Marianne Johansen's research while affiliated with IT University of Copenhagen and other places

Publications (31)

Article
We have determined initial rates of naproxen formation from dextran-naproxen ester prodrugs incubated in homogenates of various segments of the pig GI tract. Drug liberation proceeded 15-17 times faster in cecum and colon homogenates than in aqueous pH 7.4 buffer or homogenates of the small intestine. The degree of conjugate substitution did not af...
Article
The bioavailability of naproxen after oral administration of aqueous solutions of various dextran-naproxen ester prodrugs in pigs was determined. The dextran prodrugs employed ranged in molecular weight from 10,000 to 500,000. As calculated relative to an equivalent oral dose of parent naproxen, the absorption fractions of all the derivatives were...
Article
A high-performance size-exclusion chromatographic procedure, using Nucleosil Diol, for the quantitative analysis of fluoresceinyl isothiocyanate dextrans of various molecular masses (10,000-150,000) in biological media was developed. The influence of the molecular mass and the degree of substitution of the conjugates on the chromatographic behaviou...
Article
The bioavailability of naproxen after oral administration of aqueous solutions of a dextran T-70-naproxen ester prodrug in pigs was assessed. Compared to the administration of an oral solution of an equivalent dose of naproxen the average absorption fraction for the conjugate amounted to 91%. It was established that several features of the prodrug...
Article
Kinetics of regeneration of metronidazole from the corresponding monoesters of maleic acid, succinic acid and glutaric acid in aqueous buffer solution, 80% human plasma and pig liver homogenate has been investigated at 37°C. In all cases the hydrolysis followed first-order kinetics and complete reversion to metronidazole was observed as determined...
Article
A high-performance size-exclusion chromatography procedure using Nucleosil Diol has been developed which provides the simultaneous determination of macromolecular dextran metronidazole monosuccinate ester prodrugs and the hydrolysis products metronidazole and metronidazole monosuccinate. Various factors influencing the chromatographic behaviour of...
Article
The kinetics of hydrolysis of metronidazole monosuccinate dextran ester conjugates in aqueous solution over the pH range 6.61–7.80 (37°C) has been investigated. As demonstrated by HPLC the degradation of the dextran conjugates proceeds through parallel formation of metronidazole and metronidazole monosuccinate, respectively. The regeneration rates...
Article
The ability of a series of aliphatic ester prodrugs to improve cutaneous delivery of metronidazole has been investigated. In permeation studies using full thickness human skin in vitro the derivatives lead only to a 1.5-fold enhancement of permeation compared to the parent drug. The influence of non-specific cutaneous hydrolytic enzymes on the rate...
Article
Physicochemical and hydrodynamic properties of benzoyl dextran conjugates with varying molecular weights and degree of substitution have been determined. The stability experiments revealed identical pH-dependence of rates of regeneration of benzoic acid from the various conjugates employed. Similar rate data were obtained in aqueous buffer (pH 7.40...
Article
Benzoate esters of dextran (Mw = 65,600) with varying degrees of substitution have been synthesized. The kinetics and mechanism of hydrolytic cleavage of the ester bond in aqueous solution over the pH range 3.0–9.5 (60°C) has been investigated. The degradation reactions followed strict first-order kinetics and a rate expression encompassng hydrogen...
Article
The hydrolytic degradation rates of various aliphatic and aromatic esters of metronidazole in aqueous buffer solution and in human plasma were investigated at 37°C. Complete reversion to metronidazole was observed as determined by HPLC and in all cases the hydrolysis followed strict first-order kinetics. The susceptibility of the various ester deri...
Article
N-Acyloxyalkylation has become a commonly used approach to obtain prodrug forms of various NH-acidic drug substances. The regeneration of the parent drug occurs via a two-step reaction, enzymatic cleavage of the ester grouping followed by spontaneous decomposition of the N-hydroxyalkyl intermediate. The usefulness of this approach depends on the ra...
Article
The kinetics of hydrolysis of metronidazole monosuccinate in aqueous solution at pH 1.5–10 and 60°C has been investigated. The decomposition was monitored by a high-performance liquid chromatographic method capable of determining the monosuccinate ester and the parent metronidazole simultaneously. At any given pH the reactions displayed strict firs...
Article
The hydrolysis kinetics of several oxazolidines derived from (-)-ephedrine and various aldehydes and ketones were studied to assess their suitability as prodrug forms for beta-amino alcohols and/or carbonyl-containing compounds. The oxazolidines were found to undergo a facile and complete hydrolysis in the pH range of 1-11 at 37 degrees. The hydrol...
Article
A previously described spectrophotometric method for the determination of formaldehyde or other aliphatic aldehydes has been modified and demonstrated to be a highly useful and convenient means for assessing the rate of hydrolysis of various pro-drugs which upon reconversion to their parent drugs release an aldehyde. The pro-drugs tested include a...
Article
Various N-Mannich bases of carbamazepine with piperidine, diethylamine or dipropylamine as the amine component were prepared and evaluated as water-soluble pro-drugs. The hydrolysis, yielding carbamazepine, amine and formaldehyde in stoichiometric amounts, showed sigmoidal pH-rate profiles with maximum hydrolysis rates at pH > 9, At pH 7.40 and 37°...
Article
The kinetics of hydrolysis of oxazolidines derived from (-)-ephedrine or (+)- pseudoephedrine and benzaldehyde or salicylaldehyde was studied at 37°C to assess their suitability as pro-drug forms for β-aminoalcohols and carbonyl-containing compounds. The oxazolidines were found to undergo a facile and complete hydrolysis in the pH range 1–11. The o...
Article
Although N-Mannich bases of amides, imides, hydantoins and various other NH-acidic compounds have been known for a long time, and several drug substances and other compounds bearing an NH-acidic group have been modified by N-aminomethylation and tested as potential medicinal agents, the facile decomposition of several N-Mannich bases in aqueous sol...
Article
The kinetics of decomposition of various N-Mannich bases derived from succinimide or 5,5-dimethylhydantoin and a series of primary aromatic amines in aqueous solution at 37°C was studied to assess their suitability as pro-drugs for such amino compounds. The pH-rate profile for each compound showed a sigmoid shape and could be accounted for by assum...
Article
A number of N-Mannich bases of various NH-acidic compounds (benzamide, phthalimide, chlorzoxazone, phenytoin, barbital, p-toluenesulfonamide, acetazolamide, chlorothiazide and hydrochlorothiazide) with morpholine or piperidine as the amine component were evaluated as potential pro-drugs with the purpose of enhancing the aqueous solubility and disso...
Article
The kinetics of decomposition of various N-Mannich bases of salicylamide in aqueous solution at 37°C was studied to assess their suitability as pro-drugs for amino compounds. The decomposition, yielding salicylamide, amine and formaldehyde in stoichiometric amounts, showed bell-shaped pH-rate profiles which could be accounted for by assuming sponta...
Article
The kinetics and mechanism of decomposition of the N3-hydroxymethyl derivatives of various hydantoins (phenytoin, nitrofurantoin and 5,5-dimethylhydantoin) in aqueous solution at 37°C was studied to assess their potential utility as pro-drugs for the parent substances. The derivatives were found to undergo an apparent hydroxide ion-catalyzed decomp...
Article
The hydrolysis kinetics of a series of N-Mannich bases of carboxamides, thioamides, and other NH-acidic compounds were studied to assess their suitability as prodrugs for various drugs. The pH-rate profiles for the compounds were determined at 37 degrees and were accounted for by assuming the spontaneous decomposition of both free and protonated Ma...

Citations

... Besides these small molecular mass esters, only a polysaccharide (dextran) has also been reported for the formation of macromolecular prodrugs (MPDs) of naproxen (Cordeiro et al., 2020). MPDs of naproxen were made using dextran polymer with its low degree of substitution (DS) (Harboe et al., 1988). Likewise, dextran, HPC, a cellulose ether has attracted the attention of researchers for the development of NSAIDs and antibiotic prodrugs (Hussain et al., 2013). ...
... Practically identical stabilities of various esters of dextran, including benzoic acid and nonsteroidal anti-inflammatory conjugates, in aqueous buffer, pH 7.4, and human plasma have been observed (Larsen and Johansen, 1989) suggesting that hydrolysis proceeds without enzymatic catalysis. It was therefore concluded that dextran affords a certain degree of steric protection to any drug which might be fixed close to the polymer matrix. ...
... Cefcapene pivoxil (S-1108), an oral cephem antibiotic possessing a pivaloyloxymethyl ester group, is a prodrug of cefcapene acid (S-1006) [1,2]. It is easily deesterified in the intestine in a manner similar to that of other prodrugs having a pivaloyloxymethyl (POM) ester345. Its active metabolite, cefcapene acid (seeFig. ...
... Numerous methods to accomplish an effective treatment since at least the 1970s have been introduced by scientists such as Gregoriadis [1], Zafaroni [2], and Theeuwes [3]. These methods were also explored concisely in the conference held during the same period [4]. The drug delivery system's aims ...
... We next repeated the synthetic sequence using N-chloromethyl carbamate 1B bearing a -SO 2 Me modulator to provide the releasable mPEG∼TLZ conjugate 3B (Fig. 2 It has been shown that strong electron withdrawing groups at the N-substituent stabilize a Mannich base (15,30). To promote breakdown of the intermediate, we reduced the electron withdrawing ability of the N-substituent by changing the N-aryl group to a methoxyethyl moiety. ...
... Urea and thiourea derivatives have a significant role in many agricultural and medical fields due to their multi-dynamic effectiveness such as insecticidal, herbicidal [8][9][10][11][12], antioxidants [13], anticancer agents [14][15][16][17], antiviral [18], anticonvulsant [19], anti-inflammatory [20,21], urease inhibitory [22], antimalarial, antimicrobial [23][24][25][26][27][28]. N-Mannich bases known as potentially useful prodrugs, therefore several pharmaceutical compounds contain NH group modified by N-aminomethylation and experienced as possible therapeutic agents [29][30][31][32][33][34][35]. The aminomethylation of urea/thiourea by formaldehyde or substituted benzaldehyde and secondary amines have not involved so much work [36][37][38][39], Although the first report on this subject has appeared more than many years ago. ...
... The kinetics of degradation of a dextranmetronidazole-monosuccinate ester conjugate (Mol. Wt 70 000) with degree of substitution of 8.43 at 37°C in buffer pH 7.4 has also been studied (Larsen, 1986;Larsen and Johansen, 1987). Almost identical stability of the conjugate was observed in buffer and 80% human plasma (tl/2 = 32 h). ...
... The electrophilic substitution of salicylamides with iminium ions affords N-, as well as C-Mannich bases, depending on the substrate used and the reaction conditions applied. Parent salicylamide yields N-Mannich bases, which have been investigated as models for prodrug systems to deliver in water sparingly soluble drugs into systemic circulation [58,59]. Salicylamides bearing more than one hydroxy group, such as β-resorcylic acid amide or gentisic acid amide, afford C-Mannich bases upon aminomethylation [60], as well as niclosamide [61]. ...
... Their decomposition in an elimination reaction yields very reactive vinyl ketones as possible intermediates for ring closure in the synthesis of heterocycles. MKs can also be used as prodrugs [4,5] . Furthermore , unsaturated MKs are efficient alkylating agents for thiol enzymes [6,7] and their water solubility, especially in the case of the aminoketones, makes them good model compounds for antimicrobial investigations. ...