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K F Brown

Publications and source records attributed to K F Brown.

At least 19 recordsLinked to original sources
PubMed2006

Nucleotide supplementation: a randomised double-blind placebo controlled trial of IntestAidIB in people with Irritable Bowel Syndrome [ISRCTN67764449].

BACKGROUND: Dietary nucleotide supplementation has been shown to have important effects on the growth and development of cells which have a rapid turnover such as those in the immune system and the gastrointestinal tract. Work with infants has shown that the incidence and duration of diarrhoea is lower when nucleotide supplementation is given, and animal work shows that villi height and crypt depth in the intestine is increased as a result of dietary nucleotides. Dietary nucleotides may be semi-essential under conditions of ill-health, poor diet or stress. Since people with Irritable Bowel Syndrome tend to fulfil these conditions, we tested the hypothesis that symptoms would be improved with dietary nucleotide supplementation. METHODS: Thirty-seven people with a diagnosis of Irritable Bowel gave daily symptom severity ratings for abdominal pain, diarrhoea, urgency to have a bowel movement, incomplete feeling of evacuation after a bowel movement, bloating, flatulence and constipation for 28 days (baseline). They were then assigned to either placebo (56 days) followed by experimental (56 days) or the reverse. There was a four week washout period before crossover. During the placebo and experimental conditions participants took one 500 mg capsule three times a day; in the experimental condition the capsule contained the nutroceutical substances. Symptom severity ratings and psychological measures (anxiety, depression, illness intrusiveness and general health) were obtained and analysed by repeated measures ANOVAs. RESULTS: Symptom severity for all symptoms (except constipation) were in the expected direction of baseline>placebo>experimental condition. Symptom improvement was in the range 4 - 6%. A feeling of incomplete evacuation and abdominal pain showed the most improvement. The differences between conditions for diarrhoea, bloating and flatulence were not significant at the p < .05 level. There were no significant differences between the conditions for any of the psychological measures. CONCLUSION: Dietary nucleotide supplementation improves some of the symptoms of irritable bowel above baseline and placebo level. As expected, placebo effects were high. Apart from abdominal pain and urgency to have a bowel movement, the improvements, while consistent, are modest, and were not accompanied by improvements in any of the psychological measures. We suggest that the percentage improvement over and above the placebo effect is a physiological effect of the nucleotide supplement on the gut. The mechanisms by which these effects might improve symptoms are discussed.

Abdominal Pain↗
PubMed2001

High-performance liquid chromatographic analysis of mometasone furoate and its degradation products: application to in vitro degradation studies.

A method of analysis of mometasone furoate in pharmaceutical formulations and biological fluids is necessary to study the degradation kinetics and determine its stability. A simple high-performance liquid chromatographic method was developed for simultaneous determination of mometasone furoate and its degradation products in human plasma. Plasma (0.5 ml) was extracted with dichloromethane after addition of the internal standard, dexamethasone 21-acetate. Separation was achieved on a Beckman C(8) column with UV detection at 248 nm. The calibration curve was linear ranging from 0.2 to 100 microg/ml. The mean extraction efficiency was >86%. Precision of the assay was <10% (CV), and was within 10% at the limit of quantitation (0.2 microg/ml). Bias of the assay was lower than 7%. The limit of detection was 50 ng/ml for a 0.5-ml sample. The assay was applied successfully to the in vitro kinetic study of degradation of mometasone furoate in human plasma and simulated biological fluids.

Administration, Topical↗
PubMed2001

Influence of respiratory spacer devices on aerodynamic particle size distribution and fine particle mass of beclomethasone from metered-dose inhalers.

Respiratory spacer devices are used mainly with pressurized metered dose inhalers, especially those containing corticosteroids, to assist with patient coordination and reduce oropharyngeal side effects. This investigation examines the influence of different spacer devices on the delivered fine particle mass (aerodynamic diameter of <3.3 microm and <4.7 microm) of the corticosteroid beclomethasone dipropionate, which approximates the respirable dose. The Anderson Mark II Cascade Impactor was used to characterise the deposition of single doses of beclomethasone dipropionate from several metered-dose inhalers. Following actuation of one single dose the amount of beclomethasone dipropionate deposited on each stage of the impactor was quantified using reverse phase high-performance liquid chromatography and ultraviolet detection. The fine particle mass smaller than 4.7 microm for Respocort delivered by the Sanner and Fisonair spacer devices was 77.7% and 41.3% higher (p < 0.04), respectively, than the metered-dose inhaler alone, while the Breathatech spacer delivered 21.4% lower (p < 0.01). The fine particle mass of Becotide delivered by the Sanner, Fisonair, Nebuhaler, and Volumatic spacer devices were 81%, 42.4%, 46.9%, and 32.8% higher (p < 0.008), respectively, than be metered dose inhaler alone. The fine particle mass for Becloforte delivered by the Sanner, Fisonair, and Volumatic spacer devices was 82.8%, 36.9%, and 48.0% higher (p < 0.009) than that delivered by metered dose inhaler alone. This study suggests that there are significant differences in the fine particle mass of beclomethasone dipropionate delivered by respiratory spacer devices when used in conjunction with commercially available metered dose inhalers of this drug.

Aerosols↗
PubMed2000

Comparative kinetics of metabolism of beclomethasone propionate esters in human lung homogenates and plasma.

The systemic availability of inhaled beclomethasone dipropionate (BDP) is the net result of the absorption of the glucocorticoid from the lower respiratory and gastrointestinal tracts, and metabolism in the lung, plasma, and other sites. The metabolism kinetics of BDP and its active metabolite, beclomethasone 17-monopropionate (17-BMP), in human lung 1000 x g supernatant (HLu) and human plasma (HP) at 37 degrees C were compared. The effect of MgCl(2) and/or an NADPH-generating system on the decomposition of BDP and 17-BMP in HLu was also investigated. The concentrations of BDP and its metabolites were determined by HPLC with UV detection at 242 nm. Kinetics of decomposition of BDP and 17-BMP in HLu and HP were qualitatively and quantitatively different. The decomposition of BDP in HLu involved only hydrolysis. In comparison, three reactions are involved following incubation of BDP in HP; namely, hydrolysis, transesterification, and loss of hydrogen chloride. The hydrolysis of BDP and 17-BMP in HLu seem to be inhibited appreciably by MgCl(2) with the NADPH-generating system. Effective activation of BDP in HLu, in combination with transesterification of 17-BMP in HP, might favor a high ratio of local antiinflammatory activity to systemic side effects following inhalation of BDP.

Adolescent↗
PubMed2000

Metabolism kinetics of beclomethasone propionate esters in human lung homogenates.

PURPOSE: The purposes of this study were to characterize the kinetics of beclomethasone dipropionate (BDP) and its 17-monopropionate ester (17-BMP) in human lung 1000g supernatant (HLu) at 37 degrees C, and to analyze the interindividual variability in the metabolism of BDP in HLu. METHODS: The concentrations of BDP and its metabolites were determined by HPLC with UV detection at 242 nm. Kinetics of BDP and 17-BMP decomposition were characterized by least-squares fitting of rate equations. RESULTS: The active metabolite 17-BMP was rapidly formed following the incubation of BDP in HLu. Kinetics of BDP and 17-BMP in HLu were nonlinear owing to product inhibition and enzyme saturation. A model taking into account the product inhibition provides a kinetic basis for understanding the in vivo behavior of BDP and its metabolites in human lung. There was approximately a 3.5-fold difference in the initial half-life of BDP in HLu observed in seven subjects. CONCLUSIONS: An effective activation of BDP was demonstrated in HLu through the rapid formation of 17-BMP. Kinetics of BDP and 17-BMP in HLu were well characterized by the nonlinear kinetic model. Interindividual difference in the initial half-life of BDP was due mainly to esterase metabolizing activity rather than binding affinity.

Adolescent↗
PubMed2000

Differential potency of beclomethasone esters in-vitro on human T-lymphocyte cytokine production and osteoblast activity.

Beclomethasone dipropionate is an inhaled corticosteroid, used for the treatment of asthma. It is metabolised to 17-beclomethasone monopropionate, which has greater affinity for corticosteroid receptors than the parent compound, and to beclomethasone. We investigated the potency of beclomethasone dipropionate, 17-beclomethasone monopropionate and beclomethasone (compared with dexamethasone as a reference steroid) in two different human cell types, peripheral blood mononuclear cells and osteoblasts. We found that beclomethasone dipropionate, 17-beclomethasone monopropionate (EC50 10(-14) M) and beclomethasone (EC50 approx. 10(-12) M) were much more potent than dexamethasone (EC50 10(-8) M) in inhibiting interleukin-5 production by peripheral blood mononuclear cells. In contrast, beclomethasone dipropionate, 17-beclomethasone monopropionate and beclomethasone were equipotent with dexamethasone (EC50 range 0.3-1.2 x 10(-9) M) in affecting several functional assays of osteoblasts (e.g. alkaline phosphatase activity and osteocalcin synthesis). These results show that the relative bioactivities of corticosteroids vary between different human cell types, and that affinities observed in receptor binding assays are not necessarily predictive of the bioactivity in cell populations, such as peripheral blood mononuclear cells and osteoblasts, which are putatively relevant to efficacy and side effects respectively.

Administration, Topical↗
PubMed1999

Unbound cyclosporine and allograft rejection after heart transplantation.

BACKGROUND: To determine the impact of cyclosporine plasma protein binding on organ rejection after cardiac transplantation, the incidence of cardiac rejection episodes was compared among patients who had differing levels of cyclosporine plasma fraction unbound (fU). METHODS: Forty-six consecutive cardiac transplant recipients were sampled at 1, 3, 6, and 12 months after transplantation, and cyclosporine plasma fU was determined, using a specially developed equilibrium dialysis method. At the completion of the study, incidences of cardiac rejection episodes were compared among patients having mean cyclosporine fU (Csfu) that were low (LCsfu; mean+/-SD, 1.33+/-0.10%, n=15), intermediate (ICsfu; 1.60+/-0.07%, n= 16), and high (HCsfu; 1.99+/-0.30%, n=15). RESULTS: Percentage of endomyocardial biopsies (grade 3a, 3b, and 4) with respect to the total number of biopsies performed in the first 3 months after transplant was significantly higher in the LCsfu group than the other groups (40.9% in LCsfu vs. 28.5% for ICsfu and 32.1% for HCsfu groups, P=0.02). The linearized rate of rejection (episodes of rejection/100 patient-days) in the first month after transplant was 6.5+/-1.7 for LCsfu, 3.5+/-0.8 for ICsfu and 4.3+/-0.9 for the HCsfu group (P<0.05, low vs. intermediate-high). The mean (95% confidence interval) of time interval between the first and second episodes of rejections was 10.7 (5.6-16.0) days for LCsfu, 18.0 (8.6-29.0) days for the ICsfu, and 26.0 (15.1-36.9) days for the HCsfu group (P<0.01). The total number of rejections requiring treatment per patient in the first 3 months after transplant was higher in the LCsfu group compared with the others (4.0+/-1.7 episodes for LCsfu vs. 2.9+/-1.1 for ICsfu and 3.2+/-1.2 episodes for HCsfu; P<0.05). Four patients in the low group, one patient in the intermediate group, and no patients in the high group required treatment with total lymphoid irradiation (P<0.02). CONCLUSIONS: This finding suggests that patients with lower levels of cyclosporine fU are more prone to cardiac rejection and that the level of cyclosporine fraction unbound may be clinically important for determination of response to cyclosporine therapy.

Biomarkers↗
PubMed1999

Economic evaluation of high-dose and low-dose aprotinin therapy during cardiopulmonary bypass.

BACKGROUND: Aprotinin therapy is now widely used during cardiac surgery. This study examined the clinical and economic effectiveness of high-dose or low-dose aprotinin in comparison to placebo. METHODS: In a double blind, randomized study, three groups of 50 patients received high-dose aprotinin costing AUS$614 per patient (AUS$ = Australian dollars), low-dose aprotinin costing AUS$220 per patient or placebo. Resource use influenced by aprotinin therapy was measured. RESULTS: Both doses were effective in reducing chest drainage and postoperative transfusion requirements, high-dose being more effective than low-dose. Both doses reduced the rate of reoperations for hemostasis. A base case of statistically significant differences associated with the high-dose and low-dose aprotinin showed cost savings of AUS$77 and AUS$348 per patient, respectively. If the demonstrated less significant reductions in operating room and ward stay are included, these savings become AUS$463 and AUS$715, respectively. Alternately, if cross-matches are replaced by group-and-hold and cell savers are not used, the savings per patient would be AUS$196 and AUS$467, respectively. CONCLUSIONS: While high-dose aprotinin is clinically more effective than low-dose aprotinin, low-dose therapy demonstrates greater cost savings.

Aprotinin↗
PubMed1998

Decomposition of beclomethasone propionate esters in human plasma.

The kinetics of decomposition of beclomethasone dipropionate (BDP), the 17-monopropionate ester (17-BMP), and beclomethasone (BOH) were characterized in whole human plasma (HP), pH 7.1, and in solutions of 1% human serum albumin (HSA), pH 7.4, and 0.067 M phosphate buffer, pH 7.4 (mu = 0.17). A reversed-phase, high-performance liquid chromatography (HPLC) assay enabled simultaneous separation and quantification of beclomethasone propionate esters and six degradation products including three unidentified products, D1-D3, not previously reported. Following incubation of BDP, products were formed in the following sequence, D1, 17-BMP, beclomethasone-21-monopropionate (21-BMP), D3, BOH, and D2. Following incubation of 17-BMP, the same sequence of degradation products was formed with the exception of D1. Following incubation of BOH, only D2 was formed. The decomposition reactions of BDP, 17-BMP, and BOH in HP exhibit pseudo-first-order kinetics. However the degradation reactions of BDP in solutions of 1% HSA and phosphate buffer were found to follow pseudo-zero-order kinetics. At an initial concentration of 40 micrograms mL-1, the half-lives for BDP, 17-BMP, and BOH in HP were 10.9 +/- 0.4, 3.0 +/- 0.2 and 24.8 +/- 0.2 h, respectively.

Albumins↗
PubMed1998

Influence of flow rate on aerosol particle size distributions from pressurized and breath-actuated inhalers.

Particle size distribution of delivered aerosols and the total mass of drug delivered from the inhaler are important determinants of pulmonary deposition and response to inhalation therapy. Inhalation flow rate may vary between patients and from dose to dose. The Andersen Sampler (AS) cascade impactor operated at flow rates of 30 and 55 L/min and the Marple-Miller Impactor (MMI) operated at flow rates of 30, 55, and 80 L/min were used in this study to investigate the influence of airflow rate on the particle size distributions of inhalation products. Total mass of drug delivered from the inhaler, fine particle mass, fine particle fraction, percentage of nonrespirable particles, and amount of formulation retained within the inhaler were determined by ultraviolet spectrophotometry for several commercial bronchodilator products purchased in the marketplace, including a pressurized metered-dose inhaler (pMDI), breath-actuated pressurized inhaler (BAMDI), and three dry powder inhalers (DPIs), two containing salbutamol sulphate and the other containing terbutaline sulphate. Varying the flow rate through the cascade impactor produced no significant change in performance of the pressurized inhalers. Increasing the flow rate produced a greater mass of drug delivered and an increase in respirable particle mass and fraction from all DPIs tested.

Aerosols↗
PubMed1998

Indirect estimation of the unbound fraction of cyclosporine in plasma.

The unbound fraction (fU) of cyclosporine in plasma is approximately 0.02. The measurement of cyclosporine fU requires a laborious equilibrium dialysis procedure, which is not practical in a clinical setting. A mathematical model was developed to estimate cyclosporine fU from concentrations of serum lipoproteins, the major binding proteins for cyclosporine. Values of fU were determined ex vivo in 126 plasma samples obtained from 58 recipients of heart and lung transplants, using equilibrium dialysis. Concentrations of serum lipids, measured using standard enzymatic techniques, were used as concentration markers for serum lipoproteins. Patients were randomly assigned to either of two equal-sized groups. One group (subgroup 1) was used to evaluate the parameters of the model, and the other group (subgroup 2) was used to examine its predictive performance. The parameters were estimated using least squares non-linear regression. A model incorporating concentrations of serum HDL- and LDL-cholesterol, serum albumin, and time after transplantation gave the best fit. For subgroup 2, mean prediction error (ME), a measure of bias, and root mean squared error (RMSE) and median absolute error (MAE), measures of precision, and their 95% confidence intervals were estimated. For the best fit model, ME was 0.07 x 10(-2) (-0.065 x 10(-2) - 0.1 x 10(-2)), indicating that the model provided an unbiased estimate of the value of cyclosporine fU. Root mean squared error and MAE were 0.536 x 10(-2) (0.398 x 10(-2) - 0.645 x 10(-2)) and 0.27 x 10(-2) (0.226 x 10(-2) - 0.409 x 10(-2)), respectively. Prediction error was normally distributed; approximately 30% of the prediction errors were <10% and <5% of prediction errors were >50%. This model has shown a reasonable predictive performance in the patients with cardiac transplants studied; however, its predictive performance will need to be validated in a larger number of recipients of transplants of various types.

Adult↗
PubMed1998

Degradation products of beclomethasone dipropionate in human plasma.

The anti-inflammatory glucocorticosteroid beclomethasone dipropionate was found previously to degrade in human plasma at 37 degrees C to yield beclomethasone 17-monopropionate, beclomethasone 21-monopropionate, and beclomethasone together with three unknown species, D-1, D-2, and D-3. In this paper, we report the isolation of D-2 and D-3 by preparative HPLC and the elucidation of their structures. Both products D-2 and D-3 exhibited UV bathochromic shifts relative to beclomethasone dipropionate of 9 nm. From the mass spectrometry and 1H-NMR data, it is concluded that D-2 and D-3 are formed from beclomethasone and beclomethasone 21-monopropionate, respectively, with the loss of hydrogen chloride and the formation of a 9,11-epoxide. Data for 1H-NMR methyl chemical shifts are used to show that the epoxide has the mechanistically more plausible 9beta,11beta configuration. Thus, D-2 is 9beta, 11beta-epoxy-16beta-methyl-1,4-pregnadiene-17alpha,21- diol-3, 20-dione, and D-3 is its corresponding 21-propanoate. The various enzyme-catalyzed and nonenzyme-catalyzed reactions involved in the degradation of beclomethasone dipropionate in human plasma are discussed. A degradation scheme is proposed.

Anti-Asthmatic Agents↗
PubMed1997

A sensitive method for the quantification of fluticasone propionate in human plasma by high-performance liquid chromatography/atmospheric pressure chemical ionisation mass spectrometry.

A highly sensitive and selective method has been developed for the quantification of fluticasone propionate (FP) in human plasma. The drug was isolated from human plasma using C18 solid-phase extraction cartridges. The analysis was based on high-performance liquid chromatography/atmospheric pressure chemical ionisation mass spectrometry (HPLC/APCI/MS), using the 22R epimer of budesonide (BUD) acetate, synthesised using acetic anhydride, as internal standard. The mass spectrometer was operated in APCI mode with selected ions at tune masses of 473.2 and 501.2 m/z, corresponding to the MH+ of acetylated (22R)BUD and FP, respectively. The mobile phase used was a mixture of 50% ethanol in water with a flow rate of 0.45 ml min-1. The system was optimised by tuning the capillary and tube lens with a concentrated solution of FP. The recovery of FP from human plasma was 86.3%. Linearity of response was obtained over the concentration range 0.2-4.0 ng ml-1. The intra-assay and inter-assay variability were 6.3 and 2.9%, respectively. The lower limit of quantification was 0.2 ng ml-1 when a solid-phase extraction preceded the HPLC/APCI/MS.

Androstadienes↗
PubMed1997

Effect of simvastatin on cyclosporine unbound fraction and apparent blood clearance in heart transplant recipients.

AIMS: To investigate the effects of lipid lowering therapy on the fraction unbound and dosage requirement of cyclosporine in heart transplant recipients. METHODS: Cyclosporine fraction unbound (fu) was measured ex vivo in plasma obtained from heart transplant recipients (n=12) before and after lipid lowering treatment, using equilibrium dialysis. Cyclosporine trough concentration data were also collected from cardiac transplant recipients (n=32) who received simvastatin for the treatment of hyperlipidaemia. Cyclosporine daily dosage and total concentration (monoclonal FPIA method) were recorded for periods up to 6 months before and after simvastatin administration. The total number of dose rate-concentration observations was 172 before and 135 after simvastatin administration respectively. Using a population pharmacokinetic approach (implemented in P-PHARM software) the ratio of dose rate to trough concentration at steady state (DR/C[SS trough]), an estimation of apparent clearance, was determined. The posterior Bayesian estimate of DR/C(SS trough) was calculated for each patient before and after simvastatin administration. RESULTS: The mean fu increased by 29%, from 1.40 +/- 0.1% (mean +/- s.d.) to 1.82 +/- 0.22% after simvastatin administration (P < 0.01). Mean trough concentrations of cyclosporine in whole blood were 349 microg l-1 before and 242 microg l-1 after simvastatin administration (P < 0.0001). The mean cyclosporine daily dosage was 2.87 mg kg-1 and 2.33 mg kg-1 (NS), before and after simvastatin administration respectively. The average cyclosporine DR/C(SS trough) was significantly increased from 24.5 l h-1 before to 28.9 l h-1 after simvastatin administration (P < 0.05). Furthermore the median increase in cyclosporine DR/C(SS trough) was 18 l h-1 (-3.1 to 42.1 l h-1, interquartile range). CONCLUSIONS: Cyclosporine fraction unbound and clearance are increased following co-administration of lipid lowering agents, necessitating closer monitoring of cyclosporine total blood concentration when lipid lowering agents are administered concomitantly with cyclosporine.

Adult↗
PubMed1996

Determination of epimers 22R and 22S of budesonide in human plasma by high-performance liquid chromatography-atmospheric pressure chemical ionization mass spectrometry.

A highly sensitive and selective method has been developed for the simultaneous quantification of 22R- and 22S-epimers of budesonide in human plasma. The drug was isolated from human plasma using C18 solid-phase extraction cartridges and was acetylated with a mixture of 12.5% acetic anhydride and 12.5% triethylamine in acetonitrile to form the 21-acetyl derivatives. Deuterium-labelled budesonide was synthesized and determined to have an isotopic purity > 99%. This was used as the internal standard. Epimers were quantified by automated liquid chromatography-atmospheric pressure chemical ionization mass spectrometry, operating in selected ion mode at m/z 473.2 and m/z 476.2. Linear responses were observed for both epimers over the range 0.25 to 10.0 ng/ml. The average recoveries of 22R- and 22S-epimers of budesonide from human plasma were 87.4% and 87.0%, respectively. The lower limit of quantification for each epimer was 0.25 ng/ml, corresponding to 50.0 pg of analyte on column. Within- and between-day coefficients of variation were 8.6% and 4.0%, respectively.

Administration, Topical↗
PubMed1996

The photographic collection of Charles John Bond (1856-1939.

During the history of the Leicester Royal Infirmary from its foundation in 1771, Charles John Bond (1856-1939) emerges as one of the most distinguished members of the medical staff. He was born at Bittesby House in Leicestershire and brought up on his father's farm, where his early interest in natural history was fostered, and was further developed when he want to Repton school, nearby. His medical career began in February 1875, when he was apprenticed to Dr C M Sidley, a general practitioner of Welford Road, Leicester. For a short time he was an "outdoor" pupil at Leicester Infirmary before proceeding to University College London in the following October. He gained gold medals in physiology and anatomy and silver medals in surgery, midwifery, and medical jurisprudence, qualified in 1879 and was appointed house surgeon to Bedford General Infirmary. He returned to London in 1882 to study for the FRCS and shared rooms in Charlotte Street with his lifelong friend Victor Horsley, who in that year was appointed Assistant Professor of Pathology at University College Hospital. In the same year Charles Bond returned to Leicester and became house surgeon to Sir Charles Marriott. He did much to extend the use of Lister's recently introduced antiseptic methods. In the short period of four years he was appointed full surgeon at the Infirmary, and in 1893, because of his distingugished career and wide interests, he was offered the opportunity of joining the staff of University College Hospital. However, he preferred to stay in Leicester in spite of the limited opportunities for scientific investigation and research. In 1890 he married Edith, daughter of George Simpson, a justice of the peace in Derbyshire, and in 1910 they moved to a large Victorian house, Fernshaw, in Springfield Road on the then outskirts of Leicester, where various animals and birds could be kept for use in his experimental work. In this year he took the unusual step of giving up his large private practice to devote more time to study and to his research interests. three years later, at the age of 57, he retired from the staff of the Infirmary, and the governing body made him an honorary consultant surgeon and also elected him a vice president, the only doctor to be so honoured. Thus he retained a close association with his hospital until his death in 1939.

History, 19th Century↗
PubMed1989

The disposition and placental transfer of diazepam in cesarean section.

The disposition parameters and placental transfer of diazepam were determined from blood and both plasma total and free concentration data in five women who had not undergone labor and who received diazepam (5 mg intravenously for 2 minutes) 1 1/2 to 3 hours before cesarean section at term. All patients exhibited smooth log plasma free concentration-time profiles. In contrast, marked increases in plasma total (approximate 50% increase) and blood (approximate 40% increase) diazepam concentrations occurred at delivery. The plasma total and blood concentration fluctuations were associated with reciprocal variations in diazepam percent free in plasma. For each patient there was a substantial increase in plasma nonesterified fatty acid (NEFA) concentration during the surgical period. There was a significant correlation (p less than 0.02) between diazepam percent free and plasma NEFA concentration on the day of delivery, suggesting that the fluctuations in percent free, and hence plasma total and blood diazepam concentrations, were mediated in part by variations in plasma NEFA concentration. Disposition parameters were calculated for four of the patients; the mean free plasma clearance of diazepam was 42.5 ml/min/kg, similar to the mean value reported previously for nonpregnant women of comparable age. For each mother-infant pair at delivery the ratio of total plasma diazepam concentration in umbilical vein plasma to that in maternal vein plasma was considerably greater than unity (mean +/- SD = 1.73 +/- 0.47), whereas the corresponding ratio for free plasma diazepam concentration was near unity (0.92 +/- 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗