Biomedical subjects

N Bodor

Publications and source records attributed to N Bodor.

At least 55 records · Page 3Linked to original sources

PubMed1999

Soft drugs based on hydrocortisone: the inactive metabolite approach and its application to steroidal antiinflammatory agents.

PURPOSE: The soft drug approach was applied to the design of analogs of highly potent synthetic steroids but with a metabolically labile ester group which at the same time served as an activating group. METHODS: Several structural modifications of soft antiinflammatory steroids were synthesized and tested in several assays of biological activity. The hydrolytic stability of the compounds was also determined. RESULTS: One of the compounds synthesized was determined to be a very potent steroid and had a highly significant separation of topical from systemic activity. However, the compound demonstrated greater than expected stability in the hydrolysis studies. CONCLUSIONS: The goal of the soft drug approach has been achieved with the development of a highly potent drug which displays little or no systemic activity as measured in the tests presented here. The anticipated hydrolytic instability of the compounds was not corroborated; however, in view of other results, the interpretation is allowed that the rapid hydrolysis of the unbound fraction of the drug is an important factor in its lack of systemic effects.

Animals↗

PubMed1999

Loteprednol etabonate, a new soft steroid is effective in a rabbit acute experimental model for arthritis.

UNLABELLED: Loteprednol etabonate, a new soft steroid designed for use as a local therapeutic, was compared to dexamethasone in rabbit experimental model for arthritis. METHODS: Joint inflammation was induced by local injection of antigen into the patellofemoral articulation in sensitized rabbits. Co-administration of either dexamethasone or loteprednol etabonate directly into the joint effectively blocked the inflammatory response. Both the synovial fluid cellular content and synovium histology were examined. The steroid treatments prevented the adverse inflammatory effects of antigen action. These results, together with previous studies showing decreased systemic activity of the soft steroid, indicate that the loteprednol etabonate could provide a therapeutic advantage over currently used intra-articular steroids for alleviating rheumatoid arthritis.

Acute Disease↗

PubMed1998

Strategies to target kyotorphin analogues to the brain.

The design, synthesis, and pharmacological evaluation of brain-targeted chemical delivery systems (CDS) for a kyotorphin analogue (Tyr-Lys) are described. The brain-targeted compound contains the active peptide in a packaged, disguised form, flanked between the lipophilic cholesteryl ester on the C-terminus and the 1, 4-dihydrotrigonellyl redox targetor, attached to the N-terminus through strategically selected L-amino acid(s) spacer. It was found that for successful brain targeting, the epsilon-amine of Lys needs to be also converted to a lipophilic function. Through sequential enzymatic bioactivation, the Tyr-Lys dipeptide is released in a sustained manner, producing significant and prolonged analgesic activity as demonstrated by the rat tail latency test. An alternate strategy was also employed. Lys was replaced by a redox amino acid pair, Nys+ left and right arrow Nys, the nicotinamide left and right arrow 1,4-dihydronicotinamide analogues of Lys (Nys+ is 2-amino-6-(3-carbamoyl-1-pyridiniumyl)hexanoic acid). The Nys form is lipophilic and facilitates delivery in addition to the C- and N-terminal lipophilic functions. Enzymatic oxidation to Nys+ provides the lock-in, followed by removal of the lipophilic groups, releasing Tyr-Nys+ from the brain-targeted analogue (BTRA). Nys+ was shown to be an effective substitution for Arg or Lys. The activities of the CDS and BTRA, respectively, were antagonized by naloxone, supporting the designed brain-targeted processes. The most potent compound is the two-proline spacer containing CDS (CDS-PP), followed by the BTRA.

Analgesics↗

PubMed1998

Octanol-water partition of nonzwitterionic peptides: predictive power of a molecular size-based model.

A remarkably simple, molecular size-based model developed to predict octanol-water partition coefficients for organic compounds is tested on a set of 188 neutral peptides with available experimental partition data. Despite using only two parameters, it gives a promising correlation (r2 = 0.914; sigma = 0.455, F = 1978.0), and predictions are in a realistic range even for larger peptides (cyclosporin, melanotan, sandostatin) where common, overparametrized fragment methods become quite unreliable. Ion-pair partitioning and the extraction constant formalism is briefly reviewed to describe the sigmoidal lipophilicity profile of ionizable, nonzwitterionic peptides. It seems possible to extend the present model to estimate apparent partition coefficients measured around neutral pH and physiological conditions for monoionic peptides; however, as no standard conditions are yet defined and only relatively small number of experimental data are available, the situation here is more complex.

Models, Molecular↗

PubMed1998

Computer-assisted design of new drugs based on retrometabolic concepts.

Retrometabolic drug design approaches incorporate metabolic and toxicological considerations into the drug design process and represent a novel, systematic methodology for the design of safe compounds. Two major design concepts aimed to increase the therapeutic index (the activity/toxicity ratio) of drugs were developed. Chemical delivery systems (CDS) are primarily used to allow targeting of the active biological molecules to specific target sites or organs based on predictable enzymatic activation. Soft drug approaches are used to design new drugs by building in the molecule, in addition to the activity, the most desired way in which the molecule is to be deactivated and detoxified subsequent to exerting its biological effects. Special computer programs were developed that starting from a lead compound generate complete libraries of possible soft analogs and then help ranking these candidates based on isosteric-isoelectronic comparisons, predicted solubility/partition properties, and estimated metabolic rates. The novel field of large peptide-CDSs imposes special challenges, but a new, remarkably simple model was developed to estimate partition properties for a wide range of compounds, including quite large peptide derivatives. A suggested change of about five order of magnitudes in the distribution coefficient can explain the "lock in" mechanism of brain-targeting delivery systems.

Animals↗

PubMed1998

Octanol-water partition: searching for predictive models.

The log n-octanol/water partition coefficient (log Po/w) still represents one of the most informative physicochemical parameters available to medicinal chemists. In the present work, principles, methodologies, and parameters are briefly reviewed for a variety of models developed to predict this parameter based on molecular structure. To include the developments of recent years, a total of more than 40 different approaches are mentioned with relevant bibliography within four major categories: group contribution methods, atomic contribution methods, molecular methods, and other physicochemical methods. To underscore once more the utility of this partition coefficient, a comprehensive and reevaluated correlation between log Po/w and in vivo permeability data of rat brain capillaries is included. Most deviants that fell below the trendline are those that have been recently found to be substrates for P-glycoprotein, a multidrug transporter that actively removes them from the brain. Accurate predictions of log Po/w may necessitate many parameters, but there is mounting evidence that molecular size and hydrogen bonding ability can account for a major part of the variance. Our recently developed, molecular size-based approach is reviewed, and it is argued that introduction of three-dimensionality allows the elimination of many empirically derived fragment constants without a significant deterioration of the predictive accuracy. A comparison of predictive power for six different methods on 145 molecules of interest for medicinal chemists is also included.

Animals↗

PubMed1997

17 beta-estradiol attenuates fimbrial lesion-induced decline of ChAT-immunoreactive neurons in the rat medial septum.

We investigated the neuroprotective effects of 17 beta-estradiol (E2) on medial septal cholinergic neurons following partial unilateral lesion of the fimbriafornix. Adult female rats were ovariectomized (OVX) and, 5 days later, treated with a single intravenous (iv) injection of an estradiol (E2)-chemical delivery system (E2-CDS) or its vehicle hydroxypropyl-beta-cyclodextrin (HPCD). All rats were subjected to partial unilateral electrolytic fimbrial lesion the following day. At 20 days postlesion, brain slices from treated animals were assessed for choline acetyltransferase (ChAT) by immunohistochemistry. Animals treated with HPCD or E2-CDS showed a 44 or 4% decrease, respectively, in ChAT-positive neurons on the lesioned side compared to the nonlesioned side of the medial septum. In a second study using the same lesioning procedure, adult OVX rats received either a subcutaneous E2 pellet implant (n = 6), or, 5 days postovariectomy, a single iv injection of E2-CDS (n = 8) or HPCD (n = 6). Animals treated with HPCD showed a 55% decrease in ChAT-positive neurons on the lesioned side compared to the nonlesioned side of the medial septum. By contrast, rats treated with E2-CDS or E2 pellet had a 14 or 13% decrease, respectively, in ChAT-positive neurons. Interestingly, E2 treatment substantially decreased ChAT-positive neurons on the nonlesioned side of the medial septum in comparison to control animals. The present study suggests that cholinergic neurons in the medial septum are protected from lesion-induced degeneration by treatments which increase brain E2 levels. Thus, E2 may play a neuroprotective role in the basal forebrain cholinergic system.

Animals↗

PubMed1997

Intravenous and oral pharmacokinetic evaluation of a 2-hydroxypropyl-beta-cyclodextrin-based formulation of carbamazepine in the dog: comparison with commercially available tablets and suspensions.

Complexation of carbamazepine with 2-hydroxypropyl-beta-cyclodextrin was performed to provide improved formulations of this widely used antiepileptic drug. Based on this approach, liquid dosage forms were configured for both parenteral and oral use. Intravenous administration of an aqueous carbamazepine x 2-hydroxypropyl-beta-cyclodextrin (CBZ x HPbetaCD) complex at a CBZ dose of 20 mg/kg was well tolerated and generated high initial drug levels that fell monoexponentially as a function of time, yielding a plasma elimination half-life of 38 min. Oral studies were completed with three preparations: a commercially available tablet and suspension, as well as a CBZ x HPbetaCD oral solution. Oral administration of tablets gave erratic and slow absorption, leading to maximum CBZ concentrations (C(max)) of <2 microg/mL, which were manifested only at 2.5 h after drug dosing. The absolute bioavailability of CBZ from the tablets was approximately 25%. Both the suspension and CBZ x HPbetaCD solution gave a significantly improved profile. Thus, the liquid oral dosage forms approximately doubled the oral bioavailability of CBZ compared with the tablets.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1997

Ocular-specific delivery of timolol by sequential bioactivation of its oxime and methoxime analogs.

S-(-)- Timolol maleate was oxidized, using the modified Pfitzner-Mofatt method, to the corresponding keto analog, which was then coupled with either hydroxylamine or methoxyamine in the same reaction medium. The products separated, timolone oxime (TO) or timolone methoxime (TMO), were found to be a mixture of both E and Z isomers with the Z isomer in higher concentration. Both isomers could be separated on silica column. No isomerization of any of the isomers could be detected whether in buffers or biological fluids. TMO salts were found to be stable in slightly acidic buffer. The Z isomer of TMO is more stable than the E isomer. Both TO and TMO showed pronounced reduction of the intraocular pressure (IOP) in normotensive rabbits, when instilled into the conjunctival sac. Reduction of IOP caused by either TO or TMO was higher than the reduction produced with the same dose of timolol maleate. Equal doses of any of the TMO isomers or the mixture of isomers gave almost the same percent reduction of IOP. TMO and TO did not show cardiovascular effects when administered intravenously to rabbits or rats. Both are good candidates to be used for topical management of glaucoma without producing systemic side effects.

Administration, Topical↗

PubMed1997

Synthesis and evaluation of brain-targeted chemical delivery systems for the neurotrophomodulator 4-methylcatechol.

Since various 4-alkylcatechols stimulate nerve growth factor (NGF) biosynthesis both in-vitro and in-vivo, delivery of these agents to the brain may provide beneficial effect for the treatment of neurodegenerative diseases such as Alzheimer's. Several dihydropyridine-pyridinium salt type redox chemical delivery systems (CDS) of 4-methylcatechol (4-methylcatechol) were prepared as potential brain selective targetry forms for 4-methylcatechol. After preliminary evaluation by in-vitro stability studies in various buffer solutions and biological media, a selected CDS was further investigated in the rat to determine its in-vivo distribution. Selective and sustained delivery of the compound of interest to the rat brain was achieved. Furthermore, the NGF stimulatory activity in the rat brain after peripheral administration of the selected CDS was evaluated by measuring the levels of pre-pro-NGF mRNA in the rat hippocampus and frontal cortex, by dot blot hybridization and analysis. Results showed the peripheral administration of the CDS to achieve a 1.7-fold increase in NGF mRNA compared to control in the rat hippocampus, and an approximately 1.4-fold increase in the frontal cortex.

Animals↗

PubMed1997

Evaluation of a brain-targeting zidovudine chemical delivery system in dogs.

AIDS encephalopathy is an insidious complication of human immunodeficiency virus infection which is difficult to treat because of the poor uptake of many potentially useful antiretroviral drugs through the blood-brain barrier. A chemical delivery system (CDS) for zidovudine (AZT) based on redox trapping within the brain has been prepared and tested in several animal models to circumvent this limitation. The behavior of the AZT-CDS in the dog was considered. Parenteral administration of AZT resulted in rapid systemic elimination and poor uptake by the central nervous system. Ratios of the area under the concentration-time curve of AZT for cerebrospinal fluid to that for blood were 0.32, and ratios of the area under the concentration-time curve of AZT for brain to that for blood were approximately 0.25. Administration of an aqueous formulation of the AZT-CDS resulted in rapid tissue uptake and conversion of the CDS to the corresponding quaternary salt with the subsequent production of AZT. Delivered in this way, the levels of AZT in brain were 1.75- to 3.3-fold higher than those associated with conventional AZT administration. In addition, the levels of AZT in blood were 46% lower than those associated with AZT administration. The higher concentrations in brain and lower concentration in blood combined to significantly increase the ratio of the concentration of AZT in the brain to that in blood after AZT-CDS administration compared to that after AZT dosing.

Animals↗

PubMed1997

Estrogens may reduce mortality and ischemic damage caused by middle cerebral artery occlusion in the female rat.

The present study was undertaken to determine if estrogens protect female rats from the neurodegenerative effects of middle cerebral artery (MCA) occlusion. The rats were ovariectomized and 7 or 8 days later various estrogen preparations were administered before or after MCA occlusion. Pretreatment with 17beta-estradiol (17beta-E2) or a brain-targeted 17beta-E2 chemical delivery system (CDS) decreased mortality from 65% in ovariectomized rats to 22% in 17beta-E2-treated and 16% in 17beta-E2 CDS-treated rats. This marked reduction in mortality was accompanied by a reduction in the ischemic area of the brain from 25.6+/-5.7% in the ovariectomized rats to 9.8+/-4% and 9.1+/-4.2% in the 17beta-E2-implanted and the 17beta-E2 CDS-treated rats, respectively. Similarly, pretreatment with the presumed inactive estrogen, 17alpha-estradiol, reduced mortality from 36 to 0% and reduced the ischemic area by 55 to 81%. When administered 40 or 90 minutes after MCA occlusion, 17beta-E2 CDS reduced the area of ischemia by 45 to 90% or 31%, respectively. In summary, the present study provides the first evidence that estrogens exert neuroprotective effects in an animal model of ischemia and suggests that estrogens may be a useful therapy to protect neurons against the neurodegenerative effects of stroke.

Animals↗

PubMed1997

Retrometabolic approaches for drug design and targeting.

Retrometabolic drug design approaches incorporate targeting and metabolic considerations into the drug design process and represent a novel, systematic methodology for the design of safe, localized compounds. Two major design concepts aimed to increase the therapeutic index (the activity/toxicity ratio) of drugs were developed. Chemical delivery systems (CDS) are primarily used to allow targeting of the active biological molecules to specific target sites or organs based on predictable enzymatic activation. Brain-targeted delivery of different agents like estradiol or AZT was successfully achieved, and recent progresses include delivery of peptides using a complex strategy designated as molecular packaging. Sequential site- and stereospecific enzymatic activation of oxime/alkoxime precursors of beta-adrenergic antagonists allows their eye targeted delivery. Soft drug approaches are used to design new drugs by building in the molecule, in addition to the activity, the most desired way in which the molecule is to be deactivated and detoxified subsequent to exerting its biological effects. Many examples are available to illustrate soft drug design, e.g., soft anticholinergics, soft b-blockers, soft antiinflammatory steroids. Special computer programs were developed that starting from a lead compound generate complete libraries of possible soft analogs and then help ranking these candidates based on molecular size/shape, electronic properties, predicted solubility/partition properties, and atomic charge distributions. Recent developments in the field are presented in a supplement to this issue.

Drug Delivery Systems↗

PubMed1997

Ocular-specific chemical delivery systems of betaxolol for safe local treatment of glaucoma.

Novel ketomethoxime (BMO) and oxime (BO) analogs of betaxolol (B) were prepared through the oxidation of betaxolol, followed by quenching of the ketone with the appropriate oxyamine. The Z isomers were kinetically favored and thermodynamically more stable. Isomerization to reach an equilibrium mixture of Z/E was observed for all pure isomers in buffers. Equilibration is much faster, however in biological fluids. Ocular administration of any of the oxime derivatives, delivers betaxolol specifically to the eye tissues, with the highest concentration in the iris ciliary body. Both BMO and BO, when applied topically, showed marked reduction of intraocular pressure (IOP) in normotensive rabbits. No effect on isoproterenol-induced tachycardia in rabbits and rats were observed, even after iv. administration. Very mild eye irritation, which was less than that of betaxolol hydrochloride, was observed particularly with BMO maleate, which is an excellent candidate for safe treatment of glaucoma.

Administration, Topical↗

PubMed1996

Brain-targeted delivery of a leucine-enkephalin analogue by retrometabolic design.

A brain-targeted chemical delivery system (CDS) based on retrometabolic drug design was applied to a Leu-enkephalin analogue, Try-D-Ala-Gly-Phe-D-Leu (DADLE). The molecular architecture of the peptide CDS disguises its peptide nature from neuropeptide-degrading enzymes and provides lipophilic, bioreversible functions for the penetration through the blood-brain barrier. These functions were provided by a targetor, a 1,4-dihydrotrigonellyl group, on the N-terminus and a bulky, lipophilic ester group on the C-terminus. A spacer amino acid residue was also inserted between the targetor and the parent peptide to assure the release of DADLE by specific enzymes. Four CDSs were synthesized by segment-coupling method that proved to be superior to sequential elongation in obtaining this type of peptide conjugates. Intravenous injection of the compounds produced a significant and long-lasting response in rats monitored by the tail-flick latency measurements. CDSs having the bulkier cholesteryl group showed a better efficacy than those having the smaller 1-adamantaneethyl ester. The spacer was the most important factor to manipulate the rate of DADLE release and, thus, the pharmacological activity; proline as a spacer produced more potent analgesia than alanine. The antinociceptive effect of the CDSs was naloxone-reversible and methylnaloxonium-irreversible, confirming that central opiate receptors were solely responsible for mediating analgesia induced by the peptide CDS that delivered, retained, and then released the peptide in the brain.

Analgesia↗

PubMed1996

Design, synthesis, and pharmacokinetic evaluation of a chemical delivery system for drug targeting to lung tissue.

We espouse the application of a novel chemical delivery system (CDS) approach to a delivery mechanism for drug targeting to lung tissue using the 1,2-dithiolane-3-pentyl moiety of lipoic acid as the "targetor moiety". The synthesis and the physicochemical and pharmacokinetic evaluation of a CDS modeling the lipoyl and other ester derivatives of chlorambucil (an antineoplastic agent) and cromolyn (a bischromone used in antiasthma prophylaxis) as compared with their respective parent drugs are described. The chlorambucil CDS was synthesized by esterifying the alcohol derivative of lipoic acid with chlorambucil using dicyclohexylcarbodiimide as the coupling agent. The cromolyn CDS was prepared by a multistep synthetic procedure culminating in the reaction of the alkyl bromide derivative of lipoic acid with the disodium salt of the bischromone compound. All the esters were highly lipophilic unlike the parent compounds. The in-vitro kinetic and in-vivo pharmacokinetic studies showed that the respective CDSs were sufficiently stable in buffer and biological media, hydrolyzed rapidly into the respective active parent drugs, and significantly enhanced delivery and retention of the active compound to lung tissue in comparison with the underivatized parent compounds used in conventional therapy.

Animals↗

PubMed1996

Soft drugs. 21. Design and evaluation of soft analogs of propantheline.

The soft drug approach was applied to synthesize seven soft analogs of propantheline, which by design display predictable and controllable decomposition to inactive metabolites. Their synthesis involved the quatemization of several different amine groups with the chloromethyl ester of 9-methylxanthene-9-carboxylic acid. The rates of disappearance were measured for all of the compounds and were found to be more rapid than that of propantheline bromide in a variety of chemical and biological media under in vitro conditions. One of the soft analogs was found to be equipotent with propantheline in an in vitro assay. This soft analog was found to be equipotent with propantheline, in vivo, in protecting the rats against indomethacin-induced gastric ulceration and in inducing mydriasis in rabbits on intravenous administration. The pupil sizes returned faster to predrug levels with the soft analog than with propantheline, indicating increased metabolic lability of the soft analog. The equipotency of this soft analog coupled with increased metabolic lability proves the rationality of the soft drug approach for the design of safer therapeutic agents with higher therapeutic indices.

Animals↗

PubMed1995

Ocular delivery of the beta-adrenergic antagonist alprenolol by sequential bioactivation of its methoxime analogue.

Ocular delivery of alprenolol, a beta-adrenergic antagonist, by site-specific bioactivation of its methoxime analogue results in significant and prolonged decrease of the intraocular pressure in rabbits after topical administration. Alprenolone methoxime is stable in isotonic phosphate vehicle but undergoes enzymatic hydrolysis to the corresponding ketone in the eye. The ketone is then converted to alprenolol by a carbonyl reductase present in the iris-ciliary body. The benefit of this chemical delivery system approach includes the facile release of a potential antiglaucoma agent only at the site of the action; thus, unwanted systemic effects of the drug can be avoided.

Alprenolol↗