Occupancy of human brain GABA(A) receptors by the novel α5 subtype-selective benzodiazepine site inverse agonist α5IA as measured using [¹¹C]flumazenil PET imaging.

GABA(A) receptor α5-selective inverse agonists enhance cognitive performance in pre-clinical species. However, a key aspect of the clinical development of such compounds is the demonstration that in man such compounds are devoid of the anxiogenic-like activity associated with non-selective inverse agonists such as FG 7142. The triazolophthalazine α5IA (3-(5-methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-yl)methyloxy]-1,2,4-triazolo[3,4-a]phthalazine) is an α5-selective inverse agonist which enhances cognitive performance in rodents and encouragingly in human Phase I Safety and Tolerability studies it was devoid of the anxiogenic-like activity associated with FG 7142. However, in order to appropriately interpret this latter observation, it was considered important to demonstrate that the absence of anxiogenic-like activity occurs at significant levels of receptor occupancy. Consequently, the occupancy of human brain GABA(A) receptors was measured using [¹¹C]flumazenil positron emission tomography in three healthy normal young male volunteers following a single oral dose of 2 mg α5IA. One hour after dosing, mean occupancy levels were 53% and this fell to 16% by 8 h post-dose, with the plasma α5IA concentration corresponding to 50% occupancy being 10 ng/mL. These data clearly show that an α5-selective inverse agonist is not associated with anxiogenic-like side effects at doses that give ~50% occupancy.

Anabolic steroids in COPD: a review and preliminary results of a randomized trial.

Patients with severe chronic obstructive pulmonary disease (COPD) commonly develop weight loss, muscle wasting, and consequently poor survival. Nutritional supplementation and anabolic steroids increase lean body mass, improve muscle strength, and survival in patients enrolled in comprehensive rehabilitation programs. Whether anabolic steroids are effective outside an intensive rehabilitation program is not known. We conducted a prospective, double-blind, placebo-controlled, 16-week trial to study the benefits of anabolic steroids in patients with severe COPD who did not participate in a structured rehabilitation program. Biweekly intramuscular injections of either the drug (nandrolone decanoate) or placebo were administered. Sixteen patients with severe COPD were randomized to either placebo or nandrolone decanoate. The placebo group weighed 55.32 +/- 11.33 kg at baseline and 54.15 +/- 10.80 kg at 16 weeks; the treatment group weighed 68.80 +/- 6.58 at baseline and 67.92 +/- 6.73 at 16 weeks. Lean body mass remained unchanged, 71 +/- 6 vs. 71 +/- 7 kg in placebo group and 67 +/- 7 vs. 67 +/- 7 in treatment group, at baseline and 16 weeks respectively. The distance walked on 6 min was unchanged at baseline, 8 weeks, and 16 weeks in placebo (291.17 +/- 134.83, 282.42 +/- 115.39, 286.00 +/- 82.63 m) and treatment groups (336.13 +/- 127.59, 364.83 +/- 146.99, 327.00 +/- 173.73 m). No improvement occurred in forced expiratory volume in one second, forced vital capacity, maximal inspiratory pressure, maximal expiratory pressure, VO(2) max or 6-min walk distance or health related quality of life. Administration of anabolic steroids (nandrolone decanoate) outside a dedicated rehabilitation program did not lead to either weight gain, improvement in physiological function, or better quality of life in patients with severe COPD.

Pharmacokinetics of total and unbound ertapenem in healthy elderly subjects.

Ertapenem is a new once-a-day parenteral carbapenem antimicrobial agent. The pharmacokinetics of unbound and total concentrations of ertapenem in plasma were investigated in elderly subjects and compared with historical data from young adults. In a single- and multiple-dose study, healthy elderly males and females (n = 14) 65 years old or older were given a 1-g intravenous (i.v.) dose once daily for 7 days. Plasma and urine samples collected for 24 h on days 1 and 7 following administration of the 1-g doses were analyzed by reversed-phase high-performance liquid chromatography. Areas under the concentration-time curve from 0 h to infinity (AUC(0- infinity )) for elderly females and males were similar following administration of 1-g single i.v. doses, and thus, the genders were pooled in subsequent analyses. Concentrations in plasma and the half-life of ertapenem were generally higher and longer, respectively, in elderly subjects than in young adults. The mean AUC(0- infinity ) of total ertapenem in the elderly was 39% higher than that in young subjects following administration of a 1-g dose. The differences were slightly greater for the mean AUC(0- infinity ) of unbound ertapenem (71%). The unbound fraction of ertapenem in elderly subjects ( approximately 5 to 11%) was generally greater than that in young adults ( approximately 5 to 8%). As in young adults, ertapenem did not accumulate upon multiple dosing in the elderly. The pharmacokinetics of ertapenem in elderly subjects, while slightly different from those in young adults, do not require a dosage adjustment for elderly patients.

Clinical pharmacology studies in UK Phase 1 units: an AHPPI survey 1999-2000.

AIMS: This study, conducted by the Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI), was designed to determine the amount of Phase 1 activity in the UK in the period 1999-2000, the timelines involved for submissions to ethics committee and responses from ethics committees. METHODS: A questionnaire was completed by AHIPPI members from pharmaceutical companies with in-house phase 1 units, by Clinical Research Organizations (CRO's) and by academic centres. A few responses were also vailable from organisations that were not AHPPI members. Results were rendered anonymous and grouped by category. RESULTS: The response rate was > 98% and indicated that the vast majority of early drug research in humans is now CRO-based (82%). The total number of studies (as indicated by protocol numbers) was notably similar across the 2 years--629 in 1999 and 606 in 2000. Turnaround time for ethics committee review was a mean of 14 days. CONCLUSIONS: These data set important benchmarks for early-phase drug research in the UK where regulatory approval is not currently required. Furthermore, the information should be used as a guide if the competitive nature of such work in the UK is to be maintained as new national legislation is implemented following publication of the European Union (EU) Clinical Trials Directive.

Influence of beta-adrenoceptor antagonists on the pharmacokinetics of rizatriptan, a 5-HT1B/1D agonist: differential effects of propranolol, nadolol and metoprolol.

AIMS: Patients with migraine may receive the 5-HT1B/1D agonist, rizatriptan (5 or 10 mg), to control acute attacks. Patients with frequent attacks may also receive propranolol or other beta-adrenoceptor antagonists for migraine prophylaxis. The present studies investigated the potential for pharmacokinetic or pharmacodynamic interaction between beta-adrenoceptor blockers and rizatriptan. METHODS: Four double-blind, placebo-controlled, randomized crossover investigations were performed in a total of 51 healthy subjects. A single 10 mg dose of rizatriptan was administered after 7 days' administration of propranolol (60 and 120 mg twice daily), nadolol (80 mg twice daily), metoprolol (100 mg twice daily) or placebo. Rizatriptan pharmacokinetics were assessed. In vitro incubations of rizatriptan and sumatriptan with various beta-adrenoceptor blockers were performed in human S9 fraction. Production of the indole-acetic acid-MAO-A metabolite of each triptan was measured. RESULTS: Administration of rizatriptan during propranolol treatment (120 mg twice daily for 7.5 days) increased the AUC(0, infinity) for rizatriptan by approximately 67% and the Cmax by approximately 75%. A reduction in the dose of propranolol (60 mg twice daily) and/or the incorporation of a delay (1 or 2 h) between propranolol and rizatriptan administration did not produce a statistically significant change in the effect of propranolol on rizatriptan pharmacokinetics. Administration of rizatriptan together with nadolol (80 mg twice daily) or metoprolol (100 mg twice daily) for 7 days did not significantly alter the pharmacokinetics of rizatriptan. No untoward adverse experiences attributable to the pharmacokinetic interaction between propranolol and rizatriptan were observed, and no subjects developed serious clinical, laboratory, or other significant adverse experiences during coadministration of rizatriptan with any of the beta-adrenoceptor blockers. In vitro incubations showed that propranolol, but not other beta-adrenoceptor blockers significantly inhibited the production of the indole-acetic acid metabolite of rizatriptan and sumatriptan. CONCLUSIONS: These results suggest that propranolol increases plasma concentrations of rizatriptan by inhibiting monoamine oxidase-A. When prescribing rizatriptan to migraine patients receiving propranolol for prophylaxis, the 5 mg dose of rizatriptan is recommended. Administration with other beta-adrenoceptor blockers does not require consideration of a dose adjustment.

Substance P-induced vasodilatation is mediated by the neurokinin type 1 receptor but does not contribute to basal vascular tone in man.

AIMS: Following intravenous administration of its prodrug, L-758,298, we assessed the pharmacodynamics of L-754,030, a novel and highly selective NK1 receptor antagonist, by examining systemic haemodynamics and the blood flow responses to intra-arterial substance P infusion. METHODS: Sixteen healthy male volunteers participated in a double-blind, randomised, placebo controlled crossover trial of L-758 298. Forearm blood flow was measured using venous occlusion plethysmography during intrabrachial substance P infusion (0.125-128 pmol min-1 ). In part 1, eight subjects received substance P infusions before and during placebo, 0.25 mg, 1 mg or 5 mg of L-758 298. In part 2, eight subjects received substance P infusions 24 h after placebo or 1.43 mg of L-758 298. RESULTS: L-758 298 caused dose dependent inhibition of substance P induced vasodilatation (P<0.001). Placebo adjusted differences (95% CI) in baseline forearm blood flow, mean arterial pressure and heart rate showed no relevant changes with 5 mg of L-758 298 (>1400-fold shift in substance P response): 0.00 (-0.49 to +0.49) ml 100 ml-1 min-1, 1. 0 (-3.2 to +5.2) mmHg and 1.9 (-5.9 to +9.7) beats min-1, respectively. Twenty-four hours after 1.43 mg of L-758,298, there was approximately 34-fold shift in response to substance P induced vasodilatation (P<0.008) at plasma L-754 030 concentrations of 2-3 ng ml-1. L-758 298 was generally well tolerated without serious adverse events. CONCLUSIONS: Substance P induced forearm vasodilatation is mediated by the endothelial cell NK1 receptor in man but endogenous substance P does not appear to contribute to the maintenance of peripheral vascular tone or systemic blood pressure.

Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis.

Postmenopausal women with established vertebral osteoporosis were studied for 2 years to determine the terminal elimination half-life and the duration of response to treatment with intravenous alendronate (30 mg) given over 4 days. The urinary excretion of alendronate followed a multiexponential decline. Approximately 50% of the total dose was excreted over the first 5 days, and a further 17% was excreted in the succeeding 6 months. Thereafter, there was a much slower elimination phase with an estimated mean terminal half-life of greater than 10 years (n = 11). Urinary excretion of hydroxyproline and calcium decreased significantly from pretreatment values by day 3, reaching a nadir by 1 week (40% and 67% decrease, respectively). Thereafter, hydroxyproline remained suppressed for the following 2 years. In contrast, urinary calcium excretion returned gradually toward pretreatment values over the first year and during the second year was comparable to pretreatment values. Serum activity of alkaline phosphatase activity decreased over 3 months (23% reduction), increased gradually thereafter, and returned to pretreatment values at month 24. Bone mineral density measured at the spine increased by approximately 5% during the first year and remained significantly higher than pretreatment values at 2 years. We conclude that a short course of high doses of intravenous alendronate is associated with a prolonged skeletal retention of the agent. This open study also suggests that this regimen has a sustained effect on bone turnover persisting for at least 1 year.

Intra-arterial substance P mediated vasodilatation in the human forearm: pharmacology, reproducibility and tolerability.

AIMS: The current studies were designed to characterize the pharmacology, reproducibility and tolerability of the vasodilator response to intra-arterial substance P infusion in the forearm of healthy man. METHODS: On different occasions, eight healthy male volunteers received brachial artery infusions of substance P at doubling doses ranging from 0.5 to 128 pmol min(-1). Blood flow was measured in both arms using venous occlusion plethysmography. RESULTS: Substance P induced dose-dependent vasodilatation in the human forearm which had a log-linear relationship to dose. At doses of 1-8 pmol min(-1), mean responses were highly reproducible both within and between days. There were no differences between responses to discontinuous doses and continuous doses of substance P. Substance P was generally well tolerated at doses of < or = 64 pmol min(-1) with no significant alteration in arterial blood pressure or heart rate. Skin oedema in the infused forearm and systemic vasodilatation, manifested by facial flushing and non-infused forearm vasodilatation, occurred at doses of > or = 16 pmol min(-1). CONCLUSIONS: Forearm vasodilatation to substance P represents a reproducible and useful model in the assessment of peripheral endothelial cell NK1 receptor function.

Initial human experience with MK-462 (rizatriptan): a novel 5-HT1D agonist.

AIMS: We evaluated the pharmacokinetics and pharmacodynamics of oral MK-462 in comparison with oral sumatriptan in healthy male volunteers. METHODS: Sixteen healthy male volunteers were studied in a rising, single dose, alternating panel design with eight subjects per panel. Matching placebo was administered to two of eight study subjects at each dose level of MK-462 in a randomized, double-blind fashion. RESULTS: MK-462 was rapidly absorbed with a median tmax of 1.3 h (range 1-3 h) vs a tmax for sumatriptan of 2.5 h (range 1-4 h, P < 0.001). Administration of either MK-462 or sumatriptan produced maximal mean elevations of 5-10 mmHg in systolic and diastolic blood pressures without effect on heart rate; the changes occurred sooner following MK-462, consistent with more rapid absorption. Both MK-462 and sumatriptan provoked mild increases in serum growth hormone without any effect on serum prolactin concentrations. The most commonly reported symptom following MK-462 was drowsiness. CONCLUSIONS: These results indicate that the novel 5-HT1D agonist, MK-462, is rapidly absorbed following oral administration and warrants further investigation of its utility in the treatment of acute migraine.

Pharmacokinetics and food interaction of MK-462 in healthy males.

A study was conducted to assess the safety, tolerability, and pharmacokinetics of single intravenous (IV) doses of 5-90 micrograms kg-1 of MK-462, and the effect of food on the pharmacokinetics of MK-462 administered orally to healthy males. Results of this study indicate that IV doses of MK-462 from 5 to 90 micrograms kg-1 are well tolerated. The disposition kinetics of MK-462 were linear for IV doses up to and including 60 micrograms kg-1. The values of the plasma clearance (CL), steady-state volume of distribution (Vss), plasma terminal half-life (t1/2), and mean residence time in the body (MRT) of MK-462 averaged 1376 mL min-1, 140 L, 1.8 h, and 1.7 h, respectively, and remained essentially constant over the dosage range of 10-60 micrograms kg-1 of IV MK-462. However, as the dose increased from 60 to 90 micrograms kg-1, the mean value of the apparent CL decreased from 1376 to 807 mL min-1. Thus, elimination of MK-462 was dose dependent in this dosage range. Based on the disposition decomposition analysis (DDA), it was shown that the Vss value of MK-462 remained essentially constant over the dosage range of 10-90 micrograms kg-1 of IV MK-462. The following values of two dose-independent parameters were also calculated by using DDA: distribution clearance (CLd) = 2028 mL min-1, and mean transit time in the peripheral tissues (MTTT) = 0.74 h. The mean values of AUC, Cmax, tmax, and apparent t1/2 of MK-462 in 12 subjects each receiving a 40 mg tablet of MK-462 without breakfast were 330 ng.h mL-1, 77 ng mL-1, 1.6 h, and 1.8 h, respectively. Although administration of a standard breakfast prior to dosing increased the AUC value (by approximately 20%) of MK-462 and delayed its absorption, there were no significant effects of the meal on the values of Cmax and apparent t1/2 of MK-462.

L-692,429, a nonpeptide growth hormone (GH) secretagogue, reverses glucocorticoid suppression of GH secretion.

The reversal of glucocorticoid-induced negative nitrogen balance by GH supports a possible therapeutic role for GH treatment in patients receiving these catabolic steroids. A GH secretagogue might be of similar utility. However, stimulated GH secretion is generally suppressed by glucocorticoids. To test whether L-692,429, a nonpeptide mimic of GH-releasing peptide-6, can overcome such suppression, a double blind, placebo-controlled, three-period, cross-over study was performed in nine healthy young men who received 0.2 mg/kg L-692,429, i.v., preceded by 4 days of prednisolone (20 mg, orally, three times daily) or placebo, and 0.75 mg/kg L-692,429 preceded by prednisolone only. The mean (SE) GH peak and area under the curve between 0-240 min after administration of 0.2 mg/kg L-692,429 in the absence of steroid were 53.8 (7.2) micrograms/L and 3481 (1005) micrograms/min.L, which were reduced to 25.1 (3.4) micrograms/L and 1342 (285) micrograms/min.L (P < or = 0.01) when treatment was preceded by 4 days of prednisolone. However, the suppressive influence of the steroid was attenuated by the high dose of L-692,429, which achieved a GH peak and area under the curve between 0-240 min of 42.6 (5.8) micrograms/L and 2298 (425) micrograms/min.L, respectively (P < 0.01 vs. 0.2 mg/kg L-692,429 plus prednisolone). L-692,429 stimulates GH secretion even in the setting of short term, high dose, concomitant glucocorticoid treatment, suggesting that such compounds might provide an alternative means of increasing circulating GH and reversing the catabolic effects of these steroids.

The effects of a peripherally selective alpha 2-adrenoceptor antagonist, MK-467, on the metabolic and cardiovascular response to exercise in healthy man.

1. A double-blind, placebo controlled study has been conducted to investigate the consequences of i.v. treatment with MK-467, a peripherally selective alpha 2-adrenoceptor antagonist in exercising healthy male subjects. In particular, the effects on blood pressure, heart rate, circulating catecholamines (noradrenaline (NA) and adrenaline (A)), insulin, glucose and free fatty acids (FFA) were determined. 2. Exercise produced increases in catecholamines, blood pressure and heart rate. FFA increased at the start of the exercise but then declined as exercise progressed. 3. MK-467 significantly increased NA, in a dose-dependent manner, before and during exercise without altering A. Blood pressure and heart rate were not affected by drug treatment. 4. The insulin and FFA response to exercise was significantly enhanced by MK-467 although glucose was unaltered by drug. 5. It is concluded that both pre- and post-junctional peripheral alpha 2-receptors play an important role in the metabolic response to exercise in man.

Comparison of angiotensin-converting enzyme inhibition with angiotensin II receptor antagonism in the human forearm.

The object of this study was to differentiate losartan, an AT1-selective angiotensin II (ANG II) receptor antagonist, from enalapril, an angiotensin-converting enzyme (ACE) inhibitor, by measuring forearm vascular responses to AI, AII, and bradykinin. Eight healthy men were studied in a randomised, 4-period crossover study in which placebo, enalapril (10 mg), losartan (20 mg) and losartan (100 mg) were given double-blind on separate occasions. Forearm blood flow was measured by venous occlusion plethysmography during sequential infusions of ANG I, ANG II, and bradykinin into the brachial artery 4-6 h after dosing. Analysis of variance for repeated measures indicated that losartan inhibited constriction to ANG I and ANG II (both p < 0.02) in a dose-dependent manner without significantly influencing vasodilator responses to bradykinin. Enalapril (10 mg) inhibited AI similarly to losartan 100 mg without significantly influencing responses to angiotensin II, and augmented vasodilator responses to bradykinin (p < 0.0001). In human forearm vasculature, oral losartan (20-100 mg) inhibits vasoconstriction to ANG I and ANG II without significantly influencing bradykinin-induced vasodilation, whereas enalapril selectively inhibits ANG I-induced vasoconstriction while potentiating the vasodilator effect of bradykinin.

Clinical pharmacology of angiotensin and bradykinin in human forearm vasculature.

HYPOTHESIS: Losartan inhibits the renin-angiotensin system by blockade of angiotensin II receptors, whereas enalapril blocks the renin-angiotensin system by inhibiting the conversion of angiotensin I to angiotensin II by the angiotensin converting enzyme (ACE). Since ACE inactivates bradykinin in addition to its action on angiotensin I we hypothesized that losartan and enalapril have different effects on the response to angiotensin and bradykinin. METHODS: We studied healthy volunteers dosed with placebo, enalapril and losartan 4-6 h before measurement of forearm blood flow by venous occlusion plethysmography. Saline, angiotensin I, angiotensin II and bradykinin were infused into the left brachial artery. RESULTS: Losartan produced a similar inhibition of the vasoconstriction induced by angiotensin I and angiotensin II without significantly influencing the bradykinin-induced vasodilation, whereas enalapril potentiated the vasodilator effect of bradykinin and selectively inhibited the vasoconstriction induced by angiotensin I without altering the response to angiotensin II. CONCLUSION: These pharmacological differences suggest that angiotensin II receptor antagonists and ACE inhibitors may not be therapeutically equivalent.

Effects of five daily 1 h infusions of alendronate in Paget's disease of bone.

We report a randomized placebo-controlled double-blind study of amino-hydroxybutylidene bisphosphonate (alendronate), infused over 1 h, in 15 patients with Paget's disease of bone. Alendronate, 10 mg/day for 5 days, suppressed urinary hydroxyproline to 44.9 +/- 4.8% and serum alkaline phosphatase to 74.6 +/- 5.4% of their pretreatment values within 1 month of the start of treatment. Within 5 months of the start of treatment serum alkaline phosphatase fell to 47.9 +/- 6.3% of pretreatment values. These effects were associated with a decrease in serum calcium and phosphate and in urinary calcium excretion and with a rise in serum iPTH values. A transient fever was observed in 3 of 10 patients who received alendronate during the course of the infusions, and this was associated with a decrease in the total and differential white cell count. No adverse effects were noted on renal function as judged by glomerular filtration rate and indices of proximal and distal tubular function. This regimen may simplify the management of patients with Paget's disease of bone.

The role of histamine in the acute inflammatory responses to intradermal platelet activating factor.

1. The role of histamine in PAF-induced acute inflammatory responses (flare and weal) in the skin has been evaluated in a series of three separate studies. 2. Terfenadine, a potent H1-selective histamine antagonist virtually abolished the flare response and significantly inhibited the weal response. 3. Histamine depletion in the skin using compound 48/80 resulted in similar effects on the flare and weal response. Two consecutive daily injections of compound 48/80 were found to deplete comprehensively skin sites of histamine and the ability of skin to respond to PAF was completely restored within 2 weeks of compound 48/80 treatment. 4. Intradermally injected PAF was associated with acute rises in plasma histamine in blood drawn from a draining vein with peak concentrations occurring within 5 min of injection. 5. No difference in PAF-induced flare and weal response was found between atopic and non-atopic subjects and this was reflected in the peak plasma histamine results. A significantly higher baseline plasma histamine was found in the atopic group, however, when compared with the non atopic group. 6. It is concluded that histamine has an important role in the acute inflammatory responses to intradermally injected PAF, although there does appear to be a significant direct vascular component in the PAF-induced weal response.

Assessment of MK-467, a peripheral alpha 2-adrenergic receptor antagonist, with intravenous clonidine.

The activity of MK-467, a new peripherally acting alpha 2-antagonist, was assessed in volunteers by a randomized, double-blind, crossover design. One hour after administration of either 15 mg or 30 mg MK-467 or placebo, 200 micrograms clonidine was given intravenously and observations were made for a further 8 hours. Clonidine reduced plasma norepinephrine levels to 79% +/- 7% of that of control 1 hour after infusion, an effect that was antagonized by low-dose MK-467 (p less than 0.05). Mean systolic blood pressure increased by 4 mm Hg in the first hour after the 30 mg dose of MK-467 (p less than 0.01), although there was no significant difference between the 3 study days in the maximal clonidine-induced decrease in systolic pressure, diastolic pressure, or heart rate. Clonidine induced a peak increase in mean blood glucose of 13%, which was antagonized by both doses of MK-467 (p less than 0.05). Plasma insulin was suppressed by clonidine from 72 +/- 14 to 47 +/- 7 IU.L-1, an effect antagonised by both doses of MK-467 (p less than 0.05 in each case). MK-467 had no effect on clonidine-induced increased drowsiness, xerostomia, or increase in growth hormone secretion, which is consistent with it being a peripherally acting specific alpha 2-antagonist. The small effect of MK-467 on clonidine-induced changes in plasma glucose and insulin suggests that peripheral alpha 2-adrenergic receptors play only a minor role in normal glucose homeostasis.

L-648,051, a novel cysteinyl-leukotriene antagonist is active by the inhaled route in man.

1. We have studied some of the pharmacological properties of inhaled L-648,051 which has been shown to be a selective cysteinyl-leukotriene (LT) antagonist in vitro and in vivo in various animal models. 2. The effects of three different doses (1.6, 6.0 and 12.0 mg) on the bronchoconstriction induced by inhaled LTD4 have been investigated in normal male subjects in a series of double-blind, placebo controlled studies. Furthermore, the specificity of the drug has been investigated by challenging subjects with histamine after pre-inhalation of 12.0 mg L-648,051. 3. At all doses L-648,051 partially blocked the bronchoconstriction induced by LTD4 inhalation in a dose related manner. At a dose of 12.0 mg, L-648,051 decreased the maximum fall in specific airways conductance (sGaw) (placebo, 49% vs L-648,051, 21%, P less than 0.01) and shortened the time to recovery from LTD4-induced bronchoconstriction (placebo, 41 min vs L-648,051, 19 min, P less than 0.01). 4. There was no evidence of partial agonist activity, and no effect on histamine-induced bronchospasm. Inhaled L-648,051 at all doses was well tolerated. 5. We conclude that LT antagonism is possible by the inhaled route in man. Inhaled L-648,051 is an active and selective LT-antagonist in man which is well tolerated and may prove to be a useful drug for assessing the role of leukotrienes in asthma and other lung diseases.

Inflammatory responses to intradermal injection of platelet activating factor, histamine and prostaglandin E2 in healthy volunteers: a double blind investigation.

1. The local responses to intradermal injection of PAF, histamine and PGE2 were investigated in eight healthy male volunteers. Acute effects were monitored by weal and flare measurement; delayed effects were investigated by pain threshold testing and skinfold thickness measurements. 2. PAF and PGE2 were found to induce weal and flare responses which were clearly distinguishable from vehicle and dose related. 3. PAF was approximately 50 times as potent as PGE2 at inducing weal on a molar basis. 4. A dose related hyperalgesia was recorded in response to PGE2. No hyperalgesia could be demonstrated following PAF injection compared with vehicle. 5. PAF and histamine elicited an increase in skinfold thickness up to 2 h after injection which was distinguishable from vehicle.