Bioequivalence assessment of generic drugs: an American point of view.
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Adult↗
Biomedical subjects
K Chan
Publications and source records attributed to K Chan.
Danggui (Angelica sinensis) affects the pharmacodynamics but not the pharmacokinetics of warfarin in rabbits.
Danggui is a popular traditional Chinese medicinal (TCM) herb which is easily obtained by the public. The effects of Danggui on the pharmacokinetics and pharmacodynamics of warfarin were studied in rabbits. Single subcutaneous doses (2 mg/kg) of warfarin were administered to 6 rabbits with or without 3 days treatment with oral Danggui extracts (2 g/kg twice daily). Plasma warfarin concentrations were measured by high performance liquid chromatography (HPLC) for 72 h after each of the two warfarin doses. The prothrombin time (PT) was measured daily for 3 days both during the Danggui treatment period and after warfarin doses. Danggui treatment did not affect PT on its own, but significantly lowered PT values 3 days after co-treatment with single dose warfarin. No significant variations in the single dose pharmacokinetic parameters of warfarin were observed after Danggui treatment. A separate group of 6 rabbits were given daily subcutaneous doses of warfarin (0.6 mg/kg) to achieve steady state level, followed by 3 day treatment with oral Danggui extract (2 g/kg twice daily). The slight increase in PT was not significant and two rabbits died after day 7 of the treatment period. However, there was no significant difference in steady state concentrations of warfarin after the Danggui treatment. Results indicate that precautionary advice should be given to patients who self-medicate with Danggui or other TCM products while on chronic treatment with warfarin.
Animals↗
Supersensitivity to opioid analgesics following chronic opioid antagonist treatment: relationship to receptor selectivity.
The effect of chronic opioid antagonist treatment on the analgesic potency of six opioid agonists was compared to changes in opioid receptor density and the selectivity of each agonist for mu (DAMGO), delta (DPDPE) and kappa (U69,593) opioid receptors. Mice were implanted SC with a 15-mg naltrexone or placebo pellet for 8 days. The pellets were removed and 24 h later, mice were sacrificed and binding studies were conducted, or mice were tested in analgesia (tail-flick) dose-response studies. All six analgesics acted as full agonists for both placebo and naltrexone-treated mice. Naltrexone increased the analgesic potency of methadone, etorphine, fentanyl, meperidine, and oxycodone by 1.9-3.2-fold. The analgesic potency of propoxyphene was not increased significantly (1.3-fold). In saturation binding studies in brain homogenate, naltrexone increased the Bmax of mu, delta, and kappa opioid receptors by 86, 43, and 33%, respectively, without altering Kd. Competition binding studies for each receptor type were conducted in brains from untreated mice, and KIs were determined for each agonist. All agonists had greatest selectivity toward mu compared with delta and kappa receptors. There did not appear to be an obvious relationship between receptor selectivity and the magnitude of supersensitivity. These studies indicate that supersensitivity occurs for a broad range of opioid analgesics following chronic opioid antagonist treatment in the mouse. However, the selectivity of these agonists for mu, delta, and kappa receptors does not appear to correlate with differences in supersensitivity.
Analgesics↗
Primate eta-globin DNA sequences and man's place among the great apes.
Molecular studies indicate that chimpanzee and gorilla are the closest relatives of man (refs 1-7 and refs therein). The small molecular distances found point to late ancestral separations, with the most recent being between chimpanzee and man, as judged by DNA hybridization. Kluge and Schwartz contest these conclusions: morphological characters group a chimpanzee-gorilla clade with the Asian ape orang-utan in Kluge's cladistic study and with an orang-utan-human clade in Schwartz's study. Clearly, extensive sequencing of nuclear DNA is needed to resolve by cladistic analysis the branching order within Hominoidea. Towards this goal, we are sequencing orthologues of the primate psi eta-globin locus. Here, we compare the newly completed sequences of orang-utan and rhesus monkey with human, chimpanzee, gorilla, owl monkey, lemur and goat orthologues. Our findings substantially increase the evidence indicative of a human-chimpanzee-gorilla clade with ancestral separations around 8 to 6 Myr ago. We also verify that neutral hominoid DNA evolved at markedly retarded rates.
Animals↗
Implementation of a microcontroller-based semi-automatic coagulator.
The coagulator is an instrument used in hospitals to detect clot formation as a function of time. Generally, these coagulators are very expensive and therefore not affordable by a doctors' office and small clinics. The objective of this project is to design and implement a low cost semi-automatic coagulator (SAC) prototype. The SAC is capable of assaying up to 12 samples and can perform the following tests: prothrombin time (PT), activated partial thromboplastin time (APTT), and PT/APTT combination. The prototype has been tested successfully.
Blood Coagulation Tests↗
Pethidine pharmacokinetics after intramuscular dose: a comparison in Caucasian, Chinese and Nepalese patients.
The pharmacokinetics of pethidine after a single intramuscular injection were studied in 30 male patients of Caucasian, Chinese and Nepalese extraction. There were no significant differences between the three ethnic groups in the mean time for maximum absorption (tmax) and peak plasma concentration (Cmax) of pethidine. The mean (+/- S.D.) elimination half life (t1/2) of pethidine was shorter in Caucasians (4.5 +/- 1.3 h) compared with Nepalese (6.3 +/- 1.6 h) and Chinese (8.1 +/- 3.1 h) (p < 0.01). The plasma clearance of pethidine was greater in Caucasians (14.2 +/- 4.8 ml.min-1.kg-1) than in Nepalese (12.6 +/- 2.9 ml.min-1.kg-1) and Chinese (10.0 +/- 2.9 ml.min-1.kg-1) (p < 0.05); yet the apparent renal clearance was similar (64.1 +/- 22.9, 86.7 +/- 44.5 and 61.4 +/- 30.1 ml.min-1.kg-1, respectively, for the Chinese (n = 6), Caucasian (n = 6) and Nepalese (n = 9) patients). No apparent ethnic differences were found in the tmax and Cmax of norpethidine which emerged as the major metabolite in the plasma in the three races. An apparently higher area under plasma concentration-time curve (AUC infinity [symbol: see text]) and longer elimination t1/2 of the metabolite were observed in the two Asian patient groups. It appears that both the Chinese and Indian groups did not eliminate pethidine as effectively as the Caucasians after a single intramuscular injection, which may be the result of interethnic variability in the metabolism of pethidine. Caution may be required on multiple dosing of pethidine in Asian patients due to the possible accumulation of the parent drug and its toxic metabolite, norpethidine.
Adolescent↗
Comparative pharmacokinetics of propofol in Chinese adults and children.
The pharmacokinetics of propofol were studied in 14 healthy young male Chinese adults, aged 18-38 years, undergoing minor orthopedic surgery. All patients who received a single bolus dose of propofol 2.5 mg/kg were paralyzed with atracurium and mechanically ventilated. Anesthesia was maintained with 67% nitrous oxide plus 1-2% isoflurane in oxygen with alfentanil 5 micrograms/kg intravenously as a bolus injection. Blood concentrations of propofol over the subsequent 24 hours were measured using high pressure liquid chromatography with fluorimetric detection. Data were consistently described by a three compartment model but analysis revealed two significantly different blood propofol concentration-time profiles (p less than 0.05). Five patients, designated "fast" metabolizers, demonstrated a mean elimination half-life which was shorter than that described in Chinese children, while their total body clearance was similar. Nine other patients, designated "slow" metabolizers, had a longer mean elimination half-life and slower total body clearance than those in elderly Caucasian patients. This may be suggestive of propofol metabolism at some extra-hepatic site in some patients, while other patients demonstrate marked lipophilicitic constraint of the drug by the deep compartment.
Adolescent↗
The value of saline salpingosonography as a surrogate test of tubal patency in low-resource settings.
BACKGROUND: Tubal factor, which accounts for 15-30% of infertility in all women, is common in developing countries with high rates of pelvic inflammatory disease but limited resources. It is possible to outline the fallopian tubes by injecting isotonic saline transcervically during transvaginal ultrasound scanning of the pelvis, and both color flow Doppler and 3-dimensional scanning modes have been employed to improve visualization of the tubes, with varying success. METHOD: We investigated the value of saline salpingosonography (SSG), using 2-dimensional transvaginal ultrasound scanning, as a screening test of tubal patency in 113 women by comparing SSG findings to those at HSG or laparoscopy. RESULTS: The findings at SSG correlated well with the results of HSG or laparoscopy, with an overall concordance of 82.5%. SSG was more accurate at diagnosing patent tubes than blocked tubes and was well tolerated. The results are, however, unreliable when it is difficult to inject the saline and when the patient experiences severe pain during the procedure. CONCLUSION: SSG is a useful screening tool for investigating infertility, particularly in low-resource settings.
Adult↗
Effects of ephedrine and phenylpropanolamine on the antinociceptive effects of morphine and codeine in mice.
The effects of ephedrine and phenylpropanolamine on the antinociceptive activities of morphine and codeine were investigated. Both morphine and codeine exhibited dose-dependent antinociceptive activities in the tail flick test. Ephedrine (5, 10 and 20 mg/kg) and phenylpropanolamine (5, 10 and 20 mg/kg) showed no antinociceptive effect when administered alone. The antinociceptive effects of morphine were enhanced in mice pretreated with ephedrine or phenylpropanolamine. similarly, codeine antinociception was increased in mice pretreated with ephedrine or phenylpropanolamine. In all cases, the ED50 values and single dose comparisons were shifted in the same direction. These effects on the antinociceptive potencies of morphine and codeine were found to be dose-dependent, being statistically significant at the higher dose levels of ephedrine and phenylpropanolamine used in the present study.
Analgesics↗
Disposition of pethidine in man under acidic urinary pH. 4. Kinetics after oral dose in caucasian, Chinese and Indian subjects.
The pharmacokinetics of low dose pethidine (450 micrograms kg-1) after oral administration were determined in 9 Caucasian, 9 Chinese and 9 Indian healthy volunteers under conditions of acidic urinary pH. Plasma and urine concentrations of pethidine and norpethidine were determined simultaneously by gas liquid chromatography. In all three ethnic groups the oral absorption of pethidine was rapid. The Tmax was faster in the Caucasian group (0.75 h) compared with the Chinese group (1.0 h) and the Indian group (1.5 h). No significant difference was observed in their respective lag time while the absorption t1/2 was significantly shortest in the Caucasian group who also had the highest Cmax (95.5 +/- 7.8 ng ml-1) compared with the Chinese (85.9 +/- 11.0 ng ml-1) and the Indian (58.2 +/- 3.0 ng ml-1) groups. Moderate exercise and upright posture of the Asian students might interfere with absorption and distribution of pethidine, due possibly to change in blood flow during the early stage of the study while the Caucasian subjects were in supine position. No significant difference was observed in the elimination t1/2 of pethidine between the Caucasian (8.3 +/- 0.2 h) and the Chinese (8.2 +/- 0.2 h) groups, although the Indian subjects significantly had the longest elimination t1/2 (0.1 +/- 0.3 h); this could possibly be due to their significantly higher apparent volume distribution. Under acidic urinary conditions both Chinese and Indian subjects excreted significantly more norpethidine in the urine while no difference was observed in the recovery of unchanged pethidine; this may suggest an interethnic difference in the oxidative demethylation of pethidine.
Adult↗
Pruritus and paresthesia after i.v. administration of Gd-DTPA.
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Adult↗
The simultaneous determination of pethidine and norpethidine in biofluids by nitrogen selective gas chromatography.
A rapid sensitive and selective gas chromatographic method has been developed for the simultaneous determination of pethidine and its major basic metabolite, norpethidine, using a nitrogen selective detector. The procedure involved a preliminary ethereal extraction of the drug, its metabolite and internal marker (lignocaine) from the alkalinised biological fluids (plasma or urine). The extract, after concentration, was analysed by a GC system (3 per cent OV 17 on Gas Chrom Q, 80-100 mesh) linked to a nitrogen selective detector. The calibration graphs (relating peak height ratios of the drug to internal marker and concentration) of pethidine and norepethidine were linear and reproducible over the ranges of 5 ng/ml to 100 ng/ml for plasma samples and 50 ng/ml to 1000 ng/ml for urine samples. The recovery of the drug and metabolite from plasma samples at 5 ng/ml and 100 ng/ml is 100 per cent and 84.9 per cent respectively for pethidine, and 100 per cent and 90.9 per cent respectively for norpethidine. Similar recovery from urine samples of pethidine and norpethidine is also achieved at 50 ng/ml and 1000 ng/ml levels. The reproducibility of the assay procedure for pethidine and norpethidine is 100 +/- 0.02 per cent and 100 +/- 0.04 per cent at 100 ng/ml level, and 100 +/- 0.15 per cent and 100 +/- 0.12 per cent at 5 ng/ml level.
Chromatography, Gas↗
The effect of neostigmine on pyridostigmine bioavailability in myasthenic patients after oral administration.
Plasma levels of pyridostigmine and/or neostigmine were monitored in 8 myasthenic patients who were stabilised on oral pyridostigmine bromide only (60-540 mg per day), and in 9 patients who were stabilised on both neostigmine bromide (15-480 mg per day) and pyridostigmine bromide (240-1080 mg per day), over a period of 12 hr (8.00 a.m. - 8.00 p.m.). Maximum plasma concentrations of pyridostigmine in the first and second groups of patients ranged from 12.4 to 64.5 ng per ml and 15.3 to 144.0 ng per ml respectively. Despite this general intersubject variation in bioavailability of pyridostigmine, there was a direct relationship between the area under plasma concentration-time curves (AUC) and total daily dose in the first group of myasthenic patients (r = 0.95). However, no such observation was noticed neither in all 17 patients nor in the 9 patients who were treated with both drugs. Neostigmine was detected in only one of the second group of patients. It was suggested that neostigmine might interfere with the bioavailability of pyridostigmine when both drugs are concurrently administered orally.
Administration, Oral↗
Isolation and characterization of sulphoxidation metabolites of moricizine in rat and human biological fluids.
The sulphoxidation metabolites of moricizine, moricizine sulphoxide (M-sulphoxide) and moricizine sulphone (M-sulphone) were isolated and identified in the rat bile and urine and in human plasma and urine following administration of moricizine hydrochloride. The sulphoxide and sulphone were synthesized chemically by peroxidation of moricizine hydrochloride with hydrogen peroxide at 25 degree C and 60 degree C, respectively, and were characterized by melting point determination (MP), infrared spectroscopy (IR), mass spectroscopy (MS), thin layer chromatography (TLC) and high performance liquid chromatography (HPLC). In the rats (n=7), which were kept in metabolic cages and given intravenous moricizine (0.72 mg), the mean +/- SD percentages recovered in the urine as moricizine, M-sulphoxide and M-sulphone were 0.11 +/- 0.09%, 0.74 +/- 0.45% and 5.16 +/- 4.24%, respectively. The corresponding recoveries in the bile were 0.13 +/- 0.04% as moricizine, 3.39 +/- 1.62% as M-sulphoxide and 2.16 +/- 1.07% as M-sulphone. After an oral dose of moricizine HCl (300 mg) the plasma concentrations of moricizine, M-sulphoxide and M-sulphone at 4 h in two healthy subjects were 0.43, 0.11 and 0.10 microg/ml and 0.32, 0.17 and 0.27 microg/ml, respectively for Subject 1 and Subject 2. The percentages of dose recovered in the urine as moricizine, M-sulphoxide and M-sulphone were 0.14 and 0.02%, 0.27 and 0.36%, and 0.30 and 0.24%, respectively for Subject 1 and Subject 2. It is suggested that an investigation of the disposition of moricizine and its sulphoxidation metabolites in patients will be valuable for elucidating the prolonged effects in the treatment of ventricular arrhythmias.
Adult↗
Ovine fetal-placental cocaine pharmacokinetics during continuous cocaine infusion.
OBJECTIVE: To investigate fetal-placental cocaine clearance, and to determine the fetal catecholamine and cardiovascular responses to continuous intravenous cocaine infusion in fetal sheep. METHODS: Eleven pregnant ewes and their fetuses (127 +/- 2 days' gestation; term 150 days) were chronically instrumented. Fetuses received intravenous cocaine at 0.05, 0.1, or 0.2 mg/kg/minute. Fetal cardiovascular and hematologic measurements were made before and serially for 90 minutes after initiation of the cocaine infusion. RESULTS: Steady-state fetal plasma cocaine concentrations were observed by 15 minutes of infusion and averaged 136 +/- 11, 318 +/- 65, and 610 +/- 36 ng/mL, respectively, at each dose. Fetal-placental cocaine clearance rate was independent of dose (337 +/- 39 mL/kg/minute), indicating that it is a first-order pharmacokinetic process. Fetal plasma concentration of benzoylecgonine, a principle cocaine metabolite, increased throughout the study to approximately 25% above cocaine levels by 90 minutes. There were significant increases in fetal heart rate (from 169 +/- 11 to 242 +/- 36 beats per minute), mean blood pressure (from 53 +/- 4 to 63 +/- 5 mmHg), and systolic blood pressure (from 68 +/- 2 to 80 +/- 5 mmHg), with a corresponding increase in catecholamine levels seen in the fetuses infused with 0.2 mg/kg/minute. These changes were not seen in the fetuses given lower doses of cocaine. CONCLUSION: Fetal-placental clearance of cocaine is a rapid, first-order pharmacokinetic process. During prolonged cocaine exposure, plasma benzoylecgonine concentrations accumulate significantly. Significant catecholamine and cardiovascular changes are seen in fetal sheep with a continuous infusion of cocaine at 0.2 mg/kg/minute or greater.
Animals↗
Generic warfarin: implications for patient care--another view.
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Anticoagulants↗