Complexation of Hydrocortison with β-Cyclodextrin and Hydroxypropyl-β-Cyclodextrin

Hydrocortison (HC) forms water-soluble inclusion compounds with β-cyclodextrin (βCD) and hydroxypropyl-β-cyclodextrin (HPβCD), as proved by the equilibrium phase solubility diagrams and by ¹H-NMR spectroscopy. The solubility isotherm of the HC/βCD system is of the BS type, that of the HPβCD system of the AL type. The values of the complex stability constants are K = 4792 M^?1 and 1739 M^?1, respectively. 8 parallel preparations of solid HC/βCD complexes by coprecipitation resulted in a stoichiometric ratio of 0.49:1 which corresponds to a molar ratio of 1:2; the HC content is 13.2±0.2%. The ratio of the HC/HPßCD complex is 0.335 which equals a molar ratio of 1:3; the HC content is 8.6 ± 0.2%. The proof of inclusion formation was performed by X-ray diffractometry and thermoanalytical procedures (DSC, TG, thermofractography). We cannot exclude that some of the HC molecules are not included in the HPßCD cavity.     

Comparative Study on Inclusion Complexation of Maltosyl-β-cyclodextrin,Heptakis(2,6-di-O-methyl)-β-cyclodextrin and β-Cyclodextrin with Fucosterol in Aqueous and Solid State

Abstract— The complexation of fucosterol with three kinds of β-cyclodextrin (β-CyD) was investigated in aqueous solution and in the solid state. The solubility of fucosterol increased significantly on its complexation with maltosyl-β-CyD and heptakis(2,6-di-O-methyl)-β-CyD (DM-β-CyD), while no appreciable increase was observed when complexed with β-CyD. The stability constant of complexation with β-CyD estimated from solubility determinations was greater for a 1:2 complex than for a 1:1 complex. On the other hand, 1:1 complexation of fucosterol with maltosyl-β-CyD or DM-β-CyD was greater than 1:2 complexation. The solid complexes were obtained in molar ratios of 1:2 and 1:3 for β-CyD and maltosyl-β-CyD complexes, respectively. The inclusion behaviour of fucosterol with maltosyl-β-CyD was compared with β-CyD in the solid state using DSC, powder X-ray diffractometry and CP/MAS ¹³C NMR. Maltosyl-β-CyD showed different inclusion behaviour compared with β-CyD, and produced an amorphous structure of fucosterol on complex formation. The dissolution rate of fucosterol-maltosyl-β-CyD complex was significantly faster than other complexes due to its high aqueous solubility and amorphous structure.     

In-situ Ocular Absorption of Ophthalmic β-Blockers through Ocular Membranes in Albino Rabbits

Ocular membranes have been characterized by in-situ absorption of the ophthalmic β-blockers carteolol (hydrophilic) and timolol and befunolol (lipophilic) using a cylindrical cell. After introduction of drug solution into the cell on the cornea, sclera (bulbar conjunctival and scleral layer) or palpebral conjunctiva, the disappearance of the drug from the cell was determined as in-situ absorption. The ophthalmic drugs disappeared from the conjunctival and scleral membranes although disappearance from the cornea was hardly observed. The conjunctival membrane showed the highest permeability. Lipophilic drugs were more permeable than hydrophilic. In-situ apparent permeability coefficients of the ophthalmic drugs through the conjunctiva and sclera correlated with the lipophilicity of drugs. A high drug concentration in the aqueous humor was observed after corneal application. There is a relationship between concentrations of drugs in the aqueous humor and previously reported in-vitro apparent permeability coefficients of the drugs in the cornea. This in-situ method using a cylindrical cell is a useful method of investigating the ocular absorption of ophthalmic drugs.     

Ocular Absorption and Irritation of Pilocarpine Prodrug Is Modified with Buffer,Polymer, and Cyclodextrin in the Eyedrop

The influence of buffer, viscosity and cyclodextrin on the ocular absorption and irritation of a pilocarpine prodrug, O,O-dipropionyl-(1,4-xylylene) bispilocarpic acid diester, was studied in albino rabbits. The prodrug solutions, equivalent to 0.5% pilocarpine, were prepared in 0, 10, 20, 50, or 75 mM citrate buffer at pH 5.0. Viscosity of the solutions (20, 50 or 115 cP) was modified with hydroxypropyl methylcellulose. 2-hydroxypropyl--cyclodextrin (HPCD) was included at concentrations 5,10 and 15% (w/v). The formulations were compared to a commercial pilocarpine eyedrop (1.7%). Ocular irritation was graded in a double-masked experiment and miosis was used as a bioassay for pilocarpine delivery to the iris. The prodrug showed decreased peak and prolonged duration of miosis compared to pilocarpine, but it caused ocular irritation. Increasing buffer strength decreased and elevated viscosity intensified the miotic response and irritation by the pilocarpine prodrug. HPCD decreased both the ocular delivery of pilocarpine and the irritation by the pro-drug, but the net effect was positive. Thus, administering 1.0% of pilocarpine as a prodrug with 15% (w/v) HPCD, the irritation was at the same level with the commercial pilocarpine eyedrop, but the ocular delivery was substantially improved. In conclusion, the ocular delivery of the pilocarpine prodrug may be enhanced in relation to its local irritation by properly combining buffer, viscosity and HPCD.     

Einige N-funktionelle Derivate von N-(α-Tosylaminoacyl)-β-alaninen

Syntheses of dipeptidenitriles 1a-e starting from α-tosylaminoacidchlorides and β-aminopropionitrile and their conversion to the esters of dipeptide-imide acids 2a-d , esters of dipeptide acids 5a-d , to amides of dipeptide acids 6a-d and amidines of dipeptide acids 4a-e are described. Condensations of amidines of tosyldipeptide acids 3a, c with ethyl acetoacetate yield pyrimidines 7a, c .     

Penetration of β-Blockers through Ocular Membranes in A1bino Rabbits

The purpose of this study was to investigate the barrier properties of ocular membranes for controlling the extent and pathway of ocular absorption of instilled β-blockers. The penetration of β-blockers was measured across the isolated corneal, conjunctival and scleral membranes of the albino rabbit using a two-chamber glass diffusion cell. β-Blockers tested were atenolol, carteolol, tilisolol, timolol and befunolol. Corneal penetration of befunolol was much higher than that of atenolol. Scraping the epithelium increased corneal penetration of β-blockers. Conjunctival membranes showed higher permeability than corneal and scleral membranes. The penetration parameters were estimated according to Fick's equation. The corneal permeability coefficient showed an apparent linear relationship with penetrant lipophilicity. The lipophilic character of the corneal barrier was determined by the partition coefficient of drug to corneal surface, not by the diffusion coefficient. Conjunctival and scleral permeability coefficients were not determined by the lipophilicity of β-blockers. These results indicate that the conjunctiva, sclera and cornea of the rabbit eye are sufficiently different in permeation character to control the extent and pathway for ocular absorption.     

Über das Polymorphie-Verhalten von 7-(β-Hydroxypropyl)- und 7-(β,γ-Dihydroxypropyl)-theophyllin

On the Polymorphism of 7-(β-Hydroxypropyl)-and 7-(β,γ-Dihydroxypropyl)-theophylline The polymorphism of 7-(β-hydroxypropyl)- and 7-(β,γ-dihydroxypropyl)-theophylline was studied with differential scanning calorimetry and thermomicroscopy. Crystallization in vitreous supercooled melts yields polymorphic modifications. Their formation and transformation with time was studied.     

Characterization of the complexes of furosemide with 2-hydroxypropyl-β-cyclodextrin and sulfobutyl ether-7-β-cyclodextrin

The purpose of this study was to prepare and characterize complexes of furosemide with 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) and sulfobutyl ether-7-β-cyclodextrin (SBE-7-β-CD). Solid complexes of furosemide with 2-HP-β-CD and SBE-7-β-CD were prepared by using both a freeze–drying and kneading method. Physical mixtures were prepared for comparison. The inclusion complexes were characterized by differential scanning calorimetry, X-ray diffractometry (XRD) and ¹H nuclear magnetic resonance spectroscopy (¹H-NMR). ¹H-NMR, and especially the use of the two-dimensional ROESY spectrum, was used to determine the position of the furosemide molecule inside the cyclodextrin cavity. ¹H-NMR studies showed that furosemide fit into the cyclodextrin torus cavity with its furane ring nearest to the primary hydroxyl side.     

[7-Methyltryptophan 9] -β-corticotropin-(1–24): a hyperactive Synacthen analogue

[7-Methyltryptophan 9] -β-corticotropin-(1–24) has been synthesised. In an isolated adrenal cell bioassay, it had 2.7 times the steroidogenic activity of β-corticotropin-(1–24) (Synacthen).     

Conformational investigation of α,β-dehydropeptides VII*. Conformation of Ac-Pro-ΔAla-NHCH3 and Ac-Pro-(E)-ΔAbu-NHCH3: comparison with (Z)-substituted α,β-dehydropeptides†

The crystal structure and solution conformation of Ac-Pro-ΔAla-NHCH₃ and the solution conformation of Ac-Pro-(E)-ΔAbu-NHCH₃ were investigated by X-ray diffraction method and NMR, FTIR and CD spectroscopies. Ac-Pro-ΔAla-NHCH, adopts an extended-coil conformation in the crystalline state, with all-trans peptide bonds and the ΔAla residue being in a C₅ form, φ₁=– 71.4(4), ψ₁=– 16.8(4), φ₂=– 178.4(3) and ψ₂= 172.4(3)°. In inert solvents the peptide also assumes the C₅ conformation, but a γ-turn on the Pro residue cannot be ruled out. In these solvents Ac-Pro-(E)- ΔAbu-NHCH₃ accommodates a βII-turn, but a minor conformer with a nearly planar disposition of the CO—NH and C=C bonds (φ₂～0°) is also present. Previous spectroscopic studies of the (Z)-substituted dehydropeptides Ac-Pro-(Z)- ΔAbu-NHCH, and Ac-Pro-ΔVal-NHCH₃ reveal that both peptides prefer a βII-turn in solution. Comparison of conformations in the family of four Ac-Pro-ΔXaa-NHCH₃ peptides let us formulate the following order of their tendency to adopt a β-turn in solution: (Z)- ΔAbu > (E)- δAbu > ΔVal; ΔAla does not. None of the folded structures formed by the four compounds is stable in strongly solvating media. © Munksgaard 1996.     

Pharmacological profiles of β-funaltrexamine (β-FNA) and β-chlornaltrexamine (β-CNA) on the mouse vas deferens preparation

The profiles of action of β-funaltrexamine (β-FNA) and β-chlornaltrexamine (β-CNA) have been assessed in the mouse vas deferens preparation. β-FNA, but not β-CNA, demonstrated a reversible agonist action that appeared to be mediated via κ-receptor interaction. β-CNA produced an irreversible antagonism of μ-, κ- and δ-mediated agonist actions, whereas β-FNA irreversibly antagonized μ-mediated agonist effects only. This selective action of β-FNA could also be seen following administration in vivo. β-CNA and particularly β-FNA should prove valuable in the elucidation of multiple opioid receptors.     

Effects of N-substituted analogs of (−)-α-acetylmethadol and (−)-α-methadol on schedule-controlled behavior

The behavior of the pigeon maintained under a variable-interval schedule of food presentation was used to compare the activity of four novel N-substituted acetylmethadol and methadol analogs with that of methadone and (-)-α-acetylmethadol (LAAM). All of the acetylmethadol and methadol analogs had narcotic agonist activity, as defined by the reversibility of their behavioral effects by naloxone. The effect of the N-substituted analogs on variable-interval responding was similar to that of methadone and LAAM, but all these compounds had a slower onset of action than methadone and a shorter duration of action than LAAM. None of the N-substituted analogs showed narcotic antagonist activity when tested against methadone.     

Conformational investigation of α,β-dehydropeptides. IX. N-Acetyl-(E)-α,β-dehydrobutyrine N′-methylamide: stereoelectronic properties from infrared and theoretical studies*

Abstract: : The Fourier transform infrared spectra of Ac-(E)-ΔAbu-NHMe were analyzed to determine the predominant solution conformation (s) of this (E)-α,β-dehydropeptide-related compound and the electron density perturbation in its amide groups. The measurements were performed in dichloromethane and acetonitrile in the region of mode v_s (N–H), amide I, amide II and v_s (C^α= C^β). The equilibrium geometrical parameters, calculated by a method based on the density functional theory with the B3LYP functional and the 6–31G* basis set, were used to support spectroscopic interpretation and gain some deeper insight into the molecule. The experimental and theoretical data were compared with those of three previously described molecules: isomeric Ac-(Z)-ΔAbu-NHMe, Ac-ΔAla-NHMe, which is deprived of any β-substituent, and saturated species Ac-Abu-NHMe. The titled compound assumes two conformational states in equilibrium in the DCM solution. One conformer is extended almost fully and like Ac-ΔAla-NHMe is C₅ hydrogen-bonded. The other adopts a warped C₅ structure similar to that of Ac-(Z)-ΔAbu-NHMe. The C₅ hydrogen bond, unlike the H-bond in Ac-ΔAla-NHMe, is disrupted by acetonitrile. The resonance within the N-terminal amide groups in either of the (E)-ΔAbu conformers is not as well developed as the resonance in Ac-Abu-NHMe. However, these N-terminal groups, compared with the other unsaturated compounds, constitute better resonance systems in each conformationally related couple: the C₅ hydrogen-bonded Ac-(E)-ΔAbu-NHMe/Ac-ΔAla-NHMe and the warped C₅ Ac-(E)-ΔAbu-NHMe/Ac-(Z)-ΔAbu-NHMe. The resonance within the C-terminal groups of the latter couple apparently is similar, but less developed than the resonance in Ac-Abu-NHMe. The electron distribution within the C-terminal group of the hydrogen-bonded C₅ (E)-ΔAbu conformer apparently is determined mainly by the electron influx from the C^α= C^β double bond.     

On the Topically Effective Ocular Hypotensive Properties of ICI 147,798, a Natriuretic β-Adrenoceptor Antagonist,in Rabbits

Abstract: The ocular antihypertensive effects of ICI 147,798, a natriuretic, non-selective β-blocker lacking local anaesthetic and intrinsic sympathomimetic activities, were evaluated in unanaesthetized rabbits with water-load-induced ocular hypertension. The racemate was approximately 20 times more potent as a β-blocker than its d-isomer. The magnitude of reductions in intraocular pressure (IOP) elicited by both compounds was equal following topical administration of an equal dose-concentration (100–300 μl, 0.5% or 0.75%) to one or both eyes, and the activities were similar to those obtained with timolol. A five-hour duration of the IOP lowering effect was achieved by ICI 147,798 and timolol in this rabbit model. ICI d-147,798 exhibited a shorter duration, which could be prolonged by increasing the concentration of the ophthalmic solution. Timolol caused a pronounced reduction of isoproterenol-induced tachycardia after a single dose (200 μl, 0.5%) or by repeating the dose twice a day for four consecutive days. Following the same dose regimen, neither ICI 147,798 nor its d-isomer significantly altered the heart rate response produced by isoproterenol. These findings indicate that ICI 147,798, while effective as a potential antiglaucoma agent, does not display the characteristics of β-blockers on heart rate effects noted with timolol. The results also cast some doubt on the contention that the IOP lowering effect of certain β-blockers is predominantly determined by specific blockade of β-adrenoceptors.     

Influence of Hydroxypropyl β-Cyclodextrin on the Stability of Benzylpenicillin in Chloroacetate Buffer

Hydroxypropyl β-cyclodextrin (HPβCyD) has been shown to stabilize a wide variety of chemically distinct pharmaceutical entities through inclusion-complex formation between drug and cyclodextrin. The effect of HPβCyD on the acid-catalysed hydrolysis of benzylpenicillin (penicillin G) was evaluated in chloroacetate buffer at pH 2.20. At penicillin G: cyclodextrin molar concentration ratios from 1:1 to 1:10, HPβCyD effected stabilization of penicillin G by 1.56- to 5.21-fold. At all temperatures, the observed first-order rate constant (k_obs) values assumed a non-linear, Michaelis-Menten type decrease as a function of increasing HPβCyD concentration. Degradation of penicillin G complexed with HPβCyD (penicillin G-HPβCyD), was approximately ninefold slower than uncomplexed penicillin G. The proportion of penicillin G degrading in either of these forms was, in turn, determined by the equilibrium constant for the complexation. The apparent thermodynamic and activation parameters for the complexation between penicillin G and HPβCyD have also been evaluated. The negative standard enthalpy change (ΔH^°) for the complexation implied that the penicillin G-HPβCyD complex would be predisposed towards enhanced stability, and thus the k_obs value for the hydrolysis of penicillin G decreased with reduction of temperature in these systems. The lack of difference between the enthalpies of activation (ΔH?) for the hydrolysis of uncomplexed and complexed penicillin G seemed to be compensated by the significant difference between the entropies of activation (ΔS?) for these hydrolytic reactions. The results indicate that HPβCyD represents a viable means of stabilization of penicillin G solutions at the pH employed in this study.     

Elevation of serum 17-β-estradiol in channel catfish following injection of 17-β-estradiol, ethynyl estradiol, estrone, estriol and estradiol-17-β-glucuronide

17-β-Estradiol is naturally converted in numerous organisms to various derivatives/metabolites, which may be excreted from the organism into its immediate external environment. There is a paucity of data regarding the biological effects of these derivatives/metabolites on aquatic organisms. Male channel catfish (200–500 g, N=5, 12–18 months) were injected with 1 mg/kg 17-β-estradiol (E2), ethynyl estradiol (EE2), estrone, estriol or E2-17-β-glucuronide with subsequent measurements of vitellogenin (Vtg) and serum E2 concentrations 7 days post injection. EE2 and E2 gave the largest magnitude of Vtg response followed by estrone and estriol. Exposure to EE2, estrone, and E2-17-β-glucuronide all induced significant increases in serum E2 concentrations. This study indicates that metabolites of E2 are also estrogenic and may potentially disrupt estrogen feedback loops within aquatic organisms.     

N-(β-Cyanethyl)-N-nitrosoharnstoffe

N-(β-Cyanoethyl)-N-nitroso Ureas The N-(β-Cyanoethyl)-N-nitroso ureas 2a , b are prepared in a one-step nitrosation of 2-ureidoethylmalonic acids 1a , b .     

Effects of 2-methylthioadenosine 5′-β,γ-methylenetriphosphonate and 2-ethylthioadenosine 5′-monophosphate on human platelet activation induced by adenosine 5′-diphosphate

Adenosine 5′-diphosphate (ADP) induces human platelet aggregation, increases intracellular levels of free calcium, and inhibits stimulated adenylate cyclase. These effects of ADP are mediated by P_2T-purinoceptors that are inhibited specifically and competitively by adenosine 5′-triphosphate (ATP). Inhibition of ADP-induced aggregation and increases in calcium by 2-alkylthio analogs of ATP and of adenosine 5′-monophosphate (AMP) are also specific, but the inhibition is non-surmountable. To examine further the nature of inhibition of ADP-induced platelet activation by 2-alkylthio analogs, the effects of 2-methylthioadenosine 5′-β,γ-methylenetriphosphonate (2-MeS-AMP-PCP) and 2-ethylthioadenosine 5′-monophosphate (2-EtS-AMP) were tested on ADP-induced platelet aggregation and inhibition of adenylate cyclase. 2-MeS-AMP-PCP inhibited platelet aggregation induced by ADP but not by epinephrine, arachidonic acid, 5-hydroxytryptamine (5-HT), platelet activating factor (PAF), or 11α,9α-epoxymethano-prostaglandin H₂ (U46619). Inhibition of ADP-induced platelet aggregation by 2-MeS-AMP-PCP was non-surmountable, and it achieved only 50% inhibition of ADP (5 μM)-induced aggregation. 2-MeS-AMP-PCP achieved 100% inhibition of ADP (5 μM)-induced inhibition of prostaglandin E₁-stimulated adenylate cyclase, and Schild analysis showed the inhibition to be potent (pA₂ 7.3) and competitive (slope 1.12). 2-MeS-AMP-PCP inhibited platelet aggregation induced by adenosine 5′-O-2-thiodiphosphate (ADP-β-S), which inhibited stimulated adenylate cyclase activity, but did not inhibit aggregation induced by adenosine 5′-O-1-thiodiphosphate (ADP-α-S), which does not inhibit stimulated adenylate cyclase. 2-EtS-AMP behaved similarly to 2-MeS-AMP-PCP. These results suggest that ADP may induce aggregation by interacting with two forms of the calcium-mobilizing P_2T-purinoceptor, only one of which is coupled to inhibition of adenylate cyclase and at which 2-alkylthio analogs of ATP and AMP are specific competitive antagonists. © 1996 Wiley-Liss, Inc.     

β2-Microglobulin Levels in Serum and Urine of Cadmium Exposed Rabbits

Abstract: Male rabbits were exposed to cadmium during 16 weeks by subcutaneous injections of either 0.25 mg or 0.5 mg Cd as cadmium chloride per kg body weight 3 times per week. β₂-microglobulin (β₂-m) and creatinine in serum, cadmium in blood, as well as total protein, creatinine, β₂-m and cadmium in urine were determined before exposure and after 3 and 7 weeks of exposure. Measurements were also made at 19 weeks, 3 weeks after the last exposure. During exposure, there was a slight increase in the serum β₂-m/creatinine ratio among rabbits with the highest exposure, while no effect of the cadmium burden could be observed once exposure had ceased. Urinary excretion of β₂-m was related to urinary pH, which appeared to be the case also for excretion of total protein. In the high exposure group, a significant increase in urinary β₂-m excretion, indicative of renal tubular dysfunction was seen after 7 weeks of exposure. This was, however, not related to serum β₂-m levels. It was concluded that before renal damage has occurred even heavy cadmium exposure has very little influence on serum β₂-m levels.