PURPOSE: The case of a patient whose International Normalized Ratio (INR) increased with concurrent use of ophthalmic erythromycin and warfarin is reported. SUMMARY: A 77-year-old Caucasian woman began therapy with warfarin for thromboembolism prophylaxis secondary to atrial fibrillation (target INR, 2-3). Warfarin was prescribed by her cardiologist, and care was established with clinical pharmacists in an anticoagulation clinic. She was receiving a weekly maintenance dosage of 14 mg. She had a history of atrial fibrillation, hyperlipidemia, osteoarthritis, hypothyroidism, coronary artery disease, myocardial infarction, congestive heart failure, and breast cancer. In addition to warfarin, the patient had been receiving alprazolam, carvedilol, furosemide, levothyroxine sodium, lisinopril, nitroglycerin, potassium chloride, propoxyphene hydrochloride- acetaminophen, simvastatin, and trazodone. After receiving warfarin at the same weekly dosage for over four months, the patient's ophthalmologist prescribed erythromycin ophthalmic ointment for chronic bacterial conjunctivitis. Three weeks later, her INR was found to be 8.5. A total of four warfarin doses were withheld, and her weekly maintenance dosage of warfarin was subsequently decreased to 12 mg. Five weeks later, her INR was 1.5, and it was determined that the erythromycin ophthalmic ointment had been discontinued five days prior. Her weekly maintenance dosage of warfarin was increased to 16 mg. Rechallenge with erythromycin five days before her next INR measurement resulted in an INR of 4.2. A new weekly maintenance dosage of 13 mg was established, and her subsequent INRs were within normal range. CONCLUSION: An increase in INR values was reported after initiation of ophthalmic erythromycin in a patient receiving warfarin and recurred upon rechallenge with ophthalmic erythromycin. less...

To clarify the causes of low oral bioavailability (BA) of drugs in cynomolgus monkeys, the experimental method to evaluate the drug permeability and the metabolism in the intestine of cynomolgus monkeys was established. An in situ intestinal perfusion method was performed with blood sampling from both portal and peripheral veins to calculate the intestinal permeability and the metabolism of drugs simultaneously. In all experiments, antipyrine was co-perfused with test drugs as a non-metabolized reference to calculate the individual portal vein blood flow. The effective permeability coefficient (P(eff)) of acetaminophen and piroxicam were high, and the fraction of dose absorbed from the gastrointestinal tract (Fa) thought to be 1. The intestinal availability (Fg) of acetaminophen and piroxicam were calculated to be 0.39 and 1.09, respectively. The Fa*Fg values of these drugs calculated from the perfusion study almost coincided with those obtained from the in vivo PK analysis in the previous report. In addition, the Fg values of verapamil and midazolam were calculated as 0.16 and 0.26, respectively, suggesting these drugs were metabolized extensively in the intestine after oral administration to cynomolgus monkey. Furthermore, the Fg values of these drugs were increased to 0.8-0.85 in the presence of 1-aminobenzotriazole, a typical cytochrome P450 (CYP) inhibitor. In conclusion, it was clarified that acetaminophen, verapamil and midazolam were metabolized extensively in the intestine of cynomolgus monkeys. This intestinal perfusion method is considered to be useful to identify the factors of species difference in the oral absorption of drugs. less...

The US Food and Drug Administration (FDA), concerned about the incidence of acute liver failure due to acetaminophen (Tylenol) overdose, has mandated new labeling on acetaminophen packaging. It is also considering (but has not enacted) reducing the maximum daily dose from 4 g (possibly to 3,250 mg), banning acetaminophen-narcotic combination products, and changing the current maximum single dose of 1 g to prescription status, making 650 mg the highest recommended nonprescription dose. We review the epidemiology, toxicology, and management of acetaminophen overdose and steps the FDA and physicians can take to prevent it. less...

BACKGROUND AND OBJECTIVES: The utility of continuous perineural infusions for lesser painful shoulder procedures is not well established. We hypothesized that the addition of a continuous interscalene ropivacaine infusion to a single-injection interscalene block would improve analgesia after minor arthroscopic shoulder surgery. METHODS: An ultrasound-guided interscalene catheter targeting the C5-C6 roots/superior trunk was placed preoperatively in patients undergoing arthroscopic subacromial decompression, excision lateral clavicle, or stabilization. Ropivacaine 0.5% 30 mL was administered via this catheter before surgery was conducted under general anesthesia. All patients received dexamethasone and ondansetron antiemetic prophylaxis. At surgery conclusion, patients were randomly assigned to catheter removal in the postanesthesia care unit ("SS," n = 30) or to an elastomeric infusion of ropivacaine 0.2% 2 mL/hr with patient-controlled 5-mL boluses every hour ("Continuous," n = 31). Multimodal analgesia (acetaminophen, diclofenac, and rescue tramadol) was administered in both groups. Patients were questioned on postoperative days 1 and 2 for numerical rating pain score (0-10), supplemental tramadol consumption, and adverse effects of treatment. RESULTS: Median (quartiles) worst numerical rating pain score was lower in the Continuous group on day 1 on movement (SS = 4 [3-6], Continuous = 2 [0-4], P = 0.008) and at rest (SS = 2 [2-5], Continuous = 1 [0-3], P = 0.007) but was similar between groups on day 2. Median (quartiles) tramadol tablet consumption was lower in the Continuous group on both day 1 (SS = 1 [0-2], Continuous = 0 [0-0], P < 0.001) and day 2 (SS = 1 [0-2], Continuous = 0 [0-1], P = 0.017). Adverse effects of treatment were similar between groups except for numerically rated arm numbness, which was higher for the Continuous group. One patient in the SS group required 2 nights of hospitalization for intravenous opioid. CONCLUSIONS: After minor arthroscopic shoulder surgery, the addition of a continuous interscalene ropivacaine infusion to a single-shot interscalene block reduces pain, especially with movement, during the first 24 hrs. less...

Chloroform is a potent central nervous system and respiratory depressant. The toxicities associated with chloroform frequently occur after inhalation. Hepatotoxicity is secondary to production of a toxic metabolite, with a peak elevation of liver enzymes 72 hours after exposure. Acute liver failure after chloroform inhalation is rarely described, this syndrome being produced mainly by viral hepatitis, idiosyncratic drug-induced liver injury, and acetaminophen ingestion. This report describes the case of a 46-year-old woman who presented to emergency department with coma, signs of respiratory failure, and solvent odor of her breath after chloroform inhalation and binge drinking. In evolution appeared lethal acute liver failure and rhabdomyolysis, despite maximum supportive care. Necroptic examination revealed microvesicular steatosis and tubular renal necrosis, specific for chloroform toxicity. This case illustrates the dramatic impact on liver of two well-recognized hepatotoxins. Mechanisms of chloroform and alcohol-induced liver toxicity are reviewed. less...

Poly(methacrylic acid-methyl methacrylate)s (HPMMs), are pH-dependent polymers which ionise and form salts (PMMs) in neutral conditions. Despite their wide use in tablet coating, the interactions of PMMs with electrolytes present in biorelevant media and luminal fluids have been scantly investigated. The data generated in the current work provide the basic information on the effect of bivalent cations, namely Ca++, Zn++ and Mn++, on the HPMMs solubility and, consequently, on the performances (disintegration and drug dissolution) of acetaminophen gastro-resistant tablets when exposed to fluid containing such salts. The interactions between polymers and metal ions were analyzed by ATR-FTIR spectroscopy and in silico combining molecular dynamic simulations to explore the conformational profiles of several oligomers with different Mw, taken as model of the polymers, with ab initio and semi-empirical calculations in gas phase. The computational results agree with the experimental data in terms of spatial disposition of the bications with respect to PMMs (Ca++ and Mn++ as bidentate form and Zn++ as monodentate ligand) and interaction strength (Zn++ >Mn++ > Ca++). The tablet disintegration and dissolution rate of acetaminophen were strongly affected by the interactions of the dissolving copolymer with the metal ions which led to coating insolubilisation. These preliminary results underline that the ingestion of metal ions at high concentrations could affect the drug liberation from gastro-resistant dosage forms. less...

The decrease in particle size may offer new properties to drugs. In this study, we investigated the size reduction influence of the acetaminophen (C(8)H(9)O(2)N) particles by mechanical activation using a dry ball mill. The activated samples with the average size of 1 microm were then investigated in different time periods with the infrared (IR), inductively coupled plasma (ICP), atomic force microscopy (AFM), and X-ray diffraction (XRD) methods. The results of the IR and XRD images showed no change in the drug structure after the mechanical activation of all samples. With the peak height at full width at half maximum from XRD and the Scherrer equation, the size of the activated crystallite samples illustrated that the AFM images were in sound agreement with the Scherrer equation. According to the peaks of the AFM images, the average size of the particles in 30 hours of activation was 24 nm with a normal particle distribution. The ICP analysis demonstrated the presence of tungsten carbide particle impurities after activation from the powder sample impacting with the ball and jar. The greatest reduction in size was after milling for 30 hours. less...

Novel thermosensitive nano-micelles, based on Poly(D,L-lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(D,L-lactide-co-glycolide) (PLGA-PEG-PLGA), as carriers for drug delivery were researched. The critical micelle concentration of the copolymer in aqueous solution was determined to be 2.34 microgram/ml by fluorescence spectroscopy using pyrene as a fluorescence probe. The lower critical solution temperature (LCST) of the copolymer was measured in distilled water by optical transmittance, and the LCST was varied from 35 to 55 degrees C depending on polymer concentration. Acetaminophen as a model drug was loaded in nano-micelles by solvent evaporation method. In vitro acetaminophen release from micelles showed a sustained modality compared with the free drug as a control, and an obviously high release rate when temperature was increased above LCST. The studies showed that nano-micelles made from PLGA-PEG-PLGA could be ideal candidate carriers for tumor-special drug delivery. less...

The purpose of this study was to evaluate the effectiveness of pain management after electrical injury. A retrospective hospital chart review was conducted among electrically injured patients discharged from the outpatient burn clinic of a rehabilitation hospital (July 1, 1999, to July 31, 2008). Demographic data, numeric pain ratings (NPRs) at initial assessment and discharge, medications, nonpharmacologic modalities, and their effects before admission and after rehabilitation were collected. Pain management effects were compared between high (> or =1000 v) and low (<1000 v) voltage, and between electrical contact and electrical flash patients, using Student's t-test and chi, with a P < .05 considered significant. Of 82 electrical patients discharged during the study period, 27 were excluded because of incomplete data, leaving 55 patients who had a mean age +/-SD of 40.7 +/- 11.3 years, TBSA of 19.2 +/- 22.7%, and treatment duration of 16.5 +/- 15.7 months. The majority were men (90.9%), most injuries occurred at work (98.2%), mainly caused by low voltage (n = 32, 58.2%), and the rest caused by high voltage (n = 18, 32.7%). Electrical contact was more common (54.5%) than electrical flash (45.5%). Pain was a chief complaint (92.7%), and hands were the most affected (61.8%), followed by head and neck (38.2%), shoulders (38.2%), and back torso (38.2%). Before rehabilitation, the most common medication were opioids (61.8%), relieving pain in 82.4%, followed by acetaminophen (47.3%) alleviating pain in 84.6%. Heat treatment was the most common nonpharmacologic modality (20.0%) relieving pain in 81.8%, followed by massage therapy (14.5%) alleviating pain in 75.0%. During the rehabilitation program, antidepressants were the most common medication (74.5%), relieving pain in 22.0%, followed by nonsteroidal antiinflammatory drugs (61.8%), alleviating pain in 70.6%. Massage therapy was the most common nonpharmacologic modality (60.0%), alleviating pain in 75.8%, and then cognitive behavioral therapy (54.5%), alleviating pain in 40.0%. There were pain improvements in all anatomic locations after rehabilitation except for the back torso, where pain increased 0.7 +/- 2.9 points. Opioids were more commonly used in high voltage (P < .05), and cognitive behavioral therapy in low-voltage injuries (P < .05). Opioids were used in both electrical flash and electrical contact injuries. Pain in electrically injured patients remains an important issue and should continue to be addressed in a multimodal way. It is hoped that this study will guide us to design future interventions for pain control after electrical injury. less...

PURPOSE: Somatic paravertebral block (SPVB) appears to provide effective and prolonged nerve block in children; however, study of its use in this population is limited. We compared SPVB with no block in children undergoing appendectomy. METHODS: Thirty-six children aged 3-16 yr undergoing open appendectomy were involved in this prospective randomized controlled study. Anesthesia was induced with propofol and maintained with isoflurane in N(2)O/oxygen. All subjects received fentanyl, acetaminophen and ketorolac during anesthesia. Group I (SPVB) subjects received a right SPVB at T(11), T(12), and L(1) using 0.2% ropivacaine 0.25 mL.kg(-1) with epinephrine 1:200,000 preoperatively. Group II (Control) had only bandaids applied to skin. Both groups were given morphine 0.05 mg.kg(-1) iv every 2 hr if pain scores reached 5/10 on a visual analogue scale. Acetaminophen was administered postoperatively every 6 hr to both groups. Time to first dose of morphine, total dose of morphine in 24 hr, and any adverse effects up to 24 hr after surgery were recorded. RESULTS: Group I (SPVB) subjects required significantly less morphine than Group II (Control) patients (0.12 +/- 0.07 vs 0.34 +/- 0.15 mg.kg(-1), respectively; P < 0.001), and time to their first dose was significantly longer (7.1 +/- 4.4 vs 2.5 +/- 1.6 hr, respectively; P < 0.001). Incidence of vomiting was 11% with Group I and 27% with Group II (P = 0.21). No other adverse effects were observed in either group. CONCLUSIONS: In children undergoing appendectomy, SPVB provides better pain relief than no block and reduces opioid requirements. Side effects were not statistically different between groups. less...