TrastuzumabOrman, Jennifer; Perry, Caroline
doi: 10.2165/00003495-200767180-00009pmid: 18062723
▲ Trastuzumab is a humanised IgG1 monoclonal antibody, which selectively binds to the human epidermal growth factor receptor 2 (HER2), inhibiting cell proliferation and survival in HER2-dependent tumours.
▲ In a randomised phase III trial in postmenopausal women with HER2 and hormone receptor (HR) copositive metastatic breast cancer, median progression-free survival (primary endpoint) was significantly longer in patients receiving intravenous trastuzumab plus oral anastrozole than in those receiving anastrozole alone.
▲ Overall response rate and clinical benefit rate were also significantly higher, and median time to disease progression was significantly longer with trastuzumab plus anastrozole versus anastrozole alone.
▲ There were no reports of new or unexpected adverse events with trastuzumab plus anastrozole combination therapy in the randomised phase III trial.
▲ In a noncomparative phase II study of trastuzumab plus letrozole in postmenopausal women with HER2 and HR co-positive metastatic breast cancer, the majority of adverse events were mild or moderate in severity.
Treatment of Lysosomal Storage DisordersRohrbach, Marianne; Clarke, Joe
doi: 10.2165/00003495-200767180-00005pmid: 18062719
Enzyme replacement therapy (ERT) as treatment for lysosomal storage diseases (LSDs) was suggested as long ago as 1966 by De Duve and Wattiaux. However, it took >35 years to demonstrate the safety and effectiveness of ERT for type 1 Gaucher’s disease. An important breakthrough was certainly the enactment of legislation in the US, designed to encourage commercialisation of products developed in academic institutions for pharmaceutical companies to invest in treatments for rare diseases. The principles elaborated in the development of the treatment of Gaucher’s disease were subsequently applied to the development of ERT of other LSDs. The safety and effectiveness of ERT for Fabry’s disease, mucopolysaccharidoses (MPS) I, MPS II and MPS VI, as well as for Pompe’s disease have been demonstrated in well designed clinical trials, and the treatments are now commercially available throughout the world. Several questions remain to be answered. The long-term effectiveness of most of the treatments has not yet been established. What is reversible by ERT and what may not be reversible but is preventable, is not yet clear. The pathology in some tissues, such as the brain, is inaccessible to ERT, indicating that some manifestations of the LSD will not respond to the treatment. The extent of this problem is still unclear. The cost of ERT is very high, creating problems for third-party payers, which has strained reimbursement schemes based on the demonstration of acceptable cost effectiveness. ERT of LSDs represents the most important advance in the treatment of this class of diseases. The information that is currently being collected as part of large-scale observational studies will help to establish the full potential of the treatment.
Management of Epilepsy during PregnancyBattino, Dina; Tomson, Torbjörn
doi: 10.2165/00003495-200767180-00007pmid: 18062721
Managing epilepsy during pregnancy is to balance the maternal and fetal risks associated with uncontrolled seizures against the potential teratogenic effects of antiepileptic drugs (AEDs). A rational approach requires knowledge of such risks as well as an understanding of the effects of pregnancy on seizure control and of gestational effects on AED disposition. Uncontrolled tonic-clonic seizures are potentially hazardous to the mother and, although strict evidence is lacking, are generally also assumed to be more harmful to the fetus than are AEDs. However, infants who have been exposed to AEDs in utero run an increased risk of congenital malformations: approximately twice the rate reported in the general population. Earlier literature has largely failed to demonstrate differences in birth defect rates with different treatment regimens, which can be ascribed mainly to insufficient sample sizes. More recent data have indicated higher malformation rates with exposure to valproic acid compared with some other major AEDs. The teratogenic effects of valproic acid appear to be dose dependent, with higher risks at dosage levels >1000 mg/day. Polytherapy involving treatment with more than one AED also seems to be associated with an increased risk of birth defects compared with monotherapy. Recently, a few small-scale studies have investigated the possibility that exposure to AEDs in utero may adversely affect the postnatal cognitive development of the offspring. Some of these studies have suggested that valproic acid poses a higher risk compared with other AEDs in this respect. These signals are important, but must be interpreted with caution because of the methodological shortcomings of the studies and because adequately powered prospective studies are necessary to draw firm conclusions. More reassuring findings have emerged regarding the obstetric outcome of pregnancy and the risk of worsening of epilepsy during pregnancy. In particular, it seems that the risk of obstetric complications is not significantly increased. Furthermore, most of the women with epilepsy have no change in their seizure frequency during pregnancy. The disposition of many AEDs may change during pregnancy, reflected in declining plasma drug concentrations. This seems to be most pronounced for lamotrigine and possibly also for oxcarbazepine, and can result in break-through seizures.
The Role of Sulodexide in the Treatment of Diabetic NephropathyWeiss, Ram; Niecestro, Robert; Raz, Itamar
doi: 10.2165/00003495-200767180-00004pmid: 18062718
Diabetic nephropathy is an important cause of morbidity and mortality in patients with either type 1 or type 2 diabetes mellitus. The pathogenesis and natural history of diabetic nephropathy, characterised by a progressive decline in glomerular function, were initially described in patients with type 1 diabetes. Reports that describe the glomerulopathy and progression of renal disease in patients with type 2 diabetes suggest that the disease process is similar to that observed in patients with type 1 diabetes with diabetic nephropathy. An emerging body of evidence supports the notion that glomerular capillary wall and mesangial alterations in diabetic nephropathy involve pathobiochemical alterations of glycoproteins in these structures. Evidence in experimental animals rendered diabetic, reveal that the administration of heparin and other anionic glycoproteins can effectively prevent the biochemical alterations that promote albuminuria. Clinical reports of the use of sulodexide, a preparation of low molecular weight glycosaminoglycan polysaccharides, have shown that proteinuria is significantly diminished in patients with diabetic nephropathy, even when these patients are receiving either an ACE inhibitor or angiotensin receptor antagonist.