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Biomedical subjects

A Hoffman

Publications and source records attributed to A Hoffman.

At least 55 records · Page 3Linked to original sources
PubMed2000

A peptide prodrug approach for improving bisphosphonate oral absorption.

This work was aimed at improving the absorption of bisphosphonates by targeting carrier systems in the intestine and the intestinal peptide carrier system (hPEPT1), in particular. (14)C-Labeled pamidronate and alendronate as well as radiolabeled and "cold" peptidyl-bisphosphonates, Pro-[(3)H]Phe-[(14)C]pamidronate, and Pro-[(3)H]Phe-[(14)C]alendronate were synthesized. In situ single-pass perfusion studies revealed competitive inhibition of transport by Pro-Phe, suggesting peptide carrier-mediated transport. Prodrug transport in the Caco-2 cell line was significantly better than that of the parent drugs, and the prodrugs exhibited high affinity to the intestinal tissue. Oral administration of the dipeptidyl prodrugs resulted in a 3-fold increase in drug absorption following oral administration in rats, and the bioavailability of Pro-Phe-alendronate was 3.3 (F(TIBIA)) and 1.9 (F(URINE)) times higher than that of the parent drug. The results indicate that the oral absorption of bisphosphonates can be improved by peptidyl prodrugs via the hPEPT1; however, other transporters may also be involved.

Administration, Oral↗
PubMed2000

Human serum paraoxonases (PON1) Q and R selectively decrease lipid peroxides in human coronary and carotid atherosclerotic lesions: PON1 esterase and peroxidase-like activities.

BACKGROUND: Human serum paraoxonase (PON1) exists in two polymorphic forms: one that differs in the amino acid at position 192 (glutamine and arginine, Q and R, respectively) and the second one that differs in the amino acid at position 55 (methionine and leucine, M and L, respectively). PON1 protects LDL from oxidation, and during LDL oxidation, PON1 is inactivated. METHODS AND RESULTS: The present study compared PON1 isoforms Q and R for their effect on lipid peroxide content in human coronary and carotid lesions. After 24 hours of incubation with PON1Q or PON1R (10 arylesterase units/mL), lipid peroxides content in both coronary and carotid lesion homogenates (0.1 g/mL) was reduced up to 27% and 16%, respectively. The above incubation was associated with inactivation of PON1Q and PON1R by 15% and 45%, respectively. Lesion cholesteryl linoleate hydroperoxides and cholesteryl linoleate hydroxides were hydrolyzed by PON1 to yield linoleic acid hydroperoxides and linoleic acid hydroxides. Furthermore, lesion and pure linoleic acid hydroperoxides were reduced to yield linoleic acid hydroxides. These results thus indicate that PON1 demonstrates esterase-like and peroxidase-like activities. Recombinant PON1 mutants in which the PON1-free sulfhydryl group at cysteine-284 was replaced with either alanine or serine were no longer able to reduce lipid peroxide content in carotid lesions. CONCLUSIONS: We conclude that PON1 may be antiatherogenic because it hydrolyzes lipid peroxides in human atherosclerotic lesions.

Arteriosclerosis↗
PubMed2000

Oxidized monocyte-derived macrophages in aortic atherosclerotic lesion from apolipoprotein E-deficient mice and from human carotid artery contain lipid peroxides and oxysterols.

Oxidative stress is thought to play an important role in atherogenesis. The present study demonstrated, for the first time, that macrophages (originally derived from blood monocytes) isolated from aortas of the atherosclerotic apolipoprotein E deficient (E degrees ) mice or from human carotid artery, are oxidized as they contain lipid peroxides and oxysterols. The major oxysterol in arterial macrophages was found to be 7-ketocholesterol (51% of total oxysterols). To find out whether lipid peroxidation of monocytes occurs in vivo already in the blood, we analyzed the oxidative state of monocytes derived from E degrees mice in comparison to monocytes from control mice. Cellular lipid peroxides and total oxysterols were four and sevenfold higher respectively, in monocytes derived from E degrees mice in comparison to monocytes from control mice. The results of the present study thus demonstrated the presence of lipid-peroxidized monocytes already in the blood, which are further oxidized in the arterial wall after their conversion into macrophages. The arterial oxidized macrophages could be considered key contributors to foam cell formation, the hallmark of early atherosclerosis.

Animals↗
PubMed2000

Pharmacodynamic effects of bezafibrate and niacin combination: implications of the mode of administration.

The goal of this investigation was to optimize antilipid therapy by utilizing the combined activity of two lipid-lowering agents, niacin and bezafibrate, and improve their efficacy by targeting them to their presumed presystemic site(s) of action. Thus, continuous duodenal (IGI) administration of the drug combination should augment their efficacy in comparison with intermittent oral treatment. Three hyperlipidemic rat models were studied: Models A and B were based on cholesterol-enriched diets and Model C was based on on acute hyperlipidemia induced by triton injection. Continuous IGI administration of the drug combination [bezafibrate, 30mg/kg/day, and niacin, 40 mg/kg/day for 3 days (Models A and B) or for 18 h (Model C)] produced significantly greater lowering of total cholesterol and triglycerides and elevation of high-density lipoprotein (HDL) cholesterol in comparison with intermittent oral administration of the same doses either given individually or in combination (Models A and B). Similar results were found in Model C for the IGI administration of the drug combination in contrast to oral and also to intravenous infusions. The results indicate that the combination of bezafibrate and niacin produces a significant hypolipidemic response, with major site(s) of action located presystemically. Because a slow-release matrix tablet of the drug combination resulted in a similar magnitude of effect as the IGI administration, the present study provides a pharmacodynamic rationale for the use of a slow-release low-dose niacin-bezafibrate combination.

Animals↗
PubMed2000

Nicotine self-administration in rats: estrous cycle effects, sex differences and nicotinic receptor binding.

RATIONALE: Research on smoking behavior and responsiveness to nicotine suggests that nicotine's effects may depend on the sex of the organism. OBJECTIVE: The present study addressed four questions: 1) Will female rats self-administer nicotine? 2) Does self-administration by females vary as a function of estrous cycle? 3) Does self-administration by females differ from that of males? 4) Does self-administration of nicotine result in up-regulation of nicotinic receptor binding and are these changes similar in males and females? METHODS: Male and female Sprague-Dawley rats were allowed to self-administer nicotine at one of four doses (0.02-0.09 mg/kg, free base) on both fixed and progressive ratio schedules of reinforcement. RESULTS: Females acquired nicotine self-administration across the entire range of doses. Acquisition of self-administration at the lowest dose was faster in females than males. However, few sex differences were found in the number of active responses, number of infusions, or total intake of nicotine during stable fixed ratio self-administration. In contrast, females reached higher break points on a progressive ratio. For both schedules, females had shorter latencies to earn their first infusion of each session and demonstrated higher rates of both inactive and timeout responding. There was no effect of estrous cycle on self-administration during either fixed or progressive ratio sessions. Self-administered nicotine resulted in average arterial plasma nicotine levels between 53 and 193 ng/ml and left hemi-brain levels between 174 and 655 ng/g, depending on dose. Nicotine self-administration produced similar up-regulation of nicotinic receptor binding sites in males and females, as reflected by increased right hemi-brain binding of [3H]-epibatidine, when compared to the brains of untreated control rats. CONCLUSIONS: These results suggest that while males and females may regulate their intake of nicotine similarly under limited access conditions, the motivation to obtain nicotine is higher in females.

Animals↗
PubMed2000

Color-coded duplex ultrasound compared to CT angiography for detection and quantification of carotid artery stenosis.

OBJECTIVE: The purpose of this study was to compare findings on color-coded duplex ultrasound and CT angiography for grading internal carotid artery stenosis, and to investigate whether both these imaging modalities are necessary for an accurate diagnosis of carotid stenosis in the pre-surgical assessment of the internal carotid artery. PATIENTS AND METHODS: We examined 92 internal carotid arteries from 46 randomly chosen patients with suspected carotid stenosis by color-coded duplex ultrasound and by three-dimensional CT angiography (CTA). This retrospective study adhered to international guidelines with gradings of mild, moderate, severe, and occlusive carotid disease. RESULTS: The study demonstrated agreement between the degree of stenosis found on color-coded duplex ultrasound and that found on CTA in 78% of cases overall and in 79% of patients requiring surgical intervention. When compared to CTA, color-coded duplex ultrasound yielded a sensitivity of 78.9% and a specificity of 96.3%. Although findings on color-coded duplex ultrasound and CTA were comparable, disagreement affecting treatment decision occurred in 10:92 arteries. CONCLUSION: CTA was not found to be beneficial for patients exhibiting mild stenosis on color-coded duplex ultrasound, as none of the mild groupings found by sonography were interpreted as severe or occluded by CTA. However, CTA may be an important adjunct to color-coded duplex ultrasound regarding the categories of moderate, severe and occluded when carotid endarterectomy is considered.

Adolescent↗
PubMed2000

Effects of A-192621.1, a specific endothelin-B antagonist, on intrarenal hemodynamic responses to endothelin-1.

The present study examined the effects of A-192621.1, a highly selective endothelin-B- (ETB) receptor antagonist, on the renal hemodynamic and systemic actions of endothelin-1 (ET-1). Intravenous injection of ET-1 (1.0 nmol/kg) into anesthetized rats produced a sustained decrease in renal blood flow (assessed by ultrasonic flowmeter) and a significant increase in renal vascular resistance, as well as an increase in mean arterial pressure. These changes were significantly augmented by pretreatment with A-192621.1 (3.0 mg/kg/h). Analysis of intrarenal blood flow by laser-Doppler flowmeter revealed that ET-1 caused a marked and sustained decrease in cortical blood flow, associated with a transient increase in medullary blood flow. The reduction in cortical blood flow in response to ET-1 was further enhanced by pretreatment with A-192621.1, whereas the ET-1-induced medullary vasodilatation was completely abolished and reversed into a vasoconstrictor response. These findings suggest that the ETB-receptors mediate the systemic and renal vasodilatory actions of ET-1 in the rat, and that their activation may serve as a physiological counterbalance that modulates ET-1-induced vasoconstriction.

Animals↗
PubMed2000

Cumulative plot of heart rate variability spectrum assesses kinetics of action of cholinergic drugs in rats.

A new approach to assess autonomic nervous system (ANS) activity and its response to drug action is presented. Our approach is based on the use of a cumulative plot of data obtained by power spectral analysis of heart rate variability, in defined frequency bands, during short time epochs (e.g., 2 min in rats). The substantial temporal variability in power evolving from the constant balancing nature of the ANS activity is minimized by this approach and produces a measurable index of ANS activity vs. time. The cumulative plot emphasizes the temporal response pattern of different components of the ANS and thereby facilitates the investigation of the kinetics of action of drugs affecting the ANS. We used this method to measure the activity of cholinergic drugs in freely moving Sabra rats. Bolus atropine doses between 0.5 and 2 mg/kg produced a similar magnitude of effect, reduction of the ascending slope by 0. 003 power units/h, whereas the duration of this effect was dose dependent. A lower atropine dose (0.1 mg/kg) or 0.5 mg/kg scopolamine elevated the slope (0.074 and 0.054 power units/h for 206 and 216 min, respectively). The method was used similarly to assess the interaction between cholinergic drugs. Pretreatment with pyridostigmine produced temporal blockage of the anticholinergic activity of atropine.

Animals↗
PubMed2000

Mechanisms of big endothelin-1-induced diuresis and natriuresis : role of ET(B) receptors.

Endothelin-1 (ET-1) at high concentrations has marked antidiuretic and antinatriuretic activities, whereas its precursor, big endothelin-1 (big ET-1), has surprisingly potent diuretic and natriuretic actions. The mechanisms underlying the excretory effects of big ET-1 have not been fully elucidated. To explore these mechanisms, we examined the effects of a highly selective ET(B) antagonist (A-192621.1), a calcium channel blocker (verapamil), a nitric oxide synthase inhibitor (N-nitro-L-arginine methyl ester [L-NAME]), and a cyclooxygenase inhibitor (indomethacin) on the systemic and renal actions of big ET-1 in anesthetized rats. An intravenous bolus injection of incremental doses of big ET-1 (0.3, 1. 0, and 3.0 nmol/kg) produced a significant hypertensive effect that was dose dependent and prolonged (from 113+/-7 mm Hg to a maximum of 148+/-6 mm Hg). The administration of big ET-1 induced marked diuretic and natriuretic responses (urinary flow rate increased from 8.5+/-1 to 110+/-14 microL/min, and fractional excretion of sodium increased from 0.38+/-0.13% to 7.51+/-1.24%). Glomerular filtration rate and renal plasma flow significantly decreased only at the highest dose of big ET-1. Pretreatment with A-192621.1 (3 mg/kg plus 3 mg. kg(-1). h(-1)) significantly abolished the diuretic (17+/-5 microL/min to a maximum of 19+/-3 microL/min) and natriuretic (0. 29+/-0.1% to a maximum of 1.93+/-0.37%) responses induced by big ET-1. Moreover, A-192621.1 potentiated the decline in glomerular filtration rate and renal plasma flow and the increase in mean arterial blood pressure produced by the low doses of big ET-1. Similar to A-192621.1, pretreatment with a nitric oxide synthase inhibitor (L-NAME, 10 mg/kg plus 5 mg. kg(-1). h(-1)) significantly and comparably reduced the diuretic and natriuretic actions of big ET-1 and augmented the hypoperfusion/hypofiltration and systemic vasoconstriction induced by high doses of the peptide. Pretreatment with verapamil (2 mg. kg(-1). h(-1)) slightly inhibited the diuretic/natriuretic effects of the high-dose big ET-1 and completely prevented the increase in mean arterial blood pressure provoked by the peptide. Unlike verapamil and L-NAME, only indomethacin administration was associated with significant natriuretic/diuretic responses and did not influence the pressor effect and renal actions of big ET-1. Taken together, these results suggest that big ET-1-induced diuretic and natriuretic responses are mediated mainly by stimulation of nitric oxide production coupled to ET(B) receptor subtype activation.

Animals↗
PubMed2000

Extension of the organ pool in kidney transplantation: first year experience of the Israel Transplant Center.

BACKGROUND: Over a 12 month period, the Israel Transplant Center doubled the number of donors by assigning a nurse coordinator to each of 22 hospitals around the country and by using kidneys from elderly donors. OBJECTIVE: To evaluate the impact of our "marginal donors" policy on the results immediately following transplantation. METHODS: Between October 1997 and September 1998, 140 cadaveric kidney transplantations from 72 donors were performed in Israel. We defined two groups of recipients: patients with immediate graft function and patients with either delayed graft function requiring > 1 week of dialysis post-transplant or with primary graft non-function. We compared the following parameters between groups: donor and recipient age and gender, cause of donor's death, length of stay in the intensive care unit, vasopressor dosage and creatinine levels before harvesting, cold ischemic time, and the number of recipient grafts. RESULTS: There were 102 recipients (72.8%) with immediate graft function and 38 with either PNF (n = 13, 9.3%) or DGF (n = 25, 17.9%). On regression analysis, donor age > 50 year and retransplantation were significant risk factors for PNF or DGF (odds ratio 4.4 and 2.8, respectively). Of the 56 kidneys from donors > 50 years old, 21 (37.5%) developed either PNF (n = 9) or DGF (n = 12). CONCLUSIONS: We conclude that kidneys from donors over age 50 are at increased risk for graft non-function or delayed function. Better assessment of functional capacity of kidneys from "aged" donors may help to choose appropriate donors from that pool.

Adolescent↗
PubMed2000

Patients' perceptions of drug therapy counseling in Israel.

BACKGROUND: The more patients know about their medications the higher their compliance with drug therapy, reflecting an effective communication between health professionals and their patients. Numerous studies on this subject have been published, but none has been conducted in Israel. OBJECTIVES: To evaluate patients' perceptions of drug counseling by health professionals--the prescribing physician and dispensing pharmacist--and to determine whether there is a difference in the patient's perception according to his or her place of birth and mother tongue. METHODS: A total of 810 patients were interviewed following receipt of their medications from in-house pharmacies at two community clinics of Israel's largest sick fund. Each patient was interviewed in his or her mother tongue according to a constructed questionnaire, which included the patient's demographic background, type of medications received, the patient's perceptions of drug counseling given by both the physician and the pharmacist, and the patient's perception of non-prescription drug counseling given by the dispensing pharmacist. RESULTS: Of the 810 patients enrolled in this study, 32% received three or more medications at each physician visit. The main therapeutic classes of medications prescribed and dispensed were for neurological disorders, cardiovascular diseases, gastrointestinal problems and respiratory diseases. While 99% of the patients claimed that they knew how to use their medications, only 96% reported receiving an explanation from either physician or pharmacist. The quality of counseling, as evaluated by the patients, was ranked above average for 75% of the consultations with the prescribing physician and 63% with the dispensing pharmacist. CONCLUSIONS: Although few conclusions can be drawn from this study based on the initial statistical analysis of the data, the major findings were that patients value highly the counseling they receive and that 99% believe they have the requisite knowledge for using their medications. Compared to the international literature, our results--based on the patients' perceptions--indicate that counseling by pharmacists is a common and well-accepted activity in Israel and occurs at a high rate.

Counseling↗
PubMed1999

Nicotine self-administration in rats on a progressive ratio schedule of reinforcement.

RATIONALE: Robust intravenous (i.v.) nicotine self-administration (SA) in rats has been reported by several laboratories, including our own, using fixed ratio (FR) schedules of reinforcement. Studies on other drugs of abuse, however, suggest that progressive ratio (PR) schedules may provide additional information not gained using FR schedules. OBJECTIVE: Here, we attempt to establish and characterize nicotine SA on a PR. METHODS: One study allowed animals to acquire SA on a FR at four doses of nicotine (0.02, 0.03, 0.06, 0. 09 mg/kg) before being switched to a PR. A second study examined extinction by saline substitution or pretreatment with the nicotinic antagonist, mecamylamine, including a preliminary analysis into the role of secondary reinforcers in the extinction process. RESULTS: SA of nicotine on a PR was stable across repeated sessions. The number of infusions earned on a PR correlated with infusion rate on a FR; however, a large portion of the variance in SA on a PR could not be accounted for by infusion rate on a FR. Infusions on a PR increased across the same range of doses that produced a decrease in the infusion rate on a FR. Extinction of responding occurred after saline substitution or pretreatment with mecamylamine, and animals re-acquired when nicotine was again available without pretreatment. The presence of drug-paired stimuli appeared to lengthen the extinction process. CONCLUSIONS: Nicotine supports stable SA on a PR. Since PR and FR schedules may measure different aspects of nicotine reinforcement, PR schedules may be valuable in further characterizing group and individual differences in nicotine reinforcement.

Animals↗
PubMed1999

Improved lipid lowering activity of bezafibrate following continuous gastrointestinal administration: pharmacodynamic rationale for sustained release preparation of the drug.

PURPOSE: To evaluate the role of different routes and modes of administration of bezafibrate (BZF) on its hypolipidemic activity. We hypothesize that the major sites of BZF action are located presystemically as in other "gastrointestinal (GI) drugs." Thus, continuous administration of the drug to the GI tract is expected to augment its efficacy and provides a rationale for an oral sustained release preparation of the drug. METHODS: The hypothesis was investigated in three experimentally induced-hyperlipidemia rat models. Models A and B were based on cholesterol-enriched diets and Model C on induced acute hyperlipidemia by triton 225 mg/kg. The pharmacokinetics and the pharmacodynamics of the drug following various modes of administration were examined. RESULTS: In all cases, continuous administration of the drug into the duodenum (IGI) at a dose of 30 mg/kg/day for 3 days (Models A and B) or over 18 hr (Model C) reduced significantly both total cholesterol and triglycerides levels and elevated HDL cholesterol levels in comparison to bolus oral administration of the same dose, as well as in comparison to equivalent intravenous infusion (Model C). Infusion of the drug directly into the portal vein produced an equivalent activity to IGI administration. The pharmacokinetic study showed 100% oral bioavailability, good colonic absorption properties and an indication for an enterohepatic cycle. CONCLUSIONS: The results confirm that BZF has a first pass hepatic pharmacodynamic effect. Administration of BZF in a slow release matrix tablet to the rats produced the same magnitude of effect as IGI administration, thus proving the pharmacodynamic rationale for this mode of administration for GI drugs.

Animals↗
PubMed1999

Synthesis and preclinical pharmacology of 2-(2-aminopyrimidinio) ethylidene-1,1-bisphosphonic acid betaine (ISA-13-1)-a novel bisphosphonate.

PURPOSE: To validate our hypothesis that a bisphosphonate (BP) having a nitrogen-containing heterocyclic ring on the side chain, and with no hydroxyl on the geminal carbon would possess increased activity, and better oral bioavailability due to enhanced solubility of its calcium complexes/salts and weaker Ca chelating properties. METHODS: A novel BP, 2-(2-aminopyrimidinio)ethylidene-1, 1-bisphosphonic acid betaine (ISA-13-1) was synthesized. The physicochemical properties and permeability were studied in vitro. The effects on macrophages, bone resorption (young growing rat model), and tumor-induced osteolysis (Walker carcinosarcoma) were studied in comparison to clinically used BPs. RESULTS: The solubility of the Ca salt of ISA-13-1 was higher, and the log beta(Ca:BP) stability constant and the affinity to hydroxyapatite were lower than those of alendronate and pamidronate. ISA-13-1 exhibited effects similar to those of alendronate on bone volume, on bone osteolysis, and on macrophages, following delivery by liposomes. ISA-13-1 was shown to have 1.5-1.7 times better oral absorption than the other BPs with no deleterious effects on the tight junctions of intestinal tissue. CONCLUSIONS: The similar potency to clinically used BPs, the increased oral absorption as well as the lack of effect on tissue tight junction of ISA-13-1 warrant its further consideration as a potential drug for bone diseases.

Administration, Oral↗
PubMed1999

Epithelioid angiosarcoma associated with a Dacron vascular graft.

Angiosarcoma developed at the site of a Dacron vascular prosthesis 8 years after an aortobifemoral bypass graft insertion. The tumor was composed of epithelioid cells, which showed positive staining for cytokeratin and expression of the common endothelial markers CD31, CD34, and von Willebrand factor. Ultrastructural examination showed aggregates of large cells with intercellular lumina and focal perinuclear whorls of intermediate filaments. The patient, who had abdominal pain and weight loss, died of disseminated pelvic and abdominal disease 6 months after diagnosis. Sarcomas associated with vascular Dacron grafts and angiosarcomas associated with metal or polymer foreign bodies are rare. Their development is probably analogous to the common experimental development of foreign body-associated sarcomas in rodents. Physicians caring for patients with vascular grafts or metal foreign bodies should be aware of this complication.

Aged↗
PubMed1999

The effect of cimetidine on the pharmacodynamics of theophylline-induced seizures and ethanol hypnotic activity.

Due to its availability as an over-the-counter drug, the use of cimetidine is increasing, thus adverse interactions with other commonly used agents may also increase. The aim of this study was to investigate whether acute administration of cimetidine could alter the pharmacodynamics of theophylline neurotoxicity and the hypnotic action of ethanol. To examine these questions, rats received a dose of 77 mg/kg cimetidine followed by a constant infusion of either theophylline (1.2 mg/min.) or ethanol (16.3 mg/min.) until the onset of the pharmacological end point, maximal seizure or loss of righting reflex, where samples of blood and brain were obtained and assayed for either theophylline or ethanol. We report that cimetidine in doses that may cause pharmacokinetic interactions did not affect the concentration-effect relationship of either the stimulating action of theophylline or the depressant activity of ethanol. These outcomes emphasize the relative safety which patients using cimetidine in self-medication rely on.

Animals↗