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Fred M Konikoff

Publications and source records attributed to Fred M Konikoff.

14 recordsLinked to original sources
PubMed2006

ABCA1-dependent but apoA-I-independent cholesterol efflux mediated by fatty acid-bile acid conjugates (FABACs).

FABACs (fatty acid-bile acid conjugates) are synthetic molecules that are designed to treat a range of lipid disorders. The compounds prevent cholesterol gallstone formation and diet-induced fatty liver, and increase reverse cholesterol transport in rodents. The aim of the present study was to investigate the effect of FABACs on cholesterol efflux in human cells. Aramchol (3beta-arachidylamido-7alpha,12alpha,5beta-cholan-24-oic acid) increased cholesterol efflux from human skin fibroblasts in a dose-dependent manner in the absence of known efflux mediators such as apoA-I (apolipoprotein A-I), but had little effect on phospholipid efflux. An LXR (liver X receptor) agonist strongly increased Aramchol-induced cholesterol efflux; however, in ABCA1 (ATP-binding cassette transporter A1)-deficient cells from Tangier disease patients, the Aramchol effect was absent, indicating that activity of ABCA1 was required. Aramchol did not affect ABCA1 expression, but plasma membrane levels of the transporter increased 2-fold. Aramchol is the first small molecule that induces ABCA1-dependent cholesterol efflux without affecting transcriptional control. These findings may explain the beneficial effect of the compound on atherosclerosis.

ATP Binding Cassette Transporter 1↗
PubMed2005

Matrix metalloproteinases 2 and 9 are markers of inflammation but not of the degree of fibrosis in chronic hepatitis C.

BACKGROUND: The degree of liver fibrosis and inflammation is important in patients with chronic hepatitis C (CHC) in terms of therapy as well as prognosis. To obviate the need of liver biopsy, serum markers such as procollagen I, III and hyaluronic acid have been proposed but were found to be inaccurate. Controversy still exists regarding the role of matrix metalloproteinases (MMPs) as valid markers of liver fibrosis. AIM: To assess liver and serum MMP-2 and -9 as markers of fibrosis and inflammation in patients with CHC. METHODS: Thirty-five CHC patients and 8 non-hepatitis C patients with normal liver enzymes underwent liver biopsy. Activities of inflammation and fibrosis stage were determined by the Desmet score on a scale of 0-4. Serum and liver tissue MMP-2 and -9 activities were measured by zymography using substrate impregnated gels. RESULTS: Patient and control groups were similar in terms of age (50.8 +/- 15.1 vs. 50.6 +/- 15.2) and male/female ratio (18/17 vs. 4/4). In serum, MMP-9 activity was increased in patients compared to controls (308 +/- 110 vs. 163.5 +/- 35 , p < 0.05). In liver tissue, MMP-9 was also higher in patients than in controls (21 +/- 4.5 vs. 17.1 +/- 5.1, p < 0.05), whereas MMP-2 did not differ between patients and controls. Serum MMP-9 values correlated with liver histologic inflammatory grade (290.4 +/- 83 in grade 2 vs. 562.1 +/- 128 in grade 3, p < 0.05) but not with fibrosis stage. The highest rising in serum MMP-9 levels was observed between grade 2 to grade 3 and was superior to the rising in serum transaminase levels, indicating its advantage in assessing the progression of disease activity. No correlation between liver MMP activities and liver fibrosis or inflammation was observed. CONCLUSION: Serum MMPs, in particular MMP-9, can serve as markers of disease activity rather than fibrosis stage in chronic HCV patients.

Adult↗
PubMed2005

Biliary cholesterol crystallization characterized by single-crystal cryogenic electron diffraction.

Cholesterol crystals are the building blocks of cholesterol gallstones. The exact structure of early-forming crystals is still controversial. We combined cryogenic-temperature transmission electron microscopy with cryogenic-temperature electron diffraction to sequentially study crystal development and structure in nucleating model and native gallbladder biles. The growth and long-term stability of classic cholesterol monohydrate (ChM) crystals in native and model biles was determined. In solutions of model bile with low phospholipid-to-cholesterol ratio, electron diffraction provided direct proof of a novel transient polymorph that had an elongated habit and unit cell parameters differing from those of classic triclinic ChM. This crystal is exactly the monoclinic ChM phase described by Solomonov and coworkers (Biophysical J., In press) in cholesterol monolayers compressed on the air-water interface. We observed no evidence of anhydrous cholesterol crystallization in any of the biles studied. In conclusion, classic ChM is the predominant and stable form in native and model biles. However, under certain (low phospholipid) conditions, transient intermediate polymorphs may form. These findings, documenting single-crystal analysis in bulk solution, provide an experimental approach to investigating factors influencing biliary cholesterol crystal nucleation and growth as well as other processes of nucleation and crystallization in liquid systems.

Bile↗
PubMed2005

Effects of fatty acid bile acid conjugates (FABACs) on biliary lithogenesis: potential consequences for non-surgical treatment of gallstones.

Fatty acid bile acid conjugates (FABACs) are novel synthetic lipid molecules, which were designed for the treatment of cholesterol gallstones. The rationale was to combine a cholesterol solubilizing moiety (a saturated fatty acid) with a bile acid (cholic acid) as a vehicle to enable secretion into bile and entry into the enterohepatic circulation. An amide bond was used to provide stability against intestinal degradation. Initial in vitro studies showed that FABACs are indeed cholesterol solubilizers, able to prevent biliary cholesterol crystallization. Arachidyl-amido-cholanoic acid (Aramchol) was found to be the most potent FABAC in these studies. Animal studies revealed that Aramchol was absorbed after oral administration and could prevent cholesterol crystallization as well as dissolve preformed crystals in rodents fed a lithogenic diet. In gallstone susceptible mice, Aramchol prevented gallstone formation and dissolved gallstones. FABACs were found to be metabolically active substances, also able to decrease blood cholesterol, atherosclerotic plaques and fat accumulation in the liver in several animal species. The underlying mechanisms of action are under active investigation, and several effects, e.g. on cholesterol and bile salt metabolizing enzymes as well as cholesterol efflux from cells have been discovered. These findings are, however, only the beginning of our understanding of the metabolic actions as well as the potential of use of FABACs as therapeutic agents.

Animals↗
PubMed2003

Gallstones - approach to medical management.

Between 10% and 15% of individuals in the industrialized world have gallstones. The standard treatment is laparoscopic cholecystectomy, making gallstone disease the second most costly digestive disorder in most Western countries. Despite a rapid convalescence, the procedure is not devoid of morbidity or even mortality. Bile duct injury is particularly troublesome, occurring in 0.1% to 0.5% of cases, even in the most experienced hands. Moreover, some 20% of patients continue to suffer from pain (the main indication for treatment) after cholecystectomy. In patients with mild symptoms, surgical treatment has been associated with a higher morbidity than the natural course of the disease. Medical dissolution therapy with bile acids is an alternative for patients with mild-to-moderate symptoms due to cholesterol gallstones. Chenodeoxycholic acid (CDCA, chenodiol) has been largely replaced by the safer and more efficient ursodeoxycholic acid (UDCA). The main drawbacks of UDCA treatment are its low efficacy (approximately 40%), slowness in action, and the possibility of stone recurrence. However, this treatment is extremely safe, and the efficacy and slowness can be somewhat improved by stricter patient selection. Moreover, patient symptoms may respond to this therapy even without complete stone dissolution. New strategies employing more efficient bile acids or related compounds may increase the efficacy of medical dissolution. Furthermore, recent advances in the understanding of biliary lipid secretion and regulation should offer novel opportunities to further improve the prospects of medical treatment of gallstones.

Cholecystectomy, Laparoscopic↗
PubMed2003

Diagnostic yield of routine push enteroscopy with a graded-stiffness enteroscope without overtube.

BACKGROUND: Push enteroscopy has become a standard procedure for evaluation of small intestinal disorders. Its diagnostic yield and acceptability, however, has been hampered by the use of an overtube, which is both inconvenient and potentially hazardous. This study assessed the clinical value of enteroscopy with a graded-stiffness videoenteroscope without an overtube. METHODS: A total of 121 consecutive patients (mean age 59 years, range 12-89 years) underwent diagnostic enteroscopy. All procedures (n = 126) were performed with a push-type graded-stiffness videoenteroscope without an overtube. Indications were the following: unexplained iron deficiency anemia (45%), GI bleeding (29%), abdominal pain (6%), malabsorption (5.5%), imaging abnormality (5.5%), diarrhea (4%), intestinal obstruction (3%), and vomiting (2%). RESULTS: The mean depth of instrument insertion distal to the pylorus was 121 cm. A diagnosis was made in 40% of all procedures. The findings included ulcerations or erosions in 43%, angioectasia in 35%, inflammation in 14%, tumors in 6%, and varices in 2%. In all cases of a positive enteroscopic diagnosis, therapeutic maneuvers were performed, and no patient needed a further diagnostic procedure. Patient comfort was good. No complications were observed. CONCLUSIONS: Routine enteroscopy with a graded-stiffness enteroscope without an overtube is safe and comfortable for the patient and the endoscopist, and has a clinical efficacy comparable with that reported for enteroscopy with use of an overtube. A prospective, randomized study is warranted to assess the exact role of this form of enteroscopy in patient care.

Adolescent↗
PubMed2003

Prevention of diet-induced fatty liver in experimental animals by the oral administration of a fatty acid bile acid conjugate (FABAC).

Fatty acid bile acid conjugates (FABACs) are a new family of synthetic molecules designed to solubilize biliary cholesterol. They were shown to prevent and dissolve cholesterol gallstones in inbred C57L/J mice fed a lithogenic, high-fat diet (HFD). In these mice, fatty liver was observed in the controls but not in the FABAC-treated ones. The present study was designed to study the effect of FABAC (arachidyl-amido-cholanoic acid) on diet-induced fatty liver in rats, hamsters, and mice. The fatty liver score (on a scale of 0-4 by light microscopy) was 4.0 in control hamsters and 0.3 in the FABAC-fed hamsters (P <.001). In mice it was 1.5 and 0.4, respectively (P <.01). The lipid/protein ratio in the liver was 1.3 +/- 0.44 (mg lipid/mg protein) in control rats and 0.66 +/- 0.04 in the FABAC group (P =.001) after 14 days. In hamsters it was 1.41 +/- 0.27 and 1.11 +/- 0.20, respectively (P =.03), after 21 days. In Imperial Charles River (ICR) mice the ratio was 0.34 +/- 0.10 and 0.17 +/- 0.07 (P =.03), respectively, after 24 days. Liver fat concentration, measured as mg lipid/g liver tissue, decreased similarly by FABAC feeding. The decrease in liver fat affected mainly the triglyceride levels. FABAC-fed animals gained weight similarly to the controls. Triglyceride absorption was unaffected by FABAC supplementation. In conclusion, oral FABAC therapy prevents/reduces the development of fatty liver in animals consuming a HFD.

Administration, Oral↗
PubMed2003

Biliary and systemic effects of fatty acid bile acid conjugates.

BACKGROUND: Fatty acid bile acid conjugates (FABACs) are novel synthetic molecules that solubilize cholesterol, prevent cholesterol crystal and gallstone formation, and dissolve pre-existing gallstones in mice. They are thus potential agents for gallstone prevention and treatment. The available knowledge concerning their biliary, systemic or possible toxic effects is, however, incomplete. AIM: To obtain information regarding biliary and systemic effects of FABACs. METHODS: Hamsters, rats and mice were administered C20-FABAC intragastrically, and serum and bile chemistries, organ histology, animal wellbeing, and survival were monitored. RESULTS: FABAC feeding (150 mg/kg/day) caused no adverse effects in any of the animal species studied. FABAC did not influence biliary cholesterol, phospholipid, or bile-salt concentrations in mice. In hamsters, biliary cholesterol concentration decreased slightly, but effects on phospholipids and bile salts were inconsistent. In some mouse strains, FABAC supplementation increased transaminases slightly. In hamsters and rats, transaminases were mainly unaffected or even decreased. Serum alkaline phosphatase, creatinine, albumin and glucose were generally unaffected by FABAC feeding. No gross or histopathological differences between controls and FABAC-fed animals were noted in any of the organs investigated. CONCLUSIONS: C20-FABAC given at a pharmacological dose is safe and devoid of any significant toxic effects in three different animal species.

Animals↗
PubMed2002

Dissolution of cholesterol gallstones in mice by the oral administration of a fatty acid bile acid conjugate.

Gallstones, mostly cholesterol stones, affect some 15% of the population. Oral bile salts dissolve human cholesterol gallstones, but with low efficacy, and surgery remains the main therapeutic option. Fatty acid bile acid conjugates (FABACs) were shown to prevent formation of cholesterol gallstones in experimental animals. The aim of this study was to test whether these compounds could dissolve preexisting cholesterol gallstones via oral administration. Inbred, gallstone-susceptible C57J/L mice were given a lithogenic diet for 2 months, and the presence of gallstones was ascertained. The mice were then switched to a regular diet while part of them were given in addition C20-FABAC, by gavage, at a dose of 0.5 or 3 mg per animal per day. All mice tested had cholesterol gallstones after 2 months on the lithogenic diet. In study I, after 2 months on the regular diet, 3 of 4 (75%) of the controls had gallstones, whereas none of the 6 FABAC-fed animals (3 mg/d) had stones (P =.033). In study II, evaluating 2 FABAC doses, after 2 months on the regular diet, 8 of 8 (100%) of the controls had gallstones, which were found in 2 of 7 (28%) and 1 of 8 (12%) of the mice supplemented with 0.5 mg/d (P =.007) or 3 mg/d (P =.001) FABAC, respectively. On a molar basis, the dose of 0.5 mg FABAC is equivalent to 14 mg/kg/d of a bile acid. In conclusion, FABACs given orally can dissolve preexisting cholesterol gallstones in mice. This was accomplished with a dose of FABAC equivalent to the dose of bile acids used in human gallstone dissolution.

Administration, Oral↗
PubMed2002

Apolipoprotein-E genotype and the risk of developing cholelithiasis following bariatric surgery: a clue to prevention of routine prophylactic cholecystectomy.

BACKGROUND: Obesity and especially rapid weight loss following bariatric surgery are known risk factors for cholelithiasis. Since the risk may be high, prophylactic cholecystectomy has been advocated. Apolipoprotein (Apo) E, an important carrier protein in cholesterol metabolism and trafficking, is believed to play a role in gallstone pathogenesis. In particular, the Apo E4 allele has been suggested to be associated with cholesterol cholelithiasis. The aim of this study was to assess the incidence of postoperative cholelithiasis in our patient population and to determine a possible correlation with the Apo-E genotype. METHODS: 134 morbidly obese patients undergoing gastric restrictive surgery [laparoscopic assisted gastric banding (LAGB) or silastic ring vertical gastroplasty (SRVG)] had abdominal ultrasound before and 6 to 12 months after operation, to determine the presence of gallstones. None of the patients enrolled in the study had gallstones before surgery. They did not have a prophylactic cholecystectomy or receive bile salt treatment. Apo-E genotypes were determined by Polymerase Chain Reaction restriction enzyme analysis. RESULTS: 10 patients (7.5%) developed postoperative cholelithiasis. The incidence of cholelithiasis in each ApoE genotype was: E2/E3--1/20 (5%), E3/E3--3/91 (3%), E3/E4--6/21 (29%), and E4/E4--0/2. ApoE allele frequencies in the study population were identical to those of a healthy control population. The mean BMI dropped from 43.6 to 29.4 kg/m2. CONCLUSIONS: The occurrence of postoperative gallstones was low in our population. However, in subjects with the Apo-E3/E4 genotype, the incidence is of practical significance. These data suggest that Apo-E genotyping may be useful in selecting patients for gallstone prevention (surgical or medical) when undergoing bariatric surgery. Further testing in larger patient populations may be able to give more definite guidelines in the future.

Adolescent↗
PubMedDate not supplied

Effect of interferon, ribavirin and ursodeoxycholic acid in patients with hepatitis C infection.

BACKGROUND/AIMS: Combination therapy of interferon-alpha (IFNalpha) and the oral nucleoside analog, ribavirin is the standard treatment for individuals suffering from hepatitis C virus (HCV) infection. Several studies have shown combination therapy of IFN and antioxidants is therapeutically beneficial in these patients. Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid possessing antioxidant properties. This study evaluated the clinical outcome and extent of oxidative stress in a group of non-responding and disease-relapsed HCV patients treated with IFNalpha, ribavirin and UDCA (triple therapy) for 6 months. METHODOLOGY: Twenty patients with chronic HCV disease were treated with triple therapy for six months. During this period, they were monitored for the presence of HCV RNA, standard serum parameters of liver function and the plasma levels of lipid peroxides (LP) and glutathione (GSH) as indices of oxidative stress. The patients were reassessed six months after completion of treatment. RESULTS: During the 6-month treatment period, the health status of the patients improved reflected by falls in the serum activities of alanine and aspartate aminotransferases and gamma-glutamyl transpeptidase and an initial lowering of viral (HCV RNA) load. Six months after cessation of treatment, the patients showed biochemical and virological evidence of disease relapse. The elevated plasma LP levels normalized during the treatment period and remained within normal levels 6 months after completion of treatment. Plasma GSH levels fluctuated within the normal range over the 12-month observation period. CONCLUSIONS: Treatment of individuals with chronic HCV hepatitis with triple therapy comprising IFNalpha, ribavirin and UDCA improves the health status, as well as lowering the extent of oxidative stress in these individuals. This treatment regimen also resulted in a sustained lowering of plasma lipid peroxide levels in the face of laboratory evidence of disease relapse. This preliminary study is unable to provide an apt explanation for the persistence of normal plasma LP levels in the face of evidence of disease relapse 6 months after completion of treatment. However, we believe these preliminary findings are sufficiently intriguing to warrant further study. Such investigations should include more patients with assessment of the extent of hepatic fibrosis during and after completion of treatment to determine whether this treatment can modify the natural progress of the disease.

Adult↗
PubMedDate not supplied

The rolling stone.

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Cholangiopancreatography, Endoscopic Retrograde↗