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R Niemi

Publications and source records attributed to R Niemi.

11 recordsLinked to original sources
PubMed2004

Chemical and enzymatic stability evaluation of lipoamino acid esters of idebenone.

Lipophilic conjugates of idebenone (IDE) with short-chain alkylamino acids were previously synthesized and evaluated in vitro for their antioxidant properties. In this study, their susceptibility to chemical and enzymatic hydrolysis was evaluated. Results indicated that these derivatives release the parent drug quantitatively via enzymatic hydrolysis by serum and liver esterases, with a cleavage rate related to the length of the alkyl side chain. Consequently, the present lipoamino acid conjugates of IDE are prodrugs and their in vivo effects are mediated through the parent compound released in the body.

Amino Acids↗
PubMed2004

Airway pressure release ventilation as a primary ventilatory mode in acute respiratory distress syndrome.

BACKGROUND: Airway pressure release ventilation (APRV) is a ventilatory mode, which allows unsupported spontaneous breathing at any phase of the ventilatory cycle. Airway pressure release ventilation as compared with pressure support (PS), another partial ventilatory mode, has been shown to improve gas exchange and cardiac output. We hypothesized whether the use of APRV with maintained unsupported spontaneous breathing as an initial mode of ventilatory support promotes faster recovery from respiratory failure in patients with acute respiratory distress syndrome (ARDS) than PS combined with synchronized intermittent ventilation (SIMV-group). METHODS: In a randomized trial 58 patients were randomized to receive either APRV or SIMV after a predefined stabilization period. Both groups shared common physiological targets, and uniform principles of general care were followed. RESULTS: Inspiratory pressure was significantly lower in the APRV-group (25.9 +/- 0.6 vs. 28.6 +/- 0.7 cmH2O) within the first week of the study (P = 0.007). PEEP-levels and physiological variables (PaO2/FiO2-ratio, PaCO2, pH, minute ventilation, mean arterial pressure, cardiac output) were comparable between the groups. At day 28, the number of ventilator-free days was similar (13.4 +/- 1.7 in the APRV-group and 12.2 +/- 1.5 in the SIMV-group), as was the mortality (17% and 18%, respectively). CONCLUSION: We conclude that when used as a primary ventilatory mode in patients with ARDS, APRV did not differ from SIMV with PS in clinically relevant outcome.

Adult↗
PubMed2003

Combined effects of prone positioning and airway pressure release ventilation on gas exchange in patients with acute lung injury.

BACKGROUND: Prone positioning has been shown to improve oxygenation in 60-70% of patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Another way to improve matching of ventilation to perfusion is the use of partial ventilatory support. Preserving spontaneous breathing during mechanical ventilation has been shown to improve oxygenation in comparison with controlled mechanical ventilation. However, no randomized studies are available exploring the effects of preserved spontaneous breathing on gas exchange in combination with prone positioning. Our aim was to determine whether the response of oxygenation to the prone position differs between pressure-controlled synchronized intermittent mandatory ventilation with pressure support (SIMV-PC/PS) and airway pressure release ventilation with unsupported spontaneous breathing (APRV). METHODS: We undertook a prospective randomized intervention study in a medical-surgical adult intensive care unit of a university hospital. Of 45, 33 ALI patients (acute lung injury) within 72 h after initiation of mechanical ventilation, and in whom the prone position was applied according to a predefined strategy, were included in the study. After initial stabilization the patients were randomized to receive either SIMV-PC/PS or APRV with predefined general ventilatory goals (PEEP, tidal volume, inspiratory pressure and PaCO2-level). The protocol for prone positioning was the same for both treatment arms. Prone positioning was triggered by finding a PaO2/FiO2-ratio below 200 mmHg evaluated twice per day. The duration of each prone episode was 6 h. RESULTS: The first two episodes of prone positioning were analyzed. Gas exchange was measured before and at the end of prone positioning. Of the 45 patients enrolled, 33 were turned prone once and 28 twice. No significant differences were detected in baseline characteristics. Changes in oxygenation were analyzed in response to the first and second prone episodes 5 h and 24 h after randomization and initiation of SIMV-PC/PS or APRV respectively. Before the first prone episode the PaO2/FiO2-ratio was significantly better (P = 0.02) in the APRV-group (median; interquartile range) (162; 108-192 mmHg) than in the SIMV-PC/PS-group (123; 78-154 mmHg). The response in oxygenation to the first prone episode was similar in both groups: PaO2/FiO2-ratio increased 39.5; 17.75-77.5 mmHg in the SIMV-PC/PS-group and 75.0; 9.0-125.0 mmHg in the APRV-group (P = 0.49). Before the second prone episode, the PaO2/FiO2-ratio was comparable (SIMV-PC/PS 130.5; 61.0-161.0 mmHg vs. APRV 134; 98.3-175.0 mmHg). Improvement in oxygenation was significantly (P = 0.02) greater in the APRV group (82; 37.0-141.0 mmHg) than in the SIMV-PC/PS group (50; 24.0-68.8 mmHg) during the second prone episode. General ventilatory and hemodynamic variables and use of sedatives were similar in both groups during the study. CONCLUSIONS: APRV during prone positioning is feasible in the treatment of ALI patients. APRV after 24 h appears to enhance improvement in oxygenation in response to prone positioning.

Adult↗
PubMed2001

Effects of calcium and lipophilicity on transport of clodronate and its esters through Caco-2 cells.

Clodronate, like other bisphosphonates, is poorly absorbed from the gastrointestinal tract, mainly due to its high hydrophilicity and ability to form complexes with divalent cations in the gastrointestinal tract. One strategy for improving oral absorption of these types of molecules is to develop more lipophilic derivatives. The importance of lipophilicity and calcium chelation in the absorption of clodronate was evaluated by studying the penetration of clodronate and its mono-, di-, and triphenyl esters through human intestinal Caco-2 cells. The transport rates of [(14)C]-clodronate and its mono-, di-, and triphenyl esters were quantified by calculating their apparent permeability coefficients (P(app)) both in normal (1.3 mM) calcium concentration and in 'minimum-calcium model'. The transport rate of 1 mM clodronate was very low (0.25 x 10(-7) cm/s), while the removal of calcium from the apical side increased this transport rate 6-fold. The transport rate of clodronate was increased with increasing dose. Mono- and diphenyl esters did not significantly enhance the transport of clodronate. Triphenyl ester, however, increased the transport rate 17-fold compared with parent clodronate. Removal of calcium did not affect the transport rates of di- or triphenyl esters, which indicated that the esterification of hydroxyl groups of clodronate decreased calcium complex formation. These results indicate that clodronate is transported paracellularly through Caco-2 cells and that calcium decreases strongly its absorption. They further suggest that at least three phosphate hydroxyl groups need to be substituted until the permeation route is changed from paracellular to transcellular.

Analgesics, Non-Narcotic↗
PubMed2000

Bisphosphonate prodrugs: synthesis and in vitro evaluation of alkyl and acyloxymethyl esters of etidronic acid as bioreversible prodrugs of etidronate.

The synthesis and preliminary evaluation of novel alkyl and acyloxymethyl esters of etidronic acid as etidronate prodrugs is reported. Tetramethyl ester of etidronic acid was found be isomerized at pH 7.4 and P-C-P bridge was rearranged to P-C-O-P. This unwanted process was prevented via acylation of the bridging carbon's alcohol group. Acylation showed to be stable if one or more phosphonic OH- groups were substituted. However, when none of the phosphonic OH- groups were substituted, the acylation was chemically hydrolysed and the parent drug was released. This finding was successfully applied in the design of tetrapivaloyloxymethyl ester of acetylated etidronic acid which released etidronic acid via enzymatic (first step) and chemical (second step) hydrolysis in liver homogenate. However, the corresponding tri-substituted pivaloyloxymethyl ester having adequate water-solubility and lipophilicity (logP(app) 0.6 at pH 7.4), is probably the most potential prodrug candidate reported to enhance the oral bioavailability of etidronate.

Animals↗
PubMed1999

Bisphosphonate prodrugs: synthesis and in vitro evaluation of novel acyloxyalkyl esters of clodronic acid.

Novel tetra-, tri-, and P,P'-dipivaloyloxymethyl esters of clodronic acid were synthesized, and their properties as possible prodrugs of clodronate were evaluated in vitro. All pivaloyloxymethyl esters were significantly more lipophilic (log P(app) ranged from -2.1 to 7. 4) than clodronate (log P(app) < or = -5.4), which suggests that it may be possible to change the intestinal absorption mechanism of clodronate from a paracellular to a transcellular pathway by a prodrug approach. Pivaloyloxymethyl esters degraded rapidly in 10% rabbit liver homogenate, and half-lives of tri- and P,P'-diesters were 1.1 and 14 min, respectively. The intermediate degradation products were further degraded, and clodronic acid was released in quantitative amounts. In human serum, the stability of pivaloyloxymethyl esters was comparable to their stability in phosphate buffer (pH 7.4), which suggests that their degradation in human serum is mostly due to the chemical hydrolysis. Benzoyloxypropyl esters of clodronic acid were also synthesized, but they did not release clodronic acid due to the enzymatic and chemical stability of the formed 3-hydroxypropyl phosphonate esters and are, therefore, not prodrugs.

Animals↗
PubMed1999

Bisphosphonate prodrugs: synthesis and in vitro evaluation of novel clodronic acid dianhydrides as bioreversible prodrugs of clodronate.

P,P'-Diacetyl, P,P'-dibutyroyl, P,P'-dipivaloyl, and P,P'-dibenzoyl (dichloromethylene)bisphosphonic acid dianhydride disodium salts (2a-d) were synthesized and evaluated as novel bioreversible prodrugs of clodronate. The anhydrides were prepared by reacting anhydrous tetrasodium clodronate with a large excess of the corresponding acid anhydride. The dianhydrides 2a-d alone were more lipophilic than the parent clodronate, as determined by drug partitioning between 1-octanol and phosphate buffer at pH 7.4. They also were stable toward chemical hydrolysis in aqueous solutions (pH 7.4 and 2.0). The half-lives for chemical degradation in a buffer solution at 37 degrees C varied from 0.7 to 286 h and from 15 to 790 h at pH 2.0 and 7.4, respectively. The dianhydrides 2a,b,d underwent complete enzymatic hydrolysis to clodronate in 80% serum at 37 degrees C after 1 min, although 2c had a half-life of 3.3 h. The aqueous solubility of clodronate decreased considerably in the presence of Ca2+ ions. This is most probably due to formation of poorly water-soluble chelates, which may also hinder the oral absorption of clodronate. However, Ca2+ ions did not have an effect on the aqueous solubility of clodronic acid dianhydrides, and therefore, these prodrugs may improve oral absorption of the parent drug. In conclusion, these novel dianhydride derivatives may be potentially useful prodrugs of clodronate which, due to their lipophilicity and lack of Ca2+ chelating, increase its bioavailability after oral administration.

Anhydrides↗
PubMed1997

Simultaneous determination of clodronate and its partial ester derivatives by ion-pair reversed-phase high-performance liquid chromatography coupled with evaporative light-scattering detection.

A new ion-pair HPLC method coupled with evaporative light-scattering detection (ELSD) for the simultaneous determination of clodronate and its partial esters has been developed. The simultaneous chromatographic separation was achieved on a reversed-phase C8 column with a gradient system and butylamine as an ion-pair reagent. This method provides good enough reproducibility and sensitivity for in vitro determinations of clodronate and its ester derivatives. The method is applied for hydrolysis studies of clodronate monoesters which have been described as possible prodrugs of clodronate.

Chromatography, High Pressure Liquid↗
PubMed1997

[Prodrugs].

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Acyclovir↗