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Biomedical subjects

W J Wechter

Publications and source records attributed to W J Wechter.

At least 19 recordsLinked to original sources
PubMed2000

Treatment and survival study in the C57BL/6J-APC(Min)/+(Min) mouse with R-flurbiprofen.

Our previous studies with the mouse model of familial adenomatous polyposis (FAP), C57BL/6J-APC(Min)/+ or Min mouse, demonstrated the optimal dose for adenoma reduction with R-flurbiprofen was 10 mg/kg/day as an undivided dose. Divided doses exhibited no increased efficaciousness. This study examines 10 mg/kg R-flurbiprofen daily (qd) on survival as well as a second daily (q.o.d.) schedule and compares it with sulindac sulfone. The q.o.d. schedule at 10 mg/kg was equally efficacious as qd treatment at the same dose. For the q.o.d. group, tumor number decreased similarly (p<0.01); while body weight gain (p<0.01), hematocrit and average tumor area (both, p<0.05) were improved compared with qd treatment. Treatment with R-flurbiprofen (10 mg/kg/day) increased survival significantly (p=0.0004, log-rank) compared to vehicle treated animals. Major biological endpoints (hematocrit, weight gain, tumor number, average and total area [99% reduction]) were significantly improved in treated animals (p<0.01). Sulindac sulfone treatment (50 mg/kg/day) of the Min mouse produced no significant biological benefit. The dose schedule study suggests that for tumor reduction it is necessary to attain a threshold drug-level but not necessarily sustain it over 24 hrs (pharmacodynamic t1/2 >> pharmacokinetic t1/2). During the period of administration R-flurbiprofen dramatically prolongs survival for the mouse model of the human disease, FAP.

Adenomatous Polyposis Coli↗
PubMed1998

Mechanism of enhancement of intestinal ulcerogenicity of S-aryl propionic acids by their R-enantiomers in the rat.

We previously observed a marked increase in gastrointestinal toxicity of rac-flurbiprofen compared to the therapeutically equivalent dose of the S enantiomer. This paper quantitates these observations and examines the mechanism by which this paradoxical toxicity occurs. We have evaluated the ulcer scores, mucosal neutrophil infiltration, by immunostaining of CD11/18 antigen, and mucosal neutrophil activity by myeloperoxidase measurement at two dose levels of (R)-, (S)-, and rac-flurbiprofen, administered over 30 days. Dose-response for intestinal ulcer production was observed for rac- and (S)-flurbiprofen; animals given (R)-flurbiprofen exhibited no ulcers. Yet rac-flurbiprofen proved to be twice as ulcerogenic as (S)-flurbiprofen. The mechanism of the exacerbation of gastrointestinal toxicity of (S)-flurbiprofen by the noncyclooxygenase inhibiting (R)-flurbiprofen is believed to be associated with its effect on ICAM-1 up-regulation. This is followed by neutrophil adhesiveness to ICAM-1 via the LFA-1 antigen on its surface and the extravasation of neutrophils into the tissue. We also examined the effect of high dose (R)-flurbiprofen vs vehicle over 15 days in animals in which ulcers had been produced by treatment with (S)-flurbiprofen for the previous 15 days. (R)-flurbiprofen did not sustain induced ulcers. The results of this study suggest that human studies be conducted to determine if enhanced gastrointestinal toxicity occurs in man. This is at issue since rac compounds of this class are available over the counter and others may be introduced.

Animals↗
PubMed1998

Effect of minocycline on osteoporosis.

The effect of oral minocycline on osteopenia in ovariectomized (OVX) old rats was examined in this study. Rats were divided into 4 groups: sham-operated, OVX followed by treatment with vehicle, minocycline, or 17 beta-estradiol. The treatment was initiated one day after OVX and proceeded for 8 wks. OVX reduced bone mineral density (BMD) in the whole femur and in the femoral regions that are enriched in trabecular bone. Treatment with minocycline or estrogen prevented a decrease in BMD. Femoral trabecular bone area, trabecular number, and trabecular thickness were reduced, and trabecular separation was increased by OVX. Treatment with minocycline or estrogen abolished the detrimental effects induced by OVX. OVX also reduced indices that reflect the interconnectivity of trabecular bone, and the loss of trabecular connectivity was prevented by treatment with minocycline or estrogen. Based on the levels of urinary pyridinoline, we showed that the effect of estrogen, but not minocycline, was primarily through its inhibitory effect on bone resorption. Analysis of bone turnover activity suggests that OVX increased parameters associated with bone resorption (eroded surface) and formation (osteoid surface, mineralizing surface, mineral apposition rate, and bone formation rate). Treatment with minocycline reduced bone resorption modestly and stimulated bone formation substantially. In contrast, treatment with estrogen drastically reduced parameters associated with both bone resorption and formation. We have concluded that oral minocycline can effectively prevent the decrease in BMD and trabecular bone through its dual effects on bone resorption and formation.

Amino Acids↗
PubMed1997

R-flurbiprofen chemoprevention and treatment of intestinal adenomas in the APC(Min)/+ mouse model: implications for prophylaxis and treatment of colon cancer.

We used the C57BL/6J-APC(Min)/+ mouse (Min mouse) to evaluate the chemopreventive effects of R-flurbiprofen (R-FB), the noncyclooxygenase-inhibiting enantiomer of FB. Weanling Min mice were administered 6 weeks of oral treatment with R-FB using 2.5-25 mg/kg of R-FB once per day (q.d.), 2.5-10 mg/kg of R-FB twice per day (b.i.d.), and 5 mg/kg of R-FB b.i.d. challenged with a high saturated fat diet. At necropsy we determined tumor and ulcer numbers, tumor size, and plasma levels of R- and S-FB. A linear dose response was observed from 2.5 to 10 mg/kg of R-FB, regardless of whether the drug was administered as a single or divided dose. Reductions in tumor number were significant (P < or = 0.02) for doses of R-FB from 2.5 to 25 mg/kg/day. A dose of 5 mg/kg R-FB b.i.d. was able to overcome the doubling in tumor number associated with the high saturated fat diet. At 20 and 25 mg/kg/day R-FB, we obtained the maximum response with up to 90% inhibition of total tumor number. At these doses, however, there was toxicity and animal deaths. This toxicity was associated with ulceration, presumably resulting from the in vivo epimerization of R- to S-FB that occurs in the mouse. Thus, we evaluated the oral pharmacokinetics of R-FB and its conversion to S-FB in wild-type mice. These kinetics experiments revealed inversion rates of 7.3 and 11.0% for the 2.5 and 10 mg/kg R-FB doses, respectively. S-FB administered alone (0.5 and 2.0 mg/kg q.d.), in doses mimicking the concentrations of S-FB associated with the R to S epimerization of the doses of R-FB used in our experiments, had little or no antitumor efficacy (P > 0.05). Thus, we conclude that R-FB itself, not the S-FB resulting from epimerization in the mouse, inhibits adenoma formation in the Min mouse. In humans, where there is no R to S epimerization, it is possible that larger doses of R-FB can be used without causing cyclooxygenase inhibition and its resulting ulcerogenicity and other side effects. To assess the effect of R-FB on established adenomas, we allowed 40 Min mice to remain untreated until 70 days of age (the time of necropsy in the previous experiments) and then treated them for an additional 42 days with 10 mg/kg R-FB q.d. or 5 mg/kg R-FB b.i.d.. Both drug-treated groups demonstrated tumor numbers significantly less than that of the vehicle control (P < 0.01). Our results suggest that prophylaxis and treatment trials of R-FB should be extended to humans.

Adenoma↗
PubMed1997

Endogenous natriuretic factors 6: the stereochemistry of a natriuretic gamma-tocopherol metabolite LLU-alpha.

2,7,8-Trimethyl-(S)-2-(beta-carboxyethyl)-6-hydroxy chroman (S-LLU-alpha) isolated from human uremic urine is apparently an oxidative side-chain degradation product of gamma-tocopherol. This compound exhibits natriuretic activity in vivo and it appears to mediate the inhibition of the 70 pS K+ channel in the apical membrane of the thick ascending limb of the nephron. The stereochemistry at the C-2 of LLU-alpha has been unequivocally established to be S(+) by X-ray crystallographic analysis of a diastereomeric amide derivative. It was also established that the chroman ring oxidation of S-LLU-alpha proceeded without racemization at C-2. This finding can be extended to nonepimerization at C-2 of alpha-delta tocopherols (Vitamin E) during side-chain oxidation and stereospecificity (retention or inversion) of oxidative opening of the chroman ring. The resolution of the enantiomers of the parent compound and derivatives was accomplished by chiral high-performance liquid chromatography. The stereospecific enzymatic hydrolysis by an array of commercially available enzymes of the racemic methyl ester of LLU-alpha was investigated. The lipase from Humicola languinosa appears to be the best enzyme for resolution by selective hydrolysis of the racemic methyl ester.

Chromans↗
PubMed1997

Endogenous natriuretic factors 7: biospecificity of a natriuretic gamma-tocopherol metabolite LLU-alpha.

The structural elucidation and mechanism of action of a potential component, LLU-alpha, of what is possibly a multifactorial complex known as "natriuretic hormone" was recently reported [Wechter, W.J. et al. (1996a) Proc. Natl. Acad. Sci. U.S.A. 93: 6002-6007]. "Natriuretic hormone," a long-sought factor, is believed to regulate extracellular fluid volume and consequently be pathomimetic for hypertension, cirrhosis, congestive heart failure and other volume expanded states. The studies reported herein further characterize LLU-alpha. The precursor of the endogenous LLU-alpha was demonstrated to be gamma-tocopherol by radiolabeling studies. The pharmacokinetics of infused rac-LLU-alpha proved to be biphasic (half-lives: 12 min and 6 h). Specificity of the inhibition of the 70 pS potassium channel of the thick ascending limb of the loop of Henle was examined with the natural S-enantiomer being the most potent known inhibitor whereas the analogous alpha-tocopherol metabolite, rac-5-Me-LLU-alpha, showed no inhibition. Rac-LLU-alpha does not inhibit two isozymes of the Na+/K+-ATPase. LLU-alpha is natriuretic acting via inhibition of the 70 pS potassium channel and not Na+/K+-ATPase, the assumed mechanism of action of the "natriuretic hormone." LLU-alpha, a metabolite of a vitamin, if it were found to play a role in the regulation of extracellular fluid volume, would be the second example of a vitamin acting as a precursor for a hormone. Of considerable interest is the fact that this manuscript reports the first biological activity of gamma-tocopherol, a member of the vitamin E complex.

Animals↗
PubMed1996

A new endogenous natriuretic factor: LLU-alpha.

For over three decades, renal physiology has sought a putative natriuretic hormone (third factor) that might control the body's pool of extracellular fluid, an important determinant in hypertension, congestive heart failure, and cirrhosis. In our search for this hormone, we have isolated several pure natriuretic factors from human uremic urine that would appear, alone or in combination, to mark a cluster of phenomena previously presumed to be that of a single "natriuretic hormone." This paper reports the purification, chemical structure, and total synthesis of the first of these compounds, LLU-alpha, which proved to be 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman, presumably a metabolite of gamma-tocopherol. Both natural LLU-alpha and synthetic material are identical (except for optical activity) with respect to structure and biological activity. It appears that the natriuretic activity of LLU-alpha is mediated by inhibition of the 70 pS K+ channel in the apical membrane of the thick ascending limb of the kidney.

Animals↗
PubMed1996

Endogenous natriuretic factors. 5. Synthesis and biological activity of a natriuretic metabolite of diltiazem and its derivatives.

In our search for endogenous natriuretic factors from human uremic urine, we have previously identified a new metabolite of the drug diltiazem (Murray et al. Life Sci. 1995, 57, 2145-2161). The structure of this metabolite, (+)-(2S,3S)-3-hydroxy-5-(2-hydroxyethyl)-2,3-dihydro-2-(4-methoxyphenyl) -1,5-benzothiazepin-4(5H)-one (LLU-beta1; 2), was proved by unequivocal synthesis from a diltiazem synthon. The synthetic material also proved to be natriuretic as had the urinary isolate. Given the acetylation at C-3 in diltiazem, the 3-monoacetate (8) and diacetate (3) derivatives of 2 were prepared. The 4-nor-keto (6) derivative of 2 was also synthesized. Only the parent 2 induced natriuresis over a range of doses without accompanying kaliuretic activity at some doses.

Animals↗
PubMed1996

Calculation of inversion half-lives of aryl propionic acid class nonsteroidal antiinflammatory drugs.

Although inversion of the R-enantiomers of the aryl propionic acid (APA) class of nonsteroidal antiinflammatory drugs (NSAIDs) in humans and other mammals has been known for more than 20 years, no satisfactory method has been developed for evaluating the half-life of the inversion process. This parameter is useful in assessing the pharmacodynamic contribution of the R-prodrug to the cyclooxygenase-inhibiting S-enantiomers. Further, it provides a similar means of evaluating the analgesic contributions of R-enantiomers to racemic mixtures. Using human and animal data, we have mathematically determined the inversion half-life (t1/2i) for ibuprofen, ketoprofen, and fenoprofen. The relation of the sensitivity of this value to the terminal half-life (t1/2) of the R-enantiomers of APA class drugs also is discussed.

Animals↗
PubMed1996

Antiproliferative effects of the enantiomers of flurbiprofen.

Nonsteroidal antiinflammatory drugs (NSAIDs) are recognized for inhibiting growth of colon tumors in animal models, and for reducing the risk of colon cancer in humans. The mechanisms involved have not been established, but are thought to be related to reduced prostaglandin biosynthesis. The present study investigates the effect of COX-inhibiting and non-COX-inhibiting enantiomers of flurbiprofen on rat colonocyte proliferation. Intestinal ulceration was used as a surrogate indicator of COX inhibition. Sprague Dawley rats were treated orally with 6.3 mg/kg of R- or s-flurbiprofen or vehicle. Colonocyte labeling index and small bowel ulcer index were measured. R-flurbiprofen and S-flurbiprofen significantly reduced colonocyte labeling index, by 34% and 23% respectively, compared with vehicle. R-flurbiprofen caused minimal ulcer formation (4.48 mm2) compared with S-flurbiprofen (94.4 mm2). These findings suggest that R-flurbiprofen-mediated control of colonocyte proliferation is independent of prostaglandin biosynthesis.

Animals↗
PubMed1996

Human plasma concentrations of R, S, and racemic flurbiprofen given as a toothpaste.

Flurbiprofen, an arylpropionic acid (APA) class nonsteroidal antiinflammatory drug (NSAID), is commercially available only as the racemic mixture, although its pharmacologic effect has been credited primarily to the S isomer. In humans, the bioavailability of racemic flurbiprofen absorbed from the oral cavity has been studied measuring the total concentration of S- and R-flurbiprofen, and the pharmacokinetics of S- and R-flurbiprofen have been studied after oral administration of racemic flurbiprofen. In this study, the plasma concentrations of S-flurbiprofen and to some extent R-flurbiprofen were studied after brushing with a toothpaste containing different mixtures of S- and R-flurbiprofen. The toothpaste formulations contained 1% racemic (50:50), eutectic (14:86), 1%, 0.5%, and 0.25% (5:95) R- to S-flurbiprofen. Both S- and R-flurbiprofen were rapidly absorbed, with a time to reach maximum concentration (tmax) of 1.2 to 1.4 hours. Based on the AUC, the amount of S-flurbiprofen absorbed increased proportionally when given as the 0.25% (5:95) preparation to the 0.5% (5:95) mixture but did not increase significantly above the 0.5% (5:95) mixture when given as 1% (5:95) R- to S-flurbiprofen. This suggests that dose-proportional absorption of S-flurbiprofen is not maintained at higher concentrations. The elimination of S-flurbiprofen appears to be variable and prolonged after this mode of administration, as observed from plasma concentrations. Further controlled and more prolonged studies of S- and R-flurbiprofen are needed to confirm these observations.

Adult↗
PubMed1996

Time responses of cancellous and cortical bones to sciatic neurectomy in growing female rats.

Effects of unilateral sciatic neurectomy on the responses of both cancellous and cortical bones were studied in growing female rats at 0, 1, 4, 8, and 12 weeks after operation. Using double-fluorescent labeling techniques, histomorphometric analyses were performed on longitudinal sections of proximal tibial metaphyseal secondary spongiosa (PTM) and on cross sections of tibial shaft (TX). In PTM, sciatic neurectomy not only inhibited the age-related bone gain, but also reduced the trabecular bone mass by 46%, which was accompanied by decreases in trabecular number, thickness, and node to node density, and an increase in trabecular separation and free end to free end density. The bone loss occurred mainly between 1 and 4 weeks after operation. A sharp increase in bone formation indices was observed during the first week after nerve section. However, these endpoints quickly dropped to levels lower than those of sham-operated controls at 4 weeks, and were not different from the control levels at 8 weeks after operation. Eroded surface increased progressively after sciatic neurectomy during the 12 weeks experimental period. In TX, sciatic neurectomy inhibited the age-related increase in total tissue area that maintained it at the basal control level. However, the cortical bone area in neurectomized legs was lower than that in sham-operated controls. Sciatic neurectomy also stimulated the bone formation indices on both periosteal and endocortical surfaces during the first week after operation. These endpoints declined sharply between 1 and 4 weeks and then maintained at control levels between 8 and 12 weeks post surgery. Endocortical eroded surface increased 1 week after neurectomy, reached the peak at 8 weeks, and then decreased thereafter. These findings suggest that (1) sciatic neurectomy not only inhibited age-related bone gain but also induced marked bone loss in cancellous bone site and inhibited age-related bone gain in cortical bone site, which mainly resulted from the decrease in bone formation and the increase in bone resorption; (2) the changes in both cancellous and cortical bones responded to sciatic neurectomy occurred mostly within the first 4 weeks and stabilized between 8 and 12 weeks after surgical intervention. In conclusion, the unilateral sciatic neurectomized rat is a complex model in which to study osteopenia. Despite sciatic neurectomy being a simple operation, the interactions of skeletal responses to postsurgical regional acceleratory phenomenon (RAP) and disuse and adaptation changes cannot be clearly differentiated. Furthermore, the complications from growth and aging should be avoided.

Animals↗
PubMed1996

Minocycline prevents the decrease in bone mineral density and trabecular bone in ovariectomized aged rats.

In the current study, we examined the effects of minocycline, on the osteopenia of ovariectomized aged rats. Old female rats were randomly divided into five groups: sham, ovariectomized control and ovariectomized treated with minocycline, 17beta-estradiol, or both agents. Bone samples were collected 8 wk after the treatment. Ovariectomy reduced bone mineral density of the whole femur and at the condylar, distal metaphyseal and head-neck-trochanter regions 10%-19% and the loss of bone density was prevented by treatment with minocycline or 17beta-estradiol. Histomorphometric analysis of distal femur showed ovariectomy reduced the trabecular bone area, the trabecular bone number, trabecular bone thickness and increased the trabecular bone separation. The microanatomic structure of trabecular bone also showed that the number of nodes, node to node, cortical to node, node to free end was reduced by ovariectomy. Treatment with minocycline attenuated the effect of ovariectomy on trabecular bone in aged animals. In contrast, cortical bone was not affected by ovariectomy or minocycline treatment. The effect of minocycline on bone turnover was also examined. Minocycline increased osteoid surface, mineralizing surface, mineral apposition rate, bone formation rate and reduced eroded surface. We have therefore concluded that the modest increase in bone mineral density and the improvement in the trabecular bone status noted in minocycline treated ovariectomized aged rats is likely due to an increase in bone formation coupled with a decrease in bone resorption.

Absorptiometry, Photon↗