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Biomedical subjects

N Bodor

Publications and source records attributed to N Bodor.

At least 109 records · Page 6Linked to original sources
PubMed1991

Cardiac electrophysiologic effects of adaprolol maleate, a new beta-blocker, in closed chest dogs.

Adaprolol maleate (adaprolol) is a new beta-adrenergic receptor blocker. The cardiac electrophysiologic characteristics and the duration of action of adaprolol were studied in intact anesthetized dogs. The electrophysiologic parameters were evaluated before drug administration and 10 min after the administration of maintenance infusion of adaprolol (N = 5). The duration of action was measured during constant infusion of isoproterenol, giving the adaprolol as a single i.v. bolus in different concentrations (N = 5). Results of this study showed that adaprolol has marked electrophysiologic effects. Its major action was on sinus node; it prolonged the basic sinus cycle length and had significant effect on intrinsic automaticity as reflected by the prolonged corrected sinus node recovery time and sinuatrial conduction time. There was, also, direct effect on atrial function and AV nodal function. Adaprolol prolonged the effective refractory period of the His-Purkinje system and the ventricle. The onset of action was very rapid (within seconds) and the duration of action was relatively prolonged (3 hrs). The potency of adaprolol's electrophysiologic effects are higher compared to other widely used beta-blockers. Adaprolol appears to be a potent beta-blocker with particularly strong antiarrhythmic effect and it would be very useful in the treatment of both supraventricular and ventricular tachyarrhythmias and ectopic beats.

Adamantane↗
PubMed1991

Regioselective O-alkylation of cortienic acid and synthesis of a new class of glucocorticoids containing a 17 alpha-alkoxy, a 17 alpha-(1'-alkoxyethyloxy), a 17 alpha-alkoxymethyloxy, or a 17 alpha-methylthiomethyloxy function.

The synthesis of a new class of glucocorticoids, to be evaluated as anti-inflammatory agents with expected low systemic toxicity, is described. The new steroids possess a 17 beta-chloromethyl carboxylate function and a 17 alpha-alkoxy, a 17 alpha-(1'-alkoxyethyloxy), a 17 alpha-alkoxymethyloxy, or a 17 alpha-methylthiomethyloxy function. A 17 alpha-alkoxy function is a new feature in cortisol analogs.

Alkylation↗
PubMed1991

Effects of a brain-enhanced estrogen delivery system on tail-skin temperature of the rat: implications for menopausal hot flush.

The menopause results from the decreasing production of ovarian estrogens/progestins. This loss of ovarian hormones in 75-85% of women leads to a number of brain-mediated steroid-withdrawal symptoms, the most frequent being hot flushes. Thus, replacement therapy with a brain-enhanced estrogen delivery system (E2-CDS) with sustained release of estradiol (E2) in the brain may be more effective in the treatment of menopausal symptoms than currently used estrogens. The present study was designed to evaluate the effects of E2-CDS vs. E2, on the tail-skin temperature (TST) surge associated with administration of naloxone to morphine-dependent rats, an animal model for menopausal hot flush. Ovariectomized rats received a single or multiple doses of E2-CDS at 1.0 mg/kg body weight or E2 (0.5 mg pellet) weekly for 1 or 3 weeks before temperature recording. The mean maximal elevation in TST of the control animals was 6.4 +/- 0.2 degrees C. A single injection of E2-CDS attenuated the naloxone-induced rise in TST by 25%, while multiple injections resulted in significant attenuation of the rise in TST (3.4 +/- 0.6). By contrast, multiple implants of E2 pellet (3 pellets over 3 weeks) did not affect the surge of TST. Plasma E2 levels in animals treated with E2-CDS were slightly increased to 13 pg/ml for single-injected and to 44 pg/ml for multiple-injected rats. However, the E2-pellet treatment produced plasma E2 levels that were 2-fold greater than the E2 levels produced by multiple injections of E2-CDS. Plasma gonadotropins (LH and FSH) were significantly suppressed with the E2-pellet as well as the single and multiple E2-CDS treatment. Plasma prolactin levels were significantly elevated by E2 pellet and multiple injections of E2-CDS. The kinetic profiles of E2-CDS metabolites in plasma indicated an apparent t1/2 = 8 h for E2-Q+ and 3 h for E2. Collectively, these data support the view that E2-CDS may be potentially useful in the treatment of vasomotor hot flushes.

Animals↗
PubMed1991

Soft drugs--10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: loteprednol etabonate.

An improved synthesis of loteprednol etabonate (chloromethyl 17 alpha-ethoxycarbonyloxy-11 beta-hydroxy-3-oxoandrosta-1,4-diene 17 beta-carboxylate) was achieved. The design of the new type of glucocorticoid was based on the soft drug concept. The relative binding affinities of loteprednol and its putative metabolites (PJ90 and PJ91) to rat lung type II glucocorticoid receptor were determined in a competitive binding experiment with [3H]triamicinolone acetonide. The medium contained cortienic acid (10(-5) M) in order to block transcortin binding sites. Loteprednol etabonate exhibited a binding affinity which was 4.3 times that of dexamethasone, both compounds having a Hill factor close to 1 whereas PJ90 and PJ91 did not show any affinity to the receptor. Loteprednol etabonate was compared to betamethasone 17 alpha-valerate in a vasoconstriction test which was performed on the forearm skin of human volunteers. The results showed that loteprednol etabonate has good skin-permeation properties and strong glucocorticoid activity.

Androstadienes↗
PubMed1991

Improved delivery through biological membranes. LVI. Pharmacological evaluation of alprenoxime--a new potential antiglaucoma agent.

A new site-specific chemical delivery system (CDS) for alprenolol was designed and investigated as a potential novel antiglaucoma agent. The effect of this compound, alprenoxime (AO), on the intraocular pressure (IOP) of rabbits was evaluated after its uni- and bilateral administration. AO produced significant reduction of the IOP starting at 30 min and lasting for more than 6 hr after its topical administration. Both in rats and in rabbits the i.v. bolus injection of AO (6 mg/kg) led to insignificant transient bradycardia, while no activity was found after oral or topical administration. Alprenolol (ALP) in a similar dose produced a sustained and significant bradycardia for more than 30 min. When the beta-adrenergic blocking activity was assessed against isoprenaline-tachycardia, the same results were obtained, i.e., AO led to a transient brief activity, whereas ALP produced a significant long-lasting beta blockade. These results support the potent ocular hypotensive action and the weak systemic beta-adrenergic blocking and cardiovascular activity of AO: a significant improvement in the therapeutic index. This finding recommends alprenoxime as a potent site-specific antiglaucoma agent with minimal systemic side effects.

Alprenolol↗
PubMed1991

Solubilization and stabilization of a benzylpenicillin chemical delivery system by 2-hydroxypropyl-beta-cyclodextrin.

A dihydropyridine----pyridinium salt redox carrier-based chemical delivery system for benzylpenicillin (1) was complexed with 2-hydroxypropyl-beta-cyclodextrin (HPCD). The solubility of the lipophilic 1, which is incompatible with aqueous formulations, was dramatically increased and showed a linear dependency on the HPCD concentration. The degree of incorporation was 20 mg of 1 per g of complex. The stability study of 1 in various pH buffers indicated the base-catalyzed hydrolysis of the acyloxyalkyl linkage and the hydration of the 5,6 double bond of the dihydropyridine as the main degradation processes. The overall loss of 1, which follows first-order kinetics, was not influenced by changes in ionic strength and elimination of oxygen from the reaction medium. The HPCD complex of 1, which has a stability constant of 720-940 M-1, stabilized the chemical delivery system. The influence of the temperature on the stability of 1 is also discussed.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1991

Use of 2-hydroxypropyl-beta-cyclodextrin as a solubilizing and stabilizing excipient for protein drugs.

A chemically modified, amorphous beta-cyclodextrin, namely, 2-hydroxypropyl-beta-cyclodextrin (HPCD), was examined as a solubilizing and stabilizing agent for protein drugs. The aqueous solubility of ovine growth hormone at pH 7.4 was increased through the use of HPCD. This effect was manifested by higher UV transparency at 600 nm. Interleukin-2 (IL-2) is rendered insoluble upon lyophilization in the absence of stabilizers. Use of aqueous HPCD provides a clear solution, as indicated by fluorometric light scattering, and inhibits aggregate formation, as shown by ultracentrifugation and Western blot analyses. In addition, there were no major conformational changes of IL-2 in HPCD formulation as indicated by fourth-derivative ultraviolet spectroscopy. Finally, IL-2 retained 100% of its biopotency when prepared in HPCD solutions. Aggregation of insulin was also suppressed by HPCD. These data, as well as the i.v. safety of HPCD and its well-characterized chemical composition, suggest that this starch derivative may be a potentially useful excipient for protein drugs intended for parenteral use.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1991

The effects of a brain-enhanced estradiol delivery system on testosterone and androgen-dependent tissues. I. Dose-response and time-course evaluation.

The primary objective underlying hormone treatment of prostatic adenocarcinoma is to induce an effective androgen deprivation, and high dose estrogen therapy is as effective as surgical castration in abolishing the growth-promoting effects of androgens on prostatic tissue. An estradiol-chemical delivery system (E2-CDS), with sustained release of E2 in the brain, may be potentially useful in the treatment of prostatic cancer by virtue of the need for lower or less frequent doses of the estrogen. In this study we evaluated the dose- and time-dependent effects of the E2-CDS vs. 17 beta-E2 on serum testosterone (T) and weights of androgen-dependent tissues in male rats. Rats received a single iv injection of E2-CDS (0.1, 0.5, or 1.0 mg/kg), equimolar doses of 17 beta-E2, or the drug's vehicle. Sera and tissues were collected 1, 7, 14, or 21 days later for determination of hormone levels and tissue weights. The E2-CDS exhibited a dose- and time-dependent suppression of serum T and weights of the ventral prostate and seminal vesicles. In contrast, 17 beta-E2 had no significant effect on serum T or growth of these androgen-dependent tissues. Serum T levels were significantly reduced by 98%, 82%, and 59% at 1, 7, and 14 days, respectively, with the 1.0 mg/kg dose of E2-CDS. The E2-CDS significantly reduced prostate weight by 45% and 50% (1.0- and 0.5-mg/kg doses, respectively) 7 days and by 27% (0.5 mg/kg dose) 14 days after treatment. Similarly, seminal vesicle weights were reduced by 14-20% on day 1, maximally reduced by 39-48% on day 7, and still reduced by 24-36% on day 14 compared with the control levels. Weights of these tissues returned to control levels by day 21. Serum E2 was elevated through 7 days by E2-CDS or on day 1 only by 17 beta-E2. PRL secretion was stimulated for 1 week by both forms of estrogen. Anterior pituitary weights were increased by the E2-CDS through 14 days, while 17 beta-E2 had no significant effect. These data indicate that the E2-CDS causes chronic suppression of serum T, which subsequently results in regression of androgen-dependent tissue weight.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1991

The effects of a brain-enhanced estradiol delivery system on testosterone and androgen-dependent tissues. II. The role of testosterone.

The present study was undertaken to evaluate the efficacy of an estradiol-chemical delivery system (E2-CDS) for the brain vs. estradiol benzoate (E2-BNZ) in suppressing serum testosterone (T) and weights of the ventral prostate and seminal vesicle in male rats. Also, the role of serum T in the weight reduction of androgen-dependent tissues observed after E2-CDS treatment was further evaluated in these studies. Intact male rats received a single iv injection of either E2-CDS at a dose of 1.0 mg/kg or an equimolar dose of E2-BNZ (0.95 mg/kg). Sera and tissue samples were collected 1, 7, 14, or 21 days after injection for determination of hormones and tissue weights. A single injection of E2-CDS suppressed serum T levels by 96%, 83%, 46%, or 63% 1, 7, 14, or 21 days after treatment, respectively. In contrast, an equimolar dose of E2-BNZ had no significant effect on serum T at any sampling time examined. Prostate weight was maximally reduced by 53% at 7 days and remained significantly suppressed by more than 31% throughout the 21-day time course. Similarly, seminal vesicle weight was reduced by 14% on day 1, maximally reduced by 41% on day 7 and remained significantly suppressed through day 21. In contrast, E2-BNZ was ineffective in inducing weight changes in either of these tissues. Serum PRL was significantly elevated through day 14, while E2 was elevated through day 7 by E2-CDS. Both the anterior pituitary and adrenal gland weights were stimulated by E2-CDS treatment. Testis weight was moderately reduced by both esters. In a subsequent study serum T was reduced by 98% and 97% 1 and 7 days, respectively, after E2-CDS treatment, and weights of the ventral prostate and seminal vesicle were reduced by 47% and 40%, respectively, at 7 days. In contrast, in rats treated with Silastic capsules containing T, the expected E2-CDS-induced weight regression was prevented in both prostate and seminal vesicles. These data indicate that the prolonged effects of E2-CDS on weights of androgen-dependent tissues are caused by its ability to produce profound suppression of the serum T concentration.

Adrenal Glands↗
PubMed1991

Short acting soft mydriatics.

Three soft drug analogs of atropine have been tested for mydriatic activity in rabbits' eyes and their in vitro metabolic pathway has been investigated in rat, rabbit and human blood. The three soft drugs were found to produce an equieffective mydriatic activity to atropine and tropicamide. At equieffective concentrations, their durations were shorter with AUC's 12-21% that of 0.25% atropine and 44-80% that of 0.2% tropicamide. The untreated control eyes were observed to dilate after unilateral ocular administration of atropine, but not with unilateral soft drug treatment. In vitro stability studies showed that the soft ethyl analog was less stable in rat blood and rat liver homogenate than in rabbit or human blood. The metabolic product of the soft ethyl derivative in biological media was proven to be the corresponding inactive acidic metabolite predicted by the soft drug design. The ultrashort durations and the potentially nontoxic systemic properties of the soft mydriatics offer promise for use in ophthalmoscopy and in other ocular procedures where a short acting anticholinergic type of mydriatic would be indicated.

Animals↗
PubMed1991

Ocular absorption and distribution of loteprednol etabonate, a soft steroid, in rabbit eyes.

Loteprednol etabonate (LE) is a "soft" steroid belonging to a unique class of glucocorticoids. LE possesses a metabolically labile 17 beta-chloromethyl ester function which was designed in order to be hydrolyzed to an inactive carboxylic acid moiety. The ocular absorption and metabolism of a 14C-labelled LE was evaluated in New-Zealand White rabbits after administration of a 0.5% suspension in both eyes. At various time points following ocular administration, the cornea, aqueous humor, and iris-ciliary body were collected. LE and the putative inactive metabolites, PJ-90 and PJ-91, were identified in all 3 tissues. Levels of LE and its metabolites were highest in the cornea, and so was the ratio of metabolites to unchanged drug, suggesting that the primary site of deactivation of the drug is the corneal tissue. A substantial amount of metabolites were also detected in the iris-ciliary body, although to a lesser extent than in the cornea. The amount of drug and metabolites in the aqueous humor was very low. It is concluded that LE is indeed a soft steroid with good ocular permeation properties.

Absorption↗
PubMed1991

Glucocorticoid activity and structure activity relationships in a series of some novel 17 alpha-ether-substituted steroids: influence of 17 alpha-substituents.

A series of non-fluorinated glucocorticoids, cortienic acid analogs with a 17 beta-chloromethyl ester and various 17 alpha-ether functions, were tested for their affinity to the rat-lung type-II glucocorticoid receptor. The relative binding affinity of a set of 9 compounds was determined in a competitive experiment with [1,2,4-3H]triamcinolone acetonide. The highest binding affinities were observed with the 17 alpha-propoxy and butoxy analogs which were 1.3 times more active than the standard dexamethasone. Quantitative analysis of the results suggested that steric factors and lipophilicity of the side-chain were the major parameters affecting receptor affinity. Representative members of the series were compared to betamethasone 17 alpha-valerate in a vasonstriction test. The results paralleled those of the receptor binding experiment, indicating that the new steroids have good skin-permeation properties and good glucocorticoid activity.

Animals↗
PubMed1990

Effect of a novel soft steroid on the wound healing of rabbit cornea.

The effect of a 'soft' anti-inflammatory corticosteroid on the corneal wound healing was investigated in rabbits. Albino rabbits were treated with soft steroid and dexamethasone after linear perforating corneal incision. Soft drug design is aimed to control and direct the drug activity and in vivo metabolism to nontoxic moieties. These drugs are rapidly deactivated after they reach the general circulation. While having good local activity, they thus possess high therapeutic indexes without systemic side effects. The wound healing process was evaluated qualitatively by histology. Photomicrographs are presented to show that the soft steroid is as or more effective than dexamethasone in minimizing scarring in addition to its advantageous metabolic properties. This soft steroid may be an efficient anti-inflammatory and anti-allergic agent in topical application without the majority of unwanted activities of traditional drugs by deliberately simplifying their disposition.

Androstadienes↗
PubMed1990

Antihypertensive activity of redox derivatives of tryptophan.

The essential amino acid, tryptophan, has been shown to lower blood pressure in rats when administered orally or intravenously. In order to potentially enhance this action, a brain-targeting chemical delivery system (CDS) approach was applied to this compound. The CDS is based on a dihydropyridine----pyridinium ion redox system, chemically analogous to the naturally occurring NADH----NAD+ system. The dihydropyridine moiety containing carrier is chemically attached to the amino group by an amide-type bonding while the carboxylic acid functionality is esterified to various alcohols. Physicochemical studies of the new derivatives were performed. The determined chromatographic Rm values indicate an increased lipophilicity for the CDSs compared to the parent compound. Oxidation stability studies performed on selected compounds using a ferricyanide-mediated method showed that the CDSs are oxidized to the respective quaternary salt forms. Activity studies performed in deoxycorticosterone acetate induced hypertensive rats, demonstrated that the delivery system for tryptophan reduced blood pressure more efficiently for a longer time than did the parent compound.

Animals↗
PubMed1990

Site- and stereospecific ocular drug delivery by sequential enzymatic bioactivation.

Intraocular enzymes convert the ketoxime analogues of some beta-adrenergic blockers via a sequential bioactivation process involving hydrolysis to the corresponding ketones followed by reduction to the aryloxyaminoalcohols, which then exert known and predictable physiological and pharmacological effects only at the site of the action--i.e., in the eye--without any systemic side effects. The sequential nature of the process is highlighted by the observation that the administration of the ketone intermediate also leads to its conversion to the beta-adrenergic antagonist, the active compound. The reduction is stereospecific resulting in the formation of the more potent S-(-)-form of the drug, thus providing prospect to glaucoma treatment. The same activation process of the ketoximes does not take place systemically, thus administration of these ketoximes does not produce cardiovascular effects.

Adrenergic beta-Antagonists↗
PubMed1990

Application of a brain-targeting chemical delivery system to 9-amino-1,2,3,4-tetrahydroacridine.

Several chemical delivery systems (CDS) were synthesized for the cholinesterase inhibitor 9-amino-1,2,3,4-tetrahydroacridine (THA). The derivatives prepared were substituted with a 1,4-dihydropyridine in equilibrium pyridinium salt redox system at the amino functionality. These compounds were synthesized by acylation of the 9 amino group of THA with nicotinic anhydride under forced conditions, followed by a selective N-alkylation of the pyridine ring and regioselective reduction of the resulting quaternary salts. Lipophilicity parameters indicated increased lipophilic indices for various CDS's compared to the THA. Oxidation studies showed that dihydronicotinamides readily converted to the quaternary salt, both chemically and enzymatically. The transport forms of THA were also shown not to interact with acetylcholinesterase in vivo. In vivo distribution studies in the rat indicated that high and sustained levels of the pyridinium quaternary ion derivative were present in the central nervous system (CNS). In addition, THA was produced in the CNS from the quaternary salt precursor in low concentrations, indicating a slow but sustained release. The CDS for THA were found to be less acutely toxic than THA.

Aminoacridines↗
PubMed1990

Dose and time-course evaluation of a redox-based estradiol-chemical delivery system for the brain. II. Pharmacodynamic responses.

Clinically, brain-enhanced delivery and sustained release of estradiol (E2) are desirable for effective treatments of menopausal hot flushes and prostatic adenocarcinoma and for fertility regulation. Thus, we conducted studies to determine the dose- and time-dependent effects of a brain-enhanced estradiol-chemical delivery system (E2-CDS) on anterior pituitary hormones secretion in ovariectomized (OVX) rats. The E2-CDS has consistently demonstrated preferential retention of its intermediate metabolite (E2-Q+), with slow release of E2 in the brain but rapid clearance from peripheral tissues. Animals received a single iv injection of E2-CDS at doses of 0.01, 0.1, or 1.0 mg/kg or an E2 dose of 0.7 mg/kg on day 0. The responses of plasma luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), and prolactin (PRL) were then evaluated at 1, 7, 14, 21, or 28 days after drug administration. The E2-CDS caused a dose- and time-dependent suppression of LH and FSH throughout the time course studied. The maximum LH and FSH reduction occurred at 7 days postinjection. Plasma LH and FSH were significantly suppressed by 86 and 58% on day 7, respectively, and were suppressed by 35% (LH) or were at preinjection levels (FSH) at 28 days following the single injection of a 1.0-mg E2-CDS dose. An equimolar E2 dose suppressed LH and FSH by only 29 and 20% on day 7, respectively which were not significantly different from time 0 values. Plasma PRL increased significantly on day 14 with the 1.0-mg E2-CDS dose but levels returned to preinjection values by 28 days after drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗