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Biomedical subjects

M Ashton

Publications and source records attributed to M Ashton.

At least 37 records · Page 2Linked to original sources
PubMed1999

High in situ rat intestinal permeability of artemisinin unaffected by multiple dosing and with no evidence of P-glycoprotein involvement.

The objective of this study was to investigate whether the decrease in artemisinin bioavailability after repeated oral dosing in humans can be a result of increased efflux of artemisinin by P-glycoprotein or decreased membrane transport at the intestinal barrier. The effective jejunal permeability (Peff) of artemisinin was investigated using an in situ rat perfusion model. Fifty-four rats were randomized to one of three treatment arms: no pretreatment, pretreatment with artemisinin emulsion for 5 days (60 mg/kg/day, p.o. ), or pretreatment with emulsion vehicle for 5 days. The rats within each treatment arm were randomized further to be jejunally perfused with either low (500 ng/ml) or high (5000 ng/ml) artemisinin concentration or low artemisinin concentration plus the P-glycoprotein inhibitor R,S-verapamil (400 microg/ml). Perfusate samples were assayed for content of artemisinin, R,S-verapamil, and perfusion viability markers. Artemisinin Peff was 1.44 +/- 0.38, 1. 17 +/- 0.32, and 1.71 +/- 0.29 (.10(-4), cm/s) in rats receiving no pretreatment and perfused with low, high, or low artemisinin concentration plus verapamil, respectively. Multiple oral dosing of artemisinin did not affect the jejunal permeability of artemisinin. R,S-verapamil Peff was similar in artemisinin-pretreated rats (1.09 +/- 0.54. 10(-4), cm/s) and rats pretreated with only vehicle (1.07 +/- 0.37. 10(-4), cm/s). The decrease in artemisinin bioavailability after multiple oral dosing in human is probably not a result of changes in P-glycoprotein expression or general intestinal transport. It seems more likely attributed to increased hepatocellular activity. Furthermore, artemisinin exhibits high jejunal permeability and is neither a substrate nor inducer of P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

No effect of chloroquine on theophylline pharmacokinetics in the rat.

The immediate and delayed effects of chloroquine on theophylline kinetics were investigated in rats pretreated with chloroquine diphosphate (45 mg kg-1) or saline intraperitoneally. One hour or 4 days after chloroquine, theophylline (10 mg kg-1) was administered intravenously. Compared with the control animals pretreated with saline, the disposition parameters of theophylline was not altered after pretreatment with chloroquine. Chloroquine did not affect the in vivo metabolism of theophylline in the laboratory rat. A possible decrease in theophylline's volume of distribution at 4 days, but not immediately, after administration of chloroquine was suggested, although this just failed to achieve statistical significance (p = 0.055). Being marginal, it is unlikely to be of clinical concern. It is concluded that, judged from these animal data, there is no evidence of a drug-drug pharmacokinetic interaction for the combination of chloroquine and theophylline.

Animals↗
PubMed1998

Artemisinin pharmacokinetics in healthy adults after 250, 500 and 1000 mg single oral doses.

Eight healthy male, Vietnamese subjects were administered 1 x 250, 2 x 250, and 4 x 250 mg artemisinin capsules in a cross-over design with randomized sequence with a 7-day washout period between administrations. The inter-individual variability in artemisinin pharmacokinetics was large with parameter coefficient of variation (CV) typically between 50-70%. The parameter with the smallest variability was the elimination half-life (CV approximately equal to 30-40%). Analysis of variance indicated also a large intra-subject variability. (CV, or = 24%) for the dose-normalized area under the plasma concentration-time curve (AUC/dose). The pharmacokinetic results suggested artemisinin to be subject to high pre-systemic extraction. Artemisinin half-life could not predict the extent of in vivo exposure to the drug, there being no correlation between half-life and oral clearance. Artemisinin oral plasma clearance was about 400 L h-1 exhibiting a slight decrease with dose, although the effect was weak. Thus results from studies using different artemisinin doses may, within the studied dose range, be compared without the complication of disproportionate changes in drug exposure with varying dose levels. Half-lives appeared to increase with dose. An observed period effect in the analysis of variance was tentatively associated with time-dependency in artemisinin pharmacokinetics. There was a high correlation between artemisinin plasma concentrations determined at various time-points after drug administration and the AUCs after the 500 and 1000 mg doses, but less so after the 250 mg dose. This may show a tentative approach to assess the systemic exposure of the patients to artemisinin from the determination of artemisinin plasma concentrations in one or two plasma samples only. Artemisinin was well tolerated with no apparent dose or time dependent effects on blood pressure, heart rate or body temperature.

Administration, Oral↗
PubMed1998

Artemisinin kinetics and dynamics during oral and rectal treatment of uncomplicated malaria.

OBJECTIVE: To compare parasite clearance times after oral and rectal administration of artemisinin in adults with uncomplicated malaria and to relate pharmacodynamics with artemisinin kinetics and to disclose any pharmacokinetic changes during treatment. METHODS: Thirty male Vietnamese patients with falciparum malaria were randomized to treatment with 500 mg artemisinin daily by either the oral or rectal route of administration. Parasite densities in capillary blood were determined by microscopy every 4 to 6 hours. Artemisinin plasma concentrations on the first and last day of treatment were determined by HPLC and unbound fractions in plasma were determined by ultrafiltration. RESULTS: Mean parasite clearance times and 95% confidence intervals (95% CI) were 25 (95% CI, 16 to 33) and 29 (95% CI, 23 to 35) hours during oral and rectal treatment, respectively. The bioavailability after rectal relative to oral artemisinin was 30%. Artemisinin areas under the plasma concentration-time curve (AUC) on the fifth (last) day of oral or rectal treatment were 30% (95% CI, 4% to 56%) and 40% (95% CI, -6% to 91%), respectively, of those after the first dose. The fraction unbound in plasma was 15% (95% CI, 12% to 19%), increasing marginally during treatment. No relationship was found between main clinical end points and drug exposure, although indices for the rapidity of response onset were lower after oral treatment and correlated to unbound AUC values (rS = -0.7; p < 0.001). CONCLUSIONS: The similarity in parasite clearance times despite lower drug levels during rectal treatment suggests that initial oral doses may be unnecessarily high. The singular time dependency of artemisinin pharmacokinetics, attributed to autoinduction of drug elimination, has possible implications for combination chemotherapy. Decreasing artemisinin concentrations during treatment may partly explain recrudescences and increase the risk for resistance development.

Administration, Oral↗
PubMed1998

Artemisinin induces omeprazole metabolism in human beings.

OBJECTIVE: This study investigated whether time-dependent artemisinin pharmacokinetics correlated to CYP3A4 or CYP2C19 activity in vivo. METHODS: Artemisinin (two oral doses per day of 250 mg) was given to nine healthy Vietnamese subjects for 7 days (day 1 to day 7). Single 20 mg doses of omeprazole were given orally on day -7, day 1, and day 7. Single doses of artemisinin and omeprazole were given in combination on day 14 after a 6-day washout period. The pharmacokinetics of artemisinin, omeprazole, hydroxyomeprazole, and omeprazole sulfone were evaluated on days -7, 1, 7, and 14. On the same days urine was collected for the determination of 6beta-hydroxycortisol and cortisol excretion. RESULTS: Areas under plasma concentration-time curves (AUC) for artemisinin and omeprazole decreased on day 7 to 20% (95% confidence intervals, 13%, 28%) and 35% (25%, 46%), respectively, compared with values on day 1. AUC ratios for hydroxyomeprazole/omeprazole increased 2.2-fold (1.7, 2.7) on day 7 compared with values on day 1. All values were normalized at day 14. There were no significant changes in the omeprazole sulfone/omeprazole ratio or in the 6beta-hydroxycortisol/cortisol ratio between the study days. In one subject found to have poor CYP2C19 metabolization, the elimination of omeprazole increased after artemisinin exposure, with no change in the hydroxyomeprazole/omeprazole AUC ratio. CONCLUSION: Artemisinin did not alter CYP3A4 activity, whereas an increase in CYP2C19 activity was observed. The increased elimination of omeprazole in both poor and extensive CYP2C19 metabolizers suggests artemisinin induces both CYP2C19 and another enzyme.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1998

Artemisinin population pharmacokinetics in children and adults with uncomplicated falciparum malaria.

AIMS: To investigate the pharmacokinetics of the antimalarial artemisinin in the field setting using sparsely collected data. METHODS: Artemisinin concentrations were determined by h.p.l.c. in a total of 107 capillary plasma samples collected on the first day and in 33 samples on the last day of a 5-day oral artemisinin regimen of 10 mg kg(-1) day(-1) in 23 paediatric (aged 2-12 years) and 31 adult (aged 16-45 years) Vietnamese patients with uncomplicated falciparum malaria. The population model was developed using NONMEM, incorporating interoccasion variability and accounting for a systematic change in artemisinin pharmacokinetics with time, modelled as a change in oral bioavailability. RESULTS: Clinical efficacy, in terms of parasite clearance and fever subsidence times, was comparable between children and adults. A one-compartment model with separate pharmacokinetic estimates for children and adults was found best to describe the disposition of artemisinin after oral administration. The population estimates for artemisinin clearance and distribution volume, respectively, were 432 1 h(-1) and 16001 for adults and 14.41 h(-1) kg(-1) and 37.91 kg(-1) for children, with an intersubject variability (collectively for both age groups) of 45% and 104%, respectively. The oral bioavailability was estimated to decrease from Day 1 to Day 5 by a factor of 6.9, a value found to be similar for children and adults. CONCLUSIONS: Artemisinin pharmacokinetic data was successfully derived in both paediatric and adult patients using 2-3 capillary blood samples taken in conjunction with parasitaemia monitoring. This study's findings advocated the dosing of artemisinin to children according to bodyweight and to adults according to a standard dose.

Administration, Oral↗
PubMed1998

Artemisinin pharmacokinetics is time-dependent during repeated oral administration in healthy male adults.

The pharmacokinetics of the antimalarial artemisinin exhibited an unusual time dependency during a 7-day oral daily regimen of 500 mg in 10 healthy, male Vietnamese adults. Artemisinin areas under the plasma concentration-time curve (AUC) decreased to 34% (median) by day 4 with a further decrease by day 7 to only 24% of values obtained after the first day of administration. In seven subjects restudied after a 2-week washout period, artemisinin AUCs had almost normalized, demonstrating the reversibility of the time-dependent drug disposition. The results suggest artemisinin exhibits an auto-inductive effect on drug metabolism of an unusual magnitude. This may partly explain why some patients on standard doses, due to subparasiticidal drug levels toward the end of a standard regimen, do not completely clear parasites. Further, the possibility of drug-drug metabolic interactions during combination regimens is implicated.

Administration, Oral↗
PubMed1997

In-vitro interaction of artemisinin with intact human erythrocytes, erythrocyte ghosts, haemoglobin and carbonic anhydrase.

The kinetics of the interaction of the antimalarial compound artemisinin with human erythrocytes, erythrocyte ghosts, haemoglobin and carbonic anhydrase were evaluated in-vitro. Artemisinin plasma concentrations, measured by HPLC (high pressure liquid chromatography), decreased with time during incubations with whole blood and erythrocyte suspensions of varying haematocrit. Artemisinin concentrations declined more rapidly during incubations under oxygen-poor as compared to oxygen-rich conditions. Artemisinin concentrations did not decrease during incubation with erythrocyte ghosts suspended in plasma suggesting that the drug does not bind avidly to red blood cell membranes. There was no decline in concentrations of artemisinin in the presence of carbonic anhydrase. The disappearance of the drug in solutions containing haemoglobin was very rapid and was even more so when the incubation was performed under an argon-instead of oxygen-rich atmosphere. The results suggest that drug blood clearance may be considered for inclusion in a pharmacokinetic model, but does not invalidate in-vivo plasma concentration-time data and their relevance for clinical effects. Furthermore, caution is advised when relating measurements of in-vitro potency to drug levels in patients. Finally, the enhanced artemisinin disappearance when oxygen tension is low may contribute towards the explanation of the selective toxicity of the endoperoxide drugs to Plasmodium falciparum parasite.

Antimalarials↗
PubMed1997

Single-dose, comparative study of venous, capillary and salivary artemisinin concentrations in healthy, male adults.

A comparison of venous plasma, capillary plasma, and saliva pharmacokinetics of artemisinin was performed in four healthy subjects given a single 500 mg dose. Artemisinin was determined to be 88% bound in venous plasma. Saliva levels were more closely related with (unbound) capillary than with venous plasma concentrations. Matrix comparisons demonstrated artemisinin saliva/plasma and capillary/venous concentration ratios of well over one initially, which decreased with time to stabilize after a 3-hr period. Following this stabilization period, differences in capillary and saliva (relative to venous) levels were independent of both drug concentration and time. These observations, together with improved correlations of concentrations measured 3 hr following drug intake compared with correlations for the entire data set, indicate a putative arterial-venous concentration difference for the drug. The capillary and saliva matrices proved promising replacements for venous sampling in the quantitation of artemisinin concentrations. Due to their relative case of obtainment and a greater patient acceptability, capillary and saliva sampling may be of particular value in field-based and pediatric pharmacokinetic studies with artemisinin.

Administration, Oral↗
PubMed1996

Atypical apocrine adenosis of the breast: a clinicopathologic study of 37 patients with 8.7-year follow-up.

BACKGROUND: Apocrine metaplasia is occasionally superimposed on sclerosing adenosis (apocrine adenosis) in breast biopsies, and cytologic atypia is sometimes present (atypical apocrine adenosis). The long term risk of patients developing breast carcinoma subsequent to the diagnosis of this lesion is unknown. METHODS: Atypical apocrine adenosis was defined as apocrine adenosis with enlarged nucleoli and a greater than threefold variation in nuclear area. Lesions with recognizable cytoarchitectural patterns of intraductal carcinoma were excluded. Surveillance, Epidemiology and End Results (SEER) data were used as the reference population for calculations of relative risk. RESULTS: Thirty-seven women with atypical apocrine adenosis had a mean follow-up of 8.7 years. Four patients developed invasive ductal carcinoma of the breast (3 ipsilateral, 1 contralateral) after a mean of 5.6 years. The relative risk of developing carcinoma was 5.5 (95% confidence interval [CI], 1.9-16). All patients who developed carcinoma were older than age 60 at the time of breast biopsy showing atypical apocrine adenosis, and carcinoma developed at a mean age of 70 years. In the older than 60 years age group (11 patients), the relative risk of developing carcinoma was 14 (95% CI, 4.1-48). CONCLUSIONS: Atypical apocrine adenosis confers an increased risk of developing breast carcinoma in women older than age 60, and the risk in younger women is probably low. Some cases of atypical apocrine adenosis may represent in situ apocrine carcinomas that are difficult to diagnose because of the absence of the usual architectural features of intraductal carcinoma.

Adult↗
PubMed1996

Clinical efficacy and pharmacokinetics of artemisinin monotherapy and in combination with mefloquine in patients with falciparum malaria.

1. The aim of this study was to assess the pharmacokinetics, clinical efficacy and safety of artemisinin alone and in combination with mefloquine. 2. Thirty-eight adults with symptomatic Plasmodium falciparum malaria were randomly assigned to receive either artemisinin (500 mg single dose followed by another 500 mg on day 1 and then 250 mg twice daily for 4 days) or artemisinin (500 mg single dose followed by 750 mg on day 1 and then 250 mg three times daily for one more day) in co-administration with mefloquine (250 mg three times daily for the first day). All drug administration was by the oral route. Patients were hospitalized at the Kibaha Designated District Hospital, Kibaha, Tanzania, for 6 days and a follow up for 3 weeks was performed. 3. Treatment with the artemisinin/mefloquine combination resulted in a shorter parasite clearance time (PCT) of 24 (22, 27; 95% confidence interval) h vs 31 (27, 36) h and fever subsidence time (FST) of 14 (12, 16) h vs 20 (18, 23) h compared with artemisinin monotherapy. The 95% CI for the difference of the PCT and FST were 1.7, 12 and 3, 10, respectively. Parasites were detected in 7 out of 17 patients (41%) receiving artemisinin monotherapy at the 3rd and 4th week follow up visits. No parasites were detected after the combination therapy. 4. The maximum plasma concentrations (Cmax) were similar after artemisinin monotherapy (615.4 +/- 387.0 ng ml-1) and in combination with mefloquine (851.8 +/- 523.6 ng ml-1). Elimination half-lives (t1/2) were also identical at 2.2 +/- 0.6 h and 2.5 +/- 0.7 h, respectively. However, the AUC values were higher (P < 0.05) after combination therapy (3252 +/- 1873 ng ml-1 h) than after monotherapy (2234 +/- 1502 ng ml-1 h). The oral clearance values were lower (P < 0.05) after combination therapy (195.4 +/- 86.9 l h-1) than after monotherapy (314.3 +/- 189.4 l h-1). PCT and FST normalized to initial parasitaemia correlated with AUC(0, t) (rs = 0.56, P = 0.02, rs = 0.58, P = 0.01, respectively) and with Cmax (rs = 0.62, P = 0.01, rs = 0.68, P = 0.005, respectively) in the artemisinin monotherapy only. 5. One patient on the combination therapy developed a psychiatric condition and two patients on the monotherapy developed skin itch.

Administration, Oral↗
PubMed1995

Island flaps including the Bezier type in the treatment of malignant melanoma.

Despite the trend in current surgical practice in the treatment on melanoma to produce smaller excisional defects, any technique which can introduce a surgical closure that does not require split skin grafting must be of benefit. This paper introduces and illustrates a range of island flap techniques that employ no skin grafting for the treatment of malignant melanoma defects. The new cutaneous island flap described, termed the Bezier or the French Curve, employs a double V-Y appositional closure method, thus giving a more refined reconstructive result that fits into the line of the body curves aesthetically. The design of the Bezier flap is almost identical in size and shape to the excisional defect, with a facial or muscular base for vascular support. Appropriate guidelines that determine the design and application of this island flap technique are listed. They are illustrated both diagrammatically and clinically. Other flaps illustrated include fasciocutaneous island flaps and myocutaneous island flaps that use a single V-Y flap appositional closure technique. All these flaps were designed with special reference to the dermatomes, which act as an aid memoire upon which the flaps are marked.

Adolescent↗
PubMed1995

Role of elevated plasma soluble ICAM-1 and bronchial lavage fluid IL-8 levels as markers of chronic lung disease in premature infants.

BACKGROUND: Pulmonary neutrophilia characterises both the relatively transient inflammation associated with infant respiratory distress syndrome (IRDS) and the persistent inflammation of chronic lung disease. The possibility that persistently raised markers of inflammation indicate the development of chronic lung disease in low birth weight (< 1730 g) preterm (< 31 weeks) infants was therefore investigated. METHODS: Soluble ICAM-1 (sICAM-1) levels in plasma, and interleukin (IL)-8 and myeloperoxidase (MPO) levels in bronchial lavage fluid (BLF) obtained from 17 infants on days 1, 5, and 14 following birth were measured and correlations with the number of neutrophils in BLF sought. Peripheral neutrophils were isolated on Polymorphoprep and chemotactic responsiveness to IL-8 was assessed using micro Boyden chambers. RESULTS: Sixteen infants developed IRDS and, of these, 10 infants subsequently developed chronic lung disease. Levels of IL-8 in BLF at 14 days of age correlated with the long term requirement for intermittent positive pressure ventilation (IPPV). Interleukin 8 levels in BLF correlated with neutrophil numbers and MPO concentration, suggesting both recruitment and activation in response to this cytokine. Antibody depletion studies showed that approximately 50% of total neutrophil chemotactic activity in BLF was due to IL-8. No difference in peripheral neutrophil chemotactic responsiveness at any age was observed for infants with IRDS or chronic lung disease. Plasma soluble intercellular adhesion molecule (sICAM-1) was higher at 14 days of age in infants who developed chronic lung disease than in those with resolving IRDS, and correlated with severity of disease, as indicated by duration of IPPV. CONCLUSIONS: The results indicate that high levels of plasma sICAM-1 and IL-8 in BLF at day 14 correlate with the development of chronic lung disease and indicate the severity of disease.

Biomarkers↗
PubMed1995

Efficacy of oral and intravenous artesunate in male Tanzanian adults with Plasmodium falciparum malaria and in vitro susceptibility to artemisinin, chloroquine, and mefloquine.

The clinical efficacy of oral and intravenous (iv) artesunate was compared in an open randomized trial in 50 male adult patients with uncomplicated Plasmodium falciparum malaria in Kibaha, Tanzania. Oral artesunate treatment was started with 2 x 50 mg initially followed by 50 mg 12 hr later and then 50 mg twice a day for four days (total dose = 550 mg or 9.6 mg/kg). Intravenous artesunate administration began with 2 x 0.8 mg/kg initially followed by 0.8 mg/kg 12 hr later and then 0.8 mg/kg twice a day for four days (total dose = 8.8 mg/kg). The mean +/- SD parasite clearance times (PCTs) were nearly identical at 23.4 +/- 5.9 hr and 24.2 +/- 7.2 hr after oral and iv administration, respectively. Mean +/- SD fever subsidence times (FSTs) were also similar at 18.7 +/- 8.3 hr and 21.0 +/- 4.8 hr, respectively. All patients remained negative for P. falciparum for at least 14 days. Recrudescence/reinfection occurred between days 21 and 28 in five of 25 patients (20%) after oral treatment and in four of 25 patients (16%) after iv treatment. The mean erythrocyte count and hemoglobin concentration were slightly reduced after iv treatment but remained in the normal range. Otherwise, there was no change in blood biochemistry, hematology, and electrocardiograms monitored prior to and during the last dose. It is concluded that treatment with oral and iv artesunate was equally efficacious and well tolerated. A 24-hr in vitro susceptibility test of P. falciparum to artemisinin, chloroquine, and mefloquine was performed in samples from all patients. The three compounds exhibited 100% inhibition with the exception of three isolates, which showed chloroquine resistance. Parameter estimates of a sigmoid Emax model (drug concentration at which 50% of the growth inhibition occurs [EC50]), the sigmoidicity factor s and EC95 fitted to the growth inhibition data differed between compounds and isolates, indicating different sensitivity of P. falciparum isolates. There was no correlation between artemisinin and mefloquine EC50 values, while artemisinin and chloroquine EC50 values showed weak correlation (r2 = 0.223, P = 0.006). There was no correlation between parameters describing clinical outcome (the PCT, the time needed for reduction of the parasite density to 50% and 95% of the initial parasitemia, and the FST) and those describing in vitro susceptibility.

Administration, Oral↗
PubMed1993

Decreased chloramphenicol clearance in malnourished Ethiopian children.

The disposition of chloramphenicol and chloramphenicol monosuccinate has been studied in thirty-four Ethiopian children of varying nutritional status. After a single intravenous dose corresponding to chloramphenicol 25 mg per kg bodyweight, the plasma clearance of chloramphenicol monosuccinate was decreased only in severely malnourished children with kwashiorkor. Seventeen % of the dose (range 0-51%) was recovered in urine as intact prodrug, indicating incomplete and variable bioavailability of chloramphenicol. Compared to underweight children, on average marasmic and kwashiorkor subjects exhibited a 2- and 3-fold increase, respectively, in the AUC of chloramphenicol. Elevated AUCs could be traced to reduced hepatic clearance of the drug. The unbound fraction both of chloramphenicol and its prodrug were slightly elevated in serum from kwashiorkor subjects. The possibility of using a single point measurement of plasma chloramphenicol as a guide to individualized dosage are discussed.

Biological Availability↗
PubMed1993

Disposition of salicylic acid in malnourished Ethiopian children after single oral dose.

The disposition of salicylic acid and salicyluric acid was studied in 57 Ethiopian children of varying nutritional status after oral administration of sodium salicylate in single doses of either 12.5 or 25 mg/kg. There was no apparent influence of nutritional status on oral salicylate disposition when related to total plasma concentrations. Unbound concentrations were predicted from total plasma concentrations on the basis of a single time point determination of protein binding in each individual, according to a Scatchard model. Areas under the unbound plasma concentration-time curve were larger and the fractional excretion of salicyluric acid was lower in children with kwashiorkor compared with control individuals. This was interpreted as lower hepatocellular metabolic activity in patients with kwashiorkor. Children with marasmus retained an unimpaired capacity for salicylate metabolism. The influence of saturable distribution and elimination are discussed.

Administration, Oral↗