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Acute exacerbation of chronic bronchitis is a consequence of augmentation in air pathways secretions, often complicated by bacterial infections. Then, a clinical benefit can be anticipated with the join therapy of antimicrobial and mucolytic agents. In this study we aimed to compare the bioavailability and safety of an oral formulation containing ambroxol (AMBX), trimethoprim (TMP) and sulfamethoxazole (SMZ) in 24 healthy volunteers. Subjects were randomized to receive a tablet of (A) AMBX-TMP-SMZ (160, 800mg and 30mg); (B) TMP-SMZ (160mg and 800mg) and (C) AMBX (30mg), in a crossover way with 3 sequences in 3 periods (ABC, BCA, CAB) and 7 days of washout between each period. No significant changes were observed in the absorption indicators Cmax, Tmax, AUC0-t and AUC0-∞, and the elimination parameter T1/2 of SMZ, TMP or AMBX. Also Westlake 90% Confidence Intervals calculated for Cmax and AUC's were included in the bioequivalence range of 0.80-1.25 suggesting that the bioavailability of all agents in the new combined formulation is not different to that obtained following the individual administration of each. Volunteers claimed minimal side effects following all treatments. These results show the pharmacokinetic properties of a formulation containing TMP SMZ-AMBX that could contribute to improve the therapeutic adherence. [ABSTRACT FROM AUTHOR]

Several limited sampling equations were tested to predict the area under the curve (AUC) of cyclosporin A (CsA) at steady state in 10 children with end‐stage renal disease receiving oral CsA 2.5 mg/kg b.i.d. as two different formulations, namely Sandimmune® and Neoral®, according to a randomized crossover design with a one‐month washout period. AUC was significantly correlated with CsA concentration at 5 h. The equation derived from this single concentration–time point was able to adequately predict the AUC for Sandimmune but not for Neoral. The equation derived from CsA concentration data, measured at 2 and 12 h, significantly improved predictive performance in terms of bias and precision, allowing adequate AUC predictions in both formulations. CsA concentration at 2 h was also able to predict Cmax, while the concentration at 12 h corresponded to the trough value in a b.i.d. dosing scheme. Therefore, it is concluded that a limited sampling model including concentration data at 2 and 12 h allows the estimation of AUC, Cmax and trough levels, yielding a complete profile in patients exposed to CsA as Sandimmune or Neoral. Hence, this model can be used for therapeutic monitoring of CsA levels in pediatric patients being switched from one formulation to another. [ABSTRACT FROM AUTHOR]

There is currently little information available on the pharmacokinetics and pharmacodynamics of the analgesic opioid tramadol when used in the veterinary medicine of domestic species. In this study, we aimed to determine the pharmacokinetics of tramadol and its active metabolite M1 following intravenous administration of 2 (T2) and 4 (T4) mg/kg to Northeast Brazilian donkeys. Tramadol and M1 plasma levels were quantified using a validated liquid chromatography-tandem mass spectrometry method. We found that plasma levels of tramadol and M1 were higher than those reported as clinically meaningful in humans for at least 3 hr. However, the pharmacokinetic parameter calculation corrected by dose analysis identified no proportional increase with dose for the AUC of tramadol (T2: 2,663 ± 1,827 vs. T4: 2,964 ± 1,038 ng*h/ml) and M1 (T2: 378 ± 237 vs. T4: 345 ± 142 ng*h/ml). This finding appears to be attributable to a significant increase in clearance and a reduction in the terminal half-life of tramadol. The frequency of adverse effects observed at the higher dose indicates that 2 mg/kg administered intravenously would be suitable for donkeys. Clinical studies are required to determine the implications of these observations regarding the pharmacodynamic response to tramadol in Northeast Brazilian donkeys., (© 2020 John Wiley & Sons Ltd.)

Background: There is evidence that the pharmacokinetics of certain drugs in Mexicans may differ with respect to other ethnic groups. On the other hand, there is controversy about the existence of interethnic variability in the pharmacokinetics of ciprofloxacin., Aim of the Study: To study oral ciprofloxacin pharmacokinetics in Mexicans at various dose levels and make comparisons with other populations in order to gain insight on interethnic variability., Methods: Healthy Mexican volunteers received oral ciprofloxacin as 250 mg and 500 mg immediate-release tablets or a 1,000 mg extended-release formulation. Plasma concentration against time curves were constructed, and pharmacokinetic parameters were compared with those reported for other populations., Results: Ciprofloxacin pharmacokinetics in Mexicans was linear and no significant differences between males and females were detected. When several populations were compared, it appeared that bioavailability in Mexicans was similar to that of Caucasians, being lower than that of Asians. These variations were attenuated when data were normalized by body weight., Conclusions: Ciprofloxacin pharmacokinetics exhibit interethnic variability, Asians exhibiting an increased bioavailability with regard to Mexicans and Caucasians. Data suggest that these differences are due to body weight., (Copyright © 2020 IMSS. Published by Elsevier Inc. All rights reserved.)

Preclinical Research The aim of the present study was to evaluate the antinociceptive and sedative activity of an ethanol extract of Justicia spicigera an evergreen used in Mexican traditional medicine for the relief of pain, wounds, fever and inflammation. At 200 mg/kg po, the maximum dose examined, the ethanol extract of J. spicigera (JSE) had analgesic activity in mice in the acetic acid writhing test, the second phase of the formalin test and the tail flick test that was similar in efficacy to the NSAID, naproxen (150 mg/kg po). JSE was inactive in the hot plate test and and the ketamine-induced sleeping time test; it had no sedative effects. These results show that the ethanol extract from the leaves of J. spicigera has antinociceptive effects in mice without inducing sedation. Drug Dev Res 77 : 180-186, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Aim: To determinate the significance of risk factors with the presence of biofilm on catheters of patients attended at tertiary hospital cares., Material and Methods: A total of 126 patients were included, data collection by observing the handling of the CVC, clinical history and microbiological isolation methods of CVCs tips (Roll-plate, sonication and scanning electron microscopy) were evaluated., Results: Certain factors, such as the lack of proper hand washing, the use of primary barriers and preparing medications in the same hospital service, showed an important relationship between biofilm formation in CVCs. The sonication method presented that most of the samples had isolation of multispecies 29 samples (64%); in contrast with the roll-plate method, just one sample (3%) was isolated., Conclusions: The importance of the strict aseptic techniques of insertion and of the handlings of CVC was highlighted, the failure of both techniques was related to the biofilm formation and was evidenced using the scanning electron microscopy. Since this tool is not available in most hospitals, we present the correlation of those evidences with other standard microbiological methods and risk factors, which are necessary for the sensible detection of the different steps of the biofilm formation on CVC and their correct interpretation with clinical evidences., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A high-throughput ultra-performance liquid chromatography coupled to tandem mass spectrometry (LC-ESI-MS-MS) method was developed for the determination of pinaverium bromide in human plasma. Protein precipitation with acetonitrile was used to extract pinaverium and itraconazole (as internal standard) from 500 µL plasma samples. The chromatographic separation was achieved with an Acquity UPLC BEH C18 column (1.7 µm, 2.1 × 100 mm) using a mixture of acetonitrile-5 mM ammonium formate (80:20, v/v) as mobile phase. Isocratic elution at 0.3 mL/min was used. Detection was performed by positive ion electrospray tandem mass spectrometry on a XEVO TQ-S by multiple reaction monitoring mode. The mass transitions monitorized were as follows: m/z 511.2 → 230 for pinaverium bromide, and m/z 705.29 → 392.18 for the itraconazole. The method was validated over a concentration range of 12-12,000 pg/mL. The chromatographic method runtime is 2.5 min and was applied to characterize the pharmacokinetics of pinaverium bromide after the oral administration of 100 mg to healthy Mexican subjects., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Cyclooxygenase-2 selective inhibitors have been developed to alleviate pain and inflammation; however, the use of a selective cyclooxygenase-2 inhibitor is associated with mild edema, hypertension, and cardiovascular risk., Aim: To evaluate, in an experimental model in normotensive rats, the effect of treatment with parecoxib in comparison with diclofenac and aspirin and L-NAME, a non-selective nitric oxide synthetase, on mean arterial blood pressure, and cyclooxygenase-1 and -2 messenger RNA and protein expression in aortic tissue., Methods: Rats were treated for seven days with parecoxib (10 mg/kg/day), diclofenac (3.2 mg/kg/day), aspirin (10 mg/kg/day), or L-NAME (10 mg/kg/day). Mean arterial blood pressure was evaluated in rat tail; cyclooxygenase-1 and -2 were evaluated by reverse transcription-polymerase chain reaction and Western blot analysis in aortic tissue., Results: Parecoxib and L-NAME, but not aspirin and diclofenac, increased mean arterial blood pressure by about 50% (p < 0.05) without changes in cardiac frequency. Messenger RNA cyclooxygenase-1 expression in aortic tissue was not modified with any drug (p < 0.05). L-NAME and parecoxib treatment decreased messenger RNA cyclooxygenase-2 and cyclooxygenase-2 (p < 0.05). While cyclooxygenase-1 protein decreased with the three drugs tested but not with L-NAME (p < 0.05), the cyclooxygenase-2 protein decreased only with aspirin and parecoxib (p < 0.05)., Conclusion: Parecoxib increases the blood pressure of normotensive rats by the suppression of COX-2 gene expression, which apparently induced cardiovascular control.

Several clinical trials have substantiated the efficacy of the co-administration of statins like atorvastatin (ATO) and fibrates. Without information currently available about the interaction between the two drugs, a pharmacokinetic study was conducted to investigate the effect when both drugs were co-administered. The purpose of this study was to investigate the pharmacokinetic profile of tablets containing ATO 20 mg, or the combination of ATO 20 mg with fenofibrate (FNO) 160 mg administered to healthy Mexican volunteers. This was a randomized, two-period, two-sequence, crossover study; 36 eligible subjects aged between 20-50 years were included. Blood samples were collected up to 96 h after dosing, and pharmacokinetic parameters were obtained by non-compartmental analysis. Adverse events were evaluated based on subject interviews and physical examinations. Area under the concentration-time curve (AUC) and maximum plasma drug concentration (Cmax) were measured for ATO as the reference and ATO and FNO as the test product for bioequivalence design. The estimation computed (90% confidence intervals) for ATO and FNO combination versus ATO for Cmax, AUC0-t and AUC0-∞, were 102,09, 125,95, and 120,97%, respectively. These results suggest that ATO and FNO have no relevant clinical-pharmacokinetic drug interaction.

Recent clinical research has shown that atorvastatin (ATO) in combination with cholesterol absorption inhibitor ezetimibe (EZE) significantly reduces LDL-C level in patients with hypercholesterolemia, showing a superior lipid-lowering efficacy compared to statin alone. With no information currently available on the interaction between the two drugs, a pharmacokinetic study was conducted to investigate the influence of EZE on ATO and conversely when the two drugs were coadministered. The purpose of this study was to investigate the presence of differences in the pharmacokinetic profiles of capsules containing ATO 80 mg, EZE 10 mg or the combination of both 80/10 mg administered to healthy Mexican volunteers. This was a randomized, three-period, six-sequences crossover study. 36 eligible subjects aged between 20 to 50 years were included. Blood samples were collected up to 96 h after dosing, and pharmacokinetic parameters were obtained by non-compartmental analysis. Adverse events were evaluated based on subject interviews and physical examinations. Area under the concentration-time curve (AUC) and maximum plasma drug concentration (Cmax) were measured for each drug alone or together and tested for bioequivalence-based hypothesis. The estimation computed (90% confidence intervals) for AUC and Cmax, were 96.04% (85.88-107.42%) and 97.04% (82.36-114.35%), respectively for ATO-EZE combination versus ATO alone, while 84.42% (77.19-92.32%) and 95.60% (82.43-110.88%), respectively, for ATO-EZE combination versus EZE alone were estimated. These results suggest that ATO and EZE have no relevant pharmacokinetic drug-drug interaction.

Systemic coadministration of tramadol and dexketoprofen can produce antinociceptive synergism in animals. There has been only limited evaluation of this drug combination in the peripheral nervous system in terms of the antinociceptive interaction and its mechanisms. The aim of the present study was to evaluate the peripheral antinociceptive interaction between tramadol and dexketoprofen in the formalin test and the involvement of the nitric oxide (NO)-cyclic guanosine monophosphate pathway and ATP-sensitive K(+) channels. Different doses of tramadol or dexketoprofen were administered locally to the formalin-injured mouse paw and the antinociceptive effect evaluated. ED50 values were calculated for both drugs alone and in combination. Coadministration of tramadol and dexketoprofen produced an antinociceptive synergistic interaction during the second phase of the formalin test. Pretreatment with NO antagonists, including l-NG-nitroarginine methyl ester and 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one, or the ATP-sensitive K(+) channel antagonist glibenclamide reversed the antinociceptive synergistic effect of the tramadol-dexketoprofen combination, suggesting that NO and ATP-sensitive K(+) channels were involved., (© 2014 Wiley Periodicals, Inc.)

A new system for sustained release of growth factors, such as osteogenic protein 1 (OP-1) and transforming growth factor β1 (TGF-β1), intended to repair and promote dental tissue regeneration in rats was designed and characterized in this work. The release system was made with microparticles of sodium alginate, produced by ionic gelling dripping technique. The release profiles of OP-1 and TGF-β1 from biopolymer matrix were determined by high-performance liquid chromatography (HPLC), and with this purpose, an HPLC-UV method was developed. About 80% of each growth factor was released in the first 24 h, reaching almost 100% in 168 h. The system was tested during the tissue repair in rat molars in comparison with calcium hydroxide and both growth factors not encapsulated. The dentin sialoprotein (DSP) was used as a repair marker. It was detected by immunohistochemistry, after 14- and 28-d post-treatment. X (2) test (p ≤ 0.001) and Fisher exact test (p ≤ 0.05) were applied for assessment of the amount of immunostaining. The treatment with encapsulated OP-1 showed an increased DSP immunostaining after 14 d and did not find any significant difference with the immunostaining observed for calcium hydroxide treatment. Treatment with TGF-β1 did not show significant difference with calcium hydroxide. Treatment with both factors OP-1 and TGF-β1 showed higher DSP immunostaining in comparison with calcium hydroxide treatment. In conclusion, the combination of both growth factors encapsulated showed more DSP immunostaining in comparison with each one separated, either encapsulated or not.

Objective: The aim of this study was to compare preemptive analgesia of oral ketorolac plus submucous local placebo with oral ketorolac plus submucous local tramadol after impacted mandibular third molar surgery., Study Design: A double-blind, randomized, placebo-controlled clinical trial was conducted. Patients were randomized into two treatment groups (n = 15 per group): group A, oral ketorolac 10 mg, 30 minutes before surgery plus submucous local placebo (1 mL saline solution); group B, oral ketorolac 10 mg, 30 minutes before surgery plus submucous local tramadol (50 mg diluted in 1 mL saline solution). We evaluated the intensity of pain, time for the first analgesic rescue medication, and total analgesic consumption., Results: Pain intensity, number of patients requiring analgesic rescue medication, number of patients in each group not requiring analgesic rescue medication, and total analgesic consumption showed statistical significance., Conclusions: Preemptive use of oral ketorolac plus submucous local tramadol is an alternative treatment for acute pain after surgical removal of an impacted mandibular third molar.

Components of whole blood and plasma are highly altered during the presentation of nephrotic syndrome. The present study was aimed to explore the influence of nephrotic syndrome on the pharmacokinetics of cyclosporine (CsA) (10 mg/kg) administered i.v. to control or puromycin-induced nephrotic rats (P-NS). We found an increase in CsA bioavailability in the nephrotic group compared with controls. The area under the curve of blood CsA versus time (AUCiv) increased from 27.7 +/- 5.3 to 60.6 +/- 13.8 mug.h.mL-1 in control and P-NS rats, respectively. The AUCiv augmentation was positively correlated with cholesterol levels. On the other hand, the total body clearance was significantly lower (0.38 +/- 0.06 vs. 0.17 +/- 0.03 L.(kg body mass)-1.h-1) and the volume of distribution at steady state (3.70 +/- 0.52 vs. 2.85 +/- 0.32 L/kg) was significantly smaller in nephrotic rats as compared with control. These pharmacokinetic changes lead to a longer terminal half-life of CsA in P-NS rats (11.8 +/- 1.6 vs. 6.9 +/- 0.91 h). We conclude that the physiopathologic changes induced by the nephrotic syndrome in P-NS animals result in a significant increase in CsA blood exposure by both the decrease in drug distribution and the reduction in elimination rate of CsA.

In this paper, we report the pharmacokinetics changes observed in seven children with steroid-resistant nephrotic syndrome (SRNS). They received cyclosporine A (CsA) microemulsion 6 mg/kg/day and, one week later, they were admitted to perform a 12-h pharmacokinetic profile with eight time sample points. The pharmacokinetic profile was repeated at 24 weeks of treatment, when all patients achieved remission. Blood concentration against time curves were constructed for each patient at weeks 1 and 24 of CsA treatment. Peak concentrations (C (max)) and the time needed to reach peak concentrations (t (max)) were directly determined from these plots. The area under the curve (AUC) was estimated by the trapezoidal rule. There was a statistically significant difference of the AUC, trough levels, and t (max) between weeks 1 and 24, with a decrease of AUC from 5,211 ng*h/ml in week 1 to 3,289 ng*h/ml in week 24, the trough levels decreased from 157 ng/ml to 96 ng/ml, and the t (max) decreased from 1.85 h to 1.00 h. The higher CsA bioavailability during the nephrotic state has to be considered when managing patients, since the target AUC cannot be the same throughout the treatment.

Tramadol is an atypical opioid with a complex mechanism of action including a synergistic interaction between the parent drug and an active metabolite. The local action of the parent drug is poorly documented. This study was designed to evaluate the site-site interaction of the antinociception produced by tramadol given by two different routes. The effects of individual and fixed-ratio combinations of intraplantar (i.pl.) and intraperitoneal (i.p.) tramadol were evaluated using the formalin test in rats. Isobolographic analysis was employed to identify the synergy produced by combinations. In both first and second phases of the formalin test, tramadol was active not only by the systemic (ED50 10.2+/-2.1 and 7.1+/-0.5 mg/kg i.p.) but also by the local route (ED50 171.0+/-44.8 and 134.6 microg/paw i.pl.). The isobolographic analysis revealed a "self-synergism" in the antinociceptive effect between the two routes of administration, as the experimental ED50 (211.1+/-13.6 and 45.9+/-3.9 "dose units" phase 1 and 2, respectively) of the combination was significantly lower than the theoretical ED50 (422.2+/-50.5 and 138.5+/-9.2 "dose units"). The mechanism underlying this self-synergism appears to be partially opioid since systemic but not local naloxone reversed the potentiation. The observed dual-site interaction in the antinociceptive action of tramadol provides insights for alternatives in the management of pain.

We reported previously that children are exposed to deltamethrin in malarious areas. In the present work we explored the levels of this insecticide in soil samples and also obtained relevant toxicokinetic data of deltamethrin in exposed children. Results show that, after spraying, indoor levels of deltamethrin in soil samples were higher than outdoor levels. The mean half-life estimated with these data was 15.5 days for outdoor samples and 15.4 days for indoor samples. Children's exposure to deltamethrin was assessed using as biomarkers the urinary concentrations of the metabolites 3-phenoxybenzoic acid (3-PBA) and cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (Br2CA). The mean level of both biomarkers reached a peak within the first 24 hr postexposure; 6 months after the initial exposure, urinary levels of 3-PBA and Br2CA were found at levels observed before exposure. Approximately 91% of the total 3-PBA or Br2CA was excreted during the first 3 days after exposure. Therefore, we estimated a half-life for this period, the values for 3-PBA and Br2CA being almost identical (13.5 vs. 14.5 hr). Finally, considering reports about the genotoxicity of deltamethrin, we assessed DNA damage in children before and 24 hr after indoor spraying of deltamethrin; we found no differences in the comet assay end points. In conclusion, we observed exposure to deltamethrin in children, but we did not find any relationship between soil concentrations of deltamethrin and urinary levels of the metabolites. At least for genotoxicity, the exposed children appeared not to be at risk.

The objective of this study was to evaluate the analgesic efficacy produced by tramadol given by two different routes of administration in patients experiencing pain after removal of an impacted mandibular third molar under local anesthesia. A double-blind, randomized, placebo-controlled clinical trial was conducted. Patients were assigned into four groups of treatment, twelve subjects per group: Group A, tramadol 50 mg IM one hr before surgery; group B, tramadol 50 mg into the surgical site; group C, tramadol by both routes of administration, 50 mg IM one hr before surgery plus 50 mg into the surgical site; and group D, control. We evaluated intensity of pain and analgesic consumption as was requested. Demographic characteristics and variables describing the difficulty of the surgical procedure were similar between groups. The duration of the anesthetic effect was significantly longer in the groups where tramadol was injected into the surgical site (215 and 252 min). Administration of systemic and local tramadol (50 mg) suppressed the pain intensity values in comparison to the control group (p < 0.05). Also, tramadol in both routes of administration suppressed the pain intensity values in comparison to all groups (p < 0.05). A significant reduction in the consumption of ketorolac was seen in all treatments as compared to the control group. However, only in the route combination group was a significant reduction in the requirement of acetaminophen observed. Nine patients requiring additional medication were treated with ketorolac 30 mg injected intramuscularly; 2 in the systemic group, 2 in the local group, 4 in the control group and only 1 in the combination group. Adverse events were minimal and similar in all groups.

In vitro studies have suggested that arsenic can modify the activity of macrophages in the mouse producing an over-regulation of the COX-2 and increased concentrations of PGE2 in endothelial cells. These effects may lead in vivo to enhancement of inflammatory and painful responses. In this study we studied the effect of an acute intoxication with sodium arsenite (1, 5, 10, 36 and 100 nmol/kg s.c.) on the nociceptive response of mice in the formalin test. On the other hand, the effect of arsenic on the antinociceptive response mediated by tramadol was evaluated in mice administered with a single dose of the analgesic agent (10 mg/kg s.c.). Arsenic levels in the liver were measured as a marker of the intoxication degree. Our results indicated that the arsenic acute exposure increases the nociceptive behavior in mice in a dose-dependent manner. Accordingly, the exposure to arsenic partially blocked the analgesic effect of tramadol although no statistical differences were reached. These results support the previous in vitro evidences regarding the alterations in the inflammatory-painful processes produced by the acute exposure to arsenic. Moreover, our results suggest that the intoxication with arsenic might exacerbate the pathological state in inflammatory diseases.

Tramadol is an atypical opioid with a complex mechanism of action including the synergistic interaction between the parent drug and an active metabolite. However, the local action of the parent drug is poorly documented. This study was designed to evaluate the site-site interaction of the antinociception produced by tramadol given by two different routes. The effects of individual and fixed-ratio combinations of locally (subcutaneous) and systemically (intraperitoneal) dosed tramadol were evaluated using the formalin test in rats. Isobolographic analysis was employed to identify the synergy produced by combinations. In the second phase of the formalin test, tramadol was active not only by the systemic (ED50 7.15+/-0.46 mg/kg i.p.) but also by the local route (ED50 134.6+/-25.1 microg/paw). The isobolographic analysis evidenced a "self-synergism" in the antinociceptive effect between the two routes of administration since the experimental ED50 (30.8+/-0.1 "dose units") of the combination was significantly lower than the theoretical ED50 (70.9+/-12.6 "dose units"). The mechanism underlying this self-synergism appears to be partially opioid since naloxone reversed the potentiation. The observed site-site interaction in the antinociceptive action of tramadol provides insights for alternatives in the management of pain.

This study was designed to evaluate the extent of the antinociceptive interaction between codeine and diclofenac at the local, spinal and systemic level. The effects of individual and fixed-ratio combinations of locally, spinally or orally given codeine and diclofenac were assayed using the formalin test in rats. Isobolographic analysis was employed to characterize the synergism produced by the combinations. Codeine, diclofenac and fixed-ratio codeine-diclofenac combinations produced a dose-dependent antinociceptive effect when administered locally, spinally or systemically. ED(30) values were estimated for the individual drugs and isobolograms were constructed. Theoretical ED(30) values for the combination estimated from the isobolograms were 422.2+/-50.5 microg/paw, 138.5+/-9.2 microg/rat, and 9.3+/-1.1 mg/kg for the local, spinal and oral routes, respectively. These values were significantly higher than the actually observed ED(30) values which were 211.1+/-13.6 microg/paw, 45.9+/-3.9 microg/rat, and 2.5+/-0.2 mg/kg, indicating a synergistic interaction. Systemic administration resulted in the highest increase in potency, being about fourfold, while spinal and local administration increased potency in two- and threefold, respectively. The fact that the highest synergism was observed after systemic administration suggests that the interaction is occurring at several anatomical sites. The results support the clinical use of this combination in pain management.

The purpose of the present work was to study the pharmacokinetics of ketorolac, a poorly metabolized drug, in experimental cirrhosis. Cirrhosis was induced by bile duct ligation (BDL) for four weeks in male Wistar rats. Ketorolac was given intravenously (1 mg/kg ) or orally (3.2 mg/kg) to control (sham-operated) and BDL-rats. Determination of ketorolac in plasma was carried out by HPLC and estimation of pharmacokinetic parameters was performed by non-compartmental analysis. Indicators of liver damage and liver fibrosis were significantly increased (p < 0.05) in BDL compared to control rats. Experimental cirrhosis did not induce any significant alteration in intravenous ketorolac pharmacokinetics. Volume of distribution, clearance, AUC and t1/2 were similar in BDL and control animals. Notwithstanding, oral ketorolac bioavailability was significantly altered in BDL rats. AUC and Cmax were reduced, while tmax was prolonged, suggesting that both, the extent and the rate of ketorolac absorption were decreased. Results show that liver cirrhosis may result in significant pharmacokinetic alterations, even for poorly bio-transformed drugs, but that alterations may vary with the route of administration. In conclusion, uncritical generalizations on the effect of liver damage on drug kinetics should be avoided and systematic studies for every drug and every route of administration are thus recommended.

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.

The purpose of this work was to study tolmetin plasma protein binding in an experimental model of hypoalbuminemia in the rat. Hypoalbuminemia was produced by repetitive plasmapheresis, achieving a 26.2 +/- 4.6% reduction in albumin circulating levels. Rats then received a 100 mg/kg oral tolmetin dose. Control rats received oral tolmetin 10, 56 or 100 mg/kg. Tolmetin plasma protein binding was determined by an ultrafiltration technique using an in vivo pharmacokinetic approach. Plasma protein binding data for the 3 doses studies in control animals could be described considering a single binding site with Kd = 21.9 +/- 2.1 microM and N = 0.98 +/- 0.05 sites per molecule of albumin. For hypoalbuminemic rats Kd was significantly increased (p < 0.05), while there was no significant change in the number of binding site per albumin molecule (Kd = 131.6 +/- 38.1 microM and N = 1.58 +/- 0.77). Our results show that hypoalbuminemia produces a disproportionate increase in the free fraction of tolmetin, not only by reducing albumin concentration, but also by a decrease in affinity. The mechanism responsible of such changes in affinity remains to be elucidated.

At present, pharmacokinetic-pharmacodynamic (PK-PD) modeling has emerged as a major tool in clinical pharmacology to optimize drug use by designing rational dosage forms and dosage regimes. Quantitative representation of the dose-concentration-response relationship should provide information for prediction of the level of response to a certain level of drug dose. Several mathematical approaches can be used to describe such relationships, depending on the single dose or the steady-state measurements carried out. With concentration and response data on-phase, basic models such as fixed-effect, linear, log-linear, E(MAX), and sigmoid E(MAX) can be sufficient. However, time-variant pharmacodynamic models (effect compartment, acute tolerance, sensitization, and indirect responses) can be required when kinetics and response are out-of-phase. To date, methodologies available for PK-PD analysis barely suppose the use of powerful computing resources. Some of these algorithms are able to generate individual estimates of parameters based on population analysis and Bayesian forecasting. Notwithstanding, attention must be paid to avoid overinterpreted data from mathematical models, so that reliability and clinical significance of estimated parameters will be valuable when underlying physiologic processes (disease, age, gender, etc.) are considered.

Background: The analgesic efficacy and bioavailability of 30 mg intramuscular ketorolac was studied in 24 patients with severe or very severe postoperative pain., Methods: Pain and pain relief were determined by a five-point verbal rating scale and data were submitted to a probability analysis. Ketorolac plasma levels were determined by high-performance liquid chromatography., Results: Two patients chose not to finish the study; 22 patients completed the study achieving at least good pain relief. Of these 22 patients, 13 reached complete pain relief. Ketorolac was rapidly absorbed. Notwithstanding, pain relief increased gradually, showing considerable delay with regard to plasma concentrations. Analysis of the probability-time curves revealed that 25% of the patients obtained moderate pain relief at 7 min after ketorolac administration, 50% at 11 min, 75% at 29 min, and 95% at 60 min. Good pain relief was achieved in 25, 50, and 75% of the patients at 1.1, 1.8, and 2.7 h, respectively. Complete pain relief was achieved in 25% and 50% of the patients at 2.6 h and 3.7 h, respectively. The probability of exhibiting an acceptable pain relief in responsive patients for more than 5 h was 0.97. No serious side effects were detected., Conclusions: Results show that 30 mg intramuscular ketorolac is an adequate treatment for postoperative pain in the Mexican population. Therefore, the use of higher doses is not justified. Due to gradual installation of analgesia, administration of additional analgesic medication before 1 h is not recommended.

The purpose of this study was to investigate sex-related differences in the pharmacokinetics of tolmetin, a potent nonsteroidal anti-inflammatory drug, in the rat. Male and female Wistar rats received oral tolmetin at two dose levels, 3.2 and 10 mg/kg. Blood samples were drawn at selected times after drug administration, and tolmetin concentration in whole blood was determined. Tolmetin was rapidly absorbed in all cases. C(max) increased with the dose, but was similar in both sexes. Notwithstanding, tolmetin half-life was significantly prolonged in females compared with males. As a result of the prolonged half-life, area under the curve values were significantly higher in females than in males. Tolmetin clearance was significantly reduced in females. The present results strongly suggest sex-related differences in the pharmacokinetics of tolmetin in the rat. Tolmetin elimination appears to be impaired in females, compared with males. The existence of sex-related differences in tolmetin pharmacokinetics in other species, including humans, requires further investigation.

Several limited sampling equations were tested to predict the area under the curve (AUC) of cyclosporin A (CsA) at steady state in 10 children with end-stage renal disease receiving oral CsA 2.5 mg/kg b.i.d. as two different formulations, namely Sandimmune and Neoral, according to a randomized crossover design with a one-month washout period. AUC was significantly correlated with CsA concentration at 5 h. The equation derived from this single concentration time point was able to adequately predict the AUC for Sandimmune but not for Neoral. The equation derived from CsA concentration data, measured at 2 and 12 h, significantly improved predictive performance in terms of bias and precision, allowing adequate AUC predictions in both formulations. CsA concentration at 2 h was also able to predict Cmax, while the concentration at 12 h corresponded to the trough value in a b.i.d. dosing scheme. Therefore, it is concluded that a limited sampling model including concentration data at 2 and 12 h allows the estimation of AUC, Cmax and trough levels, yielding a complete profile in patients exposed to CsA as Sandimmune or Neoral. Hence, this model can be used for therapeutic monitoring of CsA levels in pediatric patients being switched from one formulation to another.

Background: Oral etoposide administration is a suitable alternative to the intravenous route; therefore, commercial capsules have been developed. Before these capsules were available in Mexico, we studied drug bioavailability after oral administration of the intravenous etoposide solution (IVES)., Methods: Eight adult cancer patients received a 50-mg oral etoposide dose as IVES and blood samples were collected over a period of 24 h. Plasma etoposide concentration was determined by high-performance liquid chromatography, plasma concentration against time curves were constructed, and bioavailability parameters were calculated., Results: Oral IVES yielded an adequate bioavailability profile because Cmax was 2.38 +/- 0.30 micrograms/mL, AUC was 12.87 +/- 2.02 micrograms/mL and half-life was 6.72 +/- 0.97 h., Conclusions: Considering that the pharmacokinetic aim is to maintain plasma concentrations between 0.5 and 1.0 microgram/mL for several hours while avoiding high concentrations, i.e., of 10 micrograms/mL or higher, oral administration of 50-mg etoposide as IVES appears to be a suitable dosing option. In addition, oral IVES is considerably less expensive than intravenous administration in terms of both drug presentation and administration.

A rapid and sensitive method for the determination of diclofenac (CAS 15307-86-5) in whole blood samples by high-performance liquid chromatography with amperometric detection has been developed. This method was then used to study the pharmacokinetics of oral diclofenac sodium in the rat. The method includes a single extraction of acidified whole blood with ethyl acetate. Extracts were analyzed on a reversed-phase column eluted with a mixture of acetonitrile and 0.075 mol/l sodium acetate solution (pH 3.3) and detected amperometrically at + 1.1 V against Ag/AgCl. Retention times for diclofenac and the internal standard (naproxen) were 3.5 and 6 min, respectively. The method was linear in the range of 25 to 2000 ng/ml and the detection limit of the method was 10 ng/ml, using 100 microliters of whole blood sample. Employing this method, the oral pharmacokinetics of diclofenac in the rat was studied. Wistar male rats received an oral dose of 1, 3.2 or 10 mg/kg of diclofenac and blood samples were drawn at selected times during 12 h. After administration of diclofenac, a rapid increase of circulating concentrations was observed reaching a maximum in about 10 min. Then concentration decayed with a half-life of about 15 h. It is concluded that the method here reported is adequate for realization of pharmacokinetic studies of diclofenac in small species.

The purpose of the present study was to examine the time dependence of oral paracetamol (acetaminophen) bioavailability in an experimental model of spinal cord injury (SCI). Female Sprague-Dawley rats were subjected to spinal cord contusion at the T8-T9 level by the weight drop method producing permanent paraplegia. Oral paracetamol bioavailability after administration of a single 100 mgkg-1 dose was determined 1, 12, and 50 d after SCI. Cmax and AUC were significantly decreased 1 d after SCI compared to sham-injured controls. This reduction, however, was temporary, as there was a recovery of bioavailability parameters which was partial 12 d after SCI, being complete by day 50. The present results confirm the usefulness of animal models for the characterization of the effect of SCI in drug kinetics. Data show that SCI induces significant changes in paracetamol pharmacokinetics. Nonetheless, despite the fact of a permanent loss of functions related to locomotion, pharmacokinetic alterations evolved with time.

Two strains of rats, Sprague-Dawley and Wistar, were assayed in order to determine which strain is the more suitable experimental model for the study of pharmacokinetic alterations induced by spinal cord injury. Animals were submitted to spinal cord contusion at the T8-T9 level by the weight drop method. A single acetaminophen oral dose (100 mg/ kg) was administered 24 h after injury and blood samples were drawn for a period of 4 h. Acetaminophen concentration in whole blood was determined by high performance liquid chromatography and pharmacokinetic parameters were estimated. For both strains, Cmax and AUC were significantly lower, whereas tmax remained unchanged, in injured animals compared to sham-injured controls. Circulating acetaminophen concentrations were higher; therefore, pharmacokinetic alterations were more easily discerned, in Sprague-Dawley than in Wistar rats. It is concluded that the Sprague-Dawley strain is a more suitable model for the study of pharmacokinetic alterations induced by spinal cord injury.

The pharmacokinetics of oral ranitidine were studied in 24 Mexican male healthy volunteers. Subjects received a tablet containing 150 mg of ranitidine (Azantac, Glaxo de México, Mexico City) after an overnight fast and blood samples were drawn at several times for a period of 24 h. Ranitidine concentration in plasma was measured by high performance liquid chromatography and pharmacokinetic parameters were determined by non-compartmental analysis. Ranitidine plasma concentration increased with time, reaching a maximum of (mean +/- SEM) 484 +/- 34 ng/ml in 2.7 +/- 0.2 h. Plasma levels then decayed with a terminal half-life of 4.8 +/- 0.3 h. The area under the plasma concentration against time curve was 2440 +/- 126 ngh/ml. Oral ranitidine pharmacokinetic parameters in Mexicans appeared to be similar to those previously reported for Caucasians.

In this work we show that the pain-induced functional impairment model (PIFIR) can be used with cannulated rats as a useful procedure for pharmacokinetic/pharmacodynamic modelling. This model evaluates analgesia by measuring motor impairment of the right limb after intra-articular administration of uric acid. Time of contact with a rotating cylinder is referred to the control limb. We studied the pharmacokinetic and pharmacodynamics of naproxen after six peroral doses to Wistar rats, and we examined the adjuvant action of caffeine with naproxen. Surgery and blood sampling did not produce any difference on functional impairment either in rats without uric acid or in the dysfunction produced by uric acid. The relation between naproxen plasma concentration and the analgesic effect was obtained with few rats. Caffeine alone did not produce any significant modification in functional impairment but the co-administration significantly increased the effect of naproxen. Plasma levels of naproxen did not change when caffeine was co-administered. The PIFIR model with blood sampling is a suitable method for pharmacokinetic/pharmacodynamic relationship studies and is specially useful to characterize drug-drug interactions.