Changes in renal function during acute spinal cord injury: implications for pharmacotherapy.

STUDY DESIGN: Laboratory investigation in rats submitted to experimental spinal cord injury (SCI). OBJECTIVE: To characterize changes in renal function during acute SCI. METHODS: Sprague Dawley rats were subjected to severe spinal cord contusion at T8 level or to laminectomy as control. Twenty-four hours after spine surgery, clearance assessments of a single dose of iohexol (120 mg kg(-1)) or of p-aminohippuric acid (PAH, 100 mg kg(-1)) were used to evaluate glomerular filtration rate (GFR) and tubular secretion (TS), respectively. Blood sampling was used to determine concentrations of both compounds by high-performance liquid chromatography for pharmacokinetic measurements. RESULTS: Iohexol clearance decreased significantly after injury, which resulted in increased concentrations and half-life of iohexol in blood; PAH clearance remained unchanged. CONCLUSION: GFR but not TS is altered during spinal shock. These observations should be of interest to professionals caring for early cord-injured patients, in order to prevent toxicity and therapeutic failure when administering drugs eliminated by the kidney.

The epidemiologic burden of hepatitis C virus infection in Latin America .

Chronic infection with hepatitis C virus (HCV) is a major and growing public health concern worldwide, including in Latin America. With more efficacious therapies becoming available, decision-makers will require accurate estimates of disease prevalence to assess the potential impact of new treatments. However, few estimates of the epidemiologic burden, either overall or by country, are available for Latin America; and the potential impact of currently-available treatments on the epidemiologic burden of HCV in Latin America has not been assessed. To address this, we systematically reviewed twenty-five articles presenting population-based estimates of HCV prevalence from general population or blood donor samples, and supplemen- ted those with publically-available data, to estimate the total number of persons infected with HCV in Latin America at 7.8 million (2010). Of these, over 4.6 million would be expected to have genotype 1 chronic HCV, based on published data on the risk of progression to chronic disease and the HCV genotype distribution of Latin America. Finally, we calculated that between 1.6 and 2.3 million persons with genotype 1 chronic HCV would potentially benefit from current treatments, based on published estimates of genotype-specific treatment responsiveness. In conclusion, these estimates demonstrate the substantial present epidemiologic burden of HCV, and quantify the impending societal and clinical burden from untreated HCV in Latin America.

Contrasting effects of cord injury on intravenous and oral pharmacokinetics of diclofenac: a drug with intermediate hepatic extraction.

STUDY DESIGN: Laboratory investigation in rats submitted to experimental spinal cord injury (SCI). OBJECTIVE: To determine the effect of acute SCI on the pharmacokinetics of diclofenac, a marker drug of intermediate hepatic extraction, administered by the intravenous and the oral routes. METHODS: Female Wistar rats were submitted to complete section of the spinal cord at the T8 level. SCI and sham-injured rats received 3.2 mg kg(-1) of diclofenac sodium either intravenously or orally, diclofenac concentration was measured in whole blood samples and pharmacokinetic parameters were estimated. Diclofenac was not selected as test drug because of its therapeutic properties, but because to its biopharmaceutical properties, that is, intermediate hepatic extraction. RESULTS: Diclofenac bioavailability after intravenous administration was increased in injured rats compared with controls due to a reduced clearance. In contrast, oral diclofenac bioavailability was diminished in SCI animals due to a reduction in drug absorption, which overrides the effect on clearance. CONCLUSION: Acute SCI induces significant pharmacokinetic changes for diclofenac, a marker drug with intermediate hepatic extraction. SCI-induced pharmacokinetic changes are not only determined by injury characteristics, but also by the route of administration and the biopharmaceutical properties of the studied drug.

Pre-transplant mycophenolate mofetil pharmacokinetics in Mexican children.

Mycophenolate mofetil is an immunosuppressive pro-drug frequently used to prevent renal graft rejection. It is hydrolyzed by esterases to obtain the active drug mycophenolic acid (MPA). There is high inter-patient variation in mycophenolic acid pharmacokinetics. Area under the concentration versus time curve (AUC) is used for therapeutic drug monitoring and recommended levels are 30-60 microg x hr/L. The aim of this study was to determine mycophenolic acid pharmacokinetics in children awaiting renal allograft in order to predict mycophenolate mofetil dose requirements. Children with end-stage renal disease on the waiting list for renal allograft transplantation were invited to participate in the study. A nine-point pharmacokinetic profile was performed. All patients received a single dose (600 mg/m2, subcutaneously) of mycophenolate mofetil at time zero. Mycophenolic acid was measured by HPLC. The AUC0-12h was estimated by the trapezoidal rule. Ten children were included in the study. Mean age was 13.5 +/- 3.5 years. The median AUC0-12h was 20.3 microg x hr/L, median Cmax = 0.7 microg/mL. Two children (20%) had no detectable levels of mycophenolic acid after a single mycophenolate mofetil dose, other two patients had AUC > 60 microg x hr/L. One patient had abdominal pain 1 hr after the mycophenolate mofetil dose. Twenty percent of our patients had AUC0-12h higher than the recommended value after a single mycophenolate mofetil dose, those patients should receive lower mycophenolate mofetil dose since the beginning of the transplant to avoid adverse events, and another 20% of patients had no detectable mycophenolic acid levels after a single mycophenolate mofetil dose. UGT1A9 gene polymorphisms remain to be studied in our patients, since they could explain the differences in bioavailability.

Efficacy and safety of conversion of mycophenolate mofetil to enteric-coated mycophenolate sodium in Mexican renal transplant children.

The aim of the study was to evaluate the efficacy and safety of the conversion of MMF to EC-MPS in pediatric renal transplant recipients. We included 12 patients with stable graft function who were receiving MMF treatment. In the first visit, a complete medical examination was performed, which included a GSRS, a nine-point pharmacokinetic profile, samples for renal, liver and hematological tests and evaluation of IMPDH2 gene expression. The patients were transferred to an equimolar dose of EC-MPS. Two wk later, a clinical evaluation and blood collection, as in the first visit were performed. There was no change in serum creatinine, leukocyte count, serum albumin, or transaminase levels, but we found a statistically significant reduction of hemoglobin after conversion (13.2 +/- 1.6 g/dL with MMF vs. 12.5 +/- 1.3 g/dL when receiving EC-MPS). The GSRS total mean score was 16 +/- 12 with MMF vs. 8 +/- 5 with EC-MPA (p < 0.05). There was no statistically significant difference between formulations in the gene expression of IMPDH 2, in the AUC(0-12h) or in C(max). However, peak concentration occurred later with EC-MPS.

Acemetacin antinociceptive mechanism is not related to NO or K+ channel pathways.

Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) used for the treatment of acute gout and inflammation. However, its use is limited due to side effects. Acemetacin is a prodrug of indomethacin that exhibits better gastric tolerability in preclinical and clinical trials. The aim of this study was to examine if the systemic administration of acemetacin involved the sequential participation of nitric oxide (NO) or K+ channel pathways to confer its antinociceptive effect, as compared to indomethacin. The antinociceptive effect of both drugs was studied with the formalin test. Equimolar doses of acemetacin or indomethacin were administered orally. The intraplantar administration of either L-NAME, glibenclamide, apamin or charybdotoxin plus indomethacin or acemetacin was studied using the formalin test and the anti-inflammatory and antihyperalgesic effects were measured. The antinociceptive effect of acemetacin or indomethacin was not significantly different when pretreatment with L-NAME, glibenclamide, apamin or charybdotoxin was done. The antihyperalgesic and antiinflammatory effects were also similar for both indomethacin and acemetacin. Our results suggest that the antinociceptive effect of indomethacin or acemetacin is not mediated by NO or K+ channel activation.

Comparison of dissolution properties of 2 enteric-coated formulations containing mycophenolate sodium: Myfortic vs Femulan.

Enteric-coated tablets containing mycophenolate sodium have been developed to reduce gastric toxicity. The objective of this study was to compare 2 enteric-coated formulations containing 360 mg of mycophenolate sodium: the innovator product, Myfortic, and an agent that recently became available in Mexico, Femulan. For both formulations, mycophenolate sodium content was within the 90% to 110% range of the label claimed dose, and no impurities were present as determined at high-performance liquid chromatography. Mycophenolate sodium release was assayed by applying the US Pharmacopeia apparatus 2 dissolution test at 2 different pH values (1.2 and 6.8) to mimic conditions in the stomach and the small intestine, respectively. At pH 1.2, mycophenolate sodium release was less than 2%, with respect to the label claimed dose, for both formulations. At pH 6.8, mean (range) mycophenolate sodium release with Myfortic was 104.9% (104.0%-105.6%), and with femulan was 62.3% (51.3%-67.7%); the difference between formulations achieved statistical significance (P = .04). Moreover, intratablet variability with the generic formulation was unacceptable. Variation between the highest and lowest drug release was 32.0% for Femulan, and 1.02% for Myfortic. Thus, it is likely that Femulan results in insufficient and irreproducible absorption of mycophenolate sodium in the small intestine, leading to inadequate immunosuppressive efficacy. It is concluded that Femulan and myfortic are not equivalent formulations. Furthermore, Femulan is not a suitable formulation for clinical use in organ transplantation because it does not meet pharmaceutical quality standards.

Pharmacokinetic-pharmacodynamic modelling of the analgesic effects of lumiracoxib, a selective inhibitor of cyclooxygenase-2, in rats.

BACKGROUND AND PURPOSE: This study establishes a pharmacokinetic/pharmacodynamic (PK/PD) model to describe the time course and in vivo mechanisms of action of the antinociceptive effects of lumiracoxib, evaluated by the thermal hyperalgesia test in rats. EXPERIMENTAL APPROACH: Female Wistar fasted rats were injected s.c. with saline or carrageenan in the right hind paw, followed by either 0, 1, 3, 10 or 30 mg*kg(-1) of oral lumiracoxib at the time of carrageenan injection (experiment I), or 0, 10 or 30 mg*kg(-1) oral lumiracoxib at 4 h after carrageenan injection (experiment II). Antihyperalgesic responses were measured as latency time (LT) to a thermal stimulus. PK/PD modelling of the antinociceptive response was performed using the population approach with NONMEM VI. RESULTS: A two-compartment model described the plasma disposition. A first-order model, including lag time and decreased relative bioavailability as a function of the dose, described the absorption process. The response model was: LT=LT(0)/(1 +MED). LT(0) is the baseline response, and MED represents the level of inflammatory mediators. The time course of MED was assumed to be equivalent to the predicted profile of COX-2 activity and was modelled according to an indirect response model with a time variant synthesis rate. Drug effects were described as a reversible inhibition of the COX-2 activity. The in vivo estimate of the dissociation equilibrium constant of the COX-2-lumiracoxib complex was 0.24 microg*mL(-1). CONCLUSIONS: The model developed appropriately described the time course of pharmacological responses to lumiracoxib, in terms of its mechanism of action and pharmacokinetics.

Interaction between Heliopsis longipes extract and diclofenac on the thermal hyperalgesia test.

Heliopsis longipes is an herbaceous plant found in Mexico, used traditionally for its analgesic and anesthetic activities. Plant extracts in combined use with synthetic drugs may represent a therapeutic advantage for the clinical treatment of pain, allowing the use of lower doses, and limiting side-effects. Therefore, the main objective of this study was to determine the possible pharmacological interaction between Heliopsis longipes ethanolic extract (HLEE) and diclofenac in the Hargreaves model of thermal hyperalgesia in the mouse. HLEE, diclofenac or fixed-dose ratio HLEE-diclofenac combinations were administered systemically to mice and the antihyperalgesic effect was evaluated using the thermal hyperalgesia test. All treatments produced a dose-dependent antihyperalgesic effect. ED(30) values were estimated for all the treatments and an isobologram was constructed. The derived theoretical ED(30) value for the HLEE-diclofenac combination was 54.4+/-9.4 mg/kg body wt, significantly higher than the actually observed experimental ED(30) value, 8.6+/-4.0 mg/kg body wt. This result corresponds to synergistic interaction between HLEE and diclofenac in the Hargreaves model of thermal hyperalgesia. Data suggest that low doses of the HLEE-diclofenac combination can interact synergistically at the systemic level and that this association may therefore represent a therapeutic advantage for the clinical treatment of inflammatory pain.

Comparison of the efficacy and safety of a novel meloxicam ophthalmic formulation with a reference diclofenac solution in cataract surgery.

A novel topical ophthalmic formulation of the preferential COX-2 inhibitor meloxicam has recently been developed. The purpose of the present study was to evaluate the efficacy and safety of this novel 0.03% meloxicam solution with regard to a reference 0.1% diclofenac formulation in a prospective, parallel, randomized, multicenter, double-blind study. Two groups of patients submitted to phacoemulsification with intraocular lens implantation were formed. Patients in one group were treated with meloxicam and those in the other group with diclofenac. Dosing was 1 drop t.i.d. for 30 days, beginning the first day after surgery, for both treatments. Inflammation was assessed by the presence of cells in the anterior chamber, anterior chamber flare, ciliary flush, photophobia and pain. Both treatments significantly reduced these indicators. Topical meloxicam and diclofenac produced a similar degree of burning sensation and conjunctival hyperemia. There was no significant difference between treatments in any of the measured parameters. It is concluded that the novel meloxicam solution is effective and safe. Meloxicam, however, did not offer any significant benefit over the diclofenac formulation in patients submitted to cataract surgery.

Lack of effects of acemetacin on signalling pathways for leukocyte adherence may explain its gastrointestinal safety.

BACKGROUND AND PURPOSE: Acemetacin is a non-steroidal anti-inflammatory drug which is rapidly bioconverted to indomethacin, but produces significantly less gastric damage than indomethacin. This study was performed to investigate several possible mechanisms that could account for the gastrointestinal tolerability of acemetacin. EXPERIMENTAL APPROACH: The gastric and intestinal damaging effects of acemetacin and indomethacin were examined in the rat. Effects of the drugs on blood levels of leukotriene B(4) and thromboxane B(2), on leukocyte-endothelial adherence in post-capillary mesenteric venules, and on gastric expression of tumour necrosis factor-alpha (TNF-alpha) were determined. The two drugs were also compared for gastric toxicity in rats pretreated with inhibitors of COX-2 and NOS. KEY RESULTS: Acemetacin induced significantly less gastric and intestinal damage than indomethacin, despite markedly suppressing COX activity. Indomethacin, but not acemetacin, significantly increased leukocyte adherence within mesenteric venules, and gastric expression of TNF-alpha. Pretreatment with L-nitro-arginine methyl ester or lumiracoxib increased the severity of indomethacin-induced gastric damage, but this was not the case with acemetacin. CONCLUSIONS AND IMPLICATIONS: The increased gastric and intestinal tolerability of acemetacin may be related to the lack of induction of leukocyte-endothelial adherence. This may be attributable to the reduced ability of acemetacin to elevate leukotriene-B(4) synthesis and TNF-alpha expression, compared to indomethacin, despite the fact that acemetacin is rapidly bioconverted to indomethacin after its absorption.

Evaluation of the quality of four Mexican drug products containing sodium naproxen.

BACKGROUND: There is currently a lot of concern about the quality and therapeutic effectiveness of Mexican pharmaceutical products, and considerable price differences between alternative products containing the same active principle. OBJECTIVE: To establish whether four Mexican drug products, a high price and three lower-cost branded drug products containing sodium naproxen (550 mg immediate release tablets) have equivalent, and consistent pharmaceutical qualities. METHODS: The four products were acquired in Mexico city. Assay for sodium naproxen, content uniformity, disintegration time and dissolution tests were performed according to USP procedures. Drug dissolution profiles were compared using a similarity factor (f(2)). RESULTS AND DISCUSSION: All of the tested products met pharmacopeial quality standards with respect to their active pharmaceutical content and a released drug percentage >70% in 45 min. Lot-to-lot lack of similarity between drug dissolution profiles was observed for two of the products tested. CONCLUSION: There was no significant differences in the quality of the pharmaceutical products tested when judged by the USP pharmaceutical quality standards. However, some differences were observed in the dissolution profiles of the brands tested. Whether these differences are clinically meaningful requires in vivo bioequivalence studies.

Mechanisms underlying the anti-inflammatory activity and gastric safety of acemetacin.

BACKGROUND AND PURPOSE: Acemetacin is regarded as a pro-drug of indomethacin and induces significantly less gastric damage but the reasons for this greater gastric safety of acemetacin are unclear. The anti-inflammatory effects of acemetacin have been attributed, at least in part, to its hepatic biotransformation to indomethacin. The aim of this study was to determine the effects of acemetacin and indomethacin in an in vivo model of acute inflammation and to examine the importance of biotransformation of acemetacin (to indomethacin) to its anti-inflammatory actions. EXPERIMENTAL APPROACH: The zymosan airpouch model was used in rats. Indomethacin or acemetacin (2.7-83.8 micromol kg(-1)) were administered orally or directly into the pouch. Leukocyte infiltration, prostaglandin (PG) E(2) and leukotriene (LT) B(4) levels in exudates, and whole blood thromboxane (TX) B(2) synthesis were measured. KEY RESULTS: Acemetacin was rapidly converted to indomethacin after its administration. Both acemetacin and indomethacin elicited comparable, dose-dependent reductions of leukocyte infiltration and of PGE(2) and TXB(2) synthesis. However, indomethacin induced more gastric damage than acemetacin and elevated LTB(4) production in the airpouch. CONCLUSIONS AND IMPLICATIONS: The similar effects of acemetacin and indomethacin on leukocyte infiltration and PG synthesis are consistent with rapid biotransformation of acemetacin to indomethacin. Some of this biotransformation may occur extra-hepatically, for instance in inflammatory exudates. Acemetacin probably exerts actions independent of conversion to indomethacin, given the different effects of these two drugs on LTB(4) production. Such differences may contribute to the relative gastric safety of acemetacin compared to indomethacin.

Acute spinal cord injury changes the disposition of some, but not all drugs given intravenously.

STUDY DESIGN: Experimental laboratory investigations in paraplegic rats. OBJECTIVE: In order to understand why acute spinal cord injury (SCI) changes the disposition of some, but not all drugs given intravenously (i.v.), pharmacokinetic parameters of drugs with different pharmacological properties were evaluated to determine the influence of SCI on physiological processes such as distribution, metabolism and excretion. SETTING: Mexico City, Mexico. METHODS: Rats were subjected to severe SCI (contusion) at T-9 level; pharmacokinetic studies of phenacetin, naproxen or gentamicin were performed 24 h after. These drugs were not chosen as markers because of their therapeutic properties, but because of their pharmacokinetic characteristics. Additional studies including plasma proteins, liver and renal function tests, and micro-vascular hepatic blood flow, were also performed at the same time after injury. RESULTS: Acute SCI significantly reduced distribution of drugs with intermediate and low binding to plasma proteins (phenacetin 30% and gentamicin 10%, respectively), but distribution did not change when naproxen - a drug highly bound to plasma proteins (99%) - was used, in absence of changes in plasma proteins. Metabolism was significantly altered only for a drug with liver blood flow - limited clearance (phenacetin) and not for a drug with liver capacity-limited clearance (naproxen). The liver function test did not change, whereas the hepatic micro-vascular blood flow significantly decreased after SCI. Renal excretion, evaluated by gentamicin clearance, was significantly reduced as a consequence of SCI, without significant changes in serum creatinine. CONCLUSIONS: Changes in drug disposition associated to acute SCI are complex and generalization is not possible. They are highly dependent on each drug properties as well as on the altered physiological processes. Results motivate the quest for strategies to improve disposition of selective i.v. drugs during spinal shock, in an effort to avoid therapeutic failure.

The systemic absorption of etoposide after intravaginal administration in patients with cervical intraepithelial lesions associated with human papillomavirus infection.

PURPOSE: The purpose of this study was to determine the systemic absorption and the release of etoposide in cervical tissue administered via a vaginal ovule to women diagnosed with cervical intraepithelial lesions associated with human papillomavirus (HPV). METHODS: Fifteen women with low- and high-grade intraepithelial neoplasia confirmed by colposcopic test received a 50-mg intravaginal etoposide dose three times a week for 3 weeks. At the end of the study period, paralleled with the last ovule administered, blood samples were collected over a period of 24 h, and in situ cervical samples were obtained at 3 and 10 h after drug administration. Etoposide concentrations were determined in plasma and in in situ cervical samples using the high-performance liquid chromatography method with electrochemical detection. RESULTS: Pharmacokinetic analyses of plasma data indicated low or lack of systemic exposure of etoposide after the vaginal administration. Nevertheless, high concentrations of etoposide were found in all in situ cervical samples, indicating that etoposide could be released from its pharmaceutical formulation. CONCLUSIONS: The results of the study suggest that the etoposide administered as intravaginal ovule is safe and tolerable and apparently could be a suitable option in patients with cervical intraepithelial neoplasia. Clinical results and the true impact on HPV infection and evolution of dysplasia need to be confirmed.

In vitro antigiardial activity of IRE-6A and IRE-7B, two ethyl-phenylcarbamate derivatives.

Resistance is a practical problem associated to the use of benzimidazoles in the antigiardial therapy. Since benzimidazole-resistant strains of fungi have shown increased sensitivity to phenylcarbamates, in this study we synthesized and in vitro tested novel substituted phenylcarbamates against the protozoa Giardia intestinalis. IRE-6A and IRE-7B, two 4-R-ethyl-phenylcarbamates demonstrated an important antigiardial activity although that was modest when compared to albendazole in axenic cultures of Giardia intestinalis. Results of this study suggest a potential role of phenylcarbamates as alternative to benzimidazoles in the therapy of giardiasis.

Mechanisms involved in the cardiovascular alterations immediately after spinal cord injury.

The early cardiovascular effects resulting from an acute spinal cord injury (SCI) produced by a contusion procedure at T5-T6 were evaluated in anaesthetized rats. The mean arterial pressure (MAP) and heart rate (HR) were measured during one hour after the injury. A marked decrease in MAP and HR was observed immediately after injury, followed by an abrupt increase in MAP. These changes were observed between 3 and 9 min and the basal values were recovered after 20 min. Fall in the MAP and HR and increase in MAP induced by SCI were abolished by atropine. The interruption of the parasympathetic outflow by vagotomy also significantly diminished the fall and increase in MAP and the fall in HR. Likewise, pre-treatment with nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) completely abolished the effects produced by SCI. These data suggest that after SCI the decrement in MAP and HR was probably due to acetylcholine release from parasympathetic fibers and NO from endothelial source probably by a cholinergic stimulation. Additionally, the MAP increase observed was probably due to a reflex compensatory vasoconstriction.

Pharmacokinetic/pharmacodynamic modeling of antipyretic and anti-inflammatory effects of naproxen in the rat.

Pharmacokinetic/pharmacodynamic modeling was used to characterize the antipyretic and anti-inflammatory effects of naproxen in rats. An indirect response model was used to describe the antipyretic effects of naproxen after short intravenous infusions. The model assumes that basal temperature (T(a)) is maintained by the balance of fever mediators given by a constant (zero order) rate of synthesis (K(syn)), and a first order rate of degradation (K(out)). After an intraperitoneal injection of lipopolysaccharide, the change in T(a) was modeled assuming an increase in fever mediators described as an input rate function [IR(t)] estimated nonparametrically. An inhibitory E(max) model adequately described the inhibition of IR(t) by naproxen. A more complex model was used to describe the anti-inflammatory response of oral naproxen in the carrageenin-induced edema model. Before carrageenin injection, physiological conditions are maintained by a balance of inflammation mediators given by K(syn) and K(out) (see above). After carrageenin injection, the additional synthesis of mediators is described by IR(t) (see above). Such mediators induced an inflammatory process, which is governed by a first order rate constant (K(IN)) that can be inhibited by the presence of naproxen in plasma. The sigmoidal E(max) model also well described the inhibition of K(IN) by naproxen. Estimates for IC(50) [concentration of naproxen in plasma eliciting half of maximum inhibition of IR(t) or K(IN)] were 4.24 and 4.13 microg/ml, for the antipyretic and anti-inflammatory effects, respectively.