Pharmacokinetics and Drug Residue in Eggs After Multiple-Day Oral Dosing of Amoxicillin-Clavulanic Acid in Domestic Chickens.

This study examined the pharmacokinetics of orally administered amoxicillin and clavulanic acid tablets (Clavamox, 125 mg/kg PO q12h for 9 doses) in domestic hens and examined both amoxicillin and clavulanic acid concentrations in eggs. Therapeutic plasma concentrations (0.5 µg/mL) of amoxicillin were not reached at any time point, and no amoxicillin was detected in plasma after 2 hours. Pharmacokinetic parameters could not be calculated. The clavulanic acid half-life was 1.1 hours and it was detected up to 8 hours after dosing. No amoxicillin was detected in eggs 4 days postdosing, nor was clavulanic acid detected in any eggs during the same time period. On the basis of these results, orally dosing hens with amoxicillin and clavulanic acid tablets at 125 mg/kg PO q12h does not reach therapeutic plasma concentrations. Additional studies are needed to examine different doses and formulations of medication to determine better dosing and withdrawal recommendations for domestic chickens.

Pharmacokinetics and Egg Residues of Meloxicam After Multiple Day Oral Dosing in Domestic Chickens.

With increased ownership of backyard poultry, veterinarians must treat these birds appropriately and take into consideration drug withdrawal times for eggs meant for consumption. Few studies have examined the pharmacokinetics or egg residues for medications commonly used in avian medicine. This study determined the pharmacokinetics of meloxicam in domestic chickens (n = 8) after oral dosing at 1 mg/kg q12h for a total of 9 doses (5 days). Additionally, the presence of meloxicam residues in eggs was determined. The terminal half-life, maximum concentration, and time to maximum concentration were 3.02 ± 1.15 hours, 7.14 ± 1.54 µg/mL, and 1.6 ± 0.52 hours, respectively. No drug was detected in yolks and whites after 8 days and 3 days, respectively. On the basis of these results, a 2-week withdrawal time should be adequate to avoid drug residues in eggs meant for consumption.

The influence of storage time and temperature on propofol concentrations in canine blood and plasma.

Propofol is an intravenous anesthetic commonly used due to its favorable pharmacokinetic and pharmacodynamic profile. There are discrepancies in the literature about the most appropriate sample for determining propofol concentrations. Although plasma has been used for determining propofol concentrations, whole blood has been the preferred sample. There is also a lack of consistency in the literature on the effect of storage time and temperature on propofol concentrations and this may lead to errors in the design of pharmacokinetic/pharmacodynamics studies. The purpose of this study was to determine the difference in propofol concentrations in whole blood versus plasma and to evaluate the influence of storage time (56 days) and temperature (4 °C, -20 °C, -80 °C) on the stability of propofol concentrations in blood and plasma samples. Results from the study indicate that whole blood and plasma samples containing propofol stored at -80 °C have concentrations as high as or higher than those stored at 4 °C or -20 °C for 56 days; thus, -80 °C is an appropriate temperature for propofol sample storage. Plasma propofol concentrations were consistently higher than whole blood for all three storage temperatures. Consequently, plasma is the most appropriate sample for propofol analysis due to its consistent determinations.

Determination of Meloxicam in Egg Whites and Yolks Using Reverse Phase Chromatography.

A new method of analysis has been developed and validated for the determination of meloxicam in egg whites and yolks. Following a liquid extraction for the whites and a solid phase extraction for the yolks, samples were separated on an XBridge C18 column and quantified using ultraviolet detection at 360 nm. The mobile phase was a mixture of water with glacial acetic acid and acetonitrile, with a flow rate of 1 mL/min. The procedure produced a linear graph over the concentration range 5-1500 ng/mL with a lower limit of quantification of 5 ng/mL. Intra- and inter-assay variability was 10% or less for both the whites and yolks. The average recovery for whites was 96% and the average recovery in yolks was 97%.

Chronobiological characteristics of neuropathic pain: clinical predictors of diurnal pain rhythmicity.

OBJECTIVES: Neuropathic pain is often worse at night; however, little is known about pain rhythmicity during waking hours. We aimed to replicate previous observations of diurnal pain progression, evaluate associations between diurnal rhythmicity and clinical factors, and evaluate the impact of diurnal rhythmicity on treatment response. METHODS: We performed exploratory analyses of 2 trials (The New England Journal of Medicine 2005; 352:1324; The Lancet 2009; 374:1252) in diabetic neuropathy and postherpetic neuralgia. Pain recorded at 8:00 AM, 4:00 PM, and 8:00 PM, at baseline and during drug treatment was examined. RESULTS: Data from the latest trial replicated our previous observation of diurnal pain progression with a relative pain intensity difference of 33% between 8:00 AM and 8:00 PM. This pattern was preserved during treatment with gabapentin, nortriptyline, and their combination. Pooled multivariable analyses suggested that difference in pain intensity from 8:00 AM to 8:00 PM was more pronounced in females (vs. males) and in diabetic peripheral neuropathy (vs. postherpetic neuralgia). The baseline magnitude of pain intensity difference from 8:00 AM to 8:00 PM failed to predict treatment response. DISCUSSION: These observations suggest that neuropathic pain progressively increases throughout the day with clinically relevant morning-evening differences and further indicate that sex and underlying etiology may be important determinants of diurnal rhythmicity in neuropathic pain. Consideration of these patterns may guide improved therapeutic strategies and stimulate new directions of research that will improve our understanding and treatment of neuropathic pain.

Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial.

BACKGROUND: Drugs for neuropathic pain have incomplete efficacy and dose-limiting side-effects when given as monotherapy. We assessed the efficacy and tolerability of combined nortriptyline and gabapentin compared with each drug given alone. METHODS: In this double-blind, double-dummy, crossover trial, patients with diabetic polyneuropathy or postherpetic neuralgia, and who had a daily pain score of at least 4 (scale 0-10), were enrolled and treated at one study site in Canada between Nov 5, 2004, and Dec 13, 2007. 56 patients were randomised in a 1:1:1 ratio with a balanced Latin square design to receive one of three sequences of daily oral gabapentin, nortriptyline, and their combination. In sequence, a different drug was given to each randomised group in three treatment periods. During each 6-week treatment period, drug doses were titrated towards maximum tolerated dose. The primary outcome was mean daily pain at maximum tolerated dose. Analysis was by intention to treat. This trial is registered, number ISRCTN73178636. FINDINGS: 45 patients completed all three treatment periods; 47 patients completed at least two treatment periods and were analysed for the primary outcome. Mean daily pain (0-10; numerical rating scale) was 5.4 (95% CI 5.0 to 5.8) at baseline, and at maximum tolerated dose, pain was 3.2 (2.5 to 3.8) for gabapentin, 2.9 (2.4 to 3.4) for nortriptyline, and 2.3 (1.8 to 2.8) for combination treatment. Pain with combination treatment was significantly lower than with gabapentin (-0.9, 95% CI -1.4 to -0.3, p=0.001) or nortriptyline alone (-0.6, 95% CI -1.1 to -0.1, p=0.02). At maximum tolerated dose, the most common adverse event was dry mouth, which was significantly less frequent in patients on gabapentin than on nortriptyline (p<0.0001) or combination treatment (p<0.0001). No serious adverse events were recorded for any patients during the trial. INTERPRETATION: Combined gabapentin and nortriptyline seems to be more efficacious than either drug given alone for neuropathic pain, therefore we recommend use of this combination in patients who show a partial response to either drug given alone and seek additional pain relief. Future trials should compare other combinations to their respective monotherapies for treatment of such pain. FUNDING: Canadian Institutes of Health Research.

Venous and arterial thromboembolism in severe sepsis.

The burden of thromboembolism (TE) in severe sepsis is largely unknown. We assessed the prevalence of venous and arterial TE in patients with severe sepsis over a four-week period. We performed a retrospective analysis of a pooled database of three randomized, placebo-controlled trials of two novel pharmacological agents for the treatment of severe sepsis, drotrecogin alfa (activated) (DrotAA) and secretory phospholipase A2 inhibitor (sPLA(2)I). The study was conducted at intensive care units of the participating institutions. A total of 2,649 patients with known or suspected infection and sepsis-associated acute organ dysfunction were enrolled in the three trials and were assigned to treatment groups (DrotAA=850; sPLA2I=578; placebo=1221). The database was queried for venous and arterial TE, using investigator reports of serious adverse events. Eighty-four of 2,649 patients (3.2%; 95% confidence interval, 2.5% to 3.9%) developed at least one thromboembolic event over 28 days. Nearly three-quarters of episodes were atheroembolic (n=62); 25% involved the deep venous system (n=25). Ischemic stroke (n=30) and venous thromboembolism (n=25) each occurred in about 1% of patients. Ischemic stroke and acute coronary syndrome had a higher peak incidence during the first five days compared to venous TE onset, which was more constant over the 28-day period. Subgroup analysis by pooled treatment groups yielded TE rates of 2.0% (DrotAA), 3.5% (placebo), and 4.0% (sPLA2I), respectively. Clinically manifest TE occurred in about 3% of severe sepsis patients treated in the intensive care unit over a 28-day period. Arterial TE may be more common than previously recognized. More accurate estimates of TE prevalence and relationship to sepsis await future studies.

Chronobiological characteristics of painful diabetic neuropathy and postherpetic neuralgia: diurnal pain variation and effects of analgesic therapy.

Clinical impressions suggest that neuropathic pain is often worse at night and significantly impairs sleep. However, the temporal pattern of neuropathic pain during waking hours has not been clearly characterized. Using clinical trial data, we have evaluated the diurnal variation of pain intensity before and during analgesic treatment in patients with diabetic neuropathy (DN) and postherpetic neuralgia (PHN). Pain intensity (0-10) measures throughout the day from a placebo-controlled trial of around-the-clock administration of gabapentin, morphine and a gabapentin-morphine combination in neuropathic pain patients were examined. Baseline data in untreated patients revealed no effect of day of week but a significant effect of time of day in both DN (P < 0.001) and PHN (P < 0.001) such that pain intensity progressively increases throughout the day. This temporal pattern is essentially preserved during treatment with gabapentin, morphine and their combination. Neuropathic pain intensity progressively increases throughout the day and this temporal profile appears to be unaffected by treatment with gabapentin and/or morphine. Advancing our understanding of the chronobiology of neuropathic pain may shed new light on various neurohormonal and neurophysiologic influences and lead to the identification of novel therapeutic targets. Furthermore, recognizing diurnal pain patterns may guide treatment strategies such as the targeted timing of analgesic therapies.

Drotrecogin alfa (activated) in patients with severe sepsis presenting with purpura fulminans, meningitis, or meningococcal disease: a retrospective analysis of patients enrolled in recent clinical studies.

INTRODUCTION: We report data from adult and pediatric patients with severe sepsis from studies evaluating drotrecogin alfa (activated) (DrotAA) and presenting with purpura fulminans (PF), meningitis (MEN), or meningococcal disease (MD) (PF/MEN/MD). Such conditions may be associated with an increased bleeding risk but occur in a relatively small proportion of patients presenting with severe sepsis; pooling data across clinical trials provides an opportunity for improving the characterization of outcomes. METHODS: A retrospective analysis of placebo-controlled, open-label, and compassionate-use trials was conducted. Adult patients received infusions of either DrotAA or placebo. All pediatric patients (<18 years old) received DrotAA. 189 adult and 121 pediatric patients presented with PF/MEN/MD. RESULTS: Fewer adult patients with PF/MEN/MD met cardiovascular (68.3% versus 78.8%) or respiratory (57.8% versus 80.5%) organ dysfunction entry criteria than those without. DrotAA-treated adult patients with PF/MEN/MD (n = 163) had an observed 28-day mortality rate of 19.0%, a 28-day serious bleeding event (SBE) rate of 6.1%, and an intracranial hemorrhage (ICH) rate of 4.3%. Six of the seven ICHs occurred in patients with MEN (three of whom were more than 65 years old with a history of hypertension). DrotAA-treated adult patients without PF/MEN/MD (n = 3,088) had an observed 28-day mortality rate of 25.5%, a 28-day SBE rate of 5.8%, and an ICH rate of 1.0%. In contrast, a greater number of pediatric patients with PF/MEN/MD met the cardiovascular organ dysfunction entry criterion (93.5% versus 82.5%) than those without. DrotAA-treated PF/MEN/MD pediatric patients (n = 119) had a 14-day mortality rate of 10.1%, an SBE rate of 5.9%, and an ICH rate of 2.5%. DrotAA-treated pediatric patients without PF/MEN/MD (n = 142) had a 14-day mortality rate of 14.1%, an SBE rate of 9.2%, and an ICH rate of 3.5%. CONCLUSION: DrotAA-treated adult patients with severe sepsis presenting with PF/MEN/MD had a similar SBE rate, a lower observed 28-day mortality rate, and a higher observed rate of ICH than DrotAA-treated patients without PF/MEN/MD. DrotAA-treated pediatric patients with severe sepsis with PF/MEN/MD may differ from adults, because all three outcome rates (SBE, mortality, and ICH) were lower in pediatric patients with PF/MEN/MD.

Morphine, gabapentin, or their combination for neuropathic pain.

BACKGROUND: The available drugs to treat neuropathic pain have incomplete efficacy and dose-limiting adverse effects. We compared the efficacy of a combination of gabapentin and morphine with that of each as a single agent in patients with painful diabetic neuropathy or postherpetic neuralgia. METHODS: In this randomized, double-blind, active placebo-controlled, four-period crossover trial, patients received daily active placebo (lorazepam), sustained-release morphine, gabapentin, and a combination of gabapentin and morphine--each given orally for five weeks. The primary outcome measure was mean daily pain intensity in patients receiving a maximal tolerated dose; secondary outcomes included pain (rated according to the Short-Form McGill Pain Questionnaire), adverse effects, maximal tolerated doses, mood, and quality of life. RESULTS: Of 57 patients who underwent randomization (35 with diabetic neuropathy and 22 with postherpetic neuralgia), 41 completed the trial. Mean daily pain (on a scale from 0 to 10, with higher numbers indicating more severe pain) at a maximal tolerated dose of the study drug was as follows: 5.72 at baseline, 4.49 with placebo, 4.15 with gabapentin, 3.70 with morphine, and 3.06 with the gabapentin-morphine combination (P<0.05 for the combination vs. placebo, gabapentin, and morphine). Total scores on the Short-Form McGill Pain Questionnaire (on a scale from 0 to 45, with higher numbers indicating more severe pain) at a maximal tolerated dose were 14.4 with placebo, 10.7 with gabapentin, 10.7 with morphine, and 7.5 with the gabapentin-morphine combination (P<0.05 for the combination vs. placebo, gabapentin, and morphine). The maximal tolerated doses of morphine and gabapentin were lower (P<0.05) with the combination than for each drug as single agent. At the maximal tolerated dose, the gabapentin-morphine combination resulted in a higher frequency of constipation than gabapentin alone (P<0.05) and a higher frequency of dry mouth than morphine alone (P<0.05). CONCLUSIONS: Gabapentin and morphine combined achieved better analgesia at lower doses of each drug than either as a single agent, with constipation, sedation, and dry mouth as the most frequent adverse effects.

Safety assessment of drotrecogin alfa (activated) in the treatment of adult patients with severe sepsis.

INTRODUCTION: Drotrecogin alfa (activated; recombinant activated protein C) was shown to reduce 28-day all-cause mortality in patients with severe sepsis and to have an acceptable safety profile in 1690 patients studied in the F1K-MC-EVAD (PROWESS) trial. We analyzed all available data on the safety of treatment with drotrecogin alfa (activated) in 2786 adult patients with severe sepsis enrolled in all phase 2 and 3 clinical trials, and in an estimated 3991 patients receiving the drug in commercial use. PATIENTS AND METHOD: Mortality and safety analyses were performed on all available data from adult severe sepsis patients enrolled in seven clinical trials as of 12 April 2002. Trial-specific safety data and spontaneously reported serious adverse events from commercial use were extracted from a pharmacovigilance database. RESULTS: The 28-day mortality rate for all adult patients who received active treatment in all clinical trials was 25.3% (704/2786). Serious bleeding events during the infusion period and 28-day study period occurred in 2.8% (79/2786) and 5.3% (148/2786) of patients, respectively. Of bleeding events during the infusion period, 43% (34/79) were procedure-related. Fatal serious bleeding events during the infusion period occurred in 0.4% (12/2786) of cases. Intracranial hemorrhage (ICH) events during the infusion period and 28-day study period occurred in 0.6% (16/2786) and 1.1% (32/2786) of patients, respectively. Ten out of the 16 ICH events occurring during the study drug infusion period were associated with severe thrombocytopenia (

Trends in opioid use for chronic neuropathic pain: a survey of patients pursuing enrollment in clinical trials.

PURPOSE: Clinical trials suggest that opioids relieve neuropathic pain and decrease pain-related disability. We conducted a pilot study of current prescribing trends and patients' attitudes towards opioids for neuropathic pain. METHODS: A patient questionnaire was completed by individuals pursuing enrollment in neuropathic pain clinical trials at our facility. RESULTS: Of 154 patients with diabetic neuropathy (55.2%), postherpetic neuralgia (29.9%), idiopathic peripheral neuropathy (9.7%) and other neuropathies (5.2%), 73.4% complained of inadequate pain control, the mean pain duration was 4.7 (SD = 4.4) yr and the mean pain intensity (0-10) was 7.7 (SD = 2.3). In this group, 40.9% had never tried opioids and 24.7% had never tried any opioids, tricyclic antidepressants or anticonvulsants. Only 9.7% were receiving long-acting opioids or "around the clock" dosing whereas 25.3% were receiving opioids on an "as needed" basis. Opioids combined with tricyclic antidepressants and/or anticonvulsants were used in 11.0%. Fear of addiction and adverse effects were expressed by 31.8% and 46.8% respectively. CONCLUSION: These data suggest that barriers to opioid therapy for neuropathic pain include patients', and possibly physicians', fears of addiction and adverse effects, which are exaggerated in light of current evidence. The merits of continuous treatment with sustained-release opioids, "as needed" dosing with short-acting preparations, or combining opioids with other agents are discussed. Continued research and communication between health professionals, law enforcement officials and legislators is vital in order to facilitate appropriate opioid use which has a minimal negative impact on the public yet optimally benefits individuals who suffer from disabling neuropathic pain.

Patients' attitudes and prior treatments in neuropathic pain: a pilot study.

BACKGROUND: Ongoing research continues to expand the knowledge of neuropathic pain. It is vital that established treatments and valuable discoveries ultimately improve patient care. OBJECTIVES: Attitudes and prior treatments of patients being screened for neuropathic pain trials were evaluated to provide further understanding of the barriers to the management of neuropathic pain. METHODS: A questionnaire was completed by patients with neuropathic pain who were either referred by local physicians or self referred in response to clinical trial advertisements from the authors' facility. RESULTS: In total, 151 patients completed the questionnaire. Diagnoses included diabetic neuropathy (55.6%), postherpetic neuralgia (29.8%), idiopathic peripheral neuropathy (9.3%) and others (5.3%). The mean pain duration was 4.7 years, and the mean daily pain (on a score of 0 to 10) was 7.6. During questioning, 72.8% complained of inadequate pain control and 25.2% had never tried any antineuropathic analgesics (tricyclic antidepressants, opioids or anticonvulsants). New antineuropathic analgesics (eg, gabapentin) were being used by only 16.6%. Opioids, tricyclic antidepressants and anticonvulsants had never been tried by 41.1%, 59.6% and 72.2%, respectively. Fears of addiction and adverse effects were expressed by 31.8% and 48.3%, respectively. CONCLUSIONS: New, and even conventional, therapies are often not pursued, despite inadequate pain control. Several issues are discussed, including patient barriers to seeking pain management, patient and physician barriers to analgesic drug therapy, and appropriate use of and access to multidisciplinary pain centres. Failure to implement therapeutic advances in pain management not only hinders improvement in patient care, but also may render futile decades of research. Widespread professional, patient and public education, as well as continued interdisciplinary research on treatment barriers, is essential.