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Biomedical subjects

L W Dittert

Publications and source records attributed to L W Dittert.

At least 19 recordsLinked to original sources
PubMed2000

Chloramine-T in radiolabeling techniques. III. Radioiodination of biomolecules containing thioether groups.

A previously reported method for iodination of the tyrosine moiety of oxidation-sensitive biomolecules was found to cause unacceptable damage to biomolecules containing thiols and thioether groups. This was due to the oxidation of the sulfur-containing residues by molecular iodine (I(2)). To selectively iodinate the tyrosine moiety with minimum oxidation to the sulfur functionality, studies of the kinetics of the reactions between I-(3) and various amino acids and small peptides at various pH values in phosphate buffer were undertaken. Within the pH range studied (5.5-8.2), the results showed that the iodination reaction is strongly catalyzed by hydroxide ions, whereas the oxidation of the sulfur group was insensitive to pH. The results also showed that both reactions are strongly catalyzed by HPO-(4) ion. In a complex molecule, such as methionine-enkephalin, oxidation of the methionine residue (undesirable reaction) proceeds in parallel with iodination of the tyrosine residue (desirable reaction). If such a molecule was iodinated in 0.01 M phosphate buffer at pH values above 7.5, the iodination reaction would proceed much more rapidly than the oxidation reaction, resulting in a high yield of iodinated substrate with little oxidative damage.

Chloramines↗
PubMed1995

Chloramine-T in radiolabeling techniques. II. A nondestructive method for radiolabeling biomolecules by halogenation.

Chloramine-T (CAT) is commonly used in the radiolabeling of bioactive molecules by halogenation. CAT may be used either as a solution or in an immobilized form (Iodobeads) to release radioactive elemental iodine or other halogens by oxidation of their salts. CAT has a very high chlorine potential, and it causes oxidative damage to sensitive substrate molecules, such as peptides and proteins. In some cases, the substrates are completely destroyed. To reduce the chlorine potential of CAT, morpholine was mixed with CAT prior to exposure to the substrates. This formed N-chloromorpholine, in situ, which readily reacted with KI to form I2. The kinetics of the formation of N-chloromorpholine from CAT and morpholine were studied spectrophotometrically by following the disappearance of CAT at 250 nm. The reaction was found to be rapid at all pH's from 5 to 11. 1-Aminocyclohexanecarboxylic acid (a model amino acid) decomposed rapidly in the presence of CAT, but there was no decomposition in the presence of N-chloromorpholine. N-Chloromorpholine was compared to CAT solution and Iodobeads for the iodination of L-tyrosine. The formation of mono- and diiodotyrosine were followed by HPLC. On an equimolar basis (0.55 microM), N-chloromorpholine produced a much greater yield of the mono- and diiodinated tyrosine than Iodobeads. Furthermore, decomposition products were observed when tyrosine was exposed to Iodobeads for 15 min. When a CAT solution was used at a higher concentration (5.5 microM), a substantial amount of decomposition occurred, and the yields of the two iodinated species were very small.(ABSTRACT TRUNCATED AT 250 WORDS)

Chloramines↗
PubMed1993

Chloramine-T in radiolabeling techniques. I. Kinetics and mechanism of the reaction between chloramine-T and amino acids.

The determination of the rate and pH dependency of chlorination of amino acids by chloramine-T (CAT) using the model compounds beta-alanine, L-alanine, and L-alanine ethyl ester was investigated. The reactions were studied under pseudo-first-order conditions where the amino acid concentration was in large excess over CAT. The rates of the reactions were determined spectrophotometrically by following the disappearance of CAT. The overall reaction was found to obey second-order kinetics. The effect of pH was studied over the range 6.1 to 12.0. The reaction rate was found to be independent of pH in the range 6.1 to 8.5, and to decrease with increasing pH above 8.5. The pH dependency was rationalized by assuming that un-ionized CAT reacts with the un-ionized amino group of the amino acid. The value of the resulting second-order rate constant (1.9 x 10(7) M-1 min-1) was of the same order of magnitude as rate constants reported for similar N-chlorination reactions. A cyclic transition state involving a water molecule is proposed.

Amino Acids↗
PubMed1992

Mechanism of diffusion of monosubstituted benzoic acids through ethylene-vinyl acetate copolymers.

Ethylene-vinyl acetate (EVAc), a biocompatible copolymer, has been employed as the rate-controlling membrane in several drug delivery systems. To study the mechanism(s) of diffusion of drugs through EVAc membranes, the diffusion, permeability, and partition coefficients of monosubstituted benzoic acids were studied as a function of vinyl acetate content. The diffusion coefficients were found to occupy a narrow range, but the permeability and partition coefficients were found to increase in a nonlinear fashion as a function of vinyl acetate content, indicating that the diffusion process was partition governed. The partitioning data were analyzed on the basis of the partitioning between the vinyl acetate moiety and the aqueous phase, assuming the formation of 1:1 benzoic acid:vinyl acetate complexes. The effects of ionization and the addition of 2-propanol to the diffusion medium were studied. The results suggest that the un-ionized neutral forms of the benzoic acids are responsible for transport across the copolymer. Altering the composition of the medium by addition of 2-propanol increased the donor phase solubility of the acid, the steady-state rate, and the permeability, suggesting that cosolvent modification provides an excellent chemical means to increase release rates.

Benzoates↗
PubMed1992

Absorption of acetylsalicylic acid from the rat nasal cavity.

The fate of salicylate in the plasma of rats was followed after nasal, intravenous, and oral administration of 2.0-mg doses of aspirin. Aspirin was well absorbed following nasal administration of a neutralized, nonirritating solution containing triethanolamine. The rate of absorption was slower than that of other nasally administered drugs, such as propranolol or progesterone. The bioavailability of aspirin following nasal administration was 100%, whereas the oral bioavailability was only 58.8% at the dose studied.

Absorption↗
PubMed1992

Kinetics and mechanism of chlorine exchange between chloramine-T and secondary amines.

The kinetics and mechanisms of chlorine transfer from chloramine-T (CAT) to several amines are second order and independent of p-toluenesulfonamide concentration; thus, the reaction does not involve disproportionation of CAT to dichloramine-T. From the profile of pH versus rate, the following mechanisms were proposed: (1) reaction of the ionized species of CAT with the ionized amine (ionic mechanism) and (2) reaction of the un-ionized species of CAT with the un-ionized amine (nonionic mechanism). The second-order, pH-independent rate constants calculated for the ionic and nonionic mechanisms were 1.6 and 5 x 10(6) M-1 s-1, respectively. Although these two mechanisms are kinetically indistinguishable, the rate constant for the nonionic mechanism is of the same order of magnitude as those calculated for similar chlorination reactions involving nonionizable chloramines, such as N-chlorosuccinimide, N-chloroquinuclidine, and N-chloro-N-methylbenzenesulfonamide. The proposed mechanism for the chlorine exchange involves a molecule of water in a cyclic, six-membered transition state.

Algorithms↗
PubMed1992

Structure-activity considerations in kinetics and mechanism of chlorine exchange between chloramine-T and secondary amines.

To study the mechanism of N-chlorination of secondary amines by chloramine-T, the kinetics of the reactions of some aromatic-substituted analogues of N-chlorobenzenesulfonamide with various secondary amines were determined. The importance of amine basicity and reactivity of the N-Cl bond of the N-chlorobenzenesulfonamide was also assessed. The results indicate that a mechanism involving the un-ionized species of both reactants (i.e., a molecular mechanism), rather than an ionic mechanism, is operating and that the reaction most likely proceeds via a six-membered-ring transition state that incorporates a water molecule.

Algorithms↗
PubMed1992

Intranasal administration of a beta adrenergic amine: an alternative to metered-dose inhalers.

In anesthetized, artificially ventilated guinea pigs, intranasal and intravenous administration of albuterol produced the same maximum degree of protection against bronchoconstriction induced by bilateral electrical stimulation of the cervical vagal nerves. Intranasal albuterol showed a slower onset of action than intravenous albuterol and exhibited equivalent cardiovascular side effects for the same level of bronchoprotection. Accordingly, intranasal albuterol may represent an alternative to metered-dose inhalation for prophylaxis and treatment of bronchoconstriction in humans.

Administration, Inhalation↗
PubMed1991

Solubility enhancement of some water-insoluble drugs in the presence of nicotinamide and related compounds.

The solubilities of five poorly water-soluble drugs, diazepam, griseofulvin, progesterone, 17 beta-estradiol, and testosterone, were studied in the presence of nicotinamide. All solubilities were found to increase in a nonlinear fashion as a function of nicotinamide concentration. The K1:1 and K1:2 stability constants were as follows: for diazepam, K1:1 = 5.23 M-1 and K1:2 = 8.6 M-2; for griseofulvin, K1:1 = 5.54 M-1 and K1:2 = 8.82 M-2; for progesterone, K1:1 = 5.48 M-1 and K1:2 = 42.47 M-2; for 17 beta-estradiol, K1:1 = 5.38 M-1 and K1:2 = 36.9 M-2; and for testosterone, K1:1 = 5.07 M-1 and K1:2 = 27.47 M-2. Two aliphatic analogues of nicotinamide (nipecotamide and N,N-dimethylacetamide) were studied as ligands with diazepam and griseofulvin and were found to increase the solubilities of both drugs in a linear fashion. The aromatic analogue, N,N-diethylnicotinamide, showed a nonlinear solubilization relationship similar to that seen with nicotinamide. In addition, three other aromatic analogues (isonicotinamide, 1-methylnicotinamide iodide, and N-methylnicotinamide) were studied. These ligands were not soluble enough in water to be studied over the wide range of concentrations used for nicotinamide and N,N-diethylnicotinamide; however, in the concentration range studied, these ligands solubilized diazepam and griseofulvin to a degree similar to that observed with comparable concentrations of nicotinamide. These results suggest that the aromaticity (Pi-system) of the pyridine ring is an important factor in complexation because the aromatic amide ligands were found to enhance the aqueous solubilities of the test drugs to a greater extent than the aliphatic amide ligands.(ABSTRACT TRUNCATED AT 250 WORDS)

Diazepam↗
PubMed1990

Mechanism of nasal absorption of drugs. III: Nasal absorption of leucine enkephalin.

The nasal absorption of a model peptide, leucine enkephalin (LE), was studied in rats using an in situ technique in which 4 mL of perfusion solution was circulated. Leucine enkephalin (LE) was found to undergo hydrolysis to its major metabolite des-tyrosine leucine enkephalin (DTLE). The addition of 1% sodium glycocholate (SGC) to the perfusion solution resulted in an increase in the overall rate of disappearance of LE and a decrease in the rate of formation of DTLE. When LE was added to nasal washings (i.e., Ringer's buffer that was precirculated through the nasal cavity to extract enzymes), LE was found to form DTLE. When SGC or puromycin was added to the nasal washings prior to the addition of LE, the rate of conversion of LE to DTLE was significantly reduced, suggesting that these two agents can inhibit peptidase enzyme activity in the nasal cavity. Since the volume of the solution has been shown to influence the kinetics of absorption of drugs administered nasally, a new experimental technique, the in vivo-in situ technique, which utilizes small volumes of solution and simulates realistic use of nose drops, was employed to further examine the mechanism of absorption and hydrolysis of LE in rats. Leucine enkephalin (LE) dissolved in 100 microL of Ringer's buffer was placed in the isolated nasal cavities of rats. The disappearance of LE and the appearance of DTLE were followed by rinsing the nasal cavity with fresh buffer. Disappearance of LE was always accompanied by appearance of DTLE, and the fraction of LE converted to DTLE decreased as the concentration of LE increased, suggesting a saturable enzymatic process.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1990

Mechanism of nasal absorption of drugs. IV: Plasma levels of radioactivity following intranasal administration of [3H]leucine enkephalin.

To study the factors influencing nasal absorption of a model pentapeptide, plasma levels of total radioactivity were determined following the administration of [3H]tyr-leucine enkephalin to rats intravenously, intranasally alone, and intranasally in the presence of puromycin. The major pathway for transport of radioactivity into the blood from the nasal cavity appeared to be hydrolysis of [3H]tyr-leucine enkephalin to [3H]L-tyrosine, followed by absorption of [3H]L-tyrosine. When puromycin was added to the nasal solution in concentrations at which the in vitro hydrolysis of leucine enkephalin was completely inhibited, the appearance of radioactivity in the plasma was slowed, but plasma concentrations of radioactivity eventually reached levels comparable to those observed in the absence of puromycin. In view of the inhibitory effect of puromycin on the hydrolysis of leucine enkephalin, it was assumed that a significant fraction of the [3H]tyr-leucine enkephalin was absorbed intact in the presence of this substance. However, an assay method for intact leucine enkephalin in plasma is needed to confirm these preliminary observations.

Administration, Intranasal↗
PubMed1990

Synthesis and mechanisms of decomposition of some cephalosporin prodrugs.

The delta-3 and delta-2 methyl esters of cefazolin were synthesized. The kinetics and mechanisms of degradation of the methyl esters and the delta-3 and delta-2 isomers of pivaloyloxymethyl prodrug esters of the new cephalosporin ceftetrame (Ro 19-5247) were investigated in buffer systems and in human plasma in vitro. The major hydrolytic products of all the delta-3 and delta-2 esters were the inactive delta-2 cephalosporin free acids. The following reaction scheme describes the in vitro hydrolysis of these compounds: [formula: see text]. In addition, there was evidence of opening of the beta-lactam ring to form cephalosporoic acid when the methyl ester of cefazolin was studied in human plasma and in the presence of penicillinase. For the methyl esters, the processes represented by k12, k21, and k20 were operative in buffers; in human plasma, the processes represented by k12, k21, and k20 were operative in addition to cephalosporoic acid formation. For the isomers of the cephalosporin prodrug ester Ro 19-5248 only k12 and k20 were operative in buffers; in human plasma all pathways were operative and there was no evidence of cephalosporoic acid formation. In all cases, the processes represented by k12, k21, and k20 were subject to general and/or specific base catalysis.

Buffers↗
PubMed1989

Pharmacokinetics of sulfasalazine metabolites in rats following concomitant oral administration of riboflavin.

Sulfasalazine, 60 mg/kg, was administered orally to groups of rats (n = 4) along with 1, 5, or 10 mg/kg of riboflavin. Plasma and urine were assayed for 5-aminosalicylic acid, acetyl-5-aminosalicylic acid, sulfapyridine, and acetyl-sulfapyridine using an HPLC method. The mean percent of dose recovered as total metabolites in urine was significantly greater (alpha = 0.01) for the group receiving 10 mg/kg riboflavin compared to the controls or the group receiving 1 mg/kg riboflavin. Plasma AUC and Cmax values were also significantly greater (alpha = 0.05) for the 10 mg/kg riboflavin group. These results suggest that at higher doses, a significant fraction of riboflavin reaches the colon intact and stimulates more efficient reduction of the azo bond in sulfasalazine. Since the concentrations of 5-ASA achieved in the colon may be directly related to the efficacy of sulfasalazine in treating inflammatory bowel disease, concomitant administration of riboflavin may enhance sulfasalazine's efficacy in humans.

Administration, Oral↗
PubMed1989

Mechanism of diffusion of monosubstituted benzoic acids through ethylene-vinyl acetate copolymers.

The present investigation was undertaken to gain insight into the factors governing diffusion of a series of monosubstituted benzoic acids across ethylene-vinyl acetate copolymers. The interactions between ethylene-vinyl acetate and the benzoic acids were studied using diffusion and partition methods. The diffusion coefficients were found to occupy a narrow range, but the permeability and partition coefficients were found to increase in a non-linear fashion as a function of vinyl acetate content. The results were mathematically consistent with the formation of 1:1 benzoic acid:vinyl acetate complexes.

Benzoates↗
PubMed1987

Disposition of moracizine (ethmozine) in healthy subjects after oral administration of radiolabelled drug.

Moracizine (ethmozine) is a phenothiazine derivative with demonstrated antiarrhythmic activity. To characterize the pharmacokinetics and material balance relationships in humans, we have given 14C-moracizine X HCl as a single oral dose of 500 mg (50 microCi) to six healthy men. Plasma, urine, and faecal samples were collected for 7 days after administration and the concentrations of total radioactivity and intact moracizine were determined by liquid scintillation counting and HPLC, respectively. Urine and faecal recovery accounted for 95% of the administered radioactivity. Most of this radioactivity was found in the faeces (59%). Only 0.05% of the dose was recovered from urine as intact moracizine. The Cmax and AUC for moracizine equivalents of total radioactivity were 4- and 18-fold higher, respectively, than the corresponding values for intact moracizine. Additionally, both the disappearance of total radioactivity from plasma and its excretion rate into urine were slower in comparison to intact drug. Terminal t1/2 values calculated from plasma concentration-time data were 85.2 and 3.5 h for total radioactivity and intact moracizine, respectively. However, based on urinary excretion rates, the t1/2 for total radioactivity was shorter (29.3 h) while the t1/2 for intact drug was comparable (2.7 h) to the results obtained from the plasma data. The oral plasma clearance of moracizine was relatively large (2.2 l X min-1), suggesting first-pass metabolism. The estimated oral systemic availability of moracizine was 34%.

Administration, Oral↗