Efficacy endpoints in migraine clinical trials: the importance of assessing freedom from pain.

Many efficacy endpoints have been used in clinical trials of acute migraine pharmacotherapy. Headache response or headache relief (i.e., moderate/severe pain reduced to mild/no pain) at a single, specified time-point, traditionally the primary endpoint, and headache recurrence (i.e., return of pain after initial postdose relief) are inadequate. Headache relief does not provide information about pain-free response and counts a partial response as a treatment success. Headache recurrence can reflect sustained efficacy but is confounded by initial response to treatment, because ineffective drugs have low recurrence rates. The International Headache Society (IHS) guidelines state that 2 hour pain-free response and sustained pain-free response (i.e., freedom from pain with no recurrence or use of rescue or study medication 2-24 hours postdose) provide the most clinically relevant information about the efficacy of migraine pharmacotherapy. The pain-free criterion counts partial responses as failures and thus is a more rigorous test of therapeutic benefit than headache relief, and the two endpoints together incorporate the main treatment attributes that determine patient satisfaction. As an example, consider needle-free subcutaneous sumatriptan and oral triptan tablets. An open-label study of needle-free subcutaneous sumatriptan by Cady and colleagues found that 2 hour pain-free response and sustained pain-free response were 64% and 42% respectively. For oral triptan tablets, the 2001 metaanalysis by Ferrari and colleagues reported 2 hour pain-free response rates ranging from 23% to 38% and sustained pain-free response rates ranging from 11% to 26%. The measures of pain-free response 2 hours postdose and sustained pain-free response can differentiate among treatments and be used to guide therapeutic choices.

Comparison of in vitro and in vivo efficiencies of a novel unit-dose liquid aerosol generator and a pressurized metered dose inhaler.

Gamma scintigraphic imaging was employed in 10 healthy volunteers to compare the total and regional lung deposition of aerosols generated by two delivery platforms that permitted microprocessor-controlled actuation at an optimal point during inhalation. An aqueous solution containing 99mTc-DTPA was used to assess the deposition of aerosols delivered by inhalation from two successive unit-dosage forms (44 microl volume) using a prototype of a novel liquid aerosol system (AERx Pulmonary Delivery System). This was compared with aerosol deposition after inhalation of two 50 microl puffs of a 99mTc-HMPAO-labeled solution formulation from a pressurized metered dose inhaler (MDI). The in vitro size characteristics of the radiolabeled aerosols were determined by cascade impaction. For the AERx system, the predicted lung delivery efficiency based on the product of emitted dose (60.8%, coefficient of variation (CV)=12%) and fine particle fraction (% by mass of aerosol particles <5.7 microm in diameter) was 53.3% (CV=13%). For the solution MDI, the emitted dose was 62.9% (CV=13%) and the predicted lung dose was 44. 9% (CV=15%). The AERx system demonstrated efficient and reproducible dosing characteristics in vivo. Of the dose loaded into the device, the mean percent reaching the lungs was 53.3% (CV=10%), with only 6. 9% located in the oropharynx/stomach. In contrast, the lung deposition from the solution MDI was significantly less (21.7%) and more variable (CV=31%), with 42.0% of the radiolabel detected in the oropharynx/stomach. Analysis of the regional deposition of the radioaerosol indicated a homogeneous pattern of deposition after delivery from the AERx system. A predominantly central pattern of distribution occurred after MDI delivery, where the pattern of deposition was biased towards a central zone depicting the conducting airways. The AERx system, in contrast to MDIs, seems highly suited to the delivery of systemically active agents via pulmonary administration.

Pulmonary insulin administration using the AERx system: physiological and physicochemical factors influencing insulin effectiveness in healthy fasting subjects.

BACKGROUND: Orally inhaled insulin may provide a convenient and effective therapy for prandial glucose control in patients with diabetes. This study evaluated the influence of formulation pH and concentration and different respiratory maneuvers on pharmacokinetic and pharmacodynamic properties of inhaled insulin. METHODS: Three, open-label crossover studies in a total of 23 healthy subjects were conducted in which the safety, pharmacokinetics, and pharmacodynamics of insulin inhalation were compared to subcutaneous (SC) injection into the abdomen of commercially available regular insulin. A novel, aerosol generating system (AERx Diabetes Management System, Aradigm Corporation, Hayward, CA) was used to deliver aqueous insulin bolus aerosols to the lower respiratory tract from formulations at pH 3.5 or 7.4 and concentrations of U250 (250 U/mL) or U500 (500 U/mL). RESULTS: Time to maximum insulin concentration in serum (Tmax) after SC dosing occurred approximately 50-60 minutes with the time to minimum plasma glucose concentration (i.e., maximum hypoglycemic effect), (TGmin), occurring later, at around 100-120 minutes. In contrast, pulmonary delivery led to a significantly earlier Tmax (7-20 minutes) and TGmin (60-70 minutes), parameters that were shown to be largely unaffected by changing the pH or concentration of the insulin. However, investigation of changes in inhaled volume (achieved by different programming of the AERx system) for administration of the same sized aerosol bolus revealed significant effects. Significantly slower absorption and time to peak hypoglycemic activity occurred when aerosol delivery of insulin occurred during a shallow (approximately 40% vital capacity) as opposed to a deep (approximately 80% vital capacity) inspiration. In addition, it was shown that serum concentration of insulin increased immediately after a series of forced expiraratory maneuvers 30 minutes after inhaled delivery. CONCLUSIONS: Pulmonary delivery of aqueous bolus aerosols of insulin in healthy subjects resulted in rapid absorption with an associated hypoglycemic effect quicker than is achieved after subcutaneous dosing of regular insulin. Inhaled insulin pharmacokinetics and pharmacodynamics were independent of formulation variables (pH, concentration) but affected by certain respiratory maneuvers.

Structural and enzymatic properties of a gastric NADP(H)- dependent and retinal-active alcohol dehydrogenase.

A class IV-type, gastric alcohol dehydrogenase (ADH) has been purified from frog (Rana perezi) tissues, meaning detection of this enzyme type also in nonmammalian vertebrates. However, the protein is unique among vertebrate ADHs thus far characterized in having preference for NADP(+) rather than NAD(+). Similarly, it deviates structurally from other class IV ADHs and has a phylogenetic tree position outside that of the conventional class IV cluster. The NADP(+) preference is structurally correlated with a replacement of Asp-223 of all other vertebrate ADHs with Gly-223, largely directing the coenzyme specificity. This residue replacement is expected metabolically to correlate with a change of the reaction direction catalyzed, from preferential alcohol oxidation to preferential aldehyde reduction. This is of importance in cellular growth regulation through retinoic acid formed from retinol/retinal precursors because the enzyme is highly efficient in retinal reduction (k(cat)/K(m) = 3.4.10(4) mM(-1) min(-1)). Remaining enzymatic details are also particular but resemble those of the human class I/class IV enzymes. However, overall structural relationships are distant (58-60% residue identity), and residues at substrate binding and coenzyme binding positions are fairly deviant, reflecting the formation of the new activity. The results are concluded to represent early events in the duplicatory origin of the class IV line or of a separate, class IV-type line. In both cases, the novel enzyme illustrates enzymogenesis of classes in the ADH system. The early origin (with tetrapods), the activity (with retinoids), and the specific location of this enzyme (gastric, like the gastric and epithelial location of the human class IV enzyme) suggest important functions of the class IV ADH type in vertebrates.

The effects of jet nebulisation on cationic liposome-mediated gene transfer in vitro.

Nebulisation is currently the most acceptable and practical delivery system for repeated applications of gene therapy to the lower airways of cystic fibrosis (CF) patients. We have assessed whether this route of administration offers other benefits with regard to respiratory gene transfer. A standard jet nebuliser (Acorn System 22, Medicaid) was used to transfer the reporter gene beta-galactosidase complexed with the cationic liposome DC-Chol/DOPE to three epithelial cell lines in vitro, two non-CF and one CF, using a novel collection system. In all three cell lines, nebulisation resulted in significantly (P < 0.05) improved transfection efficiency compared with instillation. At a constant DNA: liposome ratio of 1:5 (wt:wt), transfection efficiency was inversely related to increasing concentrations of DNA-liposomes before nebulisation. This effect was not related to the amount of DNA delivered and measurements of both zeta potential and mean aerodynamic particle size before and after nebulisation did not show concentration-related differences. The increased transfection efficiency did not relate either to the physical consequences of the nebulisation processes nor the effects of nebulisation on the complexes before instillation. Significantly increased transfection efficiency was seen following nebulisation with 95% O2/5% CO2 in comparison with 21% O2/78% N2 (air); this did not relate to changes in either the pH or temperature of the solution bathing the cells. The data confirm that nebulisation is appropriate for gene delivery to the lower airways in clinical practice and points to factors that may optimise gene transfer efficiency.

Inhalation delivery systems with compliance and disease management capabilities.

Non-compliance with prescribed medication is a major reason for poor therapeutic outcomes, leading to unnecessary contributions to healthcare costs. Poor technique in self-administration of inhalation therapy is a special type of non-compliance associated with this route of administration. However, pulmonary drug delivery has fundamental advantages for therapy of diseases of the respiratory tract because it is site-directed. The lung is also a promising portal for drug delivery into the systemic circulation. Incorporation of microprocessors into pulmonary drug delivery systems facilitates sophisticated compliance management of chronic diseases such as asthma and diabetes. Microprocessor-assisted systems afford control of patients' administration technique during the therapeutic inhalation event, thus leading to efficient and reproducible regional deposition of the inhaled drug or diagnostic agent. SmartMist is a hand-held asthma disease management device that aids patients to use optimally metered dose inhalers. It also measures pulmonary lung function and provides a long term downloadable electronic record of the therapeutic and diagnostic events. The AERx pulmonary delivery system utilizes similar microprocessor capabilities; however, it employs a novel means of generating aqueous aerosols from unit dose packages, thus providing a broad inhalation technology base for delivery of a wide variety of therapeutic and diagnostic agents into the respiratory tract, and via the lung into the systemic circulation.

Pulmonary administration of aerosolised fentanyl: pharmacokinetic analysis of systemic delivery.

AIMS: Pulmonary drug delivery is a promising noninvasive method of systemic administration. Our aim was to determine whether a novel breath-actuated, microprocessor-controlled metered dose oral inhaler (SmartMist, Aradigm Corporation) could deliver fentanyl in a way suitable for control of severe pain. METHODS: Aersolised pulmonary fentanyl base 100-300 microg was administered to healthy volunteers using SmartMist and the resultant plasma concentration-time data were compared with those from the same doses administered by intravenous (i.v.) injection in the same subjects. RESULTS: Plasma concentrations from SmartMist were similar to those from i.v. injection. Time-averaged bioavailability based upon nominal doses averaged approximately 100%, and was > 50% within 5 min of delivery. Fentanyl systemic pharmacokinetics were similar to those previously reported with no trends to dose-dependence from either route. Side-effects (e.g. sedation, lightheadedness) were the same from both routes. CONCLUSIONS: Fentanyl delivery using SmartMist can provide analgetically relevant plasma drug concentrations. This, combined with its ease of noninvasive use and transportability, suggests a strong potential for field and domicilliary use, and for patient controlled analgesia without the need for i.v. cannulae.

Transport of a series of D-phenylalanine-glycine hexapeptides across rat alveolar epithelia in vitro.

The effect of lipophilicity on the absorption of peptides from the lungs was investigated. D-phenylalanine (F)-glycine (G) hexapeptides were synthesised to differ, predominantly, only in their lipophilicity. Rat alveolar type II cells were isolated and cultured on plastic, or polycarbonate filters; by day 6 they had de-differentiated to an alveolar type I-like epithelium. The permeability of the monolayers to the hexapeptides was determined. The hexapeptides were metabolically and chemically stable for greater than 24h in the presence of the cells. They did not adhere to the cell culture plastic and were associated only to a low extent with the cell monolayer. The apical to basolateral permeability coefficients for D-F1G5, D-F2G4, and D-F3G3 were 2.19+/-0.53, 1.75+/-0.42 and 2.20+/-0.56 x 10(-7) cm s(-1) respectively. The permeability of the monolayers to D-F1G5 and D-F2G4 was concentration and direction independent, however for D-F3G3 the monolayer was more permeable in the basolateral to apical direction. There was no correlation between the lipophilicity of the hexapeptides and permeability coefficients: other physicochemical parameters did not predict hexapeptide transport. Lipophilicity does not appear to control the transport of hexapeptides across the alveolar epithelium probably as a consequence of the peptides being transported via the paracellular route.

Morphine pharmacokinetics after pulmonary administration from a novel aerosol delivery system.

BACKGROUND: Successful pharmacotherapy of pain often depends on the mode of drug delivery. A novel, unit dose, aqueous aerosol delivery system (AERx Pulmonary Drug Delivery System) was used to examine the feasibility of the pulmonary route for the noninvasive systemic administration of morphine. METHODS: The study had two parts: (1) a dose-ranging study in four subjects with three consecutive aerosolized doses of 2.2, 4.4, and 8.8 mg (nominal) morphine sulfate pentahydrate at 40-minute intervals, and (2) a crossover study, on separate days, in six subjects with 4.4 mg (nominal) aerosolized morphine sulfate administered over 2.1 minutes on three occasions and intravenous infusions of 2 and 4 mg over 3 minutes. Subjects were healthy volunteers from 19 to 34 years old. Arterial blood was sampled for a total of 6 hours and plasma morphine concentrations were measured by gas chromatography-mass spectrometry. RESULTS: In part 1, plasma morphine concentrations were proportional to dose. In part 2, the mean +/- SD peak plasma concentration (Cmax) occurred at 2.7 +/- 0.8 minutes after the aerosol dose, with mean values for Cmax of 109 +/- 85, 165 +/- 22, and 273 +/- 114 ng/ml for the aerosol and 2 and 4 mg intravenous doses, respectively. The bioavailability [AUC(0-360 min)] of aerosol-delivered morphine was approximately 100% relative to intravenous infusion, with similar intersubject variability in AUC for both routes (coefficient of variation < 30%). CONCLUSION: The time courses of plasma morphine concentrations after pulmonary delivery by the AERx system and by intravenous infusions were similar. This shows the utility of the pulmonary route in providing a noninvasive method for the rapid and reproducible systemic administration of morphine if an appropriate aerosol drug delivery system is used.

Putrescine uptake by alveolar epithelial cell monolayers exhibiting differing transepithelial electrical resistances.

Rat alveolar type II cells were isolated following elastase digestion and cultured on polycarbonate filters at various densities and in different media. Two days after seeding, the cells formed a monolayer on the filters which consisted predominantly of type II cells, these then de-differentiated to a alveolar type I-like cell monolayer by day 6. The seeding density and media utilized affected the transepithelial electrical resistance (TEER) generated by the monolayer. Only certain culture conditions allowed the production of a monolayer that mimics, putatively, the in vivo alveolar epithelium (TEER greater than 1000 omega cm2). Vmax and K(m) values for the uptake of putrescine by monolayers exhibiting low and high TEERs on day 6 were determined. The capacity of the putrescine uptake mechanisms was greater in cell monolayers exhibiting a high TEER than those exhibiting a low TEER, suggesting that the TEER does not only measure the "tightness" of the monolayer but contains an element representative of the viability of the cell monolayer. The selection of appropriate TEERs for cell culture investigations is discussed.

Development of a method for monitoring the migration of 111In-labeled eosinophils and neutrophils to the lungs of anaesthetized guinea pigs by gamma scintigraphy and bronchoalveolar lavage.

A method to introduce 111In-labelled neutrophils or eosinophils into the circulation of anaesthetized, ovalbumin-sensitized guinea pigs and monitor their pulmonary accumulation using gamma scintigraphy has been developed. The method is based on the ability to use 99mTc macroaggregated albumin (MAA) to create a pulmonary perfusion image as a template for the lungs of individual guinea pigs which can be superimposed on to the image produced by the 111In-labelled leukocytes injected into the same animal. Intravenous injection of the labelled leukocytes was shown to produce a high density radioactivity in the heart and lungs with little circulation to the rest of the body. This suggested an immediate 'trapping' of leukocytes in the pulmonary vascular bed. A more effective distribution of 111In-labelled cells was achieved by injecting them into the right carotid artery. This ensured more efficient circulation of the cells and resulted in their appearance in the lungs, liver and spleen. However, it was found that the contralateral carotid artery had to be tied off to prevent the cells only circulating to the superior left quadrant of the animal. Bronchoalveolar lavage of the lungs following i.v. injection of 111In-labelled neutrophils showed no significant difference in radioactivity of lavage fluid between guinea pigs challenged 24 h beforehand with inhaled saline or ovalbumin. In contrast, when labelled eosinophils were injected, there was a significantly greater mean radioactivity level in lavage fluid after ovalbumin challenge than after saline. In conclusion, gamma scintigraphy provides an accurate measure of the amount of activity from 111In-labelled leukocytes in the lung region which is specific for each animal

The physico-chemical basis of radiolabelling metered dose inhalers with 99mTc.

Over the past decade, a number of different approaches have been proposed for the radiolabelling of metered dose inhalers (MDIs) in order to permit gamma scintigraphic imaging of emitted aerosols following inhaled administration. More recently, methods have been described for the indirect 99mTc-labelling of drugs incorporated into commercial MDI products. This paper attempts to rationalise such methods from a surface chemical perspective in order to: I) elucidate the mechanism of association of the radiolabel and drug; 2) predict the appropriateness of the techniques to all MDI products and; 3) propose in vitro testing methods to validate the labelling efficiency prior to in vivo evaluation.

Effect of cotton, hemp, and flax dust extracts on lung permeability in the guinea pig.

Byssinosis is an occupational lung disease in textile mill workers exposed to the respirable dusts of cotton, hemp, and flax. This study investigated the influence of aqueous extracts from these dusts on overall lung permeability in the guinea pig as an index of respiratory epithelial damage. Lung permeability was assessed by absorption into blood from the lung of inhaled technetium-99m diethylenetriamine penta-acetate (Tc-DTPA) using gamma-scintigraphy. The half-life for Tc-DTPA absorption (t1/2) was significantly reduced following a 4-week inhalation treatment with cotton, hemp, or flax dust extracts when compared to saline control. There was at least a partial return to normal permeability 7 days after stopping treatment. A single inhalation of extract did not affect the t1/2, but increased the number of neutrophils in bronchoalveolar lavage fluid 24 h postexposure. Neutrophil migration into the airspaces therefore appeared to precede the increased lung permeability. Long-term exposure was not associated with respiratory epithelial shedding, suggesting that the increased permeability reflects a loss of epithelial tight junction integrity arising from repeated exposure to as yet undefined agents in these dusts.

Precorneal clearance of mucoadhesive microspheres from the rabbit eye.

The ocular disposition of hydrated 111In-labelled microspheres was investigated in the rabbit by gamma scintigraphy. Microspheres of cross-linked poly(acrylic acid) (Carbopol 907) were prepared by a w/o emulsification process. An in-vitro mucoadhesion test of prehydrated microspheres showed that greater adhesion was achieved to a mucus gel at pH 5.0 compared with pH 7.4. Clearance was a biphasic process with a rapid initial phase preceding a slower basal phase. When hydrated in pH 5.0 phosphate buffered saline, clearance during the basal phase was slowed compared with a pH 7.4 buffered preparation. Both prehydrated preparations were retained on the preocular area during the basal phase for longer periods than non-hydrated microspheres. The retention on the ocular surface of approximately 25% of the instilled dose would suggest this technology will have application for controlled ophthalmic drug delivery.

Aerosol deposition in the human lung following administration from a microprocessor controlled pressurised metered dose inhaler.

BACKGROUND: Gamma scintigraphy was employed to assess the deposition of aerosols emitted from a pressurised metered dose inhaler (MDI) contained in a microprocessor controlled device (SmartMist), a system which analyses an inspiratory flow profile and automatically actuates the MDI when predefined conditions of flow rate and cumulative inspired volume coincide. METHODS: Micronised salbutamol particles contained in a commercial MDI (Ventolin) were labelled with 99m-technetium using a method validated by the determination of (1) aerosol size characteristics of the drug and radiotracer following actuation into an eight stage cascade impactor and (2) shot potencies of these non-volatile components as a function of actuation number. Using nine healthy volunteers in a randomised factorial interaction design the effect of inspiratory flow rate (slow, 30 l/min; medium, 90 l/min; fast, 270 l/min) combined with cumulative inspired volume (early, 300 ml; late, 3000 ml) was determined on total and regional aerosol lung deposition using the technique of gamma scintigraphy. RESULTS: The SmartMist firing at the medium/early setting (medium flow and early in the cumulative inspired volume) resulted in the highest lung deposition at 18.6 (1.42)%. The slow/early setting gave the second highest deposition at 14.1 (2.06)% with the fast/late setting resulting in the lowest (7.6 (1.15)%). Peripheral lung deposition obtained for the medium/early (9.1 (0.9)%) and slow/early (7.5 (1.06)%) settings were equivalent but higher than those obtained with the other treatments. This reflected the lower total lung deposition at these other settings as no difference in regional deposition, expressed as a volume corrected central zone:peripheral zone ratio, was apparent for all modes of inhalation studied. CONCLUSIONS: The SmartMist device allowed reproducible actuation of an MDI at a preprogrammed point during inspiration. The extent of aerosol deposition in the lung is affected by a change in firing point and is promoted by an inhaled flow rate of up to 90 l/min-that is, the slow and medium setting used in these studies.

The influence of regional deposition on the pharmacokinetics of pulmonary-delivered human growth hormone in rabbits.

The pulmonary deposition and pharmacokinetics of human growth hormone (hGH), administered by aerosol and instillate, in formulations containing 99mTc-DTPA (for gamma scintigraphic imaging) have been studied in five male New Zealand White rabbits. Gamma scintigraphy indicated that the peripheral:central deposition tended to be greater for aerosol (1.54) than for instillate (0.8). Two gamma scintigraphic methods were used to quantify dose deposited by aerosol, which permitted bioavailabilities to be determined. The bioavailable fraction for aerosolized hGH (45%) was greater than for instilled hGH (16%). This was attributed to the differential effects of mucociliary clearance. Absorption rate limited pharmacokinetics prevailed for both hGH formulations with post-peak half-lives approximately 10-fold greater than the intravenous elimination half-life of 40 min. Apparent absorption rate constants resulting from instillation and aerosolization were equivalent (0.0012 min-1 and 0.0020 min-1 respectively), however lung-to-blood transfer rate constants for aerosol delivery (0.00071 min-1) were greater than for instillation (0.00018 min-1).

The in vitro characterisation and biodistribution of some non-ionic surfactant coated liposomes in the rabbit.

The degree of adsorption of some novel silicone glycol copolymers onto polystyrene microspheres was studied and compared with the sorption onto small unilamellar vesicles (SUVs) composed of egg phosphatidylcholine (EPC) and prepared by the detergent dialysis technique. These non-ionic surfactants are 'comb' polymers of the ABn type where A is a silicone chain with n pendant polyglycol chains (B). Photon correlation spectroscopy was used to measure the adsorbed layer thickness (delta h) following polymer sorption from aqueous solutions. delta h on latex particles was a function of the length of the polymer hydrophilic chains. Upon incubation with SUVs, delta h of the different polymers was similar (3 nm) and significantly less (two sample t-test, p < 0.01) than the corresponding delta h on the polystyrene latex which could be attributed to the penetration of the polymers into the outer phospholipid bilayer. The glycol chains of the silicone polymers are assumed to be in a helical and planar position. Efflux of 5(6)-carboxyfluorescein from EPC liposomes was increased by the presence of these polymers. The highest retention (49% at 5 h) was obtained with SUVs coated with the silicone polymer possessing the highest glycol content and the longest ethylene oxide chains. Sterically stabilised vesicles were also formed by coating dipalmitoyl phosphatidyl-choline (DPPC)/cholesterol (Chol) (molar ratio 1:1) with two of these silicone glycol copolymers and Poloxamer 338. The liposomes were labelled with 67gallium-desferrioxamine (67Ga-DF). Incubation of radiolabelled Poloxamer 338-coated vesicles in saline or serum at 37 degrees C for 24 h resulted in less stable liposomes compared to the more stable non-coated or silicone coated vesicles. Following intravenous (i.v.) administration in rabbits, free 67Ga-DF rapidly disappeared from the circulation (half-life = 41.4 min) and accumulated in the bladder. Two populations of vesicles were prepared (136 +/- 2.9 nm and 100 +/- 1.4 nm). 24 h after i.v. injection of the different formulations of the 100 nm liposomes in rabbits, 20-27% of the activity was retained in blood. The silicone polymer with the highest glycol content and the longest ethylene oxide chains showed the longest half-life (21.4 h). Using gamma scintigraphy, the liver/spleen uptake of the 136 nm non-coated vesicles was 57% which was significantly reduced to 37% upon coating the liposomes with the silicone glycol copolymers. At 30 min post i.v. injection, approximately 10% of the activity was associated with the heart/lung region irrespective of liposome size or polymer coating.(ABSTRACT TRUNCATED AT 400 WORDS)

Ranitidine bismuth citrate and ranitidine do not affect gastric emptying of a radio-labelled liquid meal.

Ranitidine bismuth citrate, a new chemical entity which is a salt complex of ranitidine and bismuth citrate, is being developed for the treatment of relapse of benign gastric and duodenal ulcer and eradication of Helicobacter pylori. The aim of the present study was to establish whether ranitidine bismuth citrate (800 mg) or ranitidine hydrochloride (300 mg) have any effect on gastric emptying of a liquid meal using gamma scintigraphy. On three separate occasions, each of twelve subjects received a single oral tablet of 800 mg ranitidine bismuth citrate, 300 mg ranitidine hydrochloride or placebo in random order. Thirty minutes after dosing each subject was given 375 ml of 99mTc-DTPA (diethylene triaminepentaacetic acid) labelled Clinifeed-ISO. The primary endpoint was the time to 50% gastric emptying (t50%). The proportion of the meal remaining was summarised by weighted mean proportion of the meal remaining in the stomach over 0-60 min and 0-180 min, separately. No differences were observed for t50%, weighted mean 0-60 min, and weighted mean 0-180 min between any two treatments. In man, we have detected no significant effect of single oral doses of ranitidine bismuth citrate 800 mg or ranitidine hydrochloride 300 mg on the rate of gastric emptying of a liquid meal when compared with placebo.

The accumulation of pentamidine and the toxic effects of the drug, its selected analogues and metabolites on isolated alveolar cells.

Radiolabelled [3H]pentamidine is accumulated into 48-h and 7-day cultures of alveolar epithelial type 2 cells and alveolar macrophages in a linear, time and dose-dependent manner, with the rate of uptake being 15.3, 13.4 and 17.9 pmol/micrograms protein per 30 min, respectively. Uptake was not affected by metabolic inhibitors. The differential toxicity of the parent drug pentamidine, five analogues and six metabolites was assessed on freshly isolated and type 2 cells maintained in culture over 24 h. Toxicity, determined by the attachment ability of alkaline phosphatase positive cells containing lamellar bodies was greater in freshly isolated cells. Overall, three/four of the analogues proved less damaging to type 2 cells than the pentamidine with one derivative [1,3-bis(4-amidino-2-methoxy)propane], a compound particularly efficacious against pneumocystis in rats, showing minimal toxicity. Five metabolites (chain hydroxylated derivatives) were less toxic than the parent drug. However, one metabolite (N,N-dihydroxy derivative) was much more toxic than pentamidine to both type 2 cells and alveolar macrophages. It is concluded that as the type 2 cell can accumulate the drug, it represents a target cell which is particularly sensitive to pentamidine and/or some of its metabolites.