Evaluation of the Cost of Survivorship Care After Allogeneic Hematopoeitic Stem Cell Transplantation-An Analysis of 2 German Transplantation Centers.

The aim of the presented study was to analyze the care expenditure for outpatients after allogeneic hematopoietic stem cell transplantation (alloHSCT) done in accordance with the national, European guidelines and the German Social Law. We performed an analysis of the National and European survivorship care guidelines and in parallel recorded the time expenditure and staff costs separated according to different occupational groups involved in outpatient care at two German transplantation centers [University Hospital Regensburg (UKR) and University Hospital Hamburg-Eppendorf (UKE)]. In addition, we performed a comparison of real costs vs. reimbursed costs according to the standard rating benchmark catalog (EBM), which was supplemented by a survey of German transplantation centers. The results showed that the staff costs are only covered by the EBM for patients without complications during long-term follow-up care-notably, this accounts for 15% of alloHSCT patients. Staff costs for patients requiring treatment of graft-vs.-host disease or relapse of the malignant underlying malignancy exceed to the factor 6.5 (UKR) to 12 (UKE) of the EBM revenue, caused both by the increased duration and frequency of the outpatient visits. As a result of the survey at German transplant centers, 15 out of 18 responding centers reported a lack of cost coverage for follow-up care. Two/15 centers reported that survivorship care is limited to a restricted time, independent of patient's needs, due to a lack of cost reimbursement. The results show that alloHSCT survivorship care of patients requires significant staff resources, which are not covered by the current version of the German EBM catalog. New approaches to finance labor intensive after care of transplant patients are required.

Blood pressure-independent effect of long-term treatment with the soluble heme-independent guanylyl cyclase activator HMR1766 on progression in a model of noninflammatory chronic renal damage.

Nitric oxide formation is impaired in chronic renal failure. The renoprotective effects of a nonhypotensive dose of HMR1766, a direct activator of the heme enzyme soluble guanylyl cyclase was studied in comparison to an ACE-i in the remnant kidney model. Male Sprague-Dawley rats were subtotally nephrectomized (SNX) or sham operated (sham) and left untreated or started on treatment with HMR1766 or ACE-i in non-hypotensive doses. BP, albumin excretion and parameters of renal damage were analyzed. After a 12-week study, urinary albumin excretion was significantly higher in untreated SNX than in sham; this increase was prevented by ACE-i and ameliorated by HMR1766. Relative kidney and left ventricular weight were significantly higher in untreated SNX compared to sham; these changes were completely prevented by HMR1766. In untreated SNX, glomerulosclerosis (1.02 +/- 0.13) was significantly higher than in sham (0.12 +/- 0.04), SNX+HMR1766 (0.27 +/- 0.04) and SNX+ACE-i (0.46 +/- 0.06). Tubulointerstitial changes went in parallel. Increased glomerular cell number after SNX (71.5 +/- 14 vs. 60 +/- 7.3 in sham) was prevented by HMR1766 (55.7 +/- 7.3), but not by ACE-i (66.6 +/- 9). The results document beneficial BP-independent HMR1766 effects on kidney structure and urinary albumin excretion in a noninflammatory model of renal failure and may argue for a novel therapeutic principle.

Biochemistry and pharmacology of novel anthranilic acid derivatives activating heme-oxidized soluble guanylyl cyclase.

The heme-enzyme soluble guanylyl cyclase (sGC) is an ubiquitous NO receptor, which mediates NO downstream signaling by the generation of cGMP. We studied the mechanism of action of the anthranilic acid derivatives 5-chloro-2-(5-chloro-thiophene-2-sulfonylamino-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide sodium salt (HMR1766) (proposed international nonproprietary name, ataciguat sodium) and 2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide (S3448) as a new class of sGC agonists. Both compounds activated different sGC preparations (purified from bovine lung, or crude from human corpus cavernosum) in a concentration-dependent and quickly reversible fashion (EC50 = 0.5-10 microM), with mixed-type activation kinetics. Activation of sGC by these compounds was additive to activation by NO donors, but instead of being inhibited, it was potentiated by the heme-iron oxidants 1H-[1,2,4]-oxdiazolo[3,4-a]quinoxalin-1-one (ODQ) and 4H-8-bromo-1,2,4-oxadiazolo(3,4-d) benz(b)(1,4)oxazin-1-one (NS2028), suggesting that the new compounds target the ferric heme sGC isoform. Protoporphyrin IX acted as a competitive activator, and zinc-protoporphyrin IX inhibited activation of heme-oxidized sGC by HMR1766 and S3448, whereas heme depletion of sGC by Tween 20 treatment reduced activation. Both compounds increased cGMP levels in cultured rat aortic smooth muscle cells; induced vasorelaxation of isolated endothelium-denuded rat aorta, porcine coronary arteries, and human corpus cavernosum (EC50 1 to 10 microM); and elicited phosphorylation of the cGMP kinase substrate vasodilator-stimulated phosphoprotein at Ser239. HMR1766 intravenous bolus injection decreased arterial blood pressure in anesthetized pigs. All of these pharmacological responses to the new compounds were enhanced by ODQ and NS2028. Our findings suggest that HMR1766 and S3448 preferentially activate the NO-insensitive heme-oxidized form of sGC, which exists to a variable extent in vascular tissues, and is a pharmacological target for these new vasodilator drugs.

Effects of combined inhibition of the Na+-H+ exchanger and angiotensin-converting enzyme in rats with congestive heart failure after myocardial infarction.

1 We investigated the single vs the combined long-term inhibition of Na(+)-H(+) exchanger-1 (NHE-1) and ACE in rats with congestive heart failure induced by myocardial infarction (MI). 2 Rats with MI were randomized to receive either placebo, cariporide (3000 p.p.m. via chow), ramipril (1 mg kg(-1) day(-1) via drinking water) or their combination for 18 weeks starting on day 3 after surgery. 3 Cardiac morphology and function was assessed by echocardiography and by means of a 2.0 F conductance catheter to determine left ventricular (LV) pressure volume relationships. 4 MI for 18 weeks resulted in an increase in LV end-diastolic diameter (LVDed) in the placebo-treated group when compared to sham (placebo: 1.1+/-0.04 cm; sham: 0.86+/-0.01; P<0.05). Combined inhibition of NHE-1 and ACE, but not the monotherapies, significantly reduced LVDed (1.02+/-0.02 cm). 5 Preload recruitable stroke work (PRSW), dp/dt(max) (parameter of systolic function) and end-diastolic pressure volume relationship (EDPVR, diastolic function) were significantly impaired in placebo-treated MI group (PRSW: 39+/-7 mmHg; dp/dt(max): 5185+/-363 mmHg s(-1); EDPVR: 0.042+/-0.001 mmHg microl(-1); all P<0.05). Cariporide treatment significantly improved PRSW (64+/-7 mmHg), dp/dt(max) (8077+/-525 mmHg s(-1)) and EDPVR (0.026+/-0.014 mmHg microl(-1)), and reduced cardiac hypertrophy in rats with MI. Combined inhibition of NHE-1 and ACE had even a more pronounced effect on PRSW (72+/-5 mmHg) and EDPVR (0.026+/-0.014 mmHg microl(-1)), as well as cardiac hypertrophy that, however, did not reach statistical significance compared to cariporide treatment alone. 6 The NHE-1 inhibitor cariporide significantly improved LV remodeling and function in rats with congestive heart failure induced by MI. The effect of cariporide was comparable or tended to be stronger (e.g. systolic function) compared to ramipril. Combined treatment with cariporide and ramipril tended to be more effective on LV remodeling in rats with heart failure than the single treatments. Thus, inhibition of the NHE-1 may be a promising novel therapeutic approach for the treatment of congestive heart failure.

Inhibition of Na+-H+ exchange by cariporide reduces inflammation and heart failure in rabbits with myocardial infarction.

The aim of this study was to assess the effects of the Na+-H+ exchange inhibitor cariporide on left ventricular (LV) morphology and function as well as inflammation in rabbits with heart failure. Rabbits with myocardial infarction (MI) and sham controls were randomized to receive either standard chow or chow supplemented with cariporide for 9 weeks. LV morphology was determined by echocardiography. LV systolic and diastolic function was assessed under load-dependent and -independent conditions by analysis of LV pressure-volume loops using piezo-electric crystals. Plasma concentrations of C-reactive protein and aldosterone were measured. Rabbits with MI developed LV dilatation that was reduced by cariporide. Systolic and diastolic LV function was impaired in rabbits with MI when compared to sham, as indicated by a decreased dP/dtmax (MI: 3537 +/- 718 mmHg s(-1), sham: 5839 +/- 247 mmHg s(-1), P < 0.05), the load-independent preload recruitable stroke work (PRSW)(MI: 22 +/-7 mmHg, sham: 81 +/- 23 mmHg, P < 0.05) and a reduction in the time constant of relaxation tau (tau) (MI: 27+/-1 ms, sham: 17+/-1 ms, P < 0.05), and significantly improved by cariporide (dP/dtmax: 4586 +/- 374 mmHg s(-1), PRSW: 67 +/- 18 mmHg, tau: 20 +/- 2 ms; P < 0.05 vs MI/control). Induction of MI was associated with an increase in aldosterone and CRP, indicating activation of the neurohormonal and the inflammatory system that were largely reduced by cariporide. Cariporide improves LV morphology and function post MI and suppresses inflammation and neurohormonal activation in congestive heart failure (CHF). Na+-H+ exchange inhibition may represent a new pharmaceutical approach for the treatment of CHF.

Selective Na+/H+ exchange inhibition by cariporide reduces liver fibrosis in the rat.

The aim of this study was to evaluate the effect of cariporide, a selective Na(+)/H(+) exchange inhibitor, on isolated and cultured hepatic stellate cells (HSCs) and in 2 in vivo models of rat liver fibrosis. Platelet-derived growth factor (PDGF)-induced HSC proliferation, evaluated by measuring the percentage of bromodeoxyuridine-positive cells, was significantly inhibited by cariporide, with a maximal effect at 10 micromol/L. Incubation with cariporide did not inhibit PDGF-induced extracellular-regulated kinase 1/2 (ERK1/2), Akt (a downstream component of the phosphatidylinositol [PI]-3 kinase pathway), and protein kinase C (PKC) activation but reduced PDGF-induced activation of the Na(+)/H(+) exchanger, with a maximal effect at 10 micromol/L. Rats treated with dimethylnitrosamine (DMN; 10 mg/kg) for 1 and 5 weeks received a diet with or without 6 ppm cariporide. Treatment with cariporide reduced the degree of liver injury, as determined by alanine aminotransferase (ALT) values, also when administered after the induction of hepatic damage. This was associated with reduced HSC activation and proliferation and reduced collagen deposition, as determined by morphometric evaluation of alpha-smooth muscle actin (SMA)/proliferating cell nuclear antigen-positive cells and percentage of Sirius red-positive parenchyma, respectively. Moreover, cariporide was also able to reduce alpha(1)I procollagen messenger RNA (mRNA) expression. Similar effects were observed in bile duct-ligated (BDL) rats. In conclusion, selective inhibition of the Na(+)/H(+) exchanger by cariporide may represent an effective therapeutic strategy in the treatment of hepatic fibrosis.