Anticancer therapeutic potential of phosphorylated galactosylated chitosan against N-nitrosodiethyl amine-induced hepatocarcinogenesis.

Chitosan is a natural polyfunctional polymer that can be modified to achieve compounds with tailored properties for targeting and treating different cancers. In this study, we report the development and anticancer potential of phosphorylated galactosylated chitosan (PGC). The synthesized compound was characterized by FT-IR, NMR, and mass spectroscopy. The interaction of PGC with asialoglycoprotein receptors (ASGPR) and cellular internalization in HepG2 cells was studied using in silico and uptake studies respectively. PGC was evaluated for its metal chelating, ferric ion reducing, superoxide, and lipid peroxide (LPO) inhibiting potential. Further, anticancer therapeutic potential of PGC was evaluated against N-nitrosodiethylamine (NDEA)-induced hepatocellular carcinoma in a mice model. After development of cancer, PGC was administered to the treatment group (0.5 mg/kg bw, intravenously), once a week for 4 weeks. Characterization studies of PGC revealed successful phosphorylation and galactosylation of chitosan. A strong interaction of PGC with ASGP-receptors was predicted by computational studies and cellular internalization studies demonstrated 98.76 ± 0.53% uptake of PGC in the HepG2 cells. A good metal chelating, ferric ion reducing, and free radical scavenging activity was demonstrated by PGC. The anticancer therapeutic potential of PGC was evident from the observation that PGC treatment increased number of tumor free animals (50%) (6/12) and significantly (p ≤ 0.05) lowered tumor multiplicity as compared to untreated tumor group.

Influence of traditional medicines on the activity of keratinocytes in wound healing: an in-vitro study.

Natural medicinal systems such as Ayurveda and folk medicine has remedies for wound management. However, the exact cellular and extracellular mechanisms involved in the healing process and its influence on keratinocytes is less discussed. Therefore, the present study was designed to evaluate the effect of certain natural wound healing medicines on the biology of the keratinocytes/HaCaT cells. Test materials such as honey (H), ghee (G), aqueous extracts of roots of Glycyrrhiza glabra (GG) and leaves of Nerium indicum (NI) were considered. The HaCaT cells were treated with the test materials singly and in combinations (H+G, all combined [Tot]) for a specific period (24, 48, and 72 hours). The cells were then subjected to cytotoxicity/proliferation and migration/scratch assays. All the test materials, except NI, were non-cytotoxic and showed increased cell proliferation at variable concentrations. Significant observations were made in the groups treated with honey (100 µg/ml at 48 hours, P<0.05; 1,000 µg/ml at 72 hours, P<0.05), GG (all concentrations at 48 hours, P<0.05; 750 µg/ml at 72 hours, P<0.05), H+G (250 µg/ml at 24 hours, P<0.001; 500 µg/ml at 48 and 72 hours, P<0.05), and Tot (50 µg/ml at 24, 48 and 72 hours, P<0.01). In the in-vitro wound healing assay, all the treated groups showed significant migration and narrowing of the scratch area by 24 and 48 hours (P<0.001) compared to control. The results obtained from the present study signifies the positive influence of these natural wound healing compounds on keratinocytes/HaCaT cells.

Influence of traditional medicines on the activity of keratinocytes in wound healing: an in-vitro study / 대한해부학회지

Natural medicinal systems such as Ayurveda and folk medicine has remedies for wound management. However, the exact cellular and extracellular mechanisms involved in the healing process and its influence on keratinocytes is less discussed. Therefore, the present study was designed to evaluate the effect of certain natural wound healing medicines on the biology of the keratinocytes/HaCaT cells. Test materials such as honey (H), ghee (G), aqueous extracts of roots of Glycyrrhiza glabra (GG) and leaves of Nerium indicum (NI) were considered. The HaCaT cells were treated with the test materials singly and in combinations (H+G, all combined [Tot]) for a specific period (24, 48, and 72 hours). The cells were then subjected to cytotoxicity/proliferation and migration/scratch assays. All the test materials, except NI, were non-cytotoxic and showed increased cell proliferation at variable concentrations. Significant observations were made in the groups treated with honey (100 µg/ml at 48 hours, P<0.05; 1,000 µg/ml at 72 hours, P<0.05), GG (all concentrations at 48 hours, P<0.05; 750 µg/ml at 72 hours, P<0.05), H+G (250 µg/ml at 24 hours, P<0.001; 500 µg/ml at 48 and 72 hours, P<0.05), and Tot (50 µg/ml at 24, 48 and 72 hours, P<0.01). In the in-vitro wound healing assay, all the treated groups showed significant migration and narrowing of the scratch area by 24 and 48 hours (P<0.001) compared to control. The results obtained from the present study signifies the positive influence of these natural wound healing compounds on keratinocytes/HaCaT cells.

Sodium valproate enhances doxorubicin-induced cognitive dysfunction in Wistar rats.

BACKGROUND: Increasing number of scientific reports have highlighted the role of histone acetylation/deacetylation in neurodegenerative conditions, including chemotherapy-induced cognitive dysfunction (also known as chemobrain). Multiple sources state that increased activity of histone deacetylases (HDACs) play a detrimental role in chemobrain. In the present study, sodium valproate, a well-known HDAC inhibitor, was explored for its neuroprotective potential against chemobrain development. METHODS: Doxorubicin (DOX), a chemotherapeutic agent, was used to induce chemobrain in experimental animals while treating with sodium valproate simultaneously. The animals were subjected to novel object recognition test (NORT) in order to assess their cognitive status and further, brain antioxidant levels were estimated. The animal body weights and survival were noted throughout the period of the study. Blood parameters such as red blood cell count, white blood cell count and haemoglobin levels were also measured. RESULTS: Our findings are in contradiction to the known neuroprotective properties of valproic acid. We observed that sodium valproate failed to prevent chemobrain development in DOX treated animals. In fact, treatment with sodium valproate dose dependently worsened cognitive status in DOX treated animals including their brain antioxidant status, possibly leading to neuronal damage through free radical induced toxicity. CONCLUSION: The present study highlights the caution that needs to be exercised in projecting HDAC inhibitors as in vivo neuroprotective agents, due to the complexity of existing neurological pathways and the diverse roles of histone deacetylases.

Identifying the structure-activity relationship of leelamine necessary for inhibiting intracellular cholesterol transport.

Leelamine is an anticancer chemotherapeutic agent inhibiting intracellular cholesterol transport. Cell death mediated by leelamine occurs due to the lysosomotropic property of the compound, its accumulation in the lysosome, and inhibition of cholesterol transport leading to lack of availability for key processes required for functioning of cancer cells. The present study dissects the structure-activity-relationship of leelamine using synthesized derivatives of leelamine and abietic acid, a structurally similar compound, to identify the moiety responsible for anti-cancer activity. Similar to leelamine, all active derivatives had an amino group or a similar moiety that confers a lysosomotropic property to the compound enabling its accumulation in the lysosome. Active derivatives inhibited intracellular cholesterol transport and hindered xenografted melanoma tumor development without obvious systemic toxicity. In silico studies suggested that active derivatives accumulating in lysosomes bound to NPC1, a protein responsible for cholesterol export from the lysosome, to inhibit its activity that then caused accumulation, and lack of cholesterol availability for other key cellular activities. Thus, active derivatives of leelamine or abietic acid maintained lysosomotropic properties, bound to NPC1, and disrupted cellular cholesterol transport as well as availability to retard tumor development.

Bulbophyllum sterile petroleum ether fraction induces apoptosis in vitro and ameliorates tumor progression in vivo.

Orchids of the genus Bulbophyllum have been reported to possess antitumor activity. Present study investigated the possible antitumor activity of the active fraction of bulb and root of Bulbophyllum sterile. Alcoholic extract along with petroleum ether, dichloromethane and ethyl acetate fractions were subjected to SRB assay in HCT-116, MDA-MB-231 and A549 cell lines. The active fractions were further evaluated for apoptosis, expression of apoptotic signaling proteins, comet assay and cell cycle analysis. Furthermore, they were assessed for in vivo antitumor activity in Ehrlich ascites carcinoma model. Petroleum fraction of bulbs (PFB) and roots (PFR) was found to be most active in HCT-116 cell lines with IC50 value of 94.2±6.0 and 75.7±9.8, respectively. Apoptosis was evident from acridine orange/ethidium bromide staining along with the expression of phospho-p53 and phospho-Bad. Both PFB and PFR arrested G2/M phase of the cell cycle with 32.6% and 49.4% arrest, respectively compared to 17.5% arrest with control. An increase in mean life span and hepatic antioxidant levels was observed with PFB and PFR treatment in EAC inoculated mice. The results suggested that the active fractions of bulbs and roots possess anticancer activity likely by inducing apoptosis through phospho-p53 dependent pathway.

In vitro and in vivo evaluation of novel cinnamyl sulfonamide hydroxamate derivative against colon adenocarcinoma.

The potential of cinnamic acid as an anti-inflammatory and anti-cancer agent has been studied previously. In our investigation, novel bio-isosters of cinnamyl sulfonamide hydroxamate were synthesized, characterized and confirmed for their structure and evaluated for cytotoxicity. Three NCEs namely, NMJ-1, -2 and -3 showed cell-growth inhibition in 6 human cancer cell lines with IC50 at the range of 3.3±0.15-44.9±2.6 µM. The hydroxamate derivatives of cinnamyl sulfonamide are reported inhibitors of HDAC enzyme. Thus, the effectiveness of these molecules was determined by whole cell HDAC assay in HCT 116 cell line. NMJ-2 (0.41±0.01 µM) exhibited better enzyme inhibition (IC50) compared to SAHA (2.63±0.07). In order to evaluate induction of apoptosis by treatment, Hoechst 33342 and AO/EB nuclear staining methods were used. Further, cell cycle analysis, Annexin V binding and caspase 3/7 activation assays were performed by flow cytometry where NMJ-2 significantly arrested the cell cycle at G2/M phase, increased Annexin V binding to the cell surface and activation of caspase-3/7. Bax/Bcl-2 ratio was observed by Western blot and showed an increase with NMJ-2 treatment. This was comparable to standard SAHA. The acute toxicity study (OECD-425) showed that NMJ-2 was safe up to 2000 mg/kg in rats. 1,2-Dimethyl hydrazine (DMH) was used to produce experimental colon adenocarcinoma in Wistar rats. 5-FU and NMJ-2 (100 mg/kg p.o. and 10 mg/kg i.p. once daily for 21 days, respectively) were administered to the respective groups. Both treatments significantly reduced ACFs, adenocarcinoma count, TNF-α, IL-6, nitrite and nitrate levels in colonic tissue. Our findings indicate that NMJ-2 has potent anti-cancer activity against colon cancer, by acting through HDAC enzyme inhibition and activation of intrinsic mitochondrial apoptotic pathway, with additional anti-inflammatory activity.

Discovery of benzo[d]imidazo[5,1-b]thiazole as a new class of phosphodiesterase 10A inhibitors.

The design, synthesis and structure activity relationship studies of a series of compounds from benzo[d]imidazo[5,1-b]thiazole scaffold as phosphodiesterase 10A (PDE10A) inhibitors are discussed. Several potent analogs with heteroaromatic substitutions (9a-d) were identified. The anticipated binding mode of these analogs was confirmed by performing the in silico docking experiments. Later, the heteroaromatics were substituted with saturated heteroalkyl groups which provided a tool compound 9e with excellent PDE10A activity, PDE selectivity, CNS penetrability and with favorable pharmacokinetic profile in rats. Furthermore, the compound 9e was shown to be efficacious in the MK-801 induced psychosis model and in the CAR model of psychosis.

Discovery of novel 1,4-dihydropyridine-based PDE4 inhibitors.

Substituted 1,4-dihydropyridines were discovered as a novel and potent series of phosphodiesterase 4 (PDE4) inhibitors. Structure-activity relationships within this series have been carried out and studies revealed that the dihydropyridine core, with indole moiety and 3,4-dimethoxybenzyl group, is a potent analogue for PDE4 inhibition. These novel series of compounds were prepared via a 3-component reaction in a single pot. In vitro biological activity, modeling studies and crystallography data are also reported.

Assessment of the putative binding conformation of a pyrazolopyridine class of inhibitors of MAPKAPK2 using computational studies.

The Ser/Thr protein kinase MAPKAP kinase2 (MAPKAPK2 or MK2) plays an important role in inflammation. A comparison of several crystal structures of MK2 shows that differences in active and inactive conformations result in large part from structural variations within the conformations of the glycine rich loop (p-loop) regions. We propose the most preferred binding conformation of two classes of MK2 inhibitors and suggest plausible critical interactions with active site residues. The predicted binding conformations of the two classes of MK2 inhibitors depend upon their orientation in the active site and activities were well correlated with the sum of D and G scores. A qualitative relationship between the sum of D and G scores and the measured activities can be demonstrated.

Mode of action of Ranbezolid against staphylococci and structural modeling studies of its interaction with ribosomes.

Oxazolidinones are known to inhibit protein biosynthesis and act against a wide spectrum of gram-positive bacteria. A new investigational oxazolidinone, ranbezolid, inhibited bacterial protein synthesis in Staphylococcus aureus and Staphylococcus epidermidis. In S. epidermidis, ranbezolid showed inhibition of cell wall and lipid synthesis and a dose-dependent effect on membrane integrity. A kill-kinetics study showed that ranbezolid was bactericidal against S. epidermidis. In vitro translation of the luciferase gene done using bacterial and mammalian ribosomes indicated that ranbezolid specifically inhibited the bacterial ribosome. Molecular modeling studies revealed that both linezolid and ranbezolid fit in similar manners the active site of ribosomes, with total scores, i.e., theoretical binding affinities after consensus, of 5.2 and 6.9, respectively. The nitrofuran ring in ranbezolid is extended toward C2507, G2583, and U2584, and the nitro group forms a hydrogen bond from the base of G2583. The interaction of ranbezolid with the bacterial ribosomes clearly helps to elucidate its potent activity against the target pathogen.

Survival on hemodialysis and peritoneal dialysis over 12 years with emphasis on nutritional parameters.

We analyzed the prognostic importance of nutritional markers and mortality data in 537 hemodialysis (HD) and 422 peritoneal dialysis (PD) patients followed for up to 12 years. Patients on HD had a 44% lower risk of mortality than did those treated with PD (P: < 0.0001). The difference in mortality between the modalities was even more striking among diabetics but less striking among younger patients. Over a 12-year period, survival of dialysis patients with lower enrollment levels of albumin, creatinine, and parathyroid hormone (PTH) were significantly lower. In multivariate Cox's proportional hazards models, serum prealbumin and enrollment PTH level of <65 pg/mL were independent predictors of mortality both in HD and PD patients. In conclusion, HD patients had higher cumulative survival than PD patients over a 12-year period. Nutritional markers at enrollment continue to be strong predictors of mortality for up to 12 years.

Reticulocyte hemoglobin content predicts functional iron deficiency in hemodialysis patients receiving rHuEPO.

Early detection of iron sufficiency at the level of the erythropoietic cell is necessary to optimize management of uremic anemia with recombinant human erythropoietin (rHuEPO). "Absolute" and "functional" iron deficiency are the most important factors causing resistance to administered rHuEPO. Transferrin saturation and serum ferritin measurements have been noted to be insensitive and inaccurate measures to detect functional iron deficiency. Recently, the reticulocyte hemoglobin content (CHr) has been shown to be a sensitive and specific indicator of functional iron deficiency in nondialysis patients treated with rHuEPO. The purpose of this study is to compare CHr with currently used indices of iron sufficiency in rHuEPO-treated hemodialysis (HD) patients. In study 1, 364 stable HD patients were studied at two outpatient dialysis centers. CHr was normally distributed, with a mean value of 28.3 pg, and was consistent over two consecutive monthly samples in each center. CHr was weakly but consistently correlated with transferrin saturation and serum ferritin. CHr and reticulocyte number were inversely correlated with red blood cell (RBC) number, suggesting that the erythropoietic stimulus of routinely administered rHuEPO may have resulted in functional iron deficiency. Month-to-month changes in CHr correlated weakly with changes in serum iron and percent transferrin saturation, but not at all with changes in serum ferritin. When we analyzed those patients with baseline CHr less than 26 pg, a level strongly suggestive of functional iron deficiency, these correlations strengthened, and in addition, month-to-month changes in CHr correlated strongly and directly with concomitant changes in RBC count, hemoglobin, and hematocrit, suggesting that rising CHr was indicative of an erythropoietic response. In study 2, 79 patients received a single-dose infusion of 500 mg iron dextran. After intravenous iron, CHr rose within 48 hours, peaked at 96 hours, and then fell toward baseline. Patients who were iron deficient by standard measures (serum ferritin < 100 ng/mL or transferrin saturation less than 20%) had a greater and a sustained CHr response to intravenous iron dextran. A CHr less than 28 pg at baseline predicted functional iron deficiency, defined as a corrected reticulocyte increase of greater than 1% to iron dextran, more accurately than transferrin saturation, ferritin, or their combination. Eighty-two percent of individuals who were iron deficient at baseline responded to intravenous iron with an increase in CHr of greater than 2 pg. Sixty percent of patients who were iron sufficient by usual iron indices also responded to intravenous iron with a CHr rise of greater than 2 pg, suggesting that they were, in fact, functionally iron deficient despite "normal" conventional iron parameters. We conclude that CHr may be a more sensitive marker of functional iron deficiency in rHuEPO-treated hemodialysis patients than percent transferrin saturation and ferritin, particularly in those with "normal" conventional iron parameters.

Predictive value of nutritional markers (albumin, creatinine, cholesterol, and hematocrit) for patients on dialysis for up to 30 years.

Mortality among end-stage renal disease patients in the United States remains unacceptably high despite progress in the management of renal replacement therapy. Consequently, there are few reports of long-term survivors on dialysis. We have analyzed characteristics of long-term (10 to 15 years, N = 40) and very long-term (15 to 30 years, N = 18) survivors on hemodialysis and long-term survivors (more than 10 years, N = 28) on peritoneal dialysis and compared them with "average survivors" (< 5 years, N = 65 for hemodialysis and N = 101 for peritoneal dialysis). Among hemodialysis patients, long- and very long-term survival was associated with younger age, nondiabetic status, black race, and male gender (P < 0.05 for all variables). Enrollment creatinine was higher among long- and very long-term survivors, whereas albumin and hematocrit increased significantly during the period of observation among long- and very long-term survivors compared with average survivors. Enrollment age, nondiabetic status, and albumin level predicted prolonged survival even after adjustments for confounding variables. Among peritoneal dialysis patients, younger age and nondiabetic status predicted prolonged survival. Black race was associated with improved survival, but the association was not statistically significant. Enrollment levels of albumin and creatinine were significantly higher among long-term survivors and the cholesterol increased during the period of observation in long-term survivors. Thus, demographic and biochemical indices reflecting nutritional status can predict prolonged survival in hemodialysis and peritoneal dialysis. Patient survival for periods of up to 30 years is possible on renal replacement therapy. Analyses of these outlier patients may offer clues to prolonged survival.

Enrollment parathyroid hormone level is a new marker of survival in hemodialysis and peritoneal dialysis therapy for uremia.

The relatively high morbidity and mortality during dialytic therapy for end-stage renal disease (ESRD) in the United States is the subject of current inquiry. Identified risk factors for excess mortality include advanced age, diabetes, and malnutrition exemplified by a low serum albumin level. Parathyroid hormone (PTH) has long been thought to contribute to the toxicity of the uremic syndrome. We reviewed the course of patients maintained by hemodialysis (HD) and peritoneal dialysis (PD) to detect any correlation between the level of PTH when beginning dialytic therapy and subsequent morbidity and mortality. Study cohorts consisted of 175 HD and 113 PD patients followed for up to 9 years. Demographic characteristics such as age, race, gender, diabetic status, and prior months on dialysis, as well as biochemical parameters including albumin, creatinine, cholesterol, intact PTH, calcium, and phosphorus levels at enrollment were evaluated for their effect on patient survival. Expected survival was calculated by Cox proportional hazards analysis. Older age and lower enrollment serum creatinine level were associated with increased mortality in both HD and PD patients, whereas low serum albumin and low serum cholesterol levels also predicted high mortality in HD patients. In both HD and PD, patients with enrollment PTH level of < or = 65 pg/mL had more than twice the mortality risk of those with PTH > or = 200 pg/mL. Both observed and expected survival of patients with low PTH were significantly lower than the survival in patients with higher PTH. Five-year HD survivors and four-year PD survivors had significantly higher PTH levels at initiation of dialytic therapy than did those with shorter survival. PTH level correlated with serum creatinine and serum albumin in HD but only with serum creatinine in PD, supporting the inference that patients with high enrollment PTH were better nourished than those with lower PTH.

Prealbumin is the best nutritional predictor of survival in hemodialysis and peritoneal dialysis.

Patients undergoing dialytic therapy for end-stage renal disease (ESRD) have greater morbidity and mortality than age-matched individuals with similar demographics in the general population. Risk factors for early death during treatment for ESRD include advanced age, diabetes, hypertension, and malnutrition. We questioned whether the level of serum prealbumin at the start of uremia therapy might serve as a marker of subsequent survival in patients treated with maintenance hemodialysis (HD) and peritoneal dialysis (PD). Study cohorts included 111 HD and 78 PD patients followed for up to 5 years. Selected demographic characteristics and biochemical variables were tested for correlation with survival in each cohort. Variables evaluated included age, race, gender, diabetic status, and serum concentrations of albumin, creatinine, cholesterol, and prealbumin. For comparison, expected survival was calculated with Cox proportional hazards analysis, which accounts for confounding variables. We found that a higher relative risk (RR) of death in HD patients correlated with older age, the diagnosis of diabetes, and a serum prealbumin < 30 mg/dL. In PD patients, older age and the presence of diabetes correlated with a higher RR of death than in the standard population. When nutritional variables were analyzed separately, prealbumin < 30 mg/dL was the strongest variable that predicted mortality in HD patients (RR = 2.64, P = 0.002) and also predicted increased risk of mortality in PD patients (RR = 1.8, P = 0.035). Observed and expected survival was significantly higher in patients with enrollment prealbumin greater than 30 mg/dL in both HD and PD. The serum prealbumin level correlated significantly with other measures of nutrition, including serum albumin, serum creatinine, and serum cholesterol, in both HD and PD patients. Among tested markers of nutritional status, prealbumin level appears to be the single best nutritional predictor of survival in ESRD patients.

Uremic patients have decreased shear-induced platelet aggregation mediated by decreased availability of glycoprotein IIb-IIIa receptors.

Bleeding and platelet dysfunction are prominent features of uremia. Sh ear-induced platelet aggregation (SIPA) involves the interaction of von Willebrand factor (vWF) with platelet membrane glycoproteins (GP) Ib and IIb-IIIa, the same receptor-ligand pair involved in in vivo adhesion and aggregation of platelets in the arterial circulation. We have used a modified rotational cone-plate viscometer to measure SIPA and calcium flux in platelets. Flow cytometric analysis of the surface expression of GP Ib and IIb-IIIa was performed using flourescein isothiocyanate-conjugated monoclonal antibodies CD42b and CD41a, respectively. Uremic patients showed decreased SIPA (controls, 43% +/- 2% [mean +/- SEM]; chronic renal failure patients, 36% +/- 3%; chronic hemodialysis patients, 26% +/- 2%; P < 0.001) along with a decrease in GP IIb-IIIa (controls, chronic renal failure patients, and chronic hemodialysis patients, 840 +/- 25, 649 +/- 42, 661 +/- 38 mean flourescence intensity, respectively; P < 0.0001). Glycoprotein Ib in uremic patients was not significantly different from normal. Chronic hemodialysis patients also demonstrated increased platelet-bound fibrinogen (P < 0.001) and platelet-bound vWF (p < 0.01). Calcium flux and thromboxane B(2) generation during SIPA of uremic platelets was normal. However, uremic plasma showed twice the normal concentration of vWF (P < 0.001) and sodium dodecyl sulfate agarose gel electrophoresis revealed the presence of fibrinogen fragments. Mixing experiments demonstrated an inhibitory effect of uremic plasma on SIPA of normal platelets (decreased from 39% +/- 3% at baseline to 31% +/- 3% after incubation in uremic plasma) along with an activation-independent increase in platelet-bound fibrinogen and platelet-bound vWF. When uremic platelets were incubated in normal plasma, their SIPA increased from 12% +/- 5% at baseline to 18% +/- 4% after incubation in normal plasma; (P = 0.002), although it did not return to normal. These results suggest that the uremic platelet dysfunction results from decreased GP IIb-IIa availability due to receptor occupancy by fibrinogen fragments (and possibly vWF fragments).

Is an elevated level of serum lipoprotein (a) a risk factor for cardiovascular disease in CAPD patients?

Cardiovascular disease (CVD) is the single most important cause of mortality in hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD) patients. An increased lipoprotein (a) [Lp(a)] level in HD patients is associated with CVD. However, Lp(a) levels in CAPD patients are controversial, and their association with CVD has not been established. In the present study, prevalent CAPD and HD patients [excluding those who were human immunodeficiency virus (HIV)-positive] attending the Long Island College Hospital from June, 1990 to July, 1995 underwent analysis of lipid profile including Lp(a). Total and low-density lipoprotein cholesterol, triglycerides, apolipoprotein (apo) A, and apo B were all significantly increased in CAPD patients compared to HD patients. Serum Lp(a) levels were also significantly higher in CAPD patients than in HD patients (51 +/- 32 vs 34 +/- 23 mg/dL, p < 0.001). CAPD patients who had a history of myocardial infarction (MI) or coronary artery disease (CAD) at enrollment had significantly higher Lp(a) levels compared to those who did not have a history of MI or CAD. CAPD patients who died of CVD had higher Lp(a) levels than patients who died of non-CVD causes. In the Cox model with backward stepwise selection, a history of CVD was associated with a significantly elevated relative risk (RR) of mortality (RR = 1.84, p = 0.014). Expected survival by all causes of mortality and by cardiac mortality was significantly shorter in patients with a history of CVD than in those without a history of CVD. Thus, elevated Lp(a) is related to increased CVD and therefore may contribute to increased mortality in CAPD patients.