Search PubMed⌕ Search

Biomedical subjects

M A Miranda

Publications and source records attributed to M A Miranda.

At least 55 records · Page 3Linked to original sources
PubMed1997

Photodegradation and photobinding of tiaprofenic acid: in vitro versus in vivo.

The photoreactivity of the photosensitizing nonsteroidal anti-inflammatory drug tiaprofenic acid (TA) and its photoproduct decarboxytiaprofenic acid (DTA) was studied both in the presence and in the absence of bovine serum albumin (BSA). The photoproduct DTA was found to be photostable in buffered aqueous solution at pH 7.4, but photodecomposed when BSA was present in the reaction medium. Both TA and DTA underwent irreversible photobinding to BSA in an almost quantitative way, as evidenced by radioactivity measurements using labeled (3H) compounds. In the case of TA, it has been proven that photobinding is mainly attributable to the phototoreactivity of in situ-generated DTA. The photodegradation and photobinding of TA were also investigated in the epidermis in vivo. Rats were exposed to UVA after application of TA to their shaven dorsal skin. During the initial periods of irradiation, the amount of TA decreased sharply, and the yield of the corresponding photoproduct (DTA) reached a maximum. Prolonged irradiation led to photodegradation of DTA. In vivo photobinding was studied using 3H-TA. Photobinding took place slowly at the beginning, but its rate increased sharply after complete photoconversion of TA, when the photoproduct DTA reached the maximum concentration. Thereafter, the decrease of DTA was more pronounced than that of TA. This indicates that-also in vivo-DTA rather than TA is responsible for the photobinding to biomacromolecules in the viable layer of the epidermis. Overall, the above results suggest that irradiation of TA in buffered aqueous solution, in the presence of proteins, is a reasonable model system to study the photodegradation and photobinding behavior of this drug in vivo. From the qualitative point of view, the main conclusion is that DTA plays a key role both in vivo and in vitro: it is the major photoproduct, it undergoes further photodegradation upon prolonged irradiation, and it appears to be responsible for the photobinding process.

Animals↗
PubMed1996

Gas chromatographic-mass spectrometric study of photodegradation of carbamate pesticides.

The photodegradation of seven carbamate pesticides (bendiocarb, isoprocarb, promecarb, ethiofencarb, furathiocarb, fenoxycarb and pirimicarb), in aqueous solution, has been examined by GC-MS. The most general result was formation of the corresponding phenols. Irradiation of isoprocarb and promecarb also resulted in photo-Fries rearrangement to ortho- and para-hydroxybenzamides. In the case of ethiofencarb photocleavage of the carbon-sulfur bond gave 2-methylphenyl methylcarbamate as main product. Likewise, N-S bond cleavage occurred upon irradiation of furathiocarb, to allow the formation of the carbamate insecticide carbofuran, butyl methylcarbamate and carbofuranphenol. Under similar conditions, fenoxycarb gave p-phenylphenol and 2-hydroxydibenzofuran, through primary homolysis of the aryloxy-methylene bond. Finally, pirimicarb gave rise to 2-formylamino-5,6-dimethylpyrimidin-4-yl dimethylcarbamate.

Carbamates↗
PubMed1996

Management of humeral nonunion after the failure of locking intramedullary nails.

We reviewed 21 cases of humeral nonunion following the failure of "locking" humeral nails. The nails had been inserted as the primary operative procedure following humeral fracture in fifteen cases or after the failure of closed treatment in six cases. Reconstruction after the failure of these implants was complicated by poor bone stock and difficulty in achieving union. Although technically difficult, open reduction and internal fixation with plating and bone grafting (successful in nine of nine cases) was more consistent than exchange nailing (successful in four of 10 cases) in achieving union (p = 0.01). Two patients refused further surgical intervention. The degree of bone loss associated with a loose nail, the lack of success of exchange nailing, and the insertion site morbidity associated with humeral nail removal differentiate these nonunions from similar lower extremity problems. The degree of bone loss following failed locking nailing of the humerus is a major concern, and exchange nailing alone may not be an acceptable option to deal with this problem.

Adolescent↗
PubMed1996

Pelvic ring injuries. A long term functional outcome study.

Eighty patients with pelvic fractures, without hip, spine injuries with neurologic deficits, or traumatic cognitive deficits, 61% treated with external fixators, were reviewed with greater than 5 years of followup. The Short Form-36 General Health Survey, the Iowa pelvic scores, and additional questionnaires concerning return to previous sexual function, occupation, and recreation, and a perception of the worst sequelae of their pelvic trauma were administered. Fractures were classified according to Tile as 25 undisplaced Class A, 31 rotationally displaced Class B, and 24 vertically displaced Class C fractures. Injury severity scores, associated injuries, and mechanisms of injuries were similar across Tile classes. Statistical analysis compared Tile Classes A with B with C and Classes A with B and C. Variations by Tile class among the Short Form-36 survey, Iowa pelvic score, or questionnaire result's were not seen. Approximately 75% of patients returned to their previous sexual function and 80% to their previous occupation. Similarities comparing undisplaced with displaced pelvic fractures question whether reduction of pelvic ring injuries can alter patient long term functional outcomes.

Adolescent↗
PubMed1996

Photodegradation of bezafibrate in aqueous media. Studies of its in vitro phototoxicity.

Aqueous solutions of the antihyperlipoproteinemic drug bezafibrate (CAS 41859-67-0) are photolabile towards UV-B light under aerobic conditions. Two compounds were isolated and identified spectroscopically as well as by alternative synthesis as the only photoproducts formed. Their formation involves primary cleavage of the aryloxy-carbon bond and decarboxylation followed by hydrogen abstraction or dimerization. Bezafibrate is phototoxic in vitro as indicated by the photohemolysis test. Furthermore bezafibrate photo-sensitizes peroxidation of linoleic acid as monitored by the UV detection of dienic hydroperoxides. Partial inhibition of these processes on addition of butylated hydroxyanisole (BHA), reduced glutathione (GSH), sodium azide (NaN3) or 1,4-diazabicyclo [2.2.2] octane (DABCO) suggests the involvement of type I as well as type II mechanisms.

Aerobiosis↗
PubMed1995

Synthesis and pharmacological evaluation of 2'-hydroxychalcones and flavones as inhibitors of inflammatory mediators generation.

2'-Hydroxy-3,4-dimethoxy-3',4'-dimethylchalcone (3a), 2'-hydroxy-3',4',3,4-tetramethoxychalcone (3b), and their corresponding flavones, 3',4'-dimethoxy-7,8-dimethylflavone (4a) and 3',4',7,8-tetramethoxyflavone (4b), were prepared from 3,4-dimethoxycinnamic acid and the respective phenol. The four compounds inhibited enzymic lipid peroxidation and showed weak peroxyl scavenging activity. They also reduced LTB4 release from human neutrophils stimulated by A23187. The chalcone 3b was the only compound able to inhibit in a concentration-dependent way, synovial human recombinant phospholipase A2 activity, human platelet TXB2 generation, and human neutrophil degranulation. This chalcone exerted topical antiinflammatory effects in mice.

Animals↗
PubMed1995

Nonreamed nailing of closed and minor open tibial fractures in patients with blunt polytrauma.

A retrospective comparison of dynamic and static locking mode nonreamed nails in 88 closed, Grades I and II open tibial fractures is presented. Amount of time and number of reoperations required to unite fractures were compared for dynamic (Group 1, n = 31) and static locked (Group 2, n = 13) Winquist I and II fractures, and dynamic (Group 3, n = 14) and static locked (Group 4, n = 30) Winquist III, IV, and segmental fractures. Total reoperations also were compared; Tibias treated with dynamic nails united in an average of 20 weeks, with 3 reoperations; tibias treated with static locked nails united in an average of 30 weeks, with 21 reoperations. Group 1 fractures united in an average of 20 weeks, with 1 reoperation; Group 2 fractures united in an average of 32 weeks, with 4 reoperations. Group 3 fractures united in an average of 20 weeks; Group 4 fractures united in an average of 29 weeks, with 11 reoperations. In the group of tibias treated with dynamic nails, 3 additional operations were done; in the group of tibias treated with static locked nails, 7 additional operations were done. There was 1 infection and 3 deformities. Static locking mode appeared to delay union, especially when Groups 1 and 2 are compared; these fractures can be nailed without locking screws.

Adolescent↗
PubMed1994

Photodynamic lipid peroxidation by the photosensitizing nonsteroidal antiinflammatory drugs suprofen and tiaprofenic acid.

The photochemistry of the photosensitizing nonsteroidal antiinflammatory drugs tiaprofenic acid and suprofen involves the intermediacy of short-lived species (i.e. radicals). The data obtained in the present work strongly suggest that such intermediates may be responsible for the phototoxicity of 2-arylpropionic acids by inducing photodynamic lipid peroxidation at drug concentrations likely to be reached in the skin. This has been investigated using linoleic acid as a model lipid and determining the amount of hydroperoxides by measuring the spectrophotometric absorption at 233 nm, associated with the formation of dienic hydroperoxides. The major photoproducts of tiaprofenic acid and suprofen are derivatives bearing an ethyl side chain. Photoproducts of this type, due to the lack of polar moieties, are highly lipophilic and likely to accumulate in the lipid bilayer of cell membranes. Taking into account their ability to induce photodynamic lipid peroxidation and their marked photostability, it is conceivable that such photoproducts can participate in many catalytic cycles, playing a significant role in the mechanism of photosensitization by tiaprofenic acid and suprofen.

Animals↗
PubMed1994

Photosensitization by fenofibrate. II. In vitro phototoxicity of the major metabolites.

Fenofibric acid, the major metabolite of fenofibrate, was found to be photolabile. Its irradiation in aqueous solution gave rise to two photoproducts, whose formation involves photodecarboxylation of the dissociated acid to an aryloxy-substituted carbanion, which is directly protonated or, alternatively, undergoes a Wittig rearrangement. A comparative in vitro phototoxicity study has been carried out on the anti-hyperlipoproteinemic drug fenofibrate, its metabolites and the photoproducts of fenofibric acid. Fenofibrate, fenofibric acid and its two photoproducts were found to be active when examined by the photohemolysis test and were able to photosensitize peroxidation of linoleic acid, as evidenced by the UV monitoring of dienic hydroperoxides. In summary, the major metabolite of fenofibrate (fenofibric acid), as well as its photoproducts, are phototoxic in vitro. This behavior can be attributed to the fact that the four compounds retain the benzophenone chromophore present in fenofibrate and is indicative of free radical-mediated photosensitization. In agreement with this rationalization, the metabolites with a reduced ketone functionality exhibit no detectable in vitro phototoxicity.

Fenofibrate↗
PubMed1994

Photochemical and photobiological properties of ketoprofen associated with the benzophenone chromophore.

Irradiation of ketoprofen in neutral aqueous medium gave rise to 3-ethylbenzophenone as the major photoproduct. Its formation is justified via protonation of a benzylic carbanion or hydrogen abstraction by a benzylic radical. Minor amounts of eight additional compounds were isolated. Four of them are derived from the benzylic radical: 3-(1-hydroperoxyethyl)benzophenone, 3-(1-hydroxyethyl)benzophenone, 3-acetylbenzophenone and 2,3-bis-(3-benzoylphenyl)butane. The other four products involve initial hydrogen abstraction by the excited benzophenone chromophore of ketoprofen: 1,2-bis-(3-ethylphenyl)-1,2-diphenyl-1,2-ethanediol, 2-(3-benzoylphenyl)-1-(3-ethylphenyl)-1-phenylpropan-1-ol, alpha-(3-ethylphenyl)phenylmethanol, 1,2-bis-[3-(2-hydroxycarbonylethyl) phenyl]-1,2-diphenyl-1,2-ethanediol. The latter process was found to mediate the photoperoxidation of linoleic acid through a type I mechanism, as evidenced by the inhibition produced by the radical scavengers butylated hydroxyanisole and reduced glutathione. The major photoproduct, which contains the benzophenone moiety but lacks the propionic acid side chain, also photosensitized linoleic acid peroxidation. Because lipid peroxidation is indicative of cell membrane lysis, the above findings are highly relevant to explain the photobiological properties of ketoprofen.

Dermatitis, Phototoxic↗
PubMed1994

Molecular basis of drug phototoxicity: photosensitized cell damage by the major photoproduct of tiaprofenic acid.

Tiaprofenic acid is a photosensitizing nonsteroidal anti-inflammatory drug, whose major photoproduct (decarboxytiaprofenic acid) is also a potent photosensitizer. Because of the lack of the carboxylate moiety, this photoproduct is more lipophilic and might bind more efficiently to cell membranes, thereby causing phototoxic damage. To verify the feasibility of this hypothesis, we have prepared the 3H-labeled analogs of tiaprofenic acid and its photoproduct and examined the binding, persistence and phototoxicity of the photoproduct using poorly metabolizing (fibroblasts) and actively metabolizing cells (hepatocytes). The photoproduct of tiaprofenic acid accumulates in both cell types as it is formed. Upon removal of the photoproduct from the culture medium, it rapidly disappears from hepatocytes but not from fibroblasts. Consequently, irradiation of fibroblasts previously incubated with the photoproduct and kept in culture in the dark for 20 h results in generalized cell damage while this effect is not observed in hepatocytes. Because of its long persistence in poorly metabolizing skin cells and its reluctance to photobleaching, the formation of this photoproduct in skin may be of relevance to explain the in vivo phototoxicity of tiaprofenic acid.

Binding Sites↗
PubMed1994

Femoral plating.

We have demonstrated that we are able to meet both trauma and orthopedic goals with immediate plate fixation of femoral fractures in patients with blunt polytrauma. Our femoral fracture mortality rate is less than our predicted institutional mortality rate of patients with comparative injury severity scores. Ipsilateral femoral neck and shaft fractures are easily repaired with femoral plating. Infections, even in open fractures and systemically unstable patients, are rare. Implant failures have been infrequent and are easily reconstructed with intramedullary nails. Knee motion has been restored reliably. Stainless steel DCP plate fixation requires primary bone grafting. Achieving union and subsequent knee rehabilitation often requires that patients remain on crutches for up to 6 months. Our experience with titanium LCDCP plates is preliminary, but we are seeing a significant amount of callus formation and, perhaps, earlier union and bearing weight.

Arteries↗
PubMed1993

In vitro phototoxicity of clofibrate. Photochemical and photohemolytic studies on its metabolite clofibric acid.

Aqueous or methanolic solutions of clofibrate and clofibric acid are photolabile towards UVB light under aerobic as well as anaerobic conditions. Nine photoproducts have been identified; their formation involves primary cleavage of the carbon-halogen bond or of the aryloxy-carbon bond, followed by hydrogen abstraction and/or radical recombination. Clofibric acid is phototoxic in vitro as indicated by the photohemolysis test, under both oxygen and argon atmospheres, although the photohemolysis rate is markedly higher under aerobic conditions. Partial inhibition of this process on addition of butylated hydroxyanisole (BHA), reduced glutathione (GSH), sodium azide (NaN3) or 1,4-diazabicyclo[2.2.2]octane (DABCO) suggests the involvement of type I as well as type II mechanisms.

Clofibrate↗
PubMed1993

Involvement of drug-derived peroxides in the phototoxicity of naproxen and tiaprofenic acid.

Photodegradation of naproxen and tiaprofenic acid in aqueous buffered solutions leads to decarboxylated products with ethyl, 1-hydroxyethyl and/or acetyl side chains. The photomixtures obtained in the presence of oxygen were clearly more toxic to cultured hepatocytes than those obtained under anaerobic conditions. This effect was more noticeable in the case of naproxen. Based on the composition of the oxygenated photomixtures and the relative toxicity of the different photoproducts, it is possible to account for most of the observed toxicity in the case of tiaprofenic acid but not in the case of naproxen. This is explained as a result of the presence of drug-derived peroxidic species in the photomixtures and their contribution to the observed toxicity. Peroxides were determined by the peroxidase-catalyzed oxidation of dichlorodihydrofluorescein to its fluorescent analog. The amount of peroxides present in naproxen photomixtures was much higher than in the case of tiaprofenic acid. A dose-dependent depletion of intracellular glutathione was observed when hepatocytes were incubated with peroxide-containing naproxen photomixtures. This effect was prevented by the addition of catalase or N-acetylcysteine to the culture medium.

Aerobiosis↗
PubMed1993

Photodegradation and in vitro phototoxicity of fenofibrate, a photosensitizing anti-hyperlipoproteinemic drug.

The phototoxic anti-hyperlipoproteinemic drug fenofibrate was found to be photolabile under aerobic and anaerobic conditions. Irradiation under argon of a methanol solution of this drug produced the photoproducts isopropyl 4-(1-[4-chlorophenyl]-1,2-dihydroxy)ethylphenoxyisobutyrate, 1,2-bis(4-chlorophenyl)-1,2bis (4-[isopropoxycarbonylisopropoxy]phenyl)ethane-1,2-diol and 4-(4-chlorobenzoyl)phenol, while under oxygen the photoproducts were 4-chloroperbenzoic acid, methyl 4-chlorobenzoate, 4-chlorobenzoic acid and singlet oxygen, as evidenced by trapping with 2,5-dimethylfuran. These results can be rationalized through hydrogen abstraction by excited fenofibrate, to afford a free radical as key intermediate. Biologically active antioxidants such as glutathione and cysteine efficiently reduced 4-chloroperbenzoic acid to 4-chlorobenzoic acid. The involvement of an electron transfer mechanism is suggested by detection (UV-vis spectrophotometry) of the radical cation TMP+. during the oxidation of tetramethylphenylenediamine (TMP) with 4-chloroperbenzoic acid. Fenofibrate was phototoxic in vitro when examined by the photohemolysis test, both under oxygen and argon atmosphere, although the photohemolysis rate was markedly lower under anaerobic conditions. The photoproducts 4-(1-[4-chlorophenyl]-1,2-dihydroxy)ethylphenoxyisobutyrate and 4-chloroperbenzoic acid induced hemolysis in the dark; however, this effect was quantitatively less important than photohemolysis by fenofibrate. On the other hand, fenofibrate photosensitized peroxidation of linoleic acid, monitored by the UV detection of dienic hydroperoxides. Based on the inhibition of this process upon addition of butylated hydroxyanisole, a radical chain (type I) mechanism appears to operate. In summary, fenofibrate is phototoxic in vitro. This behavior can be explained through the involvement of free radicals, singlet oxygen and stable photoproducts.

Erythrocytes↗
PubMed1992

Phototoxicity of non-steroidal anti-inflammatory drugs: in vitro testing of the photoproducts of Butibufen and Flurbiprofen.

In this work, the phototoxicity of two non-steroidal anti-inflammatory drugs, Butibufen and Flurbiprofen, was examined. Both were unstable to light, to give several photoproducts which were isolated and identified. The different photoproducts were formed by a primary photochemical mechanism which involves an initial cleavage of the C-C bond alpha to the carbonyl group, followed by several secondary processes. The cytotoxic effects of the xenobiotics were evaluated using two well-established biological in vitro tests: (a) enzyme leakage lactate dehydrogenase and glutamate-oxaloacetate transaminase from cultured fibroblasts and (b) lysis of red blood cells. The benzylic alcohols caused extensive leakage from cultured fibroblasts at the different concentrations assayed. The alcohol obtained from Butibufen was a potent lytic agent for human red blood cells. The other photoproducts, Butibufen and Flurbiprofen did not produce observable toxic effects on cells.

3T3 Cells↗