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1.
Pharmazie ; 55(3): 178-83, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10756536

ABSTRACT

Loteprednol etabonate (LE) is a corticosteroid designed using the "soft drug" concept of Bodor. LE has been extensively evaluated as a treatment for ophthalmic inflammatory conditions. LE is administered as a sterile eye drop suspension and is commercially available as either a 0.5% or a 0.2% suspension. Lotemax (0.5% LE) has been demonstrated as effective in reducing the signs and symptoms of giant papillary conjunctivitis (GPC), acute anterior uveitis and inflammation following cataract extraction with intraocular lens (IOL) implantation. It is also effective for the prophylaxis of seasonal allergic conjunctivitis (SAC) in patients with a history of that condition. Alrex (0.2% LE) is effective for the treatment of the signs and symptoms of SAC. In comparison with other steroids LE has a superior safety profile which has been attributed to its "soft drug" characteristics.


Subject(s)
Androstadienes/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Eye Diseases/drug therapy , Androstadienes/administration & dosage , Animals , Anti-Inflammatory Agents/administration & dosage , Eye Diseases/pathology , Humans , Inflammation/drug therapy , Inflammation/pathology , Loteprednol Etabonate
3.
J Ocul Pharmacol ; 10(1): 289-93, 1994.
Article in English | MEDLINE | ID: mdl-8207332

ABSTRACT

Loteprednol etabonate (LE) is a novel steroid with a low tendency to raise IOP. It is metabolized in the eye to an inactive metabolite. The current study was undertaken to assess the intra-ocular anti-inflammatory activity of LE in two models of experimental uveitis in rabbits. In the endotoxin induced rabbit model, LE was effective at reducing measures of inflammation, but less so that either fluorometholone (FML) or dexamethasone. In the Freunds adjuvant chronic uveitis model, FML was also very effective with LE and dexamethasone showing similar activity. The data demonstrate that LE is effective at reducing intra-ocular inflammation.


Subject(s)
Androstadienes/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Uveitis, Anterior/drug therapy , Androstadienes/administration & dosage , Animals , Anti-Inflammatory Agents/administration & dosage , Chronic Disease , Dexamethasone/administration & dosage , Dexamethasone/therapeutic use , Disease Models, Animal , Fluorometholone/administration & dosage , Fluorometholone/therapeutic use , Intraocular Pressure , Loteprednol Etabonate , Ophthalmic Solutions , Rabbits , Uveitis, Anterior/chemically induced , Uveitis, Anterior/pathology
4.
Curr Eye Res ; 12(4): 313-21, 1993 Apr.
Article in English | MEDLINE | ID: mdl-8319490

ABSTRACT

Loteprednol etabonate (LE) is a new corticosteroid based on the "soft drug" concept. Contact lens-associated giant papillary conjunctivitis (GPC) was studied as a model for the anti-inflammatory effect of LE. Patients with bilateral GPC were enrolled in a multicenter, randomized, double-masked, placebo-controlled, parallel group comparison of loteprednol etabonate 0.5% ophthalmic suspension and the LE vehicle (placebo). Patients were instructed to instill 1 drop of the test medication into each eye 4 times daily for 4 weeks, and follow-up examinations occurred on Days 2 or 3, 7, 14, 21, and 28 of masked therapy. Of 113 patients enrolled, 110 patients (LE = 55; placebo = 55) completed the study as planned. Patients receiving LE demonstrated significant reduction in the primary ocular signs of GPC (papillae, p < 0.001) and were rated better in the Investigator's Global Assessment (p = 0.017). LE did not elevate intraocular pressure during the study, and ratings for bulbar conjunctival injection and the Patient Opinion Assessment demonstrated statistical trends that favored treatment with LE. LE was well tolerated and was clinically effective for the treatment of GPC.


Subject(s)
Androstadienes/therapeutic use , Anti-Inflammatory Agents/adverse effects , Conjunctivitis, Allergic/drug therapy , Contact Lenses/adverse effects , Adolescent , Adult , Androstadienes/administration & dosage , Androstadienes/adverse effects , Conjunctivitis, Allergic/etiology , Double-Blind Method , Female , Follow-Up Studies , Humans , Intraocular Pressure/drug effects , Loteprednol Etabonate , Male , Middle Aged , Ophthalmic Solutions , Placebos , Prospective Studies
5.
J Ocul Pharmacol ; 9(2): 157-65, 1993.
Article in English | MEDLINE | ID: mdl-8345288

ABSTRACT

The continuing development of ophthalmic steroids has resulted in compounds that have a low tendency to raise intraocular pressure (IOP). Preliminary clinical data have suggested that loteprednol etabonate (LE) 0.5% suspension may not elevate IOP while having promise as a potent topical ophthalmic steroid. This study was designed to evaluate the comparative potential of topical LE and prednisolone acetate (PA) to raise IOP in a population of individuals known to be steroid responders. The study used a double-masked, randomized, single eye, crossover design comparing LE 0.5% and PA 1.0%. Subjects instilled 1 drop of the assigned medication 4 times daily while awake, and follow-up examinations occurred on days 14, 28, and 42. Following a washout period of at least 14 days, subjects entered the second phase of the study, which was identical to the first phase, except that subjects received the alternate study medication. The mean IOP in the LE group increased from 17.4mm Hg at baseline to 21.5mm Hg at day 42 (p > 0.05), while in the PA group the mean IOP increased from 18.1mm Hg at baseline to 27.1mm Hg at day 42 (p < 0.05). There were no serious, severe, or clinically significant events in either group, and LE's effect on IOP was differentiable from that of PA. LE has less effect on IOP when compared to the IOP response induced by PA. LE may become a clinically useful ocular steroid with a favorable IOP-safety profile.


Subject(s)
Androstadienes/administration & dosage , Anti-Inflammatory Agents/administration & dosage , Intraocular Pressure/drug effects , Ocular Hypertension/prevention & control , Adolescent , Adult , Aged , Androstadienes/adverse effects , Anti-Inflammatory Agents/adverse effects , Double-Blind Method , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Loteprednol Etabonate , Male , Middle Aged , Ocular Hypertension/physiopathology , Ophthalmic Solutions , Prednisolone/administration & dosage , Prednisolone/adverse effects , Prednisolone/analogs & derivatives
6.
J Clin Endocrinol Metab ; 64(2): 377-82, 1987 Feb.
Article in English | MEDLINE | ID: mdl-3539980

ABSTRACT

We previously reported that circulating beta-endorphin levels are increased in obese hirsute women and that plasma immunoreactive insulin (IRI) levels are increased in proportion to the degree of hyperandrogenism in women with the polycystic ovary (PCO) syndrome. We, therefore, tested the hypothesis that endogenous opiates are at least partially responsible for the hyperinsulinemia and insulin resistance in this syndrome. In the first study, acute naloxone administration significantly reduced the plasma IRI response and IRI/glucose ratio in three euglycemic obese women with PCO and acanthosis nigricans (AN) and marked insulin resistance, but did not alter the glucose response. Naloxone had no effect on these parameters in the normal weight control subjects. In the second study, nalmefene, a new, orally active opiate antagonist, reduced IRI and the IRI/glucose ratio in four women with PCO-AN and marked hyperinsulinemia in a randomized, double blind, crossover protocol. We conclude that endogenous opiates are at least partially responsible for the hyperinsulinemia and insulin resistance in PCO-AN.


Subject(s)
Acanthosis Nigricans/blood , Insulin Resistance/drug effects , Insulin/blood , Narcotic Antagonists/pharmacology , Polycystic Ovary Syndrome/blood , Adolescent , Adult , Blood Glucose/metabolism , Female , Humans , Naloxone/pharmacology , Naltrexone/analogs & derivatives , Naltrexone/pharmacology
7.
Drug Alcohol Depend ; 14(3-4): 373-80, 1985 Feb.
Article in English | MEDLINE | ID: mdl-4039650

ABSTRACT

Xorphanol is a new mixed agonist-antagonist from the morphinan class of analgesics. On the basis of animal experiments, the physical dependence liability of xorphanol is predicted to be of a low order in man. Conceptually, xorphanol is of interest since in vitro experiments have revealed anti-naloxone properties and resistance to antagonism by opioid antagonists. At the practical level, xorphanol is a well tolerated, orally active analgesic that provides effective pain relief clinically.


Subject(s)
Morphinans/pharmacology , Animals , Chemical Phenomena , Chemistry , Humans , Male , Mice , Mice, Inbred Strains , Morphinans/toxicity , Morphine/antagonists & inhibitors , Pain/drug therapy , Rats , Rats, Inbred Strains , Substance-Related Disorders/etiology , Time Factors , Urination/drug effects
8.
J Med Chem ; 27(5): 632-7, 1984 May.
Article in English | MEDLINE | ID: mdl-6716400

ABSTRACT

A method for preparing a variety of 7-alkyl-6,7- didehydromorphinans from the corresponding 6- morphinanones is described. The key intermediates in this sequence are the 7-formyl derivatives. The two epimeric B/C-trans-7-(1- hydroxypentyl ) morphinans ( 16a ,b) are stereochemically similar to the endo- ethanotetrahydrooripavines and are extremely potent in the mouse writhing test. The corresponding B/C-cis -7-(1- hydroxypentyl ) morphinans are inactive in this test.


Subject(s)
Morphinans/chemical synthesis , Narcotic Antagonists/chemical synthesis , Narcotics/chemical synthesis , Analgesia , Animals , Biological Assay , Indicators and Reagents , Magnetic Resonance Spectroscopy , Mice , Morphinans/pharmacology , Narcotic Antagonists/pharmacology , Narcotics/pharmacology , Rats , Structure-Activity Relationship
9.
J Med Chem ; 26(7): 1050-6, 1983 Jul.
Article in English | MEDLINE | ID: mdl-6864732

ABSTRACT

Structure-activity correlations in 7 beta-(arylalkyl)-3-methoxy- or hydroxy-4,5 alpha-epoxymorphinans have been investigated. 6 beta-Hydroxy-7 alpha-hydroxymethyl compounds 7 with 7 beta-substituents CH2CH2R [a, R = H; b, R = CH2CH3; c, R = C6H5; d, R = CH2C6H5; f, R = CH2CH2C6H5; g, R = (CH2)3C6H5; h, R = (CH2)4C6H5] were prepared. Wittig condensations with previously reported 4,5 alpha-epoxy-7 beta-formyl-7 alpha-(hydroxymethyl)-6 beta, 7 alpha-O-isopropylidene-3-methoxy-17-methylmorphinan-6 beta-ol (3), followed by dilute acid removal of the blocking group and then hydrogenation, gave saturated compounds 7. Compounds with a 6 alpha, 7 alpha-oxymethylene ring. 18c,d,f,g, were prepared from 7 beta-formyl derivative 16 and the appropriate Wittig reagent, followed by hydrogenation. Both the 6 beta-hydroxy-7 alpha-hydroxymethyl and 6 alpha, 7 alpha-oxymethylene series containing 7 beta-arylalkyl groups with an alkyl chain length of 2 to 4 ar potent narcotic agonists. The most potent 17-methyl compound, 4,5 alpha-epoxy-7 alpha-(hydroxymethyl)-17-methyl-17 beta-(4-phenylbutyl)morphinan-3,6 beta-diol (8f) was 700 times more potent than morphine in the acetic acid induced mouse writhing assay. 17-Methyl compounds in the c, d, f, g series were converted to 17-cyclopropylmethyl (P series) or 17-cyclobutylmethyl (B series) derivatives. Narcotic antagonistic activity could not be demonstrated for these potent agonist 17-cycloalkylmethyl derivatives. These pharmacological results parallel those previously reported for tertiary alcohol derivatives of the endo-ethenotetrahydrooripavines. Structureal considerations confirm the existence of a lipophilic site extending upward and outward from where the C ring of morphine and congeners bind to opiate receptors.


Subject(s)
Analgesics/chemical synthesis , Morphinans/chemical synthesis , Narcotic Antagonists/chemical synthesis , Indicators and Reagents , Morphinans/pharmacology , Structure-Activity Relationship
13.
J Med Chem ; 25(12): 1447-50, 1982 Dec.
Article in English | MEDLINE | ID: mdl-6296389

ABSTRACT

Synthesis of 3'-hydroxy- (7) and (+/-)-3',11-dihydroxy-delta 9-tetrahydrocannabinol (11), metabolites of delta 9-THC, is described. Condensation of the monoterpene (+/-)-cis-p-menth-2-ene-1,8-diol (1) and (+/-)-3'-acetoxyolivetol (2) in the presence of fused ZnCl2 in CH2Cl2 gave a mixture from which the delta 9-THC derivative 3, containing small amounts of the delta 8-isomer 4, was isolated after column chromatography. This mixture was separated as their diacetates 5 and 6 by high-pressure liquid chromatography. Alkaline hydrolysis (5% KOH in MeOH) of 5 furnished the metabolite 7. Condensation of (+/-)-8 with 2 in the presence of p-toluenesulfonic acid gave 9a, which was acetylated to 9b. Treatment with HgO/BF3 X Et2O in wet THF gave the aldehyde 10. Reduction with LiAlH4 furnished the metabolite 11. These metabolites were compared with delta 9-THC for their ability to depress spontaneous activity and rectal temperature in mice and for their effects on overt behavior in dogs. 3'-Hydroxy-delta 9-THC was also compared to delta 9-THC in the mouse sympatomatology test and cardiovascular system in dogs. The metabolites produced pharmacological effects similar to those of delta 9-THC in all tests. 3'-Hydroxy-delta 9-THC was 2-3 times more effective than delta 9-THC in the behavioral tests, whereas (+/-)-3',11-dihydroxy-delta 9-THC was approximately 3 times less active than delta 9-THC.


Subject(s)
Dronabinol/analogs & derivatives , Dronabinol/metabolism , Animals , Behavior, Animal/drug effects , Body Temperature/drug effects , Chemical Phenomena , Chemistry , Dogs , Dronabinol/chemical synthesis , Dronabinol/pharmacology , Female , Hemodynamics/drug effects , In Vitro Techniques , Male , Mice , Mice, Inbred ICR , Motor Activity/drug effects
14.
J Med Chem ; 25(8): 986-90, 1982 Aug.
Article in English | MEDLINE | ID: mdl-7120287

ABSTRACT

A direct conversion of deoxydihydrothebaine-phi (1) to 3-methoxymorphinan-6-one (3Ca) and its trans isomer 3Ta was achieved in excellent yield by the catalytic reduction of 1 in AcOH containing CF3COOH. Treatment of 3Ca or 3Ta with NaH and diethyl carbonate formed the corresponding 7-carbethoxy derivatives 4a which, on O-demethylation, furnished the 3-hydroxy compounds 4b. The analgesic N-methyl compounds 3 were converted to the 17-(cyclopropylmethyl) or 17-(cyclobutylmethyl) derivatives 6--8. Two of these compounds, one in the cis (7Ca) and the other in the trans (7Ta) series, showed mixed agonist/antagonist activity in the pentazocine range.


Subject(s)
Morphinans/chemical synthesis , Narcotic Antagonists/chemical synthesis , Narcotics/chemical synthesis , Animals , Chemical Phenomena , Chemistry , Mice , Morphinans/pharmacology , Rats , Reaction Time/drug effects
15.
J Med Chem ; 25(8): 983-6, 1982 Aug.
Article in English | MEDLINE | ID: mdl-6181259

ABSTRACT

A series of 7-alkanoyl-substituted hydromorphone derivatives were prepared by acylation of the morpholine enamines. The most potent compound (6i) of the series was found to have agonist activity of the same order of magnitude as that of buprenorphine. The N-cyclopropylmethyl-substituted series was found to exhibit structure-activity relationships for analgesia and narcotic antagonism similar to those of the endo-ethanotetrahydrooripavines.


Subject(s)
Hydromorphone/analogs & derivatives , Narcotic Antagonists/chemical synthesis , Narcotics/chemical synthesis , Animals , Chemical Phenomena , Chemistry , Hydromorphone/chemical synthesis , Hydromorphone/pharmacology , Mice , Reaction Time/drug effects
17.
J Med Chem ; 24(12): 1437-40, 1981 Dec.
Article in English | MEDLINE | ID: mdl-7310820

ABSTRACT

A facile procedure is described for the conversion of morphine, via the diphosphate ester derivative 1 followed by catalytic reduction and treatment with Li/NH3, to 3-deoxy-7,8-dihydromorphine (3). Oxidation with benzophenone tert-butoxide converted 3 to the ketone 4, which on treatment with Zn/NH4Cl formed (-)-4-hydroxymorphinan-6-one 5. Reaction of 5 with diazomethane formed the methyl ether 6. The N-cyclopropylmethyl analogues of 4 and 5 were also prepared, i.e., 8c and 9 from 4. The antinociceptive activity of these compounds was tested. Compounds 5, 6, 8c, and 9 showed potent antiwrithing activity and, based on these data, a structure-activity relationship in morphinans is discussed.


Subject(s)
Analgesics/chemical synthesis , Morphinans/chemical synthesis , Animals , Male , Mice , Morphinans/pharmacology , Rats , Reaction Time/drug effects
18.
J Med Chem ; 24(12): 1445-50, 1981 Dec.
Article in English | MEDLINE | ID: mdl-7310822

ABSTRACT

The preparation of a series of 7 alpha-alkylated dihydrocodeinones is described. N-(Cyclopropylmethyl) (P series) or N-(cyclobutylmethyl) (B series) 7 alpha-methyl (a series) or 7 alpha, 8 beta-dimethyl (b series) substituted dihydronorcodeinones (7) were prepared from the appropriately substituted N-(cycloalkylmethyl)-4-hydroxymorphinan-6-ones (5) by dibromination, 4,5-epoxy ring closure, and catalytic debromination. Treatment of 7 with BBr3 gave low yields of the corresponding 3-phenols 8. Alternatively, reaction of dihydrocodeinone (10) with dimethylformamide dimethyl acetal gave the 7-[(dimethylamino)methylene] adduct 11, which was hydrogenated to 7 alpha-methyl- (12) or 7 alpha-(hydroxymethyl)dihydrocodeinone (13). Treatment of 11 with lithium reagents, followed by hydrogenation, gave a mixture of 7 alpha-alkyl (15c-f) compounds and the corresponding 4,5-epoxy-cleaved products 16. Reaction of 11 with alpha-ethoxyvinyllithium gave intermediate 17, which on hydrolysis and hydrogenation yielded the 6,7-furyl (18) or pyrroyl (19) derivative. N-(Cycloalkylmethyl)-14-hydroxydihydronorcodeinones 23P,B reacted with dimethylformamide dimethyl acetal to give 25P,B, which were hydrogenated to the 7 alpha-methyl compounds 26P,B and O-demethylated to give 27P,B. The 7 alpha-methyl-N-methyl compounds were about equipotent with dihydrocodeinone. Derivatives with larger alkyl groups were less potent. Corresponding N-(cycloalkylmethyl) compounds did not show strong mixed agonist-narcotic antagonist activity.


Subject(s)
Analgesics/chemical synthesis , Codeine/analogs & derivatives , Hydrocodone/analogs & derivatives , Narcotic Antagonists/chemical synthesis , Animals , Chemical Phenomena , Chemistry , Hydrocodone/chemical synthesis , Hydrocodone/pharmacology , In Vitro Techniques , Mice , Rats , Reaction Time/drug effects
19.
J Med Chem ; 24(12): 1516-8, 1981 Dec.
Article in English | MEDLINE | ID: mdl-6796691

ABSTRACT

Series of N-(cyclopropylmethyl) (P series) or N-(cyclobutylmethyl) (B series) 3-methoxy (1) or 3-hydroxy (2) morphinan-6-ones with hydrogen (a), methyl (b), or ethyl (c) groups in the 8 beta position were converted to the 6-methylene compounds 3 or 4 by reaction with Ph3P = CH2. One member of this new series, N-(cyclobutylmethyl)-8 beta-methyl-6-methylenemorphinan-3-ol (4Bb), had potent mixed agonist-narcotic antagonist properties and, in contrast to the previously studied 6-oxo compound 2Bb, did not substitute for morphine in dependent rats or monkeys.


Subject(s)
Analgesics/chemical synthesis , Morphinans/chemical synthesis , Narcotic Antagonists/chemical synthesis , Animals , Chemical Phenomena , Chemistry , Haplorhini , Humans , Mice , Morphinans/pharmacology , Morphine Dependence/psychology , Rats , Reaction Time/drug effects , Substance Withdrawal Syndrome/chemically induced
20.
Pharmacol Biochem Behav ; 14(5): 689-92, 1981 May.
Article in English | MEDLINE | ID: mdl-6113607

ABSTRACT

The rat intraperitoneal infusion procedure was used to chronically administer drugs for evaluation of the physical dependence liability of narcotic antagonist analgesics. Three methods were used to assess dependence liability: presence of withdrawal signs upon abrupt cessation of chronic infusion (primary dependence), attenuation of the withdrawal signs produced by cessation of chronic morphine infusion (morphine substitution), and production of withdrawal signs when chronically morphine-fused rats were administered the drugs (precipitated withdrawal). Butorphanol, nalbuphine and pentazocine all caused a mild withdrawal in the rat primary dependence model which agrees with the conclusions from experiments with monkey and man. None of these agents substituted for morphine in the rat and three appeared to precipitate withdrawal. Two experimental drugs, Codorphone and TR5400, did not induce primary dependence in the rat, and in chroni-morphinized rats, they precipitated a withdrawal syndrome comparable to naloxone. Another experimental drug, TR5257, substituted for morphine. The correlation between these observations in the rat and previously published data from the monkey are excellent. It is proposed that the rat could be used as a reliable indicator of potential physical dependence liability for the narcotic antagonist analgesics.


Subject(s)
Analgesics, Opioid/pharmacology , Narcotic Antagonists/pharmacology , Substance-Related Disorders/etiology , Animals , Body Weight/drug effects , Humans , Male , Rats , Substance Withdrawal Syndrome/psychology , Substance-Related Disorders/psychology
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