Biomedical subjects

J M Jaffe

Publications and source records attributed to J M Jaffe.

At least 19 recordsLinked to original sources

PubMed2000

Association of SRD5A2 genotype and pathological characteristics of prostate tumors.

The enzyme product of SRD5A2, 5alpha-reductase type II, is responsible for converting testosterone to the more metabolically active dihydrotestosterone. Therefore, SRDSA2 may be involved in the development or growth of prostate tumors. To examine the effects of allelic variants in the gene SRDSA2 on the presentation of prostate tumors, we studied a sample, primarily Caucasian, of 265 men with incident prostate cancer who were treated by radical prostatectomy. We assessed the relationship of the A49T and V89L polymorphisms at SRD5A2 with clinical and pathological tumor characteristics of these patients. We found no association of V89L genotypes with any of the characteristics studied. The presence of the A49T variant was associated with a greater frequency of extracapsular disease [odds ratio (OR), 3.16; 95% confidence interval (CI), 1.03-9.68] and a higher pathological tumor-lymph node-metastasis (pTNM) stage (OR, 3.11; 95% CI, 1.01-9.65). In addition, the A49T variant was overrepresented in two poor prognostic groups, which have been correlated with reduced rates of biochemical disease-free survival. One group included men with at least two of the following poor prognostic variables: (a) stage T3 tumor; (b) PSA level >10; and/or (c) Gleason score, 7-10 (OR, 3.46; 95% CI, 1.04-11.49). The second group included men with positive margins and high Gleason score (OR, 6.28; 95% CI, 1.05-37.73). Our results suggest that the A49T mutation may influence the pathological characteristics of prostate cancers and, thus, may affect the prognosis of these patients.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed1999

Glutathione S-transferase-mu (GSTM1) and -theta (GSTT1) genotypes in the etiology of prostate cancer.

The glutathione S-transferases (GSTs) are involved in the metabolism of numerous potential prostate carcinogens. Common homozygous germ-line deletions exist in the genes that encode GST-mu (GSTM1) and GST-theta (GSTT1) and preclude enzyme expression. To evaluate whether GSTM1 and/or GSTT1 contribute to prostate cancer (CaP) etiology, we studied 237 incident CaP cases and 239 age- and race-matched controls. The probability of having CaP was increased in men who had nondeleted (functional) genotypes at GSTT1 (odds ratio, 1.83; 95% confidence interval, 1.19-2.80) but not GSTM1 (odds ratio, 1.07; 95% confidence interval, 0.74-1.55). No interaction of these genes in CaP etiology was observed. GST-theta is highly expressed in the prostate and can produce genotoxic effects upon exposure to specific carcinogens. These results suggest that GSTT1 is associated with CaP risk.

Adult↗

PubMed1998

Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4.

BACKGROUND: Pathways involved in androgen metabolism have been implicated in the etiology of prostate cancer. The goal of this study was to evaluate the effect of CYP3A4, a gene associated with the oxidative deactivation of testosterone, on the clinical presentation of prostate cancers. METHODS: A polymerase chain reaction-based approach was used to identify sequence variants of the human CYP3A4 gene. To ascertain whether allelic variants of the CYP3A4 gene were associated with tumor stage and grade and age of the patient at diagnosis, we determined CYP3A4 genotypes in 230 Caucasian men with incident prostate cancer. RESULTS: We identified a novel genetic variant (CYP3A4-V) that has an altered 5' regulatory element, containing an A to G mutation, upstream of the CYP3A4 gene. We then compared clinical characteristics of prostate cancers in men who did and did not carry this variant. The presence of the CYP3A4-V allele was associated with a higher tumor-lymph node-metastasis (TNM) stage and Gleason grade. The association between CYP3A4 genotype and tumor stage was most pronounced in men diagnosed at a relatively old age who reported no family history of prostate cancer. In this group, 46% of men with stage T3/T4 tumors carried CYP3A4-V, whereas only 5% of individuals with stage T1 tumors carried CYP3A4-V (adjusted odds ratio = 9.45; 95% confidence interval = 2.54-35.17; chi2(1) = 12.28; two-sided P<.001). CONCLUSIONS: We determined that a single base change in the 5' flanking region of the CYP3A4 gene was associated with higher clinical stage and grade in men with prostate tumors. Our results suggest that mutations in the CYP3A4 gene may influence prostate carcinogenesis.

Adult↗

PubMed1998

Characterization of an allelic variant in the nifedipine-specific element of CYP3A4: ethnic distribution and implications for prostate cancer risk. Mutations in brief no. 191. Online.

CYP3A4 is involved in the metabolism of numerous biologically active compounds, including testosterone. A genetic variant located in the P450NF (nifedipine) specific element (NFSE) has been identified that disrupts a transciptional regulatory element located in the 5' regulatory region of CYP3A4. The CYP3A4 variant (CYP3A4-V) is associated with the clinical presentation of prostate cancer. There are significant differences in CYP3A4 metabolism and rates of prostate cancer across ethnic groups that may be associated with CYP3A4 genotypes. Therefore, we estimated the frequency of the CYP3A4 variant in three ethnic groups with different prostate cancer incidence rates. The frequency (q) of CYP3A4-V was significantly different (p<0.0001) in African Americans (q=0.53), U.S. Caucasians (q=0.09), and Taiwanese (q=0.0). CYP3A4-V segregated in a Mendelian manner in one large African American family, and 7 of 16 (44%) biologically unrelated "marry-ins" carried a CYP3A4 variant allele. Reflecting population-specific prostate cancer incidence rates, our results suggest a high frequency of this variant in African Americans compared with U.S. Caucasians and Taiwanese.

Alleles↗

PubMed1992

Pharmacokinetics of fluvastatin after single and multiple doses in normal volunteers.

The pharmacokinetics of fluvastatin, a potent inhibitor of hydroxymethylglutaryl-CoA reductase and thus cholesterol synthesis, have been studied in 24 normal male volunteers who received [3H] fluvastatin in three different studies: a single-dose study using oral doses of 2 or 10 mg, an absolute bioavailability study using doses of 2 mg intravenously or 10 mg orally, and a multiple-dose study using 40 mg orally once daily for 6 days. Serial blood and plasma samples and complete urine and feces were collected and analyzed for total radioactivity as well as for intact fluvastatin. Fluvastatin was rapidly and almost completely (greater than 90%) absorbed from the gastrointestinal tract, although the estimated bioavailability from the 2- and 10-mg doses was only 19 to 29% because of extensive first-pass metabolism. Fluvastatin pharmacokinetics appeared to be linear over the 2- to 10-mg dose range, as indicated by dose-proportional blood levels of total radioactivity and the parent drug. Absorbed fluvastatin was completely metabolized before excretion, the biliary/fecal route being the major excretory pathway. The recovery of radioactivity after a single dose was virtually complete within 120 hours. The terminal half-lives of fluvastatin and total radioactivity averaged 0.5 to 1 hour and 55 to 71 hours, respectively, whereas the total body clearance of fluvastatin was 0.97 L/hour/kg. Repeated oral administration of 40-mg doses of [3H]fluvastatin resulted in no time-related change in pharmacokinetic characteristics, but this dose yielded greater than proportional increases in circulating levels of the parent drug, thus suggesting a saturable first-pass effect on fluvastatin.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1989

Bioavailability of isradipine in young and old rats: effect of mode of administration.

The bioavailability of isradipine has been examined in 7- and 52-week-old rats after oral (12.5 mg kg-1) or intravenous (2.5 mg kg-1) doses as a solution and administration of various doses (1.8-85.5 mg kg-1) in the diet. Serial plasma samples were obtained from each rat and the drug concentration was determined by radioimmunoassay. Absorption from the dose given by gavage was rapid but when administered in a drug diet mixture, isradipine appeared in the plasma slowly and in a manner reflecting the feeding pattern. Its absolute bioavailability from the drug-diet mixture averaged 3% over the dose range tested. By gavage its bioavailability was enhanced to 5% of dose with peak plasma values approximately 7 times higher than from a comparable dose in the diet. The low oral bioavailability of isradipine in the rat was most likely due to extensive first-pass metabolism. The decline in plasma concentrations was biexponential, with a mean terminal half-life of 3.6-3.7 h after oral or intravenous dosing. The pharmacokinetic characteristics of isradipine examined were independent of the age of the rat, except that its volume of distribution decreased with age. The older rats also showed a greater inter-animal variability in isradipine bioavailability from the drug-diet mixture.

Aging↗

PubMed1987

Pharmacokinetics of PN 200-110 (isradipine), a new calcium antagonist, after oral administration in man.

The pharmacokinetics of PN 200-110 (isradipine), a new calcium channel blocking agent, have been studied in 18 normal male volunteers who received orally a single 5-mg dose, a single 20-mg dose, or repeated administration of 5 mg every 8 h for 13 doses of [14C]PN 200-110. PN 200-110 was rapidly and almost completely (90-95%) absorbed from the gastrointestinal tract, although the estimated bioavailability was only 17% due to extensive first-pass metabolism. The pharmacokinetics of PN 200-110 appeared to be linear in the 5 to 20-mg dose range, as indicated by the dose-proportional blood levels of total radioactivity as well as the parent drug. Absorbed PN 200-110 was completely metabolized prior to excretion. The recovery of radioactivity after both the 5 and the 20-mg dose was virtually complete within the experimental period, with a renal:fecal excretion ratio of ca. 70:30. Repeated administration of [14C]PN 200-110 showed no change in pharmacokinetic characteristics. During the 5 mg thrice daily regimen, steady-state blood levels of parent drug were reached in 2 days while those of total radioactivity were reached in approximately 4 days. PN 200-110 and total radioactivity accumulated in blood by a factor of 2.1 and 3.4, respectively, indicating effective half-lives of 8.8 h and 16 h. The oral administration of [14C]PN 200-110 prescribed in the present study was safe and well tolerated.

Administration, Oral↗

PubMed1987

Biological properties of the antagonist SRI 63-441 in the PAF and endotoxin models of hypotension in the rat and dog.

Intravenous administration of platelet-activating factor (PAF) produces dose-dependent hypotension in several species. We have evaluated a recently developed PAF antagonist, SRI 63-441, for its ability to inhibit the hypotensive effect of PAF in the rat and dog. In the rat, 100 ng/kg PAF produced a 38.6 +/- 5.1% decrease in carotid mean arterial pressure (MAP), followed by a 3.2 +/- 0.7 min recovery period for MAP to return to baseline values. SRI 63-441 reduced the hypotension response in the rat, where the ED50 values for inhibition of MAP were 0.16 mg/kg i.v. and 0.19 mg/kg i.v. for the recovery period. Dogs challenged with 1.5 micrograms/kg PAF i.v. demonstrated a 52 +/- 8% decrease in MAP that persisted for at least 15 min. The ED50 for inhibition of MAP by SRI 63-441 was 0.20 mg/kg i.v. Following injection of tritium-labeled SRI 63-441, 56.8 +/- 2.4% of the dose was recovered in the urine and 43.2 +/- 8.9% in the feces in the rats while in dogs 38.7 +/- 5.6% and 60.9 +/- 23.5% of the dose was excreted in the urine and feces, respectively. In the rat model of endotoxin-induced hypotension, SRI 63-441 given 1 min after a 5 mg/kg endotoxin challenge (which produced a 52 +/- 7% decrease in MAP), reversed the systemic effects, with an ED50 of 0.18 mg/kg i.v. The ED50 for reversal 6 min after endotoxin injection was 0.01 mg/kg. These results of inhibition and reversal by SRI 63-441 strongly implicate PAF as a pivotal mediator of hypotension and shock.

Animals↗

PubMed1987

Pharmacokinetics of orally administered tizanidine in healthy volunteers.

The pharmacokinetics of tizanidine, a new centrally acting muscle relaxant, have been studied in 18 normal male volunteers who received orally a single 5 mg dose, a single 20 mg dose, or repeated administration of 4 mg every 8 hr for 13 doses of [14C]tizanidine. Serial blood and breath samples and complete urine and feces were collected and analyzed for total radioactivity as well as intact tizanidine. Tizanidine was rapidly and almost completely absorbed from the gastrointestinal tract, although the estimated bioavailability was only 21% due to extensive first-pass metabolism. The pharmacokinetics of tizanidine appeared to be linear in the 0-20 mg dose range, as indicated by the dose-proportional blood levels of total radioactivity as well as of parent drug. Absorbed tizanidine was almost completely metabolized before excretion, the major excretory route being via the kidneys. The terminal half-lives of tizanidine and radioactivity were ca 3 hr and 61 hr, respectively, and 76%-77% of the administered radioactivity was recovered within 120 hr. Repeated administration of [14C]tizanidine resulted in no apparent change in pharmacokinetic characteristics. During the 4 mg q 8 hr regimen, blood levels of tizanidine reached steady state after only 2 or 3 doses, whereas those of total radioactivity approached steady state after approximately 4 days. The degree of accumulation of radioactivity, unlike that of parent drug, was inconsistent with the terminal half-life, but instead implied a shorter effective half-life of ca. 16 hr. It appears that the terminal phase of the blood radioactivity profile represents a metabolite that is reversibly bound to and slowly released from a specific tissue depot, and that this binding involves a finite amount of drug regardless of the dose. The oral administration of [14C]tizanidine prescribed in the present study was safe and well tolerated.

Administration, Oral↗

PubMed1987

Disposition of alpha-[(dimethylamino)methyl]-2-(3-ethyl-5-methyl-4-isoxazolyl)- 1H-indole-3-methanol (59-801), a hypoglycaemic agent in rats, dogs and monkeys.

1. The disposition of alpha-[(dimethylamino)methyl]-2-(3-ethyl-5-methyl-4 isoxazolyl)-1H-[3-14C]indole-3-methanol, an oral hypoglycaemic drug, has been studied in the rat, dog and monkey. 2. Oral doses of the drug were almost completely absorbed. The rate of absorption was rapid in the rat but less rapid in dog and monkey. Due to first-pass effect, the absolute bioavailability of the drug was incomplete and ranged from 60-75% in the monkey to 90% in the dog. 3. Intravenous as well as oral doses of the radiolabelled drug were rapidly and extensively distributed to body tissues. In rat, concentrations of radioactivity in all tissues except the brain exceeded, or were similar to, corresponding blood levels. Tissue and blood radioactivity levels were higher in female than in male rats, and increased disproportionately with increasing dose. 4. The drug was partially metabolized before excretion, the extent of metabolism ranging from ca. 50% in the rat to 90% in the monkey. Although only a limited number of animals were used, metabolism appeared to be saturable within the dose range studied in dog and monkey but not in rat. The half-life of unchanged drug was dose-independent in the rat (1.4 h), but tended to increase with increasing dose in the dog (4.1-7.2 h) and monkey (2.1-4.5 h). 5. In all three species, the administered radioactivity was recovered predominantly in urine, although biliary excretion also played an important role in drug elimination. Recovery of dose was essentially complete within 1-2 days.

Animals↗

PubMed1987

Pharmacokinetics and metabolism of alpha-[(dimethylamino)methyl]-2- (3-ethyl-5-methyl-4-isoxazolyl)-1H-indole-3-methanol, a hypoglycemic agent, in man.

1. The pharmacokinetics and metabolism of alpha-[(dimethylamino)methyl]-2-(3-ethyl-5-methyl-4-isoxazolyl) -1H-[3-14C]indole-3-methanol, a new hypoglycemic agent, have been studied in 15 healthy male volunteers who received an oral dose of 50 or 200 mg. 2. The drug was rapidly and almost completely absorbed intact from the gastrointestinal tract. 3. Compared with the 50 mg dose, the 200 mg dose yielded less than proportionally higher blood concentrations of radioactivity and unchanged drug. This phenomenon has been observed previously in the rat and was probably due to an increase in drug distribution volume with increasing dose, since the metabolism and excretion patterns of the drug appeared to be dose-independent. 4. The drug was partially metabolized prior to excretion. Approximately 40% of the dose was recovered intact, almost exclusively in urine. The major metabolic pathway of the drug was by conjugation with glucuronic acid, while oxidation of the indole ring gave rise to a relatively minor metabolite. 5. The recovery of administered radioactivity was virtually complete within the experimental period, with a renal:faecal excretion ratio of ca 80:20. The elimination half-life of unchanged drug was 25-30 h while that of total radioactivity was 33-35 h.

Adolescent↗

PubMed1986

Effect of butalbital and phenobarbital pretreatment on antipyrine clearance in the rat.

The disposition kinetics of antipyrine after a single i.v. dose (75 mg/kg) of [14C]antipyrine were examined in control rats and in rats pretreated with butalbital and phenobarbital. Blood antipyrine data indicated that daily administration of phenobarbital (50 mg/kg) for 14 days resulted in significantly more rapid elimination of antipyrine than that observed after equal doses of butalbital, which was in turn significantly faster than the control values. Results of additional antipyrine tests after phenobarbital pretreatment for 2 and 5 days showed considerable enzyme induction after only 2 days of exposure to phenobarbital; the mean antipyrine clearance after the 2-day pretreatment was not significantly different from those after the 5- and 14-day pretreatments. The data suggested that the maximum increase in antipyrine clearance, ca. 190% of the control value, was achieved after approximately 5 daily doses of phenobarbital and maintained until the end of the 14-day pretreatment period. The subsequent decline in the induced enzyme activity, assessed by the antipyrine clearance values on days 1, 3, 6, and 9 post-phenobarbital treatment, appeared to be mono-exponential with a half-time of 3.8 days. Thus, the enzyme activity would return to baseline at ca. 15 days after the last dose of phenobarbital. In these studies, consistent increases in liver weight with increasing antipyrine clearance were observed, while no apparent relationship between antipyrine distribution volume and barbiturate pretreatment was found.

Animals↗

PubMed1984

Pharmacokinetics of compound 58-112, a potential skeletal muscle relaxant, in man.

The pharmacokinetics of 4-[(3-methoxyphenyl)methyl] -2,2,6,6-tetramethyl-1-oxa-4-aza-2,6-disilacyclohexane (Sandoz compound 58-112), a new chemical entity with a unique myotonolytic effect, was studied in 12 healthy male volunteers who received an oral dose of 50 or 100 mg of the 14C-labeled drug. Serial blood and breath samples and complete urine and feces were collected for 120 hours after dosing. All samples were analyzed for total radioactivity while the blood and urine were also assayed for unchanged compound 58-112. Measurable blood radioactivity levels were observed at 0.5 hour, and peak concentrations were attained at 1 to 2 hours after dosing. The absorption of the radioactive doses was complete and appeared linear in the 50-100 mg range, as indicated by blood 14C levels that were proportional to the dose. The 50- and 100-mg doses also resulted in virtually identical excretion patterns, with 95 per cent of the administered radioactivity recovered within 9 hours, almost exclusively in the urine. However, the disproportionately higher blood concentrations of unchanged compound 58-112 after the 100-mg dose could suggest saturable presystemic metabolism in the liver. Simultaneous fitting of all data in the 100-mg dose study to a pharmacokinetic model showed that unchanged compound 58-112 was distributed into a central and a peripheral compartment and was eliminated entirely by metabolism, the distribution and elimination half-lives being 0.5 and 3.9 hours, respectively. The metabolite(s) was distributed into one homogeneous space, and its elimination half-life was 0.1 hour, with a renal:fecal clearance ratio of approximately 96:4.

Adult↗

PubMed1984

Influence of mode of intravenous administration and blood sample collection on rat pharmacokinetic data.

The influence of the mode of intravenous dosing and blood sample collection on the pharmacokinetics of 4-[(3-methoxyphenyl)-methyl]-2,2,6,6-tetramethyl-1-oxa-4-aza-2, 6-disilacyclohexane hydrochloride (I) was studied in the rat. Blood samples obtained from the tail and by exsanguination following injection of the 14C-labeled drug into the caudal vein, the jugular vein, and the heart were analyzed for total radioactivity, and the concentration profiles from the different treatments were compared. Dosing and sampling from the tail vein resulted in significantly different blood levels (and related pharmacokinetic parameters) when compared to other methods, probably attributable to a local depot effect. Intracardiac administration tended to cause higher drug levels in the heart than intravenous doses, although no significant differences were found between the respective blood concentrations. The results showed that caudal vein injection is a simple and adequate method of intravenous administration in rats designated for exsanguinated blood and tissue collection. For serial blood sampling in individual animals, the dose may be given via the jugular vein and the blood collected from the cut tail. These methods require little or no surgical preparations and are particularly suitable for prolonged sampling in studies where a relatively large number of animals are involved.

Animals↗

PubMed1984

Effect of food, fluid and dosage form on the absorption of 52-522, a potential antianxiety agent, in the dog.

The absorption of 52-522 in the dog was studied by measuring blood concentrations of radioactivity after single oral doses of [14C] 52-522 in a capsule with and without water, also as a food-drug mixture, and a solution in polyethylene glycol 400. Absorption was rapid, and its rate moderate with no significant differences in peak times among treatments. The extent of absorption was lowest after the capsulated [14C] 52-522. The solution dose gave elevated blood concentrations, that were statistically significantly different when compared with the capsules. Hence, it appears that the absorption of [14C] 52-522 is governed by the degree of dispersion of drug in the dosage form.

Absorption↗

PubMed1983

Biliary excretion of [14C]temazepam and its metabolites in the rat.

The excretion of temazepam and its N-desmethyl metabolite, oxazepam, and their respective O-conjugates was examined following a single intravenous dose of [14C]temazepam to two groups of bile fistula rats, with and without bile replenishment to the animals via duodenal cannulae. During an 8-hr collection period, the two groups produced virtually identical bile volumes, and there were no significant differences between them in the amount of total radioactivity, free temazepam, or the identified metabolites in the bile, as determined by TLC and liquid scintillation counting. Elimination of the radioactive dose was rapid during 0-8 hr, with a half-life of approximately 1 hr. Approximately 85-90% of the administered radioactivity was recovered in the bile: less than 1% as free temazepam, 3% as oxazepam, and approximately 10% as their O-conjugates.

Animals↗

PubMed1983

In vivo-in vitro correlations for trisulfapyrimidine suspensions.

A UV method is described for measuring total sulfa drug concentration in dissolution samples. This in vitro measurement was found to correlate well with several in vivo parameters obtained after administration of commercial trisulfapyrimidine suspensions to humans. The UV method, which is rapid, simple, inexpensive and easily automated, is recommended for studying the dissolution of trisulfapyrimidine suspensions.

Biological Availability↗

PubMed1983

Enterohepatic circulation of radioactivity following an oral dose of [14C]temazepam in the rat.

The enterohepatic circulation of radioactive material after administering [14C]temazepam was evaluated in three sets of male Wistar strain rats connected in pairs by bile duct-duodenum cannulae. After a single oral dose (10 mg kg-1) to the donor rat, the excretion of radioactivity in the urine and faeces of both rats and in the bile of the recipient rat was determined. Mean total recovery of the administered radioactivity was 92.2%. Based on the amount remaining in the donor rat (gastrointestinal tract and faeces), 81.7% of the dose was absorbed by the donor. The total amount recovered from the recipient, 69.4% of original dose (85.1% of donor's absorbed dose), represented the amount excreted in the donor's bile. Similarly, 54.1% of the original dose (77.9% of the transferred biliary excretion from donor) was reabsorbed by the recipient, and the biliary excretion from this animal (45.9% original dose) accounted for 86.% of the amount reabsorbed.

Administration, Oral↗