PubMed Health⌕ Search

Biomedical subjects

T G Brewer

Publications and source records attributed to T G Brewer.

At least 37 records · Page 2Linked to original sources
PubMed1996

Comparative bioavailability of oral, rectal, and intramuscular artemether in healthy subjects: use of simultaneous measurement by high performance liquid chromatography and bioassay.

1. The pharmacokinetic and effect kinetic properties of oral (p.o.), intramuscular (i.m.), and intrarectal (i.r.) artemether (5 mg kg-1) were compared in a crossover study in eight healthy adult volunteers. Plasma concentrations of artemether (AM) and its active metabolite dihydroartemisinin (DHA) were measured by high performance liquid chromatography with reductive mode electrochemical detection (h.p.l.c.-ECD), and plasma antimalarial activity in vitro (effect) was assessed on the same samples by a sensitive bioassay (BA). 2. Artemether was absorbed rapidly after oral administration with a mean (95% CI) Cmax for the parent compound of 406 (249 to 561) nmol l-1 and for DHA of 1009 (639 to 1379) nmol l-1 with tmax values of 1.7 (1.2 to 2.2) and 1.8 (1.4 to 2.2) h respectively. The mean (95% CI) elimination half-life of AM was 2.6 (1.8 to 3.4) h and for DHA was 1.9 (1.4 to 2.4) h. Plasma concentration and effect profiles with h.p.l.c.-ECD and BA were similar suggesting that other unidentified bioactive metabolites contributed little to antimalarial activity in vivo. 3. Absorption was slower, more variable, and DHA concentrations were lower following the i.m. and i.r. routes of administration. The mean (95% CI) relative bioavailability compared with oral artemether in the 6 h following administration AUC (0.6h) was 25 (9 to 41)% following i.m. and 35 (10 to 60)% following i.r. artemether. 4. These data demonstrate that oral artemether undergoes extensive first pass metabolism to the more active metabolite DHA. Plasma antimalarial activity following oral administration is significantly greater than following i.m. administration. The i.r. route of administration provided similar bioavailability to i.m. injection but there was considerable variability in absorption following both routes. Further studies are needed to determine whether i.r. artemether would be an effective treatment of severe malaria in the rural tropics in situations where oral or parenteral administration is not possible.

Absorption↗
PubMed1996

Mefloquine effect on disposition of halofantrine in the isolated perfused rat liver.

Halofantrine and mefloquine are antimalarial drugs used in the treatment of malaria, including that caused by chloroquine-resistant Plasmodium falciparum. Reports of drug-associated adverse reactions, including sudden death in one patient, have prompted concerns over the safety of halofantrine and the potential for drug-drug interactions. We used the isolated perfused rat liver (IPRL) model to investigate a possible hepatic metabolic or pharmacokinetic drug-drug interaction between halofantrine and mefloquine. Pharmacokinetic parameter estimates for halofantrine in the IPRL reflected the pattern seen in in-vivo studies with doses comparable with clinical doses. Halofantrine parameter estimates (mean +/- s.d.) were: volume of distribution (Vd), 7.53 +/- 1.45 mL (g liver)-1; clearance (CL), 0.11 +/- 0.07 mL min-1 (g liver)-1; initial distribution half-life (initial t1/2), 14.62 +/- 2.38 min; terminal half-life (terminal t1/2), 138.7 +/- 178.8 min; AUC 606 +/- 194 mg mL-1 min-1 (g liver)-1; elimination rate constant (Ke), 0.0135 +/- 0.012 min-1. Prior dosing with mefloquine did not affect halofantrine perfusate pharmacokinetic parameter estimates of Vd, Ke, initial and terminal t1/2 (P > 0.05). A single dose, short term (4-6 h) interaction showed significant changes in the perfusate clearance of halofantrine in mefloquine-pretreated livers using higher doses of halofantrine. Substantial changes were seen in bile production (P < 0.05) and biliary clearance (P < 0.05) of halofantrine in mefloquine-pretreated livers. These findings may have clinical implications in models utilizing multiple drug dosages or in patients with severe malaria who have disease-related cholestasis.

Animals↗
PubMed1995

Metabolism of a candidate 8-aminoquinoline antimalarial agent, WR 238605, by rat liver microsomes.

The in vitro metabolism of the 8-aminoquinoline, 8-(4-amino-1- methylbutylamino-2,6-dimethoxy-4-methyl-5-(3-trifluromethyl- phenoxy)quinoline (WR 238605), by rat liver microsomes was studied. After incubation of WR 238605 with rat liver microsomes, the metabolites were isolated either by direct solvent extraction or by extraction in the presence of ethyl chloroformate. WR 238605 was extensively metabolized to aminophenolic compounds, which underwent air oxidation during the isolation process to a mixture of quinones and quinoneimines. Because of the instability of the metabolites toward air oxidation, most of them could only be isolated as the ethoxycarbonyl derivatives by in situ derivatization with ethyl chloroformate. The metabolism of WR 238605 involved the expected metabolic pathways, such as O-demethylation, N-dealkylation, N-oxidation, and oxidative deamination. In addition, C-hydroxylation involving the 8-aminoalkylamino side chain, which was previously unknown for 8-aminoquinoline analogs, was found to be an important metabolic pathway for WR 238605. Most of the metabolites retained the 5-(m-trifluoromethyl)phenoxy group of WR 238605. Direct and indirect supporting evidence for the structure of the metabolites of WR 238605 came from the concomitant study of the in vitro metabolism of six other compounds that are putative metabolites of WR 238605.

Aminoquinolines↗
PubMed1995

Side-chain hydroxylation in the metabolism of 8-aminoquinoline antiparasitic agents.

Primaquine, 8-(4-amino-1-methylbutylamino)-6-methoxyquinoline, is an antimalarial 8-aminoquinoline derivative. Although it has been in use since 1952, its metabolism has not been clearly defined. This is due to the instability of the expected aminophenol metabolites and their amphoteric nature, which makes their isolation difficult. Recent studies on the metabolism of WR 238605, a new primaquine analog, has shown that these problems may be solved by extracting the metabolites in the presence of ethyl chloroformate. Subsequent identification of the ethoxycarbonyl derivatives of the metabolites has made it possible to define the in vitro metabolism of primaquine. The primary metabolic pathways of primaquine involved hydroxylation of the phenyl ring of the quinoline nucleus and C-hydroxylation of the 3'-position of the 8-aminoalkylamino side chain. Ring-hydroxylation of primaquine gives rise to 5-hydroxyprimaquine, which on demethylation produces 5-hydroxy-6-demethylprimaquine. Side-chain hydroxylation of primaquine gives rise to 3'-hydroxyprimaquine, which also undergoes O-demethylation to 3'-hydroxy-6-demethylprimaquine. 6-Demethylprimaquine, a putative metabolite of primaquine, also underwent metabolism involving 3'-hydroxylation of the side chain. WR 6026, 8-(6-diethylaminohexylamino)-6-methoxy-4-methylquinoline, is an antileishmanial 8-aminoquinoline derivative. The in vitro metabolism of WR 6026 also results in the formation of side chain-oxygenated metabolites. The present results, together with previous observations on the metabolism of WR 238605 and closely related primaquine analog, suggest that side-chain oxygenation is an important metabolic pathway of antiparasitic 8-aminoquinoline compounds in general.

Aminoquinolines↗
PubMed1994

Neurotoxicity in animals due to arteether and artemether.

Several artemisinin (qinghaosu) derivatives have been developed and are in use as antimalarial drugs but scant animal or human toxicity data are available. We noted a progressive syndrome of clinical neurological defects with cardio-respiratory collapse and death in 5/6 dogs dosed daily for 8 d with intramuscular arteether (AE) at 20 mg/kg/d in a pharmacokinetic study. Neurological findings included gait disturbances, loss of spinal reflexes, pain response reflexes and prominent loss of brain-stem and eye reflexes. Electrocardiography showed prolongation of the QT interval corrected for rate (QTc). Prominent neuropathic lesions were sharply limited to the pons and medulla. Neurological injury, graded by a pathologist 'blinded' to dose group, showed a dose-related region-specific injury which was most pronounced in the pons and medulla in all animals. Rats treated with AE and artemether (AM) at 12.5 to 50 mg/kg/d for 28 d confirmed clinical neurological abnormalities with high doses (> 25 mg/kg/d) after 6-14 d. Neuropathological examination of rat brain sections at 5 levels from the rostral cerebrum to the caudal medulla showed a dose-related pattern of injury characterized by hyalinized neuron cell bodies and loss of Nissl substance; changes congruent with those noted in dogs. No significant difference was noted in the extent, type, or distribution of lesions in the brains of rats treated with equivalent doses of AE or AM.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Neurotoxicity of artemisinin analogs in vitro.

The sesquiterpene endoperoxide antimalarial agents arteether and artemether have been reported to cause neurotoxicity with a discrete distribution in the brain stems of rats and dogs after multiple doses. The nature and distribution of the brain lesions suggest a specific neuronal target, the identity of which is unknown. In order to further investigate artemisinin analog-induced neurotoxicity, we evaluated several in vitro models: fetal rat primary neuronal cultures, fetal rat secondary astrocyte cultures, and transformed neuronal cultures (rat-derived neuroblastoma NG108-15 and mouse-derived neuroblastoma Neuro-2a). Results indicate that toxicity was specific for neuronal cell types but not glial cells. Neurotoxicity, as indexed by liberation of lactate dehydrogenase and/or inhibition of radiolabelled-leucine uptake, was seen in all three neuronal culture types, implicating a common target. In vitro neurotoxicity was dose and time dependent. Acute exposure to drug results in delayed, but not immediate, manifestations of cell toxicity. Structure-activity comparisons indicate that substitutions at positions 9 and 10 and stereoisomerism at position 10 of the artemisinin backbone influence the degree of toxicity. The endoperoxide is necessary but not sufficient for toxicity. Sodium artesunate and dihydroartemisinin, a metabolite common to all artemisinin analogs currently being developed for clinical use, are the most potent of all analogs tested. These results are consistent with a specific neuronal target, but the identity of the target(s) remains unknown.

Animals↗
PubMed1994

Fatal neurotoxicity of arteether and artemether.

Artemisinin (qinghaosu) and several derivatives have been developed and are in use as antimalarial drugs but scant information is available regarding animal or human toxicity. Following a eight-day, multiple-dose, pharmacokinetic study of arteether (AE) (10 mg/kg/day [n = 6] and 20 mg/kg/day [n = 6]) in dogs, all high-dose animals displayed a progressive syndrome of clinical neurologic defects with progressive cardiorespiratory collapse and death in five of six animals. Neurologic findings included gait disturbances, loss of spinal and pain response reflexes, and prominent loss of brain stem and eye reflexes. Animals had prolongation of QT interval corrected for rate (QTc) on electrocardiograms (ECGs) with bizarre ST-T segment changes. Prominent neuropathic lesions were noted to be primarily limited to the pons and medulla. Similar lesions with dose-related severity were noted in eight other dogs studied in a second study with intramuscular (IM) administration of AE in sesame oil during a 28-day, dose-ranging study using 5, 10, 15, and 20 mg/kg/day. Injury, graded by a pathologist blinded to the dose group, showed a dose-related, region-specific injury in all animals that was most pronounced in the pons. Further studies in Sprague-Dawley rats using IM administration of AE and artemether (AM) at a dose of 12.5-50 mg/kg/day for 28 days confirmed the onset of a clinical neurologic syndrome with dose-related changes in body weight, activity, and seizure-like activity, stereotypic movement disorders, and ECG changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

High-performance liquid chromatographic method for the determination of a candidate 8-aminoquinoline antimalarial drug (WR 242511) using oxidative electrochemical detection.

WR 242511 (or I) is a new compound of the 8-aminoquinoline class designed to replace primaquine for the treatment of malaria. In order to perform preclinical and clinical testing, an assay was needed to determine drug levels in plasma samples. A simple and reliable reversed-phase high-performance liquid chromatographic (HPLC) method for the measurement of I in plasma using oxidative electrochemical detection is described. A 250-microliters plasma sample containing WR 256408 (or II) as internal standard was extracted with tert.-butyl methyl ether-2-propanol. A 25-microliters aliquot of the extractant was used for HPLC analysis. The mobile phase was 50:50 acetonitrile-sodium acetate (50 mM, pH 6) with 1 mM EDTA. Compounds I and II were separated within 10 min. The limit of detection for I was 10 ng/ml (plasma) with a recovery around 72%. The method was validated in a dog experiment where levels were followed for 48 h. The method is sensitive and robust and can be used for routine drug analysis during pharmacokinetic studies.

Animals↗
PubMed1993

Treatment of acute gastroesophageal variceal hemorrhage.

About 30% to 35% of patients with portal hypertension bleed from gastroesophageal varices and mortality remains high reflecting the challenges of effectively dealing with the bleeding event itself and the problems of underlying liver disease. Careful resuscitation and control of risk of complications is the most essential element of medical therapy (Fig. 2). Use of newer, more effective drug combinations with vasopressin or somatostatin permit control of hemorrhage in the majority of patients with fewer drug-induced complications. Endoscopic sclerotherapy and, more recently, banding therapy provide immediate control of hemorrhage and eradication of varices and rebleeding in up to 90% of patients. Persistent, recurrent bleeding in the small number of remaining patients can be effectively managed by "portacaval shunt rescue" or orthotopic liver transplantation in selected cases with acceptable surgical morbidity and mortality. The contribution and role of the TIPS procedure is unknown but very promising; at least as a bridge procedure in patients awaiting transplantation. Until appropriate prospective, comparative trials are performed, the role of TIPS as a long-term alternative to portacaval shunt surgery or other endoscopic or surgical options remains unknown.

Acute Disease↗
PubMed1993

Benzocaine-induced methemoglobinemia attributed to topical application of the anesthetic in several laboratory animal species.

In a screening study, a common benzocaine-containing anesthetic was topically applied to the following species: dogs (n = 11), domestic shorthair cats (n = 38), Long-Evans rats (n = 22), Sprague-Dawley rats (n = 11), ferrets (n = 6), rhesus monkeys (n = 10), cynomolgus monkeys (n = 10), owl monkeys (n = 10), New Zealand White rabbits (n = 18), miniature pigs (n = 9), ICR mice (n = 4), C3H mice (n = 4), and C57BL/10SnJ mice (n = 24). All animals, except mice and rats, received a 2-second spray to the mucous membranes of the nasopharynx for an estimated dose of 56 mg. A 2-second spray to rodents' oral mucous membranes delivered too great a volume of fluid for these animals; therefore, an equivalent dose was applied to the oral mucosa membranes by use of a 23-gauge needle and syringe. Initial (baseline) blood samples, as well as 4 blood samples taken every 15 minutes after drug application, were analyzed for methemoglobin (MHb), using an oximeter. Positive MHb response (> 3 SD above baseline) was seen in individuals of all groups. The study was repeated in dogs several months later to confirm low response. Response to benzocaine spray was observed in most animals tested, with response peaking between 15 and 30 minutes after dosing. Positive MHb response ranged from 3.5 to 38%, was detected in > 95% of individual animals, and ranged from 15 to 60 minutes after drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed1992

Primary and secondary metabolism of pentamidine by rats.

The antiprotozoal drug pentamidine [1,5-bis(4'-amidinophenoxy)pentane] has been previously shown to be metabolized by rat liver microsomes, and five of the seven putative primary metabolites have been identified. With the synthesis and identification of 5-(4'-amidinophenoxy)pentanoic acid and 5-(4'-amidinophenoxy)-1-pentanol as the remaining two metabolites, the primary metabolism of pentamidine in rats appears fully characterized. Use of [14C]pentamidine with rat liver microsomes confirms this conclusion, since no unidentified radioactive peaks were detected by high-performance liquid chromatography (HPLC). Isolated, perfused rat livers were used with [14C]pentamidine to identify secondary metabolites. Only two novel radioactive peaks were detected by HPLC analysis of perfused liver samples. The treatment of liver samples with sulfatase or beta-glucuronidase resulted in the reduction or elimination of these peaks and gave rise to peaks identified as para-hydroxybenzamidine and 5-(4'-amidinophenoxy)pentanoic acid. It was concluded from these results that only these two primary metabolites were conjugated with sulfate or glucuronic acid. After 4 h of incubation in the perfused liver system, approximately 15% of the recovered radiolabel was pentamidine. These results suggest that pentamidine metabolism can be rapid and extensive in rats.

Animals↗
PubMed1991

Determination of the antimalarial arteether and its deethylated metabolite dihydroartemisinin in plasma by high-performance liquid chromatography with reductive electrochemical detection.

A rapid, sensitive, and specific reversed-phase HPLC method using reductive electrochemical detection has been developed for the determination of arteether and its O-dealkylated metabolite dihydroartemisinin (DQHS) in plasma. The internal standard assay was validated between 25 and 1000 ng/mL, with a coefficient of variation of greater than 10% for both intra- and interday accuracy and precision. An assay for determination of arteether only, using the n-propyl ether of DQHS as internal standard, was also developed and validated from 5-500 ng/mL. A new automated sample deoxygenation and injection system is used to greatly increase sample throughput. These methods have been used to study the pharmacokinetics of arteether after intravenous and intramuscular administration.

Animals↗
PubMed1990

The disposition of an antileishmanial 8-aminoquinoline drug in the isolated perfused rat liver: thermospray liquid chromatography-mass spectrometry identification of metabolites.

1. The disposition of the candidate antileishmanial drug 8-(diethylaminohexylamino-6-methoxy-4-methyl quinoline dihydrochloride (I) has been investigated in the isolated perfused rat liver preparation after the administration of 5 mg/kg (25 microCi) of 14C-I. 2. The perfusate concentration of unchanged I declined biexponentially over the 4 h study period, with a distribution t1/2 of 3.3 +/- 0.3 min and a terminal t1/2 of 35.4 +/- 13.6 min. The area under the perfusate plasma concentration/time curve (AUC0-last time point) was 53.3 +/- 15.7 micrograms min/ml, representing 96% of the area under the curve extrapolated to infinity. the perfusate contained predominantly the carboxylic acid metabolite of I, as well as trace quantities of metabolites detected and identified in bile. 3. Biliary excretion of total 14C accounted for 18.2 +/- 5.0% of the dose, only 2.8 +/- 0.7% was identified by h.p.l.c. analysis as unchanged I. The remainder of the bile contained the desethyl metabolite of I as well as a minimum of 12 more polar metabolites. After 4 h, a total of 39.0 +/- 8.3% of dosed 14C was recovered from the liver tissue. Subcellular fractionation of the livers revealed 24.6 +/- 2.2% of 14C to be located in the 10,000 g pellet. 4. Thermospray liquid chromatography-mass spectrometry analysis of untreated bile and bile treated with beta-glucuronidase or aryl sulphatase permitted identification of some of these metabolites, revealing the presence of the parent drug, desethyl metabolite, 6-desmethyl glucuronide, the 6-desmethyl desethyl glucuronide and the side-chain cleaved 8-amino N-glucuronide metabolites of I, as well as the 6-desmethyl sulphate and the 6-desmethyl desethyl sulphate. Two dihydroxylated metabolites were also detected; however, further structure elucidation is required for unambiguous identification.

Aminoquinolines↗
PubMed1989

Pancreatic duct-portal vein fistula.

We describe a case of pancreatic duct-portal vein fistula discovered by endoscopic retrograde cholangiopancreatography, with confirmatory computed tomography and angiographic studies. The fistula was associated with chronic pancreatitis that was complicated by recurrent gram-negative bacteremia and peripheral subcutaneous fat necrosis, although pancreatic pseudocyst was not present. Even though surgical treatment was recommended, medical complications precluded surgery and the patient recovered with supportive therapy only. Follow-up endoscopic retrograde cholangiopancreatography showed spontaneous closure of the fistulous connection.

Cholangiopancreatography, Endoscopic Retrograde↗
PubMed1989

Diagnostic laparoscopy: a prospective review of 100 cases.

The perceived role of laparoscopy in the management of liver disease has changed because of the widespread use of image-guided biopsy. Laparoscopy, however, permits direct inspection of the liver surface and the abdominal cavity, as well as tissue sampling. In order to assess the utility of laparoscopy, and specifically, the diagnostic value of direct visualization of the liver surface, we prospectively collected information on 100 consecutive patients undergoing laparoscopy. The contribution of the laparoscopic findings to patient management and the predictive value of the laparoscopic diagnosis compared to histology were assessed. Laparoscopy had a 95% diagnostic yield. Liver surface characteristic consistent with malignancy, cirrhosis, or fibrosis were sensitive and specific predictors of histologic findings. We conclude that laparoscopy continues to be a valuable diagnostic procedure, especially in cases where accurate assessment of the liver architecture is required.

Adolescent↗
PubMed1989

The disposition of ethiofos (WR-2721) in the isolated perfused rat liver.

We have investigated the disposition of ethiofos (20 mg, 4 microCi [14C]ethiofos) in the isolated perfused rat liver preparation to determine the hepatic contribution to the poor oral bioavailability of the drug. Ethiofos clearance (10.6 +/- 3.3 ml h-1) was only a small fraction (1.2 +/- 0.03%) of the perfusate flow rate. The elimination half-life was calculated at 7.1 +/- 1.9 h. The area under curve, AUC0-4 h, for ethiofos (2858 +/- 314 nM h ml-1) was not significantly different from that of 14C (3038 +/- 692 nM h ml-1) or total material convertible to WR-1065 (total WR-1065, 3324 +/- 612 nM h ml-1), indicating a low level of metabolism. The AUC0-4 h for free WR-1065 (37.5 +/- 23.3 nM h ml-1) was less than 2% of ethiofos. Biliary elimination of ethiofos, WR-1065, and 14C was below 1%. At 4 h postdose, 7.9 +/- 1.9% of the dose of radioactivity remained in the liver. Less than 1.5% could be identified as ethiofos (0.12 +/- 0.09%) or total WR-1065 (1.09 +/- 0.05%). Ethiofos, 14C, and total WR-1065 were approximately evenly distributed between the 10,000-g pellet and supernatant. However, significantly more ethiofos, WR-1065, and 14C were recovered from the 105,000-g supernatant compared with the pellet. In summary, both the metabolism and biliary elimination of ethiofos and its derivatives were sparing. Hence it is likely that in the rat, the contribution of the liver to the presystemic biotransformation and poor bioavailability of ethiofos is relatively minor.

Amifostine↗