Biomedical subjects

R E Bullingham

Publications and source records attributed to R E Bullingham.

At least 19 recordsLinked to original sources

PubMed1999

Stereoselective pharmacokinetics of ketorolac in children, adolescents and adults.

BACKGROUND: Previous pharmacokinetic studies on racemic ketorolac using nonstereoselective analytical methods have indicated that the plasma clearance of ketorolac is higher and the volume of distribution greater in children than in adults. The aim of this study was to study the stereoselective pharmacokinetics of racemic ketorolac in children, adolescents and adults. METHODS: 18 children (6-11 yrs), 18 adolescents (12-17 yrs) and 18 adults (18-44 yrs) participated in the study. At the end of eye surgery they were given intravenous racemic ketorolac tromethamine 0.5 mg/kg. Plasma samples were assayed for (R)- and (S)-ketorolac with high-pressure liquid chromatography. Clearance (CL), volume of distribution at steady state (Vss) and elimination (Vz) and elimination half-life (t1/2,z) were calculated with standard methods. Incidence of side-effects were recorded. RESULTS: CL, Vss, Vz and t1/2,z were higher (P<0.05) for (S)-ketorolac than for the (R)-enantiomer. Vss of the active (S)-enantiomer was higher in children than in adolescents (P<0.05) and adults (P<0.001) but the values for CL were similar. Due to the higher volume of distribution, t1/2,z was also higher in children than in adults. The pharmacokinetics of the (R)-enantiomer were essentially unaffected by age. CONCLUSION: On a pharmacokinetic basis, the maintenance dose requirements of ketorolac are similar in children, adolescents and adults.

Adolescent↗

PubMed1998

The pharmacokinetic-pharmacodynamic relationship for mycophenolate mofetil in renal transplantation.

BACKGROUND: Mycophenolate mofetil, a pro-drug for mycophenolic acid, reduces the likelihood of allograft rejection after renal transplantation. We studied the relationship between mycophenolic acid pharmacokinetics and the likelihood of rejection in a randomized concentration-controlled trial. METHODS: Under double-blind conditions, recipients of kidney transplants were followed for evidence of allograft rejection for 6 months. In addition to mycophenolate mofetil, patients received usual doses of cyclosporine (INN, ciclosporin) and corticosteroids. The dose of mycophenolate mofetil (given twice daily) was controlled by feedback, with mycophenolic acid area under the concentration-time curve (AUC) as the controlled variable. Patients were randomly assigned to 1 of 3 target AUC groups. RESULTS: Logistic regression analysis showed a significant (P < .0001) relationship between mycophenolic acid AUC and the likelihood of rejection. High mycophenolic acid values were associated with a very low probability of rejection. An AUC of 15 micrograms.h/mL yielded 50% of maximal achievable efficacy with a 4% change of efficacy for a 1 microgram.h/mL change in AUC at the midpoint of the logistic curve. Exploratory analyses showed other variables (e.g., the maximum observed plasma concentration, predose plasma concentration, and drug dose) had poorer predictive power for the rejection outcome. Bivariate regression confirmed the importance of AUC as a highly predictive variable and showed low predictive value of other variables, once the contribution of AUC had been considered. The characteristic side effects of mycophenolate mofetil therapy appeared related to drug dose but not to mycophenolic acid concentration. CONCLUSIONS: The AUC of mycophenolic acid is predictive of the likelihood of allograft rejection after renal transplantation in patients receiving mycophenolate mofetil.

Area Under Curve↗

PubMed1998

Clinical pharmacokinetics of mycophenolate mofetil.

The pharmacokinetics of the immunosuppressant mycophenolate mofetil have been investigated in healthy volunteers and mainly in recipients of renal allografts. Following oral administration, mycophenolate mofetil was rapidly and completely absorbed, and underwent extensive presystemic de-esterification. Systemic plasma clearance of intravenous mycophenolate mofetil was around 10 L/min in healthy individuals, and plasma mycophenolate mofetil concentrations fell below the quantitation limit (0.4 mg/L) within 10 minutes of the cessation of infusion. Similar plasma mycophenolate mofetil concentrations were seen after intravenous administration in patients with severe renal or hepatic impairment, implying that the de-esterification process had not been substantially affected. Mycophenolic acid, the active immunosuppressant species, is glucuronidated to a stable phenolic glucuronide (MPAG) which is not pharmacologically active. Over 90% of the administered dose is eventually excreted in the urine, mostly as MPAG. The magnitude of the MPAG renal clearance indicates that active tubular secretion of MPAG must occur. At clinically relevant concentrations, mycophenolic acid and MPAG are about 97% and 82% bound to albumin, respectively. MPAG at high (but clinically realisable) concentrations reduced the plasma binding of mycophenolic acid. The mean maximum plasma mycophenolic acid concentration (Cmax) after a mycophenolate mofetil 1 g dose in healthy individuals was around 25 mg/L, occurred at 0.8 hours postdose, decayed with a mean apparent half-life (t1/2) of around 16 hours, and generated a mean total area under the plasma concentration-time curve (AUC infinity) of around 64 mg.h/L. Intra- and interindividual coefficients of variation for the AUC infinity of the drug were estimated to be 25% and 10%, respectively. Intravenous and oral administration of mycophenolate mofetil showed statistically equivalent MPA AUC infinity values in healthy individuals. Compared with mycophenolic acid, MPAG showed a roughly similar Cmax about 1 hour after mycophenolic acid Cmax, with a similar t1/2 and an AUC infinity about 5-fold larger than that for mycophenolic acid. Secondary mycophenolic acid peaks represent a significant enterohepatic cycling process. Since MPAG was the sole material excreted in bile, entrohepatic cycling must involve colonic bacterial deconjugation of MPAG. An oral cholestyramine interaction study showed that the mean contribution of entrohepatic cycling to the AUC infinity of mycophenolic acid was around 40% with a range of 10 to 60%. The pharmacokinetics of patients with renal transplants (after 3 months or more) compared with those of healthy individuals were similar after oral mycophenolate mofetil. Immediately post-transplant, the mean Cmax and AUC infinity of mycophenolic acid were 30 to 50% of those in the 3-month post-transplant patients. These parameters rose slowly over the 3-month interval. Slow metabolic changes, rather than poor absorption, seem responsible for this nonstationarity, since intravenous and oral administration of mycophenolate mofetil in the immediate post-transplant period generated comparable MPA AUC infinity values. Renal impairment had no major effect on the pharmacokinetic of mycophenolic acid after single doses of mycophenolate mofetil, but there was a progressive decrease in MPAG clearance as glomerular filtration rate (GFR) declined. Compared to individuals with a normal GFR, patients with severe renal impairment (GFR 1.5 L/h/1.73m2) showed 3-to 6-fold higher MPAG AUC values. In rental transplant recipients during acute renal impairment in the early post-transplant period, the plasma MPA concentrations were comparable to those in patients without renal failure, whereas plasma MPAG concentrations were 2- to 3-fold higher. Haemodialysis had no major effect on plasma mycophenolic acid or MPAG. Dosage adjustments appear to not be necessary either in renal impairment or during dialysis. (ABSTRACT TRUN

Absorption↗

PubMed1996

Pharmacokinetics of mycophenolate mofetil (RS61443): a short review.

Overall, the PK of MMF is reasonably straightforward and relatively unaffected by the complex pathophysiological changes involved in the management of renal transplant recipients. The ability to relate plasma MPA concentrations to efficacy through the PK/PD correlation implies that, unlike for many other drugs, plasma PK has direct relevance to the clinical outcome. These features should not only greatly help the exploration of immunosuppressive regiments using MMF but also the development of clinical use of MMF in situations other than renal transplantation.

Body Weight↗

PubMed1995

Speed of onset of analgesic effect of intravenous ketorolac compared to morphine and placebo.

The speed of onset of analgesia following intravenous ketorolac, morphine and placebo was investigated in a single-dose, double-blind, randomized, parallel group study of 105 patients. The onset of analgesia was defined as the time at which the pain intensity score reached 50% of the baseline score in 25% of patients. Post-operative patients with moderate or severe pain were dosed and followed for 1 h. Pain reduction by at least 50% occurred in 25% of patients within 40 min (placebo), 15 min (morphine 5 mg), 6 min (morphine 10 mg) and 20 min (ketorolac 10 mg). The pain reduction time for morphine (10 mg) was significantly shorter than that for ketorolac (P = 0.01) or placebo (P < 0.01).

Adult↗

PubMed1994

Low dose intranasal nafarelin for the treatment of endometriosis.

Twenty-five women with regular menstruation and laparoscopically confirmed endometriosis received 100 mcg nafarelin intranasally twice daily for six months in an open study. American Fertility Society (AFS) laparoscopic scores pre- and post-treatment, symptom severity, hormonal status, bone density and biochemical indices of bone turnover were studied. Five patients were still menstruating at three months and nafarelin was increased to 400 mcg daily. At the end of treatment, the median serum estradiol was 57 pmol/l and all patients were amenorrhoeic. AFS scores for endometriosis improved significantly in 19/23 (82.6%) patients (p = 0.001). Adhesions were not affected. Symptom severity scores were markedly decreased (p < 0.0001) and remained so six months after the end of treatment. Biochemical indices of bone activation were increased but bone loss was insignificant. During treatment, 23/25 patients reported hot flushes. Nafarelin 200 mcg daily significantly reduced signs and symptoms of endometriosis, although five patients needed a dosage increase before menses stopped. The study suggests that lower doses of nafarelin may be efficacious, although symptomatic changes should be treated with caution due to the open and non-comparative nature of the study.

Abdominal Pain↗

PubMed1992

A new method for rate of analgesic onset: two doses of intravenous morphine compared with placebo.

A new method of frequent early pain assessments for 1 hour only was used to determine time of onset of analgesia after intravenous administration of 10 mg morphine, 5 mg morphine, or placebo in a double-blind study; 79 patients were randomized if they required parenteral analgesia in the early postoperative period. Pain intensity was determined by a four-point categoric verbal rating scale and on a verbal ordinal scale from 0 to 100 (0 = no pain, 100 = worst pain imaginable) during the first hour after analgesic administration. The onset time of analgesia, assessed by 50% of patients achieving 25% reduction from their baseline pain assessment, was significantly faster for 10 mg morphine compared with 5 mg morphine (p = 0.02) and placebo (p less than 0.01). More familiar analgesic efficacy measures, including the sum of pain intensity differences and time to next analgesic dose, similarly showed the superiority of 10 mg morphine to placebo in the first hour, confirming sensitivity according to the conventional paradigm.

Adult↗

PubMed1992

Comparison of intravenous ketorolac with morphine for postoperative pain in children.

Ninety-two children from 3 to 12 years of age were given intravenous morphine or ketorolac by titration, or ketorolac by bolus injection for moderate or severe postsurgical pain in a double-blind randomized parallel-group study. Pain scores were assessed every 5 minutes until pain relief was complete, and then every 15 minutes for 8 hours or until pain returned. Twenty-nine of 30 patients receiving morphine and 25 of 30 patients in each group receiving ketorolac achieved pain relief. The subjects in the morphine group required statistically fewer doses for analgesia than the subjects in the ketorolac groups. The sums of pain intensity differences calculated from the start of the study numerically favored morphine, but the sum of pain intensity differences from pain relief until 50% withdrew were significantly better in the ketorolac groups. Median durations of analgesia from initial drug administration were 170, 190, and 225 minutes in the morphine, ketorolac titration, and ketorolac bolus groups, respectively. The most common side effect was injection site pain. Analgesia after intravenous ketorolac developed more slowly but was sustained better than morphine.

Analgesics↗

PubMed1992

Effects on biliary tract pressure in humans of intravenous ketorolac tromethamine compared with morphine and placebo.

This study compared the effect of ketorolac tromethamine with that of morphine and placebo on biliary tract pressure. Intraoperatively, 31 anesthetized patients received either ketorolac (30 mg IV, n = 16) or morphine (5 mg IV, n = 15) after a cholecystectomy or gallstone removal. Intrabiliary tract pressure was measured 5 min after dosing. Postoperatively, 11 patients who had undergone biliary tract surgery received 10 mg of ketorolac or placebo, according to a randomized crossover design on 2 consecutive days. Intraoperatively, the biliary tract pressure did not change significantly from baseline after ketorolac administration. In the morphine group, there was significant increase in pressure over baseline. Postoperatively, there was no significant difference between ketorolac and placebo. We conclude that ketorolac has little or no effect on biliary tract dynamics; therefore, ketorolac may be a logical choice for analgesia in those situations in which spasm of the biliary tract is undesirable.

Adult↗

PubMed1991

Double-blind comparison of the morphine sparing effect of continuous and intermittent i.m. administration of ketorolac.

The morphine sparing effect of ketorolac 10 mg administered 4-hourly by intermittent i.m. injection was compared with a continuous i.m. infusion in a double-blind, placebo-controlled trial in patients undergoing upper abdominal surgery. During the 48-h postoperative period, each patient was provided with a patient-controlled analgesia (PCA) system which delivered bolus doses of morphine and administered the intermittent i.m. doses automatically via a computer controlled pump. In the first 24 h after surgery, there was a significant reduction in morphine demanded by both groups receiving ketorolac compared with placebo. Patients who received a continuous infusion of ketorolac after abdominal surgery required a median dose of morphine by PCA which was 49% less than controls. In the second 24 h and over the entire 48 h of the study, patients in the continuous group required significantly less morphine than those in the placebo group. The intermittent group used less than the placebo group, but this was not significant.

Abdomen↗

PubMed1991

A double-blind study of the speed of onset of analgesia following intramuscular administration of ketorolac tromethamine in comparison to intramuscular morphine and placebo.

A double-blind, randomised, parallel group, placebo-controlled study was performed in 85 patients to compare the speed of onset of analgesia following the intramuscular administration of a single dose of 30 mg of ketorolac tromethamine, 10 mg of morphine or placebo. A new, sensitive, method was used to measure the latency of analgesia. The onset of analgesia was defined by the time taken for the pain intensity score to reach a specified percentage of the baseline value. Twenty-five percent of patients achieving a 50% reduction in baseline pain intensity score appears to be the most appropriate parameter to assess the speed of onset of analgesia of ketorolac and morphine in the postoperative setting. Paired comparison demonstrated that ketorolac had a significantly faster onset of analgesia (p = 0.03) when compared to placebo, whilst comparison of morphine to placebo analgesic latency (p = 0.06) just failed to reach significance. There was no significant difference between the analgesic onset time of ketorolac and morphine (p = 0.73). Intramuscular ketorolac and intramuscular morphine have comparable analgesic onset times in the postoperative pain context. However, the sensitive method of measuring onset of analgesia described, highlights the slow onset of analgesia when analgesics of known efficacy are given by the intramuscular route in the postoperative period. More attention should be given to the speed of onset of analgesia in future assessments of analgesics.

Adult↗

PubMed1988

Haemostatic effects of ketorolac with and without concomitant heparin in normal volunteers.

Ketorolac is a potent cyclo-oxygenase inhibitor used for the treatment of postoperative pain. It is known to have anti-platelet properties. The aim of this study was to determine the effect of ketorolac on haemostasis both alone and in combination with low dose heparin in 12 healthy male volunteers. Each volunteer received the following drug combinations in a double blind, placebo controlled, cross over manner: ketorolac placebo/heparin placebo, ketorolac active/heparin placebo, ketorolac active/heparin active and ketorolac placebo/heparin active. Ketorolac significantly prolonged bleeding time, inhibited platelet aggregation to arachidonic acid and collagen and platelet thromboxane production. Heparin had no effect on bleeding time or platelet function, but significantly prolonged the kaolin cephalin clotting time and increased anti-Xa levels. Ketorolac had no effect on the kaolin cephalin clotting time or anti-Xa levels and no interaction was found between ketorolac and heparin in any of the investigations. The prolongation of bleeding time seen with ketorolac is unlikely, to be of any major clinical significance as almost all subjects remained within the normal range; however, it should be used with caution in subjects with haemostatic problems.

Adult↗

PubMed1987

The morphine sparing effect of ketorolac tromethamine. A study of a new, parenteral non-steroidal anti-inflammatory agent after abdominal surgery.

A randomised, double-blind study of patients after upper abdominal surgery was undertaken to assess the analgesic efficacy of ketorolac tromethamine, a new, parenteral non-steroidal anti-inflammatory agent. Postoperatively, patients received a 24-hour intramuscular infusion of either saline (n = 20), ketorolac 1.5 mg/hour (n = 21) or ketorolac 3.0 mg/hour (n = 20). Cumulative morphine requirements were measured using a patient-controlled analgesia system which delivered intravenous increments of morphine on demand. Pain was assessed by visual analogue scores. Arterial blood gas analyses were performed pre-operatively and on the first postoperative day. Patients who received low and high dose ketorolac infusions required less morphine than the control group (p less than 0.05 and p = 0.06, respectively). This was associated with significantly lower pain scores. Patients who received the higher ketorolac dose had significantly less postoperative increase in arterial carbon dioxide tensions than controls. This study suggests that ketorolac tromethamine is a useful analgesic drug with significant morphine sparing properties.

Abdomen↗

PubMed1987

Noninvasive measurement of gastric emptying in obstetric patients.

An epigastric impedance technique was used to measure gastric emptying in nonpregnant women, women in the third trimester of pregnancy, and women within 60 min of delivery. The basis of the technique is the increase in epigastric impedance after the ingestion of a nonionic fluid. The subsequent decline in impedance is used as a measure of gastric emptying. The impedance epigastrograph used consisted of a four-electrode array (two source, two detector) that was applied over the epigastrium. The method was sufficiently sensitive to measure the effects of pregnancy, labor, and narcotics on gastric emptying. There was no difference in the rate of gastric emptying between pregnant and nonpregnant females. Labor appeared to cause a significant delay in gastric emptying; the mean +/- SEM time taken for the gastric volume to decrease to 50% (T0.5) was 7.2 +/- 0.6 min during pregnancy and 13.0 +/- 1.9 min in the immediate postpartum period. However, the principal factor associated with the delay in gastric emptying in the group studied within 60 min of delivery was probably the use of meperidine and promethazine, because there was a significant difference (P less than 0.05) between subjects who received meperidine and promethazine during labor and those in another group who had received either no analgesia or extradural analgesia, the T0.5 values for the two groups being 18.2 +/- 4.0 and 10.3 +/- 1.4 min, respectively.

Drinking↗

PubMed1986

Ketorolac and acetaminophen for orthopedic postoperative pain.

In a double-blind, single-dose, parallel-group study, ketorolac (5, 10, or 20 mg) was compared with acetaminophen (500 or 1000 mg) when taken by mouth for postoperative orthopedic pain. Analgesic measurements were made by trained nurse observers who used standard verbal rating and visual analog scales. Acetaminophen, 1000 mg, was statistically superior to 500 mg acetaminophen, demonstrating assay sensitivity. Ketorolac, 20 mg, was distinguished from 500 mg acetaminophen, 5 mg ketorolac, and 10 mg ketorolac, but not from 1000 mg acetaminophen. The higher doses of ketorolac induced a longer lasting peak analgesic effect than did acetaminophen, but the magnitude of the peak pain relief was changed little by an increased ketorolac dose. Overall, 10 mg ketorolac appeared equivalent to 1000 mg acetaminophen. Acetaminophen, 500 mg, induced less sedation than the higher doses of ketorolac, but neither drug caused untoward side effects.

Acetaminophen↗

PubMed1985

Zomepirac, dihydrocodeine and placebo compared in postoperative pain after day-case surgery. The relationship between the effects of single and multiple doses.

Zomepirac 100 mg and dihydrocodeine 30 mg were compared with placebo in a controlled randomized, double-blind, single-dose postoperative study. Patients continued to receive either zomepirac or dihydrocodeine for pain relief for 5 days at home in a double-blind study, being allowed to titrate the consumption of tablets to their degree of pain. The efficacy and side effects of the medication were evaluated. In the single-dose phase, both active treatments were significantly better than placebo. In the multiple dosing phase, zomepirac was statistically better than dihydrocodeine. Non-parametric statistical tests indicated highly significant correlations between single- and multiple-dose analgesic measurements for both zomepirac and dihydrocodeine.

Administration, Oral↗

PubMed1985

Influence of meptazinol on metabolic and hormonal responses following major surgery. A comparison with morphine.

Opioid drugs in high doses can obtund the stress response to major surgery but only at the expense of marked cardiorespiratory depression. The postoperative hormonal response to surgical stress was measured in 20 patients undergoing hysterectomy who were given either meptazinol 100 mg or morphine 15 mg intramuscularly at the end of the surgery. Both drugs at the doses used failed to diminish the stress response. Those patients who received meptazinol showed elevated prolactin levels: this may be an indicator of agonist activity at the mu 1 opioid receptor.

Adult↗

PubMed1985

The effect of magnesium trisilicate mixture, metoclopramide and ranitidine on gastric pH, volume and serum gastrin.

Eighty women (40 for elective Caesarean section and 40 for elective gynaecological surgery) were randomly assigned to one of five treatment groups and received pre-operatively either no medication; magnesium trisilicate mixture (BP) 30 ml; metoclopramide 10 mg intramuscularly; ranitidine 150 mg orally on the night prior to, and the morning of, surgery; or metoclopramide 10 mg intramuscularly in combination with oral ranitidine 150 mg (the latter again given on the night prior, and the morning, of surgery). The effect of these medications on intragastric pH, volume and serum gastrin-17 was measured. No patient receiving ranitidine had a pH of less than 4. Magnesium trisilicate mixture resulted in the largest intragastric pH change although one woman in this group had a pH of 1.7. The largest intragastric volumes were seen in the patients who had received magnesium trisilicate mixture, whilst the patients who had received metoclopramide in combination with ranitidine had the smallest intragastric volumes. Magnesium trisilicate mixture and metoclopramide resulted in no change in serum gastrin levels. However, in the subjects who had received ranitidine on the night prior to surgery, the fasting serum gastrin was significantly higher (p less than 0.01) than the values in the remaining subjects, the mean (SEM) values being 60.3 (6.3) pg/ml in those not receiving ranitidine and 111.3 (19.5) pg/ml in those who had been given ranitidine.

Adult↗