Differential cytotoxicity of phospholipid analogues to pathogenic Acanthamoeba species and mammalian cells

OBJECTIVES: Previous studies have reported the ability of several phospholipid analogues to successfully inhibit the growth of Acanthamoeba species in vitro. This study tests further phospholipid analogues, either as free drug or in liposomal formulations, and unlike previous studies, examines their comparative toxicities to mammalian cells. METHODS: The relative cytotoxic activities of the phospholipid derivatives hexadecyl-PC, octadecyl-PC, elaidyl-PC, erucyl-PC and edelfosine, against Acanthamoeba castellanii, Acanthamoeba polyphaga and a rabbit corneal epithelial (RCE) cell line, was determined by the alamarBlue assay. Free and liposomal formulations were compared for hexadecyl-PC and elaidyl-PC. RESULTS: Both hexadecyl-PC and octadecyl-PC (IC50 values between 3.9 and 7.8 microM) demonstrated considerable activity against A. castellanii, as did elaidyl-PC (IC50 values between 15.6 and 31.25 microM). Both hexadecyl-PC and elaidyl-PC also proved effective against A. polyphaga (IC50 values between 15.6 and 31.25 and between 31.25 and 62.5 microM, respectively). In contrast, neither erucyl-PC nor edelfosine was inhibitory against either Acanthamoeba species. The growth of RCE cells was inhibited by octadecyl-PC, erucyl-PC and edelfosine (octadecyl-PC and erucyl-PC IC50 values between 7.8 and 15.6 microM and edelfosine IC50 values between 31.25 and 62.5 microM). Liposomal formulations of hexadecyl-PC and elaidyl-PC were less effective than free drug against both Acanthamoeba species. CONCLUSIONS: These results demonstrate that hexadecyl-PC has the highest therapeutic index and is the most promising for the treatment of acanthamoebiasis.     

Erythrocyte nucleotide stability and plasma hypoxanthine concentrations: improved ATP stability with short-term storage at room temperature

We have measured erythrocyte nucleotide concentrations at timed intervals over 24 h in heparinised blood stored at 4 degrees C, room temperature, or 37 degrees C. The objective was to determine whether the grossly altered NAD concentrations found in the erythrocytes of patients with two different inherited purine disorders could be related to altered stability or turnover rates. An unexpected finding was the improved stability of all erythrocyte nucleotides in blood stored at room temperature compared with 4 degrees C. Not only was the breakdown of ATP greater at 4 degrees C compared with room temperature, higher hypoxanthine concentrations were present in the plasma associated with a fictitious increment in inosine. NAD and NADP, by contrast, showed remarkable stability in both control and patient erythrocytes, irrespective of their original value. Although these studies failed to establish an explanation for the altered NAD levels in the patients, the superior ATP stability in blood stored at room temperature in the erythrocytes from both patients and controls suggests that current practices of storing blood on ice for short-term studies require re-evaluation.     

Head Computed Tomography Is Not Useful for Evaluating Patients Change in Mental Status Following Total Joint Arthroplasty

We retrospectively reviewed 187 patients who presented with neurologic abnormality after total joint arthroplasty to establish the incidence of diagnosed organic brain disorders in these patients and determine the utility of advanced head imaging studies. 139 of 187 (74.3%) patients underwent imaging for altered mental status (AMS) and 48 patients for a focal neurologic deficit (FND). Acute findings on head imaging were more common in the FND group. The incidence of stroke and transient ischemic attack was significantly lower in the AMS group compared to FND group (Stroke: 0% vs 12.5%, p < 0.001; TIA: 0% vs. 16.7%, P < .001). Advanced head imaging for evaluation of TJA patients with a change in mental status is of low yield. An algorithm for evaluation of these patients is proposed.     

Formulary Selection Criteria for Biosimilars: Considerations for US Health-System Pharmacists

Pharmacists will play a key role in evaluating biosimilars for formulary inclusion in the United States. As defined by US law, a biosimilar is a biologic that is highly similar to its reference product, notwithstanding minor differences in clinically inactive components, and should not have clinically meaningful differences from its reference product in safety, purity, and potency. We review biosimilars and the current European Union and US regulatory pathways for biosimilars. Furthermore, we propose a checklist of considerations to ensure that US pharmacists thoroughly evaluate future biosimilars for formulary inclusion. Included in the checklist are considerations related to the availability of preapproval and postapproval safety and efficacy data; differences in product characteristics and immunogenicity between the biosimilar and reference product; manufacturer-related parameters that can affect a reliable supply of quality products; health-system and patient perspectives on product packaging, labeling, storage, and administration; costs and insurance coverage; patient education; interchangeability and differences in the range of indications; and evaluation of institutions’ information technology systems.Key Words: biologics, biosimilars, formulary, pharmacovigilance, reference productThe first biosimilar was licensed for use in humans in the European Union (EU) in 2006; since that time, a total of 11 distinct biosimilar products have been approved for marketing in the EU under 19 different trade names (2 have since been withdrawn) (1 As more patents for biologic drugs approach expiration, the number of biosimilars entering the market is expected to grow.^2,3 Yet, as the market awaits the first US biosimilar approval, questions remain about how this new class of drugs will be evaluated for incorporation into US formularies. In the US, the Biologics Price Competition and Innovation Act of 2009 (BPCI Act)—a part of the Affordable Care Act of 2009—provided for an abbreviated regulatory approval pathway for biosimilars.^4,5 As defined by the BPCI Act, a biosimilar is a biologic product that is highly similar to its reference product, notwithstanding minor differences in clinically inactive components; a biosimilar is to have no clinically meaningful differences from its reference product in terms of safety, purity, and potency. ⁴

Table 1.

Biosimilars authorized in the European Union^a