Clinical pharmacokinetics of tiaprofenic acid and its enantiomers

Tiaprofenic acid is a chiral nonsteroidal anti-inflammatory drug (NSAID) of the 2-arylpropionic acid (2-APA) class. A common structural feature of 2-APA NSAIDs is a sp3-hybridised tetrahedral chiral carbon heteroatom within the propionic acid side chain moiety, with the S-enantiomer possessing most of the beneficial anti-inflammatory activity. However, all tiaprofenic acid preparations to date are marketed as the racemate. Tiaprofenic acid has been suggested to exhibit limited pharmacokinetic stereoselectivity. The synovium is the proposed site of action of NSAIDs when used for musculoskeletal disorders, and substantial concentrations of tiaprofenic acid are attained in synovial fluid. Recent data suggested that possibility of stereoselective distribution of tiaprofenic acid into synovium and cartilage. Hence, data generated using non-stereospecific assays may not always be extrapolated to explain the disposition of the individual enantiomers. Tiaprofenic acid is rapidly and almost completely absorbed when given orally. The area under the plasma concentration-time curve (AUC) of tiaprofenic acid is proportional to the oral dose administered. A sustained release dosage form is available, which may be beneficial due to the short terminal phase half-life of tiaprofenic acid (3 to 6 hours). The bioavailability is the same as that with conventional rapid release preparations, although the peak plasma drug concentration is reduced and time peak is prolonged. Tiaprofenic acid binds extensively to plasma albumin. These is negligible R to S inversion upon oral administration. Tiaprofenic acid is eliminated following extensive biotransformation to glucuronide-conjugated metabolites. Approximately 60% is eliminated as conjugates excreted in urine, and little drug is eliminated unchanged. The rate of excretion of tiaprofenic acid and its conjugates may be related to renal function; accumulation of conjugates occurs in end-stage renal disease, but not in young individuals or elderly patients. Potentially clinically important drug interactions with tiaprofenic acid have been demonstrated for some anticoagulants and probenecid. Relationships between tiaprofenic acid concentrations in biological matrices and therapeutic or toxic effects have not yet been elucidated for this drug.     

Biographical sketch of Dr. Manuel Arnoldo Barrera Maldonado

There is increasing awareness that the long-term use of the non-steroidal anti-inflammatory agent tiaprofenic acid (Surgam) is associated with a severe form of cystitis. The condition is usually reversible with complete resolution of symptoms on stopping the drug. We present a case of tiaprofenic acid-induced cystitis resulting in bilateral hydronephrosis suggesting ureteric obstruction. The previous reported cases are reviewed and the risks of delay in withdrawal of the drug and of permanent ureteric damage are discussed.     

Quantitative analysis of non-steroidal anti-inflammatory drugs by capillary zone electrophoresis

The potential utility of capillary zone electrophoresis (CZE) for the separation and quantitative determination of some non-steroidal anti-inflammatory drugs (NSAIDs) was investigated. The influence of different parameters on migration times, peak symmetry, efficiency and resolution was studied; these parameters included the nature and concentration of the anionic and cationic components of the separation buffer. A buffer consisting of 75 mM glycine adjusted to pH 9.1 with triethanolamine was found to provide a very efficient and stable electrophoretic system for the CZE analysis of NSAIDs, giving RSD values of about 0.1 and 0.5% for the within-day reproducibility of migration times and peak areas, respectively at a concentration of 25 micrograms ml-1 (n = 5). Response was linear from 2-100 micrograms ml-1 for both sulindac and tiaprofenic acid, for which the LOQ values were 2.8 and 1.9 micrograms ml-1, respectively, using UV detection at 280 nm. Accuracy for each drug was 102-103%.     

Adverse interactions between warfarin and nonsteroidal antiinflammatory drugs: mechanisms, clinical significance, and avoidance

OBJECTIVE: To review the mechanisms and clinical significance of adverse interactions between warfarin and nonsteroidal anti-inflammatory drugs (NSAIDs) and discuss how these interactions can be avoided. DATA SOURCES: Previous studies of interactions between warfarin and NSAIDs or reports of adverse interactions were identified from a MEDLINE search (1976 to present) and from the reference lists of pertinent articles. STUDY SELECTION AND DATA EXTRACTION: All articles were considered for inclusion in the review. Pertinent information was selected for discussion. DATA SYNTHESIS: All NSAIDs can prolong bleeding time by inhibiting platelet function. High-dose aspirin has a direct hypoprothrombinemic effect. Phenylbutazone and its analogs enhance the hypoprothrombinemic effect of warfarin through a pharmacokinetic interaction by inhibiting the hepatic metabolism of warfarin. Mefenamic acid also enhances the anticoagulant effect of warfarin, but the mechanism is not known. The clinical relevance of protein binding displacement in the interaction between warfarin and NSAIDs has been overstated, although a significant one may be more likely in the presence of high concentrations of NSAIDs in patients with slow elimination of warfarin (e.g., those with severe heart failure or impaired liver function). NSAIDs can induce gastrointestinal bleeding, which is likely to be more severe if warfarin is also given. CONCLUSIONS: The combined use of warfarin and NSAIDs is generally discouraged because of the increased risk of bleeding in these patients. In patients receiving warfarin who also require NSAIDs, phenylbutazone and its analogs, high-dose aspirin, mefenamic acid, excessive use of topical methyl salicylate, and NSAIDs that are associated with a higher risk of bleeding peptic ulcers should be avoided. Patients should be closely monitored for anticoagulant control and bleeding complications during the combined use of warfarin and NSAIDs.     

Surgery for asymptomatic carotid stenosis: a study of three patient subgroups

Increasing evidence suggests that non-steroidal anti-inflammatory drugs (NSAID) differ in gastrotoxicity. This study aimed to compare the effects of a short-acting NSAID, tiaprofenic acid, with indomethacin on experimental gastric ulcer healing in a rat model. Similar anti-inflammatory and prostaglandin-inhibitory doses of indomethacin (1 mg/kg) and tiaprofenic acid (2 mg/kg) were administered to rats with acetic acid-induced ulcers. After 2 weeks treatment, rats were killed and ulcer size determined. In addition, histological sections of ulcers were assessed for ulcer contraction and mucosal regeneration. The degree of inhibition of prostaglandin E2 (PGE2) synthesis was 72% at 2 h after tiaprofenic acid and 64% at 2 h after indomethacin administration, respectively. Rats treated with indomethacin for 2 weeks had significantly larger ulcers, both macroscopically and microscopically, than controls. Rats treated with tiaprofenic acid for 2 weeks had ulcers of a similar size to those of controls. Indomethacin-treated ulcers showed a failure in mucosal regeneration. Tiaprofenic acid-treated ulcers had significantly more regeneration than indomethacin-treated ulcers. We conclude that tiaprofenic acid inhibits mucosal prostaglandin levels but does not inhibit experimental gastric ulcer healing. These findings suggest that inhibition of PGE2 synthesis is not the only factor in generating gastrotoxicity and that a shift to low gastrotoxic NSAID may be clinically worthwhile.     

Assisted circulation to the right ventricle through pulmonary counterpulsation using a biological method

The association between asthma exacerbations and use of antiasthmatics has been studied with a drug dispensing database. Exacerbations were identified through use of oral corticosteroids and the risk was determined for each medication. use of fenoterol and oral xanthines increases the frequency of exacerbations, but a channelling phenomenon is not excluded. This method could be used in the study of treatment combinations or new treatments, facilitating the monitoring of asthmatic populations. A second study collects ambulatory drug use data (POM and OTC drugs) of elderly patients. These data are analysed for the distribution of several variables, such as concomitant use of several medications of the same therapeutic class. As an example, about 15 per cent of NSAIDs users also use aspirin, exposing themselves to increased risk for gastrointestinal effects. These studies illustrate the use of drug dispensing databases in monitoring populations at risk and assessing treatment quality.     

Increased serum lithium concentration secondary to treatment with tiaprofenic acid and fosinopril

OBJECTIVE: To describe a patient in whom the administration of tiaprofenic acid and fosinopril was associated with decreased lithium clearance, resulting in increased serum lithium concentrations. CASE SUMMARY: A woman treated with lithium for bipolar affective disorder was concurrently treated with tiaprofenic acid 200 mg tid for shoulder pain. Previously initiated treatment with fosinopril was maintained during this time. The urinary lithium clearance was decreased during this combination therapy, necessitating a reduction in the lithium dosage. DISCUSSION: Lithium is approximately 80% reabsorbed in the proximal tubule, and the addition of tiaprofenic acid may have resulted in enhanced tubular lithium reabsorption. The possible influence of concurrent fosinopril therapy may also have contributed to altered lithium pharmacokinetics in this case. CONCLUSIONS: Serum lithium concentrations should be monitored if patients taking lithium are treated with tiaprofenic acid.     

Nonsteroidal antiinflammatory drug-photosensitized formation of pyrimidine dimer in DNA

Phototoxic nonsteroidal antiinflammatory drugs (NSAIDs) may induce DNA damage in vitro upon irradiation. In this study, we investigated the ability of ketoprofen (KP), tiaprofenic acid (Tia), naproxen (NP) and indomethacin (IND) to photosensitize the formation of pyrimidine dimers and single strand breaks. Both kinds of damage were sought by analyzing DNA-drug mixtures irradiated at 313 nm by agarose gel electrophoresis. The formation of pyrimidine dimers was evidenced by using endonuclease V from bacteriophage T4 and compared to that induced by acetophenone, a well-known photosensitizer of thymine dimerization. Upon irradiation of DNA alone, pyrimidine dimers were observed while single strand breaks were not detected under our conditions. DNA, in the presence of NSAIDs, undergoes single strand breaks, the quantum yield of the DNA cleavage so induced (phiC) varying from 5 x 10(-4) for KP to 10(-5) for IND. The formation of dimers was only increased in the presence of KP or Tia. The quantum yields of pyrimidine dimers formed by photosensitization (phiD) were 2 x 10(-4) for KP and 10(-5) for Tia, respectively. The oxygen and concentration dependence of both processes was analyzed in the case of KP. In aerated solution, KP-photoinduced cleavage of DNA was predominant on the photodimerization process of pyrimidines, whereas in deaerated solution the cleavage was decreased and the dimerization increased. These results reflect competition between a radical process leading to DNA cleavage and a poorly efficient energy transfer between the drug and the pyrimidines at the origin of the dimerization process.     

Morphologic high-risk factors in IgA nephropathy

The 2-benzoylthiophene chromophore of the photosensitizing drug tiaprofenic acid and of its decarboxylated derivative is characterized by a unusually high energy gap between the T1 (pi, pi*) and T2 (n, pi*) excited states, which makes this a unique system to study the intrinsic photoreactivity of the two states. Weak fluorescence and phosporescence emission were detected at room temperature. Tiaprofenic acid undergoes photodecarboxylation from the triplet manifold as the main reaction. The photoprocess is temperature dependent with activation energy of 7-10 kcal/mol, close to the energy gap between T1 and T2. The decarboxylated product abstracts hydrogen in type I reactions. The involvement of T2 in the above processes is proposed. Moreover the decarboxylated derivative exhibits reactivity toward phenols, consistent with a participation of the T1 state as electron acceptor. The observed photoprocesses can account for biological photosensitization reactions, like membrane damage and protein modification.     

Causal or casual? The role of causality assessment in pharmacovigilance

As with any other study method, 'spontaneous reporting' in pharmacovigilance is a process of data acquisition, assessment, presentation and interpretation. The provision of information (i.e. of interpreted data) concerning previously unknown, or otherwise important adverse drug reactions is a major goal. The assessment of case reports in spontaneous reporting takes place in 2 steps: first the assessment of each case individually, and secondly the interpretation of the aggregated data. The latter step is only completed for a minority of case reports, such as when actions or measures are deemed necessary. Uncertainty in case reports regarding the involvement of the suspected drugs is an inherent drawback of spontaneous reporting. Standardised case-causality assessment has become a routine at pharmacovigilance centres around the world. It aims at a decrease in ambiguity of the data and plays a role in data exchange and the prevention of erroneous conclusions. A variety of systems for standardised causality assessment have been developed, ranging from short questionnaires to comprehensive algorithms. Since none of the available assessment systems has been validated (i.e. shown to consistently and reproducibly produce a fair approximation of the truth), causality assessment has only limited scientific value. Causality assessment neither eliminates nor quantifies uncertainty but, at best, categorises it in a semiquantitative way. Routine causality assessment is usually part of the first step in case assessment, and is based on a general system that is intended for all reactions and all drugs. During the subsequent phase of aggregated assessment, causality assessment is likely to be repeated and the use of a specific aetiological-diagnostic system may be more appropriate. It may be recommended to restrict case-causality assessment to selected case reports that are likely to play an active role in pharmacovigilance and to use specific systems, adapted to the reaction or problem involved. It is an inherent limitation of spontaneous reporting that, with the exception of rare proof-positive case reports, conclusive evidence cannot usually be produced. Standardised causality assessment has not really changed this situation. As a rule, confirmation of the connection between a drug and an adverse reaction requires further analytical or experimental study.     

Why does monitoring fail in jargon aphasia? comprehension, judgment, and therapy evidence

Many people with jargon aphasia seem unaware of their speech disorder. The first section of this paper reports data from four subjects which indicate that self-monitoring can fail even when subjects' input skills are apparently adequate to detect their errors. Explanations for this dissociation have attributed monitoring failure to a deficit in auditory feedback, or to a resource limitation which prevents concurrent speaking and monitoring. Section 2 reports a series of naming and judging experiments with one of the subjects which rule out these explanations. These show that the subject can detect his neologisms when he is repeating, but not when he is naming. These results suggest that his monitoring difficulties arise when he is accessing phonology from semantics. Section 3 presents a study which supports this inference, since it shows that semantically focused intervention yields improvements in self-monitoring. It is concluded (1) that monitoring failure can arise from deficits within the production process which preclude comparison of actual with intended output, and (2) that this deficit is best explained within a connectionist model in which monitoring is performed by feedback mechanisms in the word production process.     

Clinical relevance of drug interactions with lithium

Although lithium continues to be regarded as the treatment of choice for bipolar disorders, the clinical use of this mood stabiliser is associated with an extremely narrow therapeutic range. Relatively minor increases in serum concentrations may induce serious adverse sequelae, and concentrations within the therapeutic range may result in toxic reactions. The safety of combining lithium with other medications, therefore, is a major concern, and extensive clinical experience has served to identify several significant drug interactions. Lithium removal from the body is achieved almost exclusively via renal means. As a result, any medication that alters glomerular filtration rates or affects electrolyte exchange in the nephron may influence the pharmacokinetic disposition of lithium. Concomitant use of diuretics has long been associated with the development of lithium toxicity, but the risk of significant interactions varies with the site of pharmacological action of the diuretic in the renal tubule. Thiazide diuretics have demonstrated the greatest potential to increase lithium concentrations, with a 25 to 40% increase in concentrations often evident after initiation of therapy. Osmotic diuretics and methyl xanthines appear to have the opposite effect on lithium clearance and have been advocated historically as antidotes for lithium toxicity. Loop diuretics and potassium-sparing agents have minor variable effects. Nonsteroidal anti-inflammatory drugs (NSAIDs) have also been associated with lithium toxicity, although the relative interactive potential of specific NSAIDs is difficult to determine. Small prospective studies have demonstrated large interindividual differences in lithium clearance values associated with different NSAIDs. A growing body of evidence also suggests that ACE inhibitors may impair lithium elimination, but further investigations are needed to identify patients at risk. Anecdotal reports have linked numerous medications with the development of neurotoxicity without an apparent effect on the pharmacokinetic disposition of lithium. Antipsychotics, anticonvulsants and calcium antagonists have all be implicated in a sufficient number of case reports to warrant concern. As these medications have all been commonly coadministered with lithium, the relative risk of serious interactions appears to be quite low, but caution is advised.     

Recombinant human monoclonal Fab fragments against rotavirus from phage display combinatorial libraries

PURPOSE: To test the hypothesis that modification of release pattern of nonsteroidal anti-inflammatory drugs (NSAIDs) formulations shifts gastrointestinal (GI) toxicity of the drugs from the upper GI region to the distal intestine. METHODS: We assessed tiaprofenic acid (TA)-induced upper and lower increased GI permeability (a surrogate marker of toxicity) after administration of 20 mg and 40 mg/kg regular release (powder) and modified release formulations [sustained release (SR) beads and diethyl-beta-cyclodextrin (DCD):TA inclusion complex (INC)]. Urinary excretion of oral doses of GI permeability probes sucrose and 51Cr-EDTA was determined as measures of gastroduodenal and distal intestine, respectively. Pharmacokinetics of TA enantiomers were also studied following administration of a single 20 mg/kg dose of racemic TA as oral SR beads and iv solution. For powder and INC, previously reported pharmacokinetic data were used. RESULTS: Regular powder significantly increased the permeability at the gastroduodenal level. Modified-release formulations, on the other hand, did not cause damage in the gastroduodenum but produced significant increase in the permeability of the lower intestine. Consequently, to assess the pharmacokinetic-pharmacodynamic relationship, a new model was developed in which contribution of toxicity resulted from direct exposure to the drug was considered. CONCLUSIONS: Since the observed site of GI damage corresponds to the site of release and absorption of NSAID from the formulation, the possibility of a shift in the site of damage must be considered for the modified release formulations. A parallel evaluation of upper and lower GI toxicity is essential for a complete assessment of NSAID-induced GI damage.     

Congenital ectopic nail with bone deformity

We have presented a case of fulminating TEN with a fatal outcome. We believe there is strong probability that the TEN was caused by a propionic acid NSAID oxaprozin. This is the first reported case of TEN related to this particular agent. Toxic epidermal necrolysis has been reported with all types of NSAIDs. It appears from this case that switching from one class of nonsteroidal anti-inflammatories to another is not always without risk. Despite the class of nonsteroidal anti-inflammatory agent used, the possibility of systemic reaction cannot be excluded.     

Elevated tryptase, nerve growth factor, neurotrophin-3 and glial cell line-derived neurotrophic factor levels in the urine of interstitial cystitis and bladder cancer patients

PURPOSE: The 2 prominent features of interstitial cystitis are pain and increased numbers of mast cells in the bladder. In this pilot study we determined the concentration of soluble mediators associated with activation of sensory neurons and/or mast cells that were present in the urine. MATERIALS AND METHODS: The study groups included 4 interstitial cystitis patients, 7 kidney donors with no history of bladder disease as negative controls, 6 bladder cancer patients and 7 patients with urinary tract infection as reference controls. Urine samples were assayed for different soluble mediators using immunoassays for tryptase (a marker for mast cell activation), neurotrophic factors (markers of neuronal plasticity) and chemokines (markers of inflammatory cell activity). Results were normalized based on creatinine concentration. RESULTS: There was a marked increase in the average amounts of tryptase and 3 neurotrophic factors in patient urine. Interestingly, the mediator profile in the urine of bladder cancer patients was indistinguishable from that of interstitial cystitis patients with respect to these same 4 proteins. There was no difference between normal control and urinary tract infection urine samples. CONCLUSIONS: These findings may account for several clinical and pathological features found in interstitial cystitis and bladder cancer. Although preliminary due to the limited numbers of patients, they also suggest that increased levels of neurotrophin-3, nerve growth factor, glial cell line-derived neurotrophic factor and tryptase in the urine could serve as a basis for adjunct diagnosis, monitoring and treatment of interstitial cystitis.     

NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics

BACKGROUND: Both diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used, in particular among the elderly. The use of NSAIDs may decrease the efficacy of diuretics and induce congestive heart failure (CHF) in patients treated with diuretics. OBJECTIVE: To investigate the risk of CHF associated with combined use of diuretics and NSAIDs in patients older than 55 years. METHODS: We conducted a study in a base cohort of 10,519 recipients of diuretics and NSAIDs identified in the PHARMO database during the period from 1986 through 1992. The incidence density of hospitalizations for CHF during exposure to both diuretics and NSAIDs (index) was compared with that during exposure to diuretics only (reference). RESULTS: We found an overall increased risk of hospitalization for CHF during periods of concomitant use of diuretics and NSAIDs compared with use of diuretics only (crude relative risk, 2.2; 95% confidence interval, 1.7-2.9). After adjusting for cofactors including age, sex, history of hospitalization, and drug use, a 2-fold increased risk remained (relative risk, 1.8; 95% confidence interval, 1.4-2.4). CONCLUSION: Use of NSAIDs in elderly patients taking diuretics is associated with a 2-fold increased risk of hospitalization for CHF, especially in those with existing serious CHF.     

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.