Evaluation of the opioid addiction test in an out-patient drug dependency unit.

BACKGROUND: The opioid addiction test is based on the measurement of pupil dilatation in opioid-dependent people in response to conjunctivally applied naloxone hydrochloride. A positive response (pupil dilatation) indicates that the subject is dependent on opioids. AIMS: To evaluate the test in an out-patient setting and to identify factors affecting its outcome. METHOD: Pupil size was measured using binocular pupillometry in 100 new patients attending an out-patient clinic for assessment and treatment of opioid use. Measurement was repeated 40 minutes after the unilateral instillation of naloxone drops into the conjunctival sac. RESULTS: We performed 127 tests, of which 103 (81.1%) were positive. Males, and those not on methadone at the time of the test, were more likely to have a negative test result. CONCLUSIONS: The opioid addiction test proved to be a very useful tool for the rapid diagnosis of opioid dependence in the out-patient clinic. Specialist pupillometric equipment increases the number of patients correctly identified as opioid-dependent on the first visit, but is not essential.

Levobupivacaine: a new safer long acting local anaesthetic agent.

The choice of local anaesthetic is influenced by several factors; it must provide effective anaesthesia and analgesia for the duration of the procedure and meet the expectations for post-operative pain management. Of primary concern is patient safety. Bupivacaine, currently the most widely used long acting local anaesthetic agent in both surgery and obstetrics, generally has a good safety record but its use has resulted in fatal cardiotoxicity, usually after accidental intravascular injection. Hence, for several years there has been a need for a long acting local anaesthetic, similar to bupivacaine, but with an improved cardiovascular safety profile. Levobupivacaine, the single enantiomer version of bupivacaine, offers a new long acting local anaesthetic, clinically equivalent in anaesthetic potency to bupivacaine, but with a reduced toxicity profile. Preclinical studies, from in vitro in single ion channels to whole large animal models, have unquestionably demonstrated that levobupivacaine is significantly less CNS toxic and cardiotoxic than bupivacaine. Cardiotoxicity is less easy to study in man, as the clinical signs are not usually seen until the CNS toxicity is marked, and well beyond that which is tolerable to volunteers or patients. Nevertheless, levobupivacaine has been shown to have less effect on myocardial contractility and QTc prolongation, early signs of cardiotoxicity, than bupivacaine in healthy subjects. In clinical use levobupivacaine has been shown to be equally efficacious as bupivacaine at comparable doses and concentrations, and has been found to produce similar anaesthetic characteristics (onset, duration and density of block). As levobupivacaine now becomes commercially available, the database available with which to make efficacy and safety comparisons with other local anaesthetics will increase, and the true value of this new long acting local anaesthetic should become even more apparent.

Influence of dexaminoglutethimide, an optical isomer of aminoglutethimide, on the disposition of estrone sulfate in postmenopausal breast cancer patients.

Aminoglutethimide (AG) has been the most widely used aromatase inhibitor in breast cancer patients to date. Commercially, AG (Orimeten) is available as a racemate (DL-AG). Previous studies suggested the stereoisomers of AG (D-AG and L-AG) to differ considerably in their affinities and potencies to inhibit different cytochrome P-450-dependent enzymes, with D-AG being the potent aromatase inhibitor. DL-AG, apart from being an aromatase inhibitor, is known to enhance the metabolism of plasma estrone sulfate (E1S). In the present study we compared the effects of D-AG (500 mg daily) and DL-AG (1000 mg daily) on plasma estrogen levels and estrone (E1) and E1S clearance rates, determined after the injection of [14C]E1 and [3H]E1S, in a cross-over study involving 12 postmenopausal breast cancer patients. Treatment with DL-AG and D-AG suppressed plasma E1S to 18.6% and 15.0% of pretreatment levels, whereas E1 and estradiol E2 levels fell to 18.6% and 23.4% of their pretreatment levels during treatment with DL-AG and to 17.7% and 23.4% during treatment with D-AG, respectively. Thus, both treatment options suppressed all estrogens measured to a similar extent. The clearance rate of E1S increased from a mean pretreatment value of 5.9 to 14.0 and 10.0 L/h during treatment with DL-AG and D-AG, respectively (P < 0.05, comparing the two on-treatment situations), whereas the production rate of E1S decreased from a pretreatment value of 1.44 to 0.64 nmol/h with DL-AG and 0.36 nmol/h with D-AG (P < 0.05, comparing on-treatment values). These findings are consistent with the hypothesis that the D- as well as the L-form of AG may enhance the clearance rate of E1S. The finding of a higher estrogen production rate during treatment with DL-AG compared to D-AG probably reflects an increased plasma level of the estrogen precursor androstenedione (mean levels of androstenedione of 2.54 and 1.27 nmol/L during treatment with D-AG and DL-AG, respectively; P < 0.05).

[The effect of pretreatment with ranitidine on the pharmacokinetics and gastrointestinal transit of a sustained-release theophylline preparation]. / Wirkung der Vorbehandlung mit Ranitidin auf Pharmakokinetik und gastrointestinale Passage eines Theophyllin Retard-Präparates.

A scintigraphic and pharmacokinetic study of the behavior of Bronchoretard forte (theophylline, CAS 58-55-9) was carried out in 8 healthy male volunteers to evaluate the sensitivity of the preparation to changes in gastric pH. The volunteers were pretreated with ranitidine (CAS 66357-35-5) (150 mg b.i.d.) or placebo for three days prior to and on the study day to reduce gastric acidity. The effect of the pretreatment with ranitidine on gastric pH was measured on the day before study begin and the mean pH was significantly increased compared to the placebo (ranitidine pH 2.2 +/- 2.4; placebo pH 1.6 +/- 2.0, p < 0.01 Wilcoxon Signed Rank test). All subjects were pretreated with theophylline for 3 days (500 mg b.i.d.) to achieve steady state. On the study day, the volunteers swallowed two theophylline sustained release capsules, radiolabelled by inclusion of indium-111 micronised Amberlite resin, and the gastrointestinal transit was followed continuously for 14 h using gamma scintigraphy with a further image at 24 h. Blood samples were taken from each subject throughout the study to determine the pharmacokinetic profile of theophylline in the sustained release formulation. No significant differences were found in the gastrointestinal transit of the labelled microparticulates between the data obtained from the group treated with ranitidine and that from the placebo group. Plasma theophylline concentration profiles were identical for the two treatments. These data indicate that the theophylline sustained release formulation is not sensitive to the effects of major changes in gastric H+ concentration.

Effect of a test meal on the intragastric distribution of urea in the 13C-urea breath test for Helicobacter pylori.

Test meals are invariably used in the 13C-urea breath test (UBT) but their effect on the intragastric distribution and gastric residence time of urea given in the test is unknown. The site of Helicobacter pylori urease measured in the test is unknown and whether the test measures total or regional gastric urease is uncertain. This study reports the results of paired UBTs with simultaneous gastric distribution studies, one with and one without a fatty test meal, two weeks apart on seven H pylori infected subjects. The test meal did not affect UBT results at 10 minutes, but increased values at 30 minutes and thereafter. The amount of scintigraphic label in the antrum at 10 minutes was also unaffected by the meal but increased at 30 minutes and thereafter, whereas the amount in the body/fundus was greatly increased both at 10 minutes and throughout the test. There was considerable variation in intragastric distribution of urea between subjects, both with and without the test meal. This study shows that a test meal profoundly affects intragastric distribution of urea solution in the UBT, and increases UBT values at 30 minutes and later. Variability between subjects, however, means that accurate measurement of total or regional gastric urease is probably unrealistic.

The opiate addiction test: a clinical evaluation of a quick test for physical dependence on opiate drugs.

1. Mydriasis (pupil dilation) in response to conjunctivally applied naloxone hydrochloride has been demonstrated using an innovative electronic binocular pupillometer in 40 opiate dependent patients, on maintenance methadone treatment. 2. No pupillary response to naloxone was seen when an identical procedure was carried out in a control population of 12 healthy volunteers. 3. After a baseline measurement of pupil size, two drops of naloxone hydrochloride were instilled into the conjunctival sac of one eye. Serial binocular pupillometry was then carried out at 5, 10, 15, 20, 25, 30, 35, 40 and 45 min post-instillation. 4. Discriminant analysis between the control and patient groups showed that the false negative rate (error of misclassification to the wrong population) was lowest (20%) at 40 min post-eyedrop instillation, with no false positives in the control group. 5. The study has therefore shown an improvement in the previously reported false negative rate (25%) [1,2], of the conjunctival naloxone test of opiate dependence, with the use of our innovative electronic binocular pupillometer.

Scintigraphic assessment of the intragastric distribution and gastric emptying of an encapsulated drug: the effect of feeding and of a proton pump inhibitor.

BACKGROUND: Local delivery of therapeutic agents to the stomach may be a useful strategy in the treatment of Helicobacter pylori infection. We aimed to see whether the intragastric distribution and gastric retention of a therapeutic agent could be improved, either by giving omeprazole or by dosing after a meal. METHODS: Twelve healthy volunteers took part in this double-blind placebo-controlled crossover study comparing the effects of omeprazole 20 mg twice daily for 5 days with placebo, and the fasted with the fed state, on the gastric emptying and intragastric distribution of a soluble scintigrapic marker contained in a drug capsule. RESULTS: Dosing after food profoundly prolonged gastric residence of the drug label, prolonging mean time to 50% emptying (T50) from 0.5 +/- 0.1 h in the fasted state to 2.0 +/- 0.2 h when given after food. Food also improved intragastric distribution by increasing delivery to the body and fundus. Omeprazole enhanced the effect of food, prolonging T50 to 2.9 +/- 0.3 h, but had no effect in fasted subjects. CONCLUSIONS: Dosing after food markedly improves the aspects of local drug delivery to the stomach investigated in this study, and omeprazole enhances this effect. Post-prandial dosing may, therefore, be useful for improving delivery of some anti-Helicobacter agents.

Non-invasive detection of gastro-oesophageal reflux using an ambulatory system.

The aim of this study was the separate measurement of reflux of food and acid into the oesophagus in 37 healthy, ambulant subjects. This was performed by radiolabelling the food and monitoring its reflux with a small directional gamma detector, which was placed externally over the oesophagus, and connected to an ambulatory data recorder. The pH was measured with a conventional oesophageal pH electrode. This method permitted the separate characterisation of acid and neutral (food) components of gastro-oesophageal reflux. The gastric emptying characteristics of the test meal were also monitored by gamma scintigraphy in a separate experiment. The oesophageal pH fell below 4 for 3.2 + 8.6/-2.3% (mean (SD)) of the recording time. Food reflux alone occurred for 17.8 + 53.2/-13.8% of the recording time. Simultaneous food and acid reflux occurred for only 0.95 + 5.2/-1.2% of the time. Not every reflux event detected by a fall in pH was seen as an increase in counts as a result of reflux of food, and vice versa. This poor correlation of food and acid reflux implies incomplete mixing of food and acid in the stomach, and further shows the inadequacy of reflux diagnosis methods that depend on pH detection alone.

Assessment of the precorneal residence of an ophthalmic ointment in healthy subjects.

1. The precorneal residence of an ophthalmic ointment radiolabelled by inclusion of technetium-99m tin colloid was assessed in seven volunteer subjects using the technique of gamma scintigraphy and compared with a solution of 0.3% w/v hydroxypropylmethylcellulose, (HPMC) radiolabelled by inclusion of technetium-99m diethylenetriaminepentaacetic acid in the same subjects. 2. The mean half-times (+/- s.d.) of corneal residence were 6490 +/- 5404 s (108 min) for the ointment and 13 +/- 24 s for the 0.3% w/v HPMC solution (P < 0.01). 3. The area-under-curve value (AUC(0,540 s)), which reflects the total residence time of the preparation on the ocular surface, was calculated for each vehicle in each subject. The mean (+/- s.d.) AUC(0,540 s) value for the ointment was 42170 (+/- 5032)% s and for the 0.3% w/v HPMC solution it was 8394 (+/- 4641)% s (P < 0.01).

A comparison of gastro-oesophageal reflux in volunteers assessed by ambulatory pH and gamma monitoring after treatment with either Liquid Gaviscon or Algicon Suspension.

This study was designed to compare the effectiveness of single doses of either Liquid Gaviscon or Algicon Suspension in the suppression of food and acid reflux into the oesophagus after a test meal in volunteers. After the pH electrode and gamma detector were positioned 5 cm above the cardia, the volunteers received a refluxogenic radiolabelled meal. The subjects then remained untreated, or thirty minutes later they were given a dose of unlabelled Algicon Suspension, or Liquid Gaviscon and a recording was made for a minimum of 3 hours. Allocation to the treatment group was randomized with the cross-overs performed 1 week apart. Liquid Gaviscon suppressed gastro-oesophageal reflux of both food and acid whereas only an insignificant reduction in reflux was seen after Algicon Suspension. The oesophageal pH remained below 4 for 3.21 +/- 0.92% (S.E.M.) of the recording period in the control study, 0.88 +/- 0.33 after Gaviscon and 2.91 +/- 0.68 after Algicon. The reflux of food was reduced from 17,070 x 10(3) +/- 4713 x 10(3) counts in the control study to 224 x 10(3) +/- 93 x 10(3) counts after the Gaviscon and 16,080 x 10(3) +/- 7131 x 10(3) counts after Algicon. The suppression of reflux by Liquid Gaviscon was significantly better than that produced by Algicon Suspension.

Ocular surface residence times of artificial tear solutions.

Solutions of hydroxypropylmethylcellulose (HPMC) and polyvinyl alcohol (PVA) are widely used as artificial tears. However, their usefulness is limited by the short duration of their effect. Dilute sodium hyaluronate (SH) solutions exhibit non-Newtonian rheology with high viscosities at low shear rates, which would be expected to enhance their ocular surface residence time. Using quantitative gamma scintigraphy, estimates of the ocular surface residence times of 0.3% HPMC, 1.4% PVA, and 0.2% SH were made in six patients with keratoconjunctivitis sicca. The sodium hyaluronate solution had a mean half-life on the ocular surface of 321 s, significantly longer than hydroxypropylmethylcellulose (44 s; p = 0.012) and polyvinyl alcohol (39 s; p = 0.013).

Scintigraphic studies on the corneal residence of a New Ophthalmic Delivery System (NODS): rate of clearance of a soluble marker in relation to duration of pharmacological action of pilocarpine.

1. A gamma scintigraphic study has been carried out on the precorneal residence and pharmacodynamic action of a radiolabelled New Ophthalmic Delivery System (NODS) containing pilocarpine nitrate in 12 healthy volunteers. 2. The NODS was radiolabelled with the soluble marker technetium-99m labelled diethylenetriaminepentaacetic acid, to mark the release characteristics of soluble drugs contained within the matrix. 3. The relationship between the precorneal residence time of the marker and the duration of drug effect on intraocular pressure and pupil diameter was monitored. Results obtained following administration of the NODS were compared with those obtained after administration of a 25 microliters drop of a 2% w/v pilocarpine nitrate solution. Each formulation was administered to one eye only, the other eye acting as a control. 4. Dissolution of the radiolabel from the NODS in vivo showed considerable intersubject variation with half-times of dissolution ranging from 46 s to 833 s (mean +/- s.d. -280 +/- 217 s), the mean (+/- s.d.) half-time of clearance of the radiolabel from the NODS and corneal region of interest was 406 +/- 214 s whereas the radiolabelled solution had a mean (+/- s.d.) ocular surface residence time of 2.9 +/- 1.5 s. 5. Pupil diameter and intraocular pressure were measured for 5 h post-administration of the NODS and the solution. After both treatments pupil diameter was significantly constricted in the test eye when compared with the control eye (P less than 0.001; Student's paired t-test). Pupil diameter was constricted by 52% after administration of the NODS and by 35% after administration of the solution.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of pretreatment with ranitidine on the pharmacokinetics and gastrointestinal transit of a sustained release theophylline preparation.

A scintigraphic and pharmacokinetic study of the behaviour of (Bronchoretard forte, CAS 58-55-9) was carried out in 8 healthy male volunteers to evaluate the sensitivity of the preparation to changes in gastric pH. Volunteers were pretreated with ranitidine (CAS 66357-35-5) (150 mg b.d.) or placebo for three days prior to and on the study day to reduce gastric acidity. The effect of the pretreatment with ranitidine on gastric pH was measured on the prestudy day and the mean pH was significantly reduced compared to the placebo (ranitidine pH 2.2 +/- 2.4; placebo pH 1.6 +/- 2.0, p less than 0.01 Wilcoxon Signed Rank test). All subjects were pretreated with theophylline for 3 days (500 mg b.d.) to achieve steady-state. On the study day the volunteers swallowed two theophylline sustained release capsules radiolabelled by inclusion of indium-111 micronised Amberlite resin and the gastrointestinal transit followed continuously for 14 h using gamma scintigraphy with a further image at 24 h. Blood samples were taken from each subject throughout the study to determine the pharmacokinetic profile of theophylline when presented in the sustained release formulation. No significant differences were found in the gastrointestinal transit of the labelled microparticulates between the data obtained from the group when treated with ranitidine or placebo. Plasma theophylline concentration profiles were identical for the two treatments. These data indicate that the theophylline sustained release formulation is not sensitive to the effects of major changes in gastric H+ concentration.

A comparison of the precorneal residence of an artificial tear preparation in patients with keratoconjunctivitis sicca and normal volunteer subjects using gamma scintigraphy.

The precorneal residence of an artificial tear preparation has been compared in twelve patients with keratoconjunctivitis sicca (KCS) and twelve normal healthy volunteers. The artificial tear solution was radiolabelled by the inclusion of 1 MBq technetium-99m diethylenetriaminepentaacetic acid (99Tcm-DTPA), and 25 microliters was instilled into one eye only. Deposition of the preparation was followed by gamma scintigraphy. Precorneal clearance of the solution was found to follow bi-exponential kinetics in all subjects with no significant differences in clearance rates between the two study populations. There was also no significant difference in the area under the time-activity profile for the two study groups. This suggests that the reduced reflex tearing and basal lacrimation in KCS patients, indicated by the Schirmer's test, are not important in the clearance of isotonic solutions from the eye surface.

The use of a radiolabelled saccharin solution to monitor the effect of the preservatives thiomersal, benzalkonium chloride and EDTA on human nasal clearance.

The effect of thiomersal, benzalkonium chloride and ethylenediaminetetraacetic acid (EDTA) on the nasal mucociliary clearance of healthy volunteers has been investigated using a modified saccharin test and gamma scintigraphy concomitantly. A significant correlation was found between the two techniques. Using each subject as his/her own control, none of the preservatives significantly altered the rate of clearance or proportion cleared from the nasal cavity after the administration of a single dose. This result is at variance with some in-vitro findings.

Scintigraphic assessment of an ophthalmic gelling vehicle in man and rabbit.

Studies of the rate of clearance of a gellan gum formulation (Gelrite) radiolabelled by the inclusion of technetium-99m labelled diethylenetriaminepentaacetic acid were carried out in volunteer subjects and in rabbits. Disposition was followed by gamma scintigraphy and compared with 0.5% w/v hydroxyethylcellulose (HEC) solution and isotonic saline administered to the same subjects. Clearance of all solutions was found to follow bi-exponential kinetics with differences in clearance rates between the two species studied. A significant retention of the gellan gum formulation compared to HEC (p = 0.006) or saline (p = 0.009) was noted in man, but not in the rabbit. In this latter species the HEC showed greater retention compared to Gelrite. The species-specific differences in the precorneal residence of the formulations are attributed to the different physiological responses following instillation of solutions into the eye.

Precorneal residence times of sodium hyaluronate solutions studied by quantitative gamma scintigraphy.

Sodium hyaluronate solutions have been advocated in the management of a variety of dry-eye states. By virtue of their non-Newtonian rheological properties, formulations exhibiting high zero-shear viscosities may be used as an artificial tear with the expectation of prolonged precorneal residence times and improved tolerance. Quantitative gamma scintigraphy was used to evaluate the residence times of 0.2% and 0.3% sodium hyaluronate solutions and a polymer-free solution of buffered saline in 12 patients with keratoconjunctivitis sicca and a group of six normal volunteers. Using several indices of residence time, mean values for the sodium hyaluronate solutions were significantly longer than those for buffered saline. Parallel changes in tear film thickness were also demonstrated using a technique based on laser interferometry.

Effect of time of dosing relative to a meal on the raft formation of an anti-reflux agent.

Gamma scintigraphy was used in twelve healthy volunteers to establish whether the time of dosing of Liquid Gaviscon relative to a meal influenced its therapeutic action. Indium-113m labelled Liquid Gaviscon was administered to fasted subjects, 30 min after a technetium-99m labelled meal or immediately before ingestion of the meal. The time for 50% of the Gaviscon to empty from the stomach was 0.36 +/- 0.13 h, 3.10 +/- 0.31 h and 0.68 +/- 0.04 h (s.e.m.), respectively. The preparation was found to empty rapidly from the fasted stomach and could not be floated on a meal consumed subsequently. For raft formation to occur, Liquid Gaviscon should be taken 30 min after a meal.

An investigation into the floating behaviour of a pectin-containing anti-reflux formulation (FF5005) by means of gamma scintigraphy.

The gastric distribution and residence time of a new pectin-containing formulation, FF5005 (Farma Food A/S, Denmark), was investigated by using the technique of gamma scintigraphy in six healthy volunteers after administration with a radiolabelled meal. The formulation and test meal were radiolabelled with indium-113m and technetium-99m, respectively, and the formulation was administered to the subjects 30 min after the labelled meal. FF5005 was shown to float and form a discrete phase on top of the stomach contents and emptied from the stomach more slowly than the food (p less than 0.05, Wilcoxon signed rank test). The times taken for the formulation and test meal to half-empty from the stomach (T50) were 4.13 +/- 0.69 h (mean +/- SD) and 2.17 +/- 0.15 h (mean +/- SD), respectively. Greater than 50% of the formulation remained in the fundal region of the stomach for 3 h. FF5005 produced in vivo behaviour similar to that of established alginate-containing anti-reflux agents, and the pectin content of the formulation was shown to decrease the rate of emptying of the meal.