Social austerity versus structural reform in European health systems: a four-country comparison of health reforms.

Cost containment has captured the attention of health policymakers in most OECD countries, and deliberations about creating powerful financial incentives dominate health care politics. Some European health systems are now implementing hospital payment schemes that mirror the U.S. model of diagnosis-related groups (DRGs) and are raising premiums and copayment levels in an effort to limit public expenditures. Though financial incentives may indeed help rein in health expenditures, focusing predominantly on financial incentives hinders due consideration of needed structural reforms that improve the continuity, quality, and appropriateness of health care service delivery. This article focuses on the structural specifics of two legally enacted health insurance systems (Germany and Austria) and two national health systems (Great Britain and Denmark) to discuss the influence of structural characteristics on cost-containment efforts. Structural reform strategies discussed include increasing reliance on general practitioners, improving coordination of community and hospital-based specialty care, addressing the stark divide between ambulatory and hospital-based care that exists in some European health systems, and improving continuity of care by better integrating medical and social care sectors. Also discussed is the relative focus on financial incentives versus structural deficits in recent European-health care reform strategies.     

Assessment of the combined approach of N-alkylation and salt formation to enhance aqueous solubility of tertiary amines using bupivacaine as a model drug.

Quaternary prodrug types of poorly water-soluble tertiary amines have been shown to exhibit significantly enhanced solubilities as compared to the parent amine. In the present study the combined effect of N-alkylation and salt formation to enhance aqueous solubility of tertiary amines have been investigated using bupivacaine as a model compound. X-ray structure analyses of selected salts were included to investigate the potential existence of correlations between salt solubility and crystal packing modes. Alkyl groups were methyl, ethyl, propyl, and butyl and the derivatives were isolated as their iodide salts. Chloride, mesylate, formate, acetate, glycolate, and tosylate salts were obtained by anion exchange of the N-methyl-bupivacaine derivative. N-Alkylation and salt formation afforded quaternary ammonium salts possessing pH-independent aqueous solubilities far exceeding that of the parent tertiary amine (up to a factor of 3200 at pH 8). A moderate reduction in solubility with increasing length of the alkyl chain was observed for the iodide salts of the N-alkylated bupivacaine derivatives. In case of the N-methyl-bupivacaine derivative variation of the counterion had a significant impact on the solubility with the iodide salt being 200 times less soluble than the chloride salt. X-ray analysis revealed that both the alkyl substituent and the anionic counterion influenced salt packing modes, however, in an unpredictable manner making establishment of quantitative correlations between crystal packing and solubility difficult even for a series of closely related derivatives.     

Implications of the prostate cancer prevention trial: a decision analysis model of survival outcomes.

PURPOSE: To assess the estimated effect of finasteride prevention of prostate cancer on overall survival. METHODS: Data for our decision tree model came from men in the two arms (finasteride or placebo) of the Prostate Cancer Prevention Trial (PCPT) and from clinically localized prostate cancer patients studied for long-term survival outcomes. Our model compared survival outcomes for men treated with finasteride or placebo. Prostate cancer rates were based on the 7-year period prevalence of prostate cancer detected in the PCPT; survival probabilities were abstracted from the long-term outcome studies. We assessed variability in the PCPT and long-term survival studies to test the variability of our model. RESULTS: Survival advantages for a finasteride-treated (v those not treated with finasteride) population include gains of 1.7 months in 15-year cause-specific survival (assuming finasteride-altered Gleason scores and prostate cancer prevalence rates in the PCPT), of up to 3 months for cancers treated conservatively or surgically (assuming finasteride does not alter Gleason scores), and of 0.35 months (assuming the rate of cancers detected by for-cause biopsies in the PCPT), which increased to 1.7 months when assuming a 30% rate of biopsy-detected cancer in the PCPT placebo group. Model-variability analyses support several survival benefits associated with finasteride (eg, the uniform benefits assuming finasteride does not alter Gleason scores) but question certain others (eg, in 15-year recurrence-free survivals assuming finasteride does alter Gleason scores). CONCLUSION: Finasteride can impart survival benefits according to our model, especially when we assume that finasteride does not alter Gleason scores.     

Cooperative cytotoxicity of proteasome inhibitors and tumor necrosis factor-related apoptosis-inducing ligand in chemoresistant Bcl-2-overexpressing cells.

PURPOSE: Bcl-2 overexpression is frequently detected in lymphoid malignancies, being associated with poor prognosis and reduced response to therapy. Here, we evaluated whether Bcl-2 overexpression affects the cytotoxic activity of proteasome inhibitors taken alone or in association with conventional anticancer drugs or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). EXPERIMENTAL DESIGN: Jurkat cells engineered to overexpress Bcl-2 were treated with proteasome inhibitors (MG132, epoxomicin, and bortezomib), anticancer drugs (etoposide and doxorubicin), TRAIL, or combinations of these compounds. Cell death and loss of mitochondrial transmembrane potential were detected by flow cytometry. Cytosolic relocalization of cytochrome c and SMAC/Diablo, caspase cleavage, and Bcl-2 and Mcl-1 levels were determined by immunoblotting. Nuclear factor-kappaB inhibition was done by retroviral transduction with a dominant-negative mutant of IkappaBalpha. RESULTS: Bcl-2 overexpression results in significant inhibition of apoptosis in response to proteasome inhibitors, antiblastics, and TRAIL. Addition of TRAIL to proteasome inhibitors results in a synergistic cytotoxic effect in Bcl-2-overexpressing cells, whereas this result is not reproduced by the combination of proteasome inhibitors with antiblastic drugs. Importantly, proteasome inhibitors plus TRAIL induce mitochondrial dysfunction irrespective of up-regulated Bcl-2. Bcl-2 cleavage to a fragment with putative proapoptotic activity and elimination of antiapoptotic Mcl-1 may both play a role in proteasome inhibitors-TRAIL cooperation. Conversely, nuclear factor-kappaB inhibition by proteasome inhibitors is per se insufficient to explain the observed synergy. CONCLUSIONS: Combined proteasome inhibitors and TRAIL overcome the apoptotic threshold raised by Bcl-2 and may prove useful in the treatment of chemoresistant malignancies with up-regulated Bcl-2.     

Bioreversible quaternary N-acyloxymethyl derivatives of the tertiary amines bupivacaine and lidocaine—synthesis, aqueous solubility and stability in buffer, human plasma and simulated intestinal fluid

Design of water-soluble prodrugs may constitute a means to improve the oral bioavailability of drugs suffering from dissolution rate-limited absorption. The model drug bupivacaine containing a tertiary amine function has been converted into bioreversible quaternary N-acyloxymethyl derivatives. The pH-independent solubility of the N-butanoyloxymethyl derivate exceeded 1000 mg ml⁻¹ corresponding approximately to a 10,000-fold increase in water solubility compared to that of bupivacaine base. The kinetics of hydrolysis of the prodrugs was studied in the pH range 0.1–9.8 (37 °C). Decomposition was found to follow first-order kinetics and U-shaped pH-rate profiles were constructed. The observed differences between the hydrolytic lability of the derivatives might most likely be ascribed to steric effects. In most cases, the prodrugs were quantitatively converted into bupivacaine. However, for the hydrolysis of the N-butanoyloxymethyl derivative at neutral to slightly alkaline pH parallel formation of bupivacaine (80%) and an unknown compound X (20%) was observed. LC–MS analysis of the latter compound suggests that an aromatic imide structure has been formed from an intramolecular acyl transfer reaction involving a nucleophilic attack of the amide nitrogen atom on the ester carbonyl carbon atom. Whereas the derivatives were poor substrates for plasma enzymes; they were hydrolyzed rapidly to parent bupivacaine in the presence of pancreatic enzymes (simulated intestinal fluid) at 37 °C. The data indicate that such prodrugs possess sufficient stability in the acidic environment of the stomach to reach the small intestine in intact form where they can be cleaved efficiently by action of pancreatic enzymes prior to drug absorption. Thus, the N-acyloxymethyl approach might be of potential utility to enhance oral bioavailability of tertiary amines exhibiting pK_a values below approximately 6 and intrinsic solubilities in the low μM range.     

Attention to Background Strain Is Essential for Metabolic Research: C57BL/6 and the International Knockout Mouse Consortium

The International Knockout Mouse Consortium (IKMC) introduces its targeted constructs into C57BL/6N embryonic stem cells. However, breeding with a Cre-recombinase and/or Flp-recombinase mouse is required for the generation of a null allele with the IKMC cassette. Many recombinase strains are in the C57BL/6J background, resulting in knockout animals on a mixed strain background. This can lead to variability in metabolic data and the use of improper control groups. While C57BL/6N and C57BL/6J are derived from the same parental C57BL/6 strain, there are key genotypic and phenotypic differences between these substrains. Many researchers may not even be aware of these differences, as the shorthand C57BL/6 is often used to describe both substrains. We found that 58% of articles involving genetically modified mouse models did not completely address background strain. This review will describe these two substrains and highlight the importance of separate consideration in mouse model development. Our aim is to increase awareness of this issue in the diabetes research community and to provide practical strategies to enable researchers to avoid mixed strain animals when using IKMC knockout mice.