandronate reduced metastatic processes and tumor growth, induced tumor cell apoptosis, decreased bone pain, and enhanced biomechanical indices. Skeletal destruction was completely prevented with ibandronate, and this directly correlated with histomorphometry and markers of bone turnover. Ibandronate efficacy in combination with anticancer therapies is discussed. Preclinical studies demonstrated that ibandronate does not compromise safety, including renal health. Intravenous and oral ibandronate had comparable efficacy in three Phase III clinical trials. Ibandronate achieved significant risk reductions in the incidence of skeletal-related events and bone pain. In additional clinical studies, ibandronate reduced markers of bone turnover. Furthermore, loading-dose ibandronate rapidly reduced bone pain in Phase II trials. Adjuvant trials are ongoing. The clinical safety profile (including a 4-year follow-up study) has demonstrated renal health is maintained with ibandronate. Overall, ibandronate preserves skeletal integrity, has a favorable safety profile, maintains renal function, and can rapidly reduce and maintain bone pain below baseline levels in patients with cancer metastatic to bone.

Pulmonary arterial hypertension (PAH) is a disease characterized by an elevation in pulmonary artery pressure that can lead to right ventricular failure and death. Conventional treatment is based on non-specific drugs (warfarin, oxygen, diuretics). Pure vasodilators like calcium channel antagonists have little or no effect on the vast majority of patients. Although there is no cure for PAH, newer medical therapies have been shown to improve a variety of clinically relevant end-points including survival, functional class, exercise tolerance, haemodynamics, echocardiographic parameters and quality of life measures. Intravenous prostacyclin, was the first introduced drug for treatment of PAH and remains the first-line treatment for the most severe patients. Since then the list of approved drugs for PAH has expanded to include prostacyclin analogues with differing routes of administration, a dual endothelin receptor antagonist, and a phosphodiesterase- 5 inhibitor. Novel drugs have also shown promise in experimental trials and are likely to be added to the list of options. This article reviews the current treatments strategies for PAH.

The science of antiviral research was well advanced when HIV/AIDS appeared as a major new virus disease in the early 1980s. The first effective antiviral compound (AZT, azidothymidine, zidovudine) was already among the library of compounds screened and was promptly reported to be a specific inhibitor of retroviruses, including HIV. Due to the pivotal role of AZT in HIV treatment, this review summarizes the most known effects -some of which are toxic side effects- induced by AZT a drug which is still used in the combined therapy of HIV-infected patients. Among the toxic side effects, a severe bone marrow toxicity manifested as anemia, neutropenia and siderosis, and caused by inhibition of heme and globin synthesis together with a general derangement of iron supply, have been reported. In this regard, we proved that while AZT and its monophosphorylated derivative AZTMP were unable to chelate iron, the triphosphate form AZTTP displayed a significant capacity to remove iron from transferrin. Moreover, we have previously demonstrated that AZT-exposed K562 cells showed an increase of transferrin receptors located on the cell membrane without affecting their biosynthesis, but slowing down their endocytotic pathway. Interestingly, literature data report the impairement of glycosylation reactions by AZT. Indeed, we have shown that AZT-treated K562 cells exhibited a reduced sialylation of proteins and lipids, and a strong inhibition of β,(2→8) sialyltransferase activity while α,(1→4)galactosyltransferase and β- galactosidase activities were significantly increased. These latter observations could be of clinical relevance since alterations of intracellular and cell surface carbohydrate expression and composition, often are associated with several diseases. However, contrarily to previous reports by other authors on AZT as an inhibitor of plant and bacterial toxins activity, we have demonstrated that AZT not only did not inhibit saporin toxicity, but even increased the cytotoxic activity of this plant toxin on K562 cells. Furthermore, the review enlightens the potential utilization of AZT as a tool in proteomics since in the recent years several genes responding to this drug have been identified in different cell lines. We have shown, for the first time, an over-expression of two proteins (PDI-A3 and sthatmin), and a full repression of two others (HSP-60 and SOD1) in AZT-exposed K562 cells. At present, we are investigating if the above reported alterations are a general feature of AZT-treatment of cultured cells, or they represent a peculiar characteristic of a specific cell line. Finally, the paper reviews a number of novel methodologies aimed at enhancing the AZT plasma levels and its bioavailability in all human organs in order to improve its therapeutic efficacy against HIV infection. These new possibilities, namely the AZT prodrug strategy, the AZT transdermal delivery and the targeted brain delivery, are yet not in use for humans but they are under experimental studies.

The peripheral benzodiazepine receptor (PBR), is an 18 kDa protein of the mammalian mitochondrial membrane and is a highly conserved protein among the mammalian. PBR is involved in numerous biological functions, including steroid biosynthesis, mitochondrial oxidative phosporylation and cell proliferation. The presence of PBR at the nuclear subcellular level has been demonstrated in aggressive breast cancer cell line and human glioma cells, where it seems to be involved in cell proliferation. In our previous studies we investigated the presence of nuclear PBR in different hepatic tumour cell lines with regard to binding to [3H] PK 11195 and protein analysis. The results obtained by saturation binding experiments and Scatchard analysis of nuclear PBR density in parallel with the results on the growth curves of the cell lines tested, indicate that the nuclear PBR density correlates inversely with cell doubling time. Moreover, the cell line with high nuclear PBR proliferates in response to PBR ligands, whereas that with low nuclear PBR does not. All these findings support the idea that PBR could play a pivotal role in cell proliferation and this receptor protein could be potentially important either in early diagnosis or chemopreventive strategies against degenerative disease.

Paraneoplastic neurological syndromes (PNS) are remote effects of cancer that may involve any part of the nervous system. Rarity hinders their diagnosis and management and at least 60% of cases do not present a tumor at neurological symptoms onset. An important diagnostic element is detection, in patients' serum or cerebrospinal fluid, of onconeuronal antibodies which recognize antigens expressed by the nervous system and by neoplastic cells during dedifferentiation. Their detection also implies that PNS have autoimmune origin and that immunomodulation could be an effective treatment. The lack of clinical trials due to the rarity of PNS makes it hard to test the efficacy of immunomodulatory therapy, but dividing the diseases into two groups permits preliminary analysis. A humoral immunoresponse prevails in group one and antibodies seem to have a pathogenetic role, indicating antibody removal strategies. Group two are mainly PNS of the central nervous system with autoantibodies directed against intracellular antigens, probably involving a cell-mediated mechanism. Immunotherapy with steroids or cytotoxic immunosuppressive agents may be useful here. Immunomodulatory treatment is always indicated when a tumor is not found but neurological symptoms are progressing, since first line treatment is tumor identification and, where possible, removal.

Trastuzumab is a monoclonal antibody that targets the extracellular domain of HER2, a member of the epidermal growth factor receptor (EGFR) family. Trastuzumab is currently approved for the treatment of breast cancer overexpressing HER2, given alone or in combination with paclitaxel or docetaxel. Trastuzumab pharmacokinetics are characterized by a low systemic clearance, a low volume of distribution (4l) and a very long half-life (28 days) comparable to that of endogenous immunoglobulins G. The elimination pathways are not yet defined and the clinical relevance of trastuzumab kinetic variability is unknown. Whether exposure might correlate with toxic effects or inadequate response has not been explored. No drug-drug interactions have been reported. This is not surprising because based on the current knowledge, no monoclonal antibody (including trastuzumab) has been found to interact with major molecular pharmacokinetic determinants such enzymes, drug transporters or orphan nuclear receptors. Dosage regimens of trastuzumab are similar either it is used in the adjuvant setting (postoperative) or in metastatic disease. According to the official labelling, trastuzumab is given by intravenous perfusion at a dose based on body weight, weekly (metastatic, adjuvant) or 3-weekly (adjuvant). The schedule also includes a loading dose at the initiation of the treatment. The recommended duration of treatment is currently one year (adjuvant) or until the progression of the disease (metastatic). Regarding the adjuvant setting, different dosage regimens have been tested (from 9 weeks to 2 years) but the optimal duration of treatment is unknown. The short course of trastuzumab (9 weeks) appears promising in terms of activity, tolerance and cost but should be compared to 1 or 2-years treatments. In addition, dosing regimens might be optimized by integrating pharmacokinetic elements. In the adjuvant setting, given the more favorable kinetic situation (absence of tumor penetration), a less intense dosage regimen might be appropriate when compared with that used in metastatic disease. Further body weight is weakly related to trastuzumab exposure and it is not proven that it significantly affects clinical activity. These pharmacokinetic considerations may support the use of fixed doses given monthly, on short periods, for the treatment of early breast cancer.

This article reviews the influence of liver functional status on pharmacokinetic interactions due to inhibition and induction of drug-metabolizing enzymes. Recent human studies have shown that the magnitude of inhibitory interactions caused by the reversible CYP1A2 inhibitor fluvoxamine decreases as liver function worsens, and virtually vanishes in patients with more advanced hepatocellular insufficiency. This effect of liver dysfunction is independent of the pharmacokinetic characteristics of the CYP1A2 substrate, since it has been observed with both high- and low-clearance drugs. It is most probably due to reduced uptake of the inhibitory drug by the cirrhotic liver. In order to ascertain whether this is a general phenomenon, the following questions remain to be addressed: 1) whether the inhibition of any CYP isoform is reduced in liver disease; 2) whether the effect of liver dysfunction depends on the chemical nature of the inhibitory drug, since both reduced in vivo inhibition and in vitro uptake by the cirrhotic liver have so far been shown only for basic drugs; 3) lastly, if similar effects can also be observed with irreversible and quasi-irreversible inhibitors, as their accumulation kinetics in the hepatocyte may differ from those of a reversible inhibitor. Although many in vivo and in vitro studies have examined the inducibility of drug-metabolizing enzymes in liver disease, available data are incomplete and conflicting, since both well-preserved and severely curtailed responses to inducing agents have been reported. The reasons for these variable responses are most probably methodological, i.e., differences in the type and degree of liver dysfunction of the animals and patients examined, and in the type and dosage of the inducing agent used. Nonetheless, the results of those few studies which used pathologically homogeneous animal or patient groups suggest that, like basal enzyme expression, drug-inducible expression is also substantially preserved in mild to moderate liver disease, whereas it is lost in severe hepatic dysfunction. For a definitive conclusion, further studies are necessary which examine etiologically homogeneous patient groups and stratify patients rigorously according to their functional hepatic reserve. Such studies should also examine inducers with different physicochemical properties and acting by different mechanisms, since the expression of both hepatic transporters and nuclear receptors may be differentially affected by liver function impairment.