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We perform a tracer counterpermeation (TCP) analysis for a stochastic model of diffusive transport through a narrow linear pore where passing of species within the pore is inhibited or even excluded (single-file diffusion). TCP involves differently labeled but otherwise identical particles from two decoupled infinite reservoirs adsorbing into opposite ends of the pore, and desorbing from either end. In addition to transient behavior, we assess steady-state concentration profiles, spatial correlations, particle number fluctuations, and diffusion fluxes through the pore. From the profiles and fluxes, we determine a generalized tracer diffusion coefficient D_{tr}(x), at various positions x within the pore. D_{tr}(x) has a plateau value in the pore center scaling inversely with the pore length, but it is enhanced near the pore openings. The latter feature reflects the effect of fluctuations in adsorption and desorption, and it is also associated with a nontrivial scaling of the concentration profiles near the pore openings.

Inhibited passing of reactant and product molecules within the linear pores of nanoporous catalytic materials strongly reduces reactivity. The dependence of the passing propensity P on pore radius R is analyzed utilizing Langevin dynamics to account for solvent effects. We find that P ∼ (R-R(c))(σ), where passing is sterically blocked for R≤R(c), with σ below the transition state theory value. Deeper insight comes from analysis of the corresponding high-dimensional Fokker-Planck equation, which facilitates an effective small-P approximation, and dimensional reduction enabling utilization of conformal mapping ideas. We analyze passing for spherical molecules and also assess the effect of rotational degrees of freedom for elongated molecules.

Statistical mechanical modeling is performed of a catalytic conversion reaction within a functionalized nanoporous material to assess the effect of varying the reaction product-pore interior interaction from attractive to repulsive. A strong enhancement in reactivity is observed not just due to the shift in reaction equilibrium towards completion but also due to enhanced transport within the pore resulting from reduced loading. The latter effect is strongest for highly restricted transport (single-file diffusion), and applies even for irreversible reactions. The analysis is performed utilizing a generalized hydrodynamic formulation of the reaction-diffusion equations which can reliably capture the complex interplay between reaction and restricted transport.

Behavior of catalytic reactions in narrow pores is controlled by a delicate interplay between fluctuations in adsorption-desorption at pore openings, restricted diffusion, and reaction. This behavior is captured by a generalized hydrodynamic formulation of appropriate reaction-diffusion equations (RDE). These RDE incorporate an unconventional description of chemical diffusion in mixed-component quasi-single-file systems based on a refined picture of tracer diffusion for finite-length pores. The RDE elucidate the nonexponential decay of the steady-state reactant concentration into the pore and the non-mean-field scaling of the reactant penetration depth.

We analyze the spatiotemporal behavior of species concentrations in a diffusion-mediated conversion reaction which occurs at catalytic sites within linear pores of nanometer diameter. Diffusion within the pores is subject to a strict single-file (no passing) constraint. Both transient and steady-state behavior is precisely characterized by kinetic Monte Carlo simulations of a spatially discrete lattice-gas model for this reaction-diffusion process considering various distributions of catalytic sites. Exact hierarchical master equations can also be developed for this model. Their analysis, after application of mean-field type truncation approximations, produces discrete reaction-diffusion type equations (mf-RDE). For slowly varying concentrations, we further develop coarse-grained continuum hydrodynamic reaction-diffusion equations (h-RDE) incorporating a precise treatment of single-file diffusion in this multispecies system. The h-RDE successfully describe nontrivial aspects of transient behavior, in contrast to the mf-RDE, and also correctly capture unreactive steady-state behavior in the pore interior. However, steady-state reactivity, which is localized near the pore ends when those regions are catalytic, is controlled by fluctuations not incorporated into the hydrodynamic treatment. The mf-RDE partly capture these fluctuation effects, but cannot describe scaling behavior of the reactivity.

We report atomistic simulations for both self- and transport diffusivities of light gases in carbon nanotubes and in two zeolites with comparable pore sizes. We find that transport rates in nanotubes are orders of magnitude faster than in the zeolites we have studied or in any microporous material for which experimental data are available. The exceptionally high transport rates in nanotubes are shown to be a result of the inherent smoothness of the nanotubes. We predict that carbon nanotube membranes will have fluxes that are orders of magnitude greater than crystalline zeolite membranes.

Medical records of patients diagnosed with primary fallopian tube carcinoma between 1979 and 1989 were reviewed. Twenty-six patients were eligible; 8 patients were excluded after pathologic review, leaving 18 patients included in the study for this analysis. The median and mean age were 61 and 59 years, respectively, with a range of 39-80 years. There were three Stage I, five Stage II, seven Stage III, and three Stage IV patients. The most common presenting symptoms were abdominal/pelvic pain, abdominal distension, and vaginal discharge/bleeding. The primary site of the lesion was determined to be the right tube in 44% of the cases, the left tube in 39% of the patients, bilateral lesions in 11% of the patients, and indeterminate in 6%. Histologic grade was poorly differentiated (Grade III) in 13 patients, moderately differentiated (Grade II) in 4 patients, and well differentiated (Grade I) in one. No patient was correctly diagnosed preoperatively. Survival at 5 years of the entire group was 35% with a 3 year minimum followup. Corresponding disease free survival was 30%. Mean and median survival times were 74 and 37 months, respectively. The range of survival times was from 1 to 120 months. All Stage I patients, 80% (4/5) of Stage II, and 29% (2/7) of Stage III patients are alive without disease. None (0/3) of the Stage IV patients are alive. Treatment regimens consisted of intraperitoneal P-32, external beam radiotherapy, and/or chemotherapy. Radiotherapy was associated with a low incidence of treatment-related complications, the majority being gastrointestinal related. There was one chemotherapy-related death. These patients and their treatment outcomes add to the data base of numerous previous reports on fallopian tube carcinoma. Stage I and II patients fared excellently with primary surgical and adjuvant therapy. While the prognosis of Stage III and IV patients is much worse, significant levels of long term survival can be achieved with aggressive treatment.

Although both epidemiological and experimental evidence suggests that estrogen replacement therapy reduces the risk of coronary heart disease, the mechanisms for this beneficial effect are largely unknown. Furthermore, the addition of progestins or androgens to estrogen replacement therapy is of concern. The objective of this study was to examine the effects of esterified estrogens alone or in combination with an androgen on arterial LDL metabolism and early atherogenesis in ovariectomized female cynomolgus monkeys. Arterial LDL metabolism was assessed by using dual-labeled LDL that was injected 24 hours before necropsy. Arterial LDL degradation was reduced by 64% to 84% and cholesteryl ester content was decreased by approximately 50% in the thoracic aorta in both treatment groups compared with controls. In addition, aortic lipid peroxidation products, as assessed by thiobarbituric acid reaction, were significantly lower in animals treated with esterified estrogens, with a similar trend for combined estrogen-androgen treatment. Both treatments also reduced plasma concentrations of apoB-containing lipoproteins, reduced LDL particle size, and increased total-body LDL catabolism. The combination of decreased arterial LDL metabolism, decreased arterial lipid peroxidation, and improved plasma lipoprotein metabolism may explain some of the protective effects of estrogens on coronary heart disease and indicate that beneficial actions extend to a combination of estrogen and androgen.

We measured the relative binding affinity (RBA) of 17-alpha-methyltestosterone (MET) for the rat prostate androgen receptor and human sex hormone-binding globulin (SHBG) in vitro. The reference compound in both instances was dihydrotestosterone (DHT), the RBA of which was set at 100%. The RBA of methyltestosterone was 44% for the androgen receptor, but 11% for SHBG. The androgen receptor, therefore, would appear to recognize a different part of an androgen compared to the recognition site on SHBG. The difference in RBAs may amplify the biologic action of methyltestosterone.

Normal human placental trophoblasts have recently been shown to contain receptors for hCG/hLH. The present studies investigated the expression of these receptors in hyperplastic and anaplastic trophoblasts in gestational trophoblastic neoplasms. The results demonstrated that both hydatidiform moles and choriocarcinomas contained receptor messenger RNA (mRNA) and receptor protein. A variety of nontrophoblast tumors, on the other hand, contained neither receptor mRNA nor receptor protein. Choriocarcinomas contained more receptor mRNA and receptor protein than hydatidiform moles which in turn contained more than normal human placenta. Midluteal phase human corpus luteum contained more receptor mRNA than normal human placenta and about the same as choriocarcinomas. The hyperplastic and anaplastic trophoblasts in hydatidiform moles and choriocarcinomas contained more receptor immunostaining than the normal trophoblasts in the same tissue or those from normal placentas from about the same gestational age. The receptor immunostaining increased as the degree of trophoblast hyperplasia increased in hydatidiform moles. Anaplastic trophoblasts of choriocarcinomas contained a similar amount of receptor immunostaining as severely hyperplastic trophoblasts of hydatidiform moles. Invading anaplastic trophoblasts of choriocarcinoma contained greater amount of receptor immunostaining than the surrounding endometrial stromal and myometrial smooth muscle cells. In summary, this is the first study to our knowledge demonstrating the expression of hCG/hLH receptor gene in gestational trophoblastic neoplasms. The increased receptor expression in these neoplasms suggests that hCG, via its receptors, could play a fundamental and previously unsuspected autocrine role in the regulation of trophoblast transformation, growth, invasion, and high hCG secretion.

To understand the nephrotoxicity of xenobiotics, the species, strain, sex, and the presence of other chemicals must be considered. This review has considered the importance of these factors in determining the nephrotoxic liability of a drug. For example, cephaloridine is more nephrotoxic in rabbit than rats and is least nephrotoxic in mice. This species-dependent susceptibility to cephaloridine nephrotoxicity appears to be related to the degree in which cephaloridine depletes renal cortical glutathione. Additionally, only male mice of certain strains are susceptible to chloroform-induced nephrotoxicity. Lastly, the presence of certain ketones or ketogenic substances such as acetone and hexane enhance chloroform-induced nephrotoxicity in male Sprague-Dawley rats. Knowing which factors can enhance or limit nephrotoxicity of drugs will lend to a better understanding of the mechanism of these toxicities as well as to design compounds with lesser toxicities.

Epidermal regeneration depends on mitosis and migration of keratinocytes. Epidermal growth factor is known to stimulate growth of keratinocytes in vitro, thus it might be expected to promote wound healing. The results of this study show that topical application of biosynthetic human epidermal growth factor accelerates epidermal regeneration in split-thickness wounds and partial-thickness burns. The significant enhancement of epidermal regeneration suggests the potential for clinical use of epidermal growth factor for accelerating healing of burns, wounds from trauma, diabetic ulcers, skin graft donor sites, and others.

Tri- and tetrapeptide analogues were synthesized and evaluated as renal vasodilators. These peptides were prepared by standard coupling reactions, which also provided good yields with hindered alpha-methyl amino acid derivatives. Preliminary evidence of renal vasodilator activity was determined in anesthetized dogs by measuring the effects on renal blood flow and calculating the accompanying changes in renal vascular resistance. The most potent compounds contained, in their basic structure, the L-prolyl-DL-alpha-methylphenylalanyl-L-arginine and L-prolyl-DL-alpha-methylphenylalanylglycyl-L-proline arrays. Substitution on the N-terminal proline with 4-phenylbutyryl and 4-(4-hydroxyphenyl)butyryl side chains produced enhanced renal vasodilator activity and, in certain cases, selectivity for the renal vasculature.

The effect of experimental diabetes on hepatic drug metabolism was studied in male Holtzman rats. Treatment of animals with streptozotocin and 6-aminonicotinamide, both agents which produce an insulin-deficient animal, caused prolongation of hexobarbital sleeping times and inhibition of the rate of metabolism of both hexobarbital and, to a lesser extent, aniline in vitro. Treatment of animals with N-methylacetamide, a diabetogen which does not cause insulin deficiency in the animal but rather produces an insulin-resistant state, did not affect the metabolism in vitro of either hexobarbital or aniline. Neither insulin nor any of the diabetogenic agents had any direct effect on drug metabolism in vitro. Furthermore, hepatic microsomal protein and cytochrome P-450 contents were not significantly different in any of the diabetic animals from those of the control animals. Hyperglycemia produced by glucose infusion did not affect the metabolism of hexobarbital in vitro. The effects of streptozotocin and 6-aminonicotinamide appeared to be at least partially due to the presence of an inhibitor in the liver cytosol which correlated with elevated hepatic cyclic AMP concentrations.

SK&F 82526 and its enantiomers have been shown to increase renal blood flow and decrease renal vascular resistance in the anesthetized dog. The effect of the racemate on lowering systemic blood pressure in the anesthetized dog and the spontaneously hypertensive rat has been shown to be caused by the R-enantiomer with the S-enantiomer being devoid of significant activity on blood pressure. The mechanism by which the R-enantiomer decreases blood pressure is not systemic vasodilatation or prejunctional inhibition of norepinephrine release but appears to result from a unique stimulation of the postjunctional dopamine receptor. Racemic SK&F 82526 also has been shown to increase renal blood flow in an ischemic model of acute renal failure.

Recent clinical data strongly suggest that elevated urinary albumin excretion (UAE) identifies diabetic subjects at risk of developing nephropathy. Elevated UAE is attributed to increased transglomerular pressure, which is associated with poor metabolic control in rats. Because excess glucose in diabetes is metabolized via the polyol pathway, we were interested in whether the diabetes-induced elevation in UAE in rats could be prevented by inhibiting aldose reductase (AR), the first enzyme in the polyol pathway, with the AR inhibitor tolrestat. In fact, in rats made diabetic with streptozocin (35 mg/kg IV), treatment for 6 months with tolrestat (25 mg/kg/day in the diet) prevented both sorbitol accumulation in the kidney and the increase in UAE. Sorbitol accumulation and the increased UAE were not associated with statistically significant mesangial expansion, and the thickening of glomerular basement membranes was not affected by tolrestat treatment. The authors conclude that the 4.7-fold elevation in UAE in chronically diabetic rats is linked to the increased flux of glucose through the polyol pathway since it was prevented by inhibiting aldose reductase with tolrestat.

AY-31,906, exo-2-amino-4-[(bicyclo[2.2.1]hept-2-yl)amino-N-[[1- methylethyl)amino]carbonyl]-5-pyrimidinesulfonamide, exhibited potent diuretic and natriuretic activity in rats and dogs. After p.o. administration, AY-31,906 was 1.5- and 12.3-times more potent as a natriuretic than furosemide in rats and dogs, respectively, whereas it was 0.5- and 6.1-times as potent after i.v. administration. The maximum natriuretic effect of AY-31,906 in both species was similar to that observed with furosemide. At equiactive natriuretic p.o. doses in both species, AY-31,906 produced a greater increase in the urinary ratio of Na/K than furosemide, indicating a relative potassium-sparing effect. AY-31,906 produced significant increases in the fractional excretion of sodium and chloride in dogs at a dose that produced no statistically significant changes in the fractional excretion of potassium, glomerular filtration rate or renal plasma flow. After p.o. administration, the onset of activity of AY-31,906 occurred within the 1st hr in both rats and dogs and preliminary data demonstrated that the activity lasted for approximately 2 hr in rats and 4 hr in dogs. Clearance studies in conscious dogs suggest that AY-31,906 inhibited electrolyte reabsorption in the ascending limb of the loop of Henle and, unlike furosemide, AY-31,906 had no activity at the proximal tubule. These results indicate that AY-31,906 is a potent, high ceiling diuretic with relative potassium-sparing properties. The compound is well absorbed after p.o. administration with diuretic activity occurring in the 1st hr.

Dopamine-4-O-sulfate (DA-4-S), a major metabolite of dopamine, was examined for pharmacologic activity both in vivo and in vitro. Intravenous doses of DA-4-S ranging from 1.3-34.3 micrograms/kg had no effect on renal blood flow or blood pressure in the anesthetized dog, demonstrating lack of agonist activity at vascular DA1 receptor sites. These data also suggest that DA-4-S is not metabolically converted to an active dopamine agonist in the dog. No beta-adrenoceptor agonist activity of DA-4-S could be detected in the isolated guinea-pig left atrium, and no alpha 1-agonist activity of DA-4-S could be detected in the perfused rabbit ear artery, although sympathetic neurotransmission was inhibited in this tissue at high concentrations (EC50 = 3.9 X 10(-6) M). This latter response was competitively inhibited by S-sulpiride. This lack of affinity for dopaminergic and adrenergic receptors was confirmed by biochemical assays (striatal adenylate cyclase stimulation; 3H-spiroperidol, 3H-clonidine, and 3H-WB 4101 binding using brain tissue preparations). In all the above tests, the activity of DA-4-S was much weaker than dopamine, showing this metabolite has little intrinsic dopaminergic or adrenergic pharmacological activity.

p-Hydroxytriamterene, the phase I metabolite of triamterene, increased sodium excretion without affecting urinary volume or potassium when administered orally to rats on sodium deficient diets at doses of 15 and 30 mg/kg. The urine of these animals also contained p-hydroxytriamterene sulfuric acid ester, the phase II metabolite of triamterene but did not contain p-hydroxytriamterene. This evidence indicates that p-hydroxytriamterene is orally active as a potassium-sparing natriuretic in rats.