A microdose study of ¹4C-AR-709 in healthy men: pharmacokinetics, absolute bioavailability and concentrations in key compartments of the lung.

PURPOSE: To explore, in a microdose (phase-0) study, the pharmacokinetics, bioavailability and concentrations in key compartments of the lung, of AR-709, a novel diaminopyrimidine antibiotic for the treatment of respiratory infection. METHODS: Four healthy men each received two single, 100 µg microdoses of ¹4C-AR-709, 7 days apart: the first was administered intravenously (IV), the second orally. Plasma pharmacokinetics of ¹4C and unchanged AR-709 were obtained by high-performance liquid chromatography and accelerator mass spectrometry (AMS). Next, 15 healthy men received a single, 100 µg microdose of ¹4C-AR-709 IV. Plasma, bronchoalveolar lavage fluid, alveolar macrophages and bronchial mucosal biopsy samples were analysed by AMS. RESULTS: After IV administration, clearance of AR-709 was 496 mL/min, volume of distribution was 1,700 L and the absolute oral bioavailability was 2.5 %. Excretion in urine was negligible. At 8-12 h after IV dosing, ¹4C concentrations in lung samples were 15- (bronchial mucosa) to 200- (alveolar macrophages) fold higher than in plasma. In alveolar macrophages, ¹4C was still mostly associated with AR-709 at 12 h after dosing. CONCLUSIONS: The results of this microdose study indicate that AR-709 attains concentrations appreciably higher within the lung than in plasma. Its low oral bioavailability however, precludes oral administration. Although IV administration would appear to be an effective route of administration, this would limit the use of AR-709 to a clinical setting and would therefore be economically unsustainable. If further clinical development were to be undertaken, therefore, an alternative route of administration would be necessary.

Concentrations in plasma, epithelial lining fluid, alveolar macrophages and bronchial mucosa after a single intravenous dose of 1.6 mg/kg of iclaprim (AR-100) in healthy men.

OBJECTIVES: A validated microbiological assay was used to measure concentrations of iclaprim (AR-100) in plasma, bronchial mucosa (BM), alveolar macrophages (AM) and epithelial lining fluid (ELF) after a single 1.6 mg/kg intravenous 60 min iv infusion of iclaprim. METHODS: Male volunteers were randomly allocated to three nominal sampling time intervals 1-2 h (Group A), 3-4 h (Group B) and 5.5-7.0 h (Group C) after the start of the drug infusion. RESULTS: Mean iclaprim concentrations in plasma, BM, AM and ELF, respectively, were for Group A 0.59 mg/L (SD 0.18), 0.51 mg/kg (SD 0.17), 24.51 mg/L (SD 21.22) and 12.61 mg/L (SD 7.33); Group B 0.24 mg/L (SD 0.05), 0.35 mg/kg (SD 0.17), 7.16 mg/L (SD 1.91) and 6.38 mg/L (SD 5.17); and Group C 0.14 mg/L (SD 0.05), no detectable level in BM, 5.28 mg/L (SD 2.30) and 2.66 mg/L (SD 2.08). CONCLUSIONS: Iclaprim concentrations in ELF and AM exceeded the MIC(90) for penicillin-susceptible Streptococcus pneumoniae (MIC90 0.06 mg/L), penicillin-intermediate S. pneumoniae (MIC90 2 mg/L), penicillin-resistant S. pneumoniae (MIC90 4 mg/L) for 7, 7 and 4 h, respectively, and Chlamydia pneumoniae (MIC90 0.5 mg/L) for 7 h. Mean iclaprim concentrations in ELF exceeded the MIC90 for Haemophilus influenzae (MIC90 4 mg/L) and Moraxella catarrhalis (MIC90 8 mg/L) for up to 4 and 2 h, respectively; in AM the MIC90 was exceeded for up to 7 h. Furthermore, the MIC90 for methicillin-resistant Staphylococcus aureus of 0.12 mg/L was exceeded at all sites for up to 7 h. These data suggest that iclaprim reaches lung concentrations that should be effective in the treatment of community-acquired pneumonia.

Tolerability, pharmacokinetics and concentration-dependent hemodynamic effects of oral CF101, an A3 adenosine receptor agonist, in healthy young men.

OBJECTIVES: To assess safety, tolerability, pharmacokinetics and hemodynamic effects of oral CF 101, an A3 adenosine receptor (A3AR) agonist, in healthy men. METHODS: One single and 1 repeated dose, parallel-group, ascending dose, double-blind and placebo-controlled study in normal volunteers. In the single dose study, n = 15 subjects received 1, 5 or 10 mg oral CF101; in each group 1 subject received placebo, the remainder active CF101. In the repeat-dose study, n = 28 subjects received repeated 12-hourly oral doses of CF 101 (2, 3, 4 or 5 mg) for 7 days, in each group 2 subjects received placebo, the remainder active CF101. TEST MATERIALS: Single-dose study: CF101 in 30% Cremophor RH40. Multiple-dose sudy: CF101 in 0.5% methylcellulose suspension. Both studies: the corresponding vehicles were used as placebos. Galenicals were prepared remotely from the clinical study site to ensure double-blind nature of the study. RESULTS TOLERABILITY: Single doses up to 5 mg CF101 were safe and well-tolerated. However, the single dose of 10 mg CF101 was associated with flushing, tachycardia, nausea and vomiting, which were viewed as dose-limiting in normal volunteers. Single doses of CF101 (as well as the first of the multiple doses) were associated with increases in heart rate (8 - 24 beats/min after 5 mg and 18 - 55 beats/min after 10 mg). Multiple doses up to 4 mg 12-hourly for 7 days were safe and well-tolerated. However, the 5 mg multiple-dose group reported headache, drowsiness, hot flushes and dizziness on standing; this declined with dosing duration and was not dose-limiting in this study. Adverse events were commonest near t(max). RESULTS PHARMACOKINETICS: For oral CF101, the t(max) was always 1 - 2 h post-dose and t 1/2 about 9 h, in both the single- and multiple-dose studies. For a single 5 mg dose (mean +/- SD) C(max) = 81.6 +/- 23.6 ng/ml in the single dose study, and 63.6 +/- 22.0 ng/ml after the first of the multiple doses; AUC if was 904.0 +/- 221.9 ng.h/ml and 596.1 +/- 196.6 ng.h/ml for the 2 studies, respectively. After 7 days of multiple dosing there was little change, and AUC(0-24h) = 601.0 +/- 163.6 ng.h/ml. These pharmacokinetic parameters were linearly proportional to dose in the other treatment groups. RESULTS PHARMACODYNAMICS: Increases in heart rate were related to plasma concentration and evident only in the upper range of concentrations observed. There were no changes on ECG monitoring beyond sinus tachycardia, and, in particular, no evidence of PR prolongation in any subject (n = 43). In comparison with single doses, this response was almost absent after 7 days of dosing. Leucocytosis (increases up to about 1.5 x 10(9)/l after 5 and 10 mg) was similarly transient and reversible after multiple dosing. CONCLUSIONS: Single oral doses up to 5 mg CF101 and repeated doses up to 4 mg 12-hourly for 7 days were safe and well-tolerated. Multiple-dose CF101 pharmacokinetics were unchanged and predictable from single-dose estimates, and were linearly proportional to dose. Increases in heart rate and neutrophil count were reversible during multiple dosing and were not dose-limiting in the repeat dose study. CF101 warrants further study for its efficacy in treating human disease.

Safety, tolerability and pharmacokinetics of subcutaneous A6, an 8-amino acid peptide with anti-angiogenic properties, in healthy men.

AIMS: To assess the safety, tolerability and pharmacokinetics of subcutaneous A6, an 8-amino acid peptide with anti-angiogenic properties, in healthy men. METHODS: Double-blind, placebo-controlled, parallel-group, dose-rising, phase I study of single and repeated doses. In the single dose phase, successive groups of 5 subjects received A6 15, 35, 75, 150, 300 mg, or placebo, as subcutaneous injections in the upper thigh. In the repeat dose phase, 2 groups of 6 subjects received repeat doses of A6 35 mg and 75 mg, or placebo, and 1 group of 5 subjects received 150 mg, or placebo, 12-hourly for 6 days (11 doses in total). In each group, 4 subjects received active treatment, the remainder placebo. Pharmacokinetics of A6 were assessed up to 24 h after single doses, for 12 h after the first of the repeated doses, and up to 24 h after the last of the repeated doses. MATERIALS: A6 for subcutaneous injection in phosphate buffer, pH 5.6-6.0. Phosphate-buffered saline was used as placebo. RESULTS: All dose regimens of A6 were safe and well-tolerated, both systemically and locally. Time to peak plasma concentration was similar (0.5-2.1 h) in all dosage groups. Cmax and AUC(0-inf) were linearly proportional to dose. Mean Cmax ranged from 454-10,333 ng/ml and mean AUC(0-inf) from 1,690-43,371 ng x h/ml after the 15 and 300 mg single doses, respectively. Terminal t(1/2) was 1.4-1.8 h, and there was no evidence of unexpected drug accumulation. Urinary excretion of unchanged A6 was 94.6% (SD 20.7) after the 300 mg single dose (0-24 h collection), and 78.4% (SD 13.0) after the 150 mg repeated dose (0-12 h collection). A6 did not trigger production of anti-A6 IgG antibodies within 14 days of the first dose. CONCLUSION: Single doses of A6 up to 300 mg, and repeated doses up to 150 mg, were well-tolerated and safe in healthy young men. A6 was rapidly absorbed; it was eliminated, mainly unchanged, in urine. Plasma concentrations were dose-proportional. A6 did not trigger an early immunogenic response.

Clinical effects of human macrophage inflammatory protein-1 alpha MIP-1 alpha (LD78) administration to humans: a phase I study in cancer patients and normal healthy volunteers with the genetically engineered variant, BB-10010.

BB-10010 is a genetically engineered variant of human macrophage inflammatory protein-1 alpha (hMIP-1 alpha) with improved pharmaceutical formulation properties. Although initially described as a pro-inflammatory cytokine, it is now recognised that hMIP-1 alpha has additional effects on haemopoietic stem cell cycling and on human immunodeficiency virus uptake by macrophages. In view of the potential clinical utility of the molecule, we have embarked on a clinical trials programme to evaluate the safety, tolerability and haematological effects of BB-10010. We now report the results of two phase I clinical studies in which 49 subjects (9 patients with advanced breast carcinoma and 40 normal healthy volunteers) received escalating doses of BB-10010, from 0.1 to 300 micrograms/kg using the subcutaneous (s.c.) or intravenous route (i.v.) of administration. Treatment was associated with a dose-related increase in monocyte count which peaked at 200% of steady-state levels and was preceded by an acute, short-lived, monocytopenia, 50-100% of baseline. no measurable effects were noted on other leucocyte subsets or on circulating progenitor cell numbers. In all cases, BB-10010 was extremely well tolerated with no significant toxicity observed at any dose level and a maximum tolerated dose was not defined. Pharmacokinetic analysis revealed that serum concentrations of BB-10010 were detectable using doses of > or = 10 micrograms/kg i.v. or > or = 30 micrograms/kg s.c., and that a single s.c. injection resulted in sustained plasma levels over a 24 h period. These preliminary studies have confirmed the safety and tolerability of BB-10010 using a dose range up to 300 micrograms/kg. Further clinical studies are ongoing to determine the biological effects and to investigate the potential myeloprotective properties using a variable dose range and schedule of BB-10010 in combination with cytotoxic chemotherapy.

Optimal timing for collection of PBPC after glycosylated G-CSF administration.

Daily administration of granulocyte colony-stimulating Factor (G-CSF) results in progenitor cell mobilization with maximum blood levels achieved after 4-7 days. In this study the short-term effects of glycosylated G-CSF at a dose of 5 microg/kg s.c. were determined so as to allow optimization of the timing of progenitor cell collection. In the first study involving 20 normal volunteers, a significant fall in neutrophil count and G-CSF levels was observed 2 h after the G-CSF injection. To investigate this phenomenon serial measurements were made in a further six volunteers after the 6th daily injection of G-CSF. A fall in the neutrophil count occurred which was maximal at 1 h and recovered to baseline within 3 h. There was also a fall in CD34+ cells (P = 0.034), GM-CFC (P = 0.025) and BFU-E (P = 0.066) and recovery to baseline levels took 4-12 h. We conclude that glycosylated G-CSF should not be given immediately prior to stem cell collection.

The intrapulmonary half-life and safety of aerosolized alpha1-protease inhibitor in normal volunteers.

Aerosol delivery of alpha1-protease-inhibitor (alpha1-PI) has the potential for reducing the amount of alpha1-PI needed to treat persons who are severely alpha1-PI-deficient, thereby decreasing the high cost of treatment and making alpha1-PI available to treat many alpha1-PI-deficient persons who do not now have access to that product. Aerosolized alpha1-PI may also be useful in cystic fibrosis. The goal of our study was to evaluate the duration of action of aerosolized alpha1-PI and possible side effects in normal volunteers. Twenty-nine volunteers underwent bronchoalveolar lavage (BAL) and 3 to 7 d later inhaled 200 mg of alpha1-PI. Subjects were subsequently assigned to one of five groups; a second BAL was performed 0.5, 6, 12, 24, or 36 h after the aerosol, respectively. The BAL fluid samples were analyzed for alpha1-PI concentrations, anti-neutrophil elastase (NE) activity, cell count and differential, alpha1-PI-NE complex level, and uptake of alpha1-PI by alveolar macrophages. Overall we observed no substantial side effects. The one-time alpha1-PI aerosol induced a significant increase of alpha1-PI concentrations as well as anti-NE activity. Even in the BAL fluid samples obtained 36 h after aerosol administration alpha1-PI concentrations and anti-NE activity were about double baseline values. The half-time in the lungs for alpha1-PI concentrations and anti-NE activity were about double baseline values. The half-time in the lungs for alpha1-PI was 69.2 h and for anti-NE activity was 53.2 h, respectively. We conclude from our data in normal volunteers that inhalation of aerosolized alpha1-PI may be a safe, effective, and conveniently administered therapy for persons with severe alpha1-PI deficiency; this mode of administration warrants further study.

Interrelationships between Helicobacter pylori infection, nonsteroidal antiinflammatory drugs and gastroduodenal disease. A prospective study in healthy volunteers.

Helicobacter pylori and nonsteroidal antiinflammatory drugs independently cause gastroduodenal mucosal injury but the relationship between them remains unclear. We have performed a double-blind, parallel-group, placebo-controlled prospective study in 77 healthy volunteers aged 19-35 years who were randomly allocated to indomethacin (N = 15), one of three oxicams (piroxicam, chlortenoxicam, or CHF 1194; N = 36), or placebo (N = 26). Esophagogastroduodenoscopy was performed before and after four weeks of treatment and the mucosal appearances graded. Colonization with H. pylori was established at each endoscopy and gastrointestinal symptoms were assessed by daily diary card. Seven subjects (9%) were positive for H. pylori before treatment (one placebo, one indomethacin, and five an oxicam); their H. pylori status remained unchanged. Two of 70 H. pylori-negative subjects became H. pylori-positive (2.9%), both of whom had received placebo. The endoscopic score deteriorated in 1/6 drug-treated H. pylori-positive subjects and in 0/1 taking placebo. Of the H. pylori-negative subjects whose endoscopic score deteriorated, three (13%) were taking placebo, four (28.6%) indomethacin, and eight (25.8%) an oxicam. Upper gastrointestinal symptoms were reported in eight (30.8%) of the subjects taking placebo (one subject negative for H. pylori became positive), eight (53.3%) indomethacin (one H. pylori-positive), and 10 (27.8%) an oxicam (one H. pylori-positive). There were no statistically significant differences between the H. pylori-negative and H. pylori-positive groups whether on drug or placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of piroxicam-beta-cyclodextrin on the gastrointestinal tract.

Piroxicam-beta-cyclodextrin (PBC), a complex of piroxicam with beta-cyclodextrin, was developed with the aim of improving the hydrosolubility and bioavailability of piroxicam. The complex is more rapidly absorbed, with a consequent reduction in the time of contact of piroxicam with the gastric and duodenal mucosa. It is hoped that the shorter contact time might reduce the local toxicity of piroxicam, but it is also possible that transiently higher local concentrations of the drug might worsen the injury to the gastro-duodenal mucosa. Four studies have been conducted in healthy volunteers in order to investigate the effects of PBC on the gastro-intestinal tract. In 3 of these trials, all of similar design, PBC (containing 20 mg of piroxicam) was compared with piroxicam 20mg and placebo given once daily with assessment of faecal blood loss using the 51Cr-labelled red-cell technique, and endoscopic appearance of gastroduodenal mucosa before and after 28 consecutive days of treatment. One study showed a significant difference in respect of faecal blood loss towards the end of the 4-week study period favouring PBC over piroxicam, while the 2 others showed comparable but non-significant trends in favour of PBC. In a fourth study, 32 non-patient volunteers received either piroxicam 20mg once daily; PBC 20mg equivalence; indomethacin 50mg twice daily; or placebo. The treatment was given double blind for 14 days. Endoscopy was performed and gastric potential differences were measured by neutral observers before and at the end of treatment. There were no significant differences in the endoscopic scores between the active treatment groups. The gastric potential difference showed greater changes with indomethacin and piroxicam than with placebo and PBC.(ABSTRACT TRUNCATED AT 250 WORDS)

Lornoxicam, indomethacin and placebo: comparison of effects on faecal blood loss and upper gastrointestinal endoscopic appearances in healthy men.

Forty-five healthy men aged 21-34 years took part in a double-blind, parallel-group, placebo-controlled study of the effects of 28 days' treatment with lornoxicam 4 mg twice daily or indomethacin 50 mg twice daily on faecal blood loss and the endoscopic appearances of gastric and duodenal mucosa. After an initial endoscopic examination, subjects received, intravenously, on day 0, autologous erythrocytes labelled with 51Cr. Complete daily faecal collections were then made from days 6-12, 20-26 and 34-40. The drug treatments or placebo were given from days 13-41. Faecal blood loss was calculated from 51Cr-specific activity of blood and faeces. Endoscopy was repeated 4-8 hours after the last dose of medication; mucosal appearance was graded on a 5-point scale. Lornoxicam caused no more adverse events than placebo; indomethacin caused more indigestion and central nervous system effects, and one subject in this group was withdrawn from the study. Median total blood losses during the pre-treatment and the second and fourth weeks of treatment were respectively 3.33, 3.95 and 5.71 ml for lornoxicam, 2.87, 7.04 and 7.75 ml for indomethacin, and 4.55, 3.64 and 4.13 ml for placebo. Differences between treatments were not statistically significant (P = 0.081 for second week of treatment, P = 0.383 for fourth week of treatment; Kruskal-Wallis test). The effect of chlortenoxicam on faecal blood loss in this study was thus intermediate between placebo and indomethacin, but within- and between-subject variability was such that the differences were not statistically significant. Endoscopic findings were normal in most subjects before and after all treatments, but indomethacin was associated with a slightly greater deterioration in endoscopic score and was the only treatment associated with Grade 3 appearance (in a single patient) in post-treatment endoscopy.

Research and development of new medicines.

In order that a new chemical entity may be marketed as a drug its pharmacological effects must first be evaluated using animals. Its bioavailability must also be determined and toxicological studies are performed to assess its acute and chronic toxicity, mutagenicity, effects on fertility, perinatal effects, teratogenicity and carcinogenicity. If the results of efficacy and toxicity studies in animals are favourable, the drug is then tested in a few human volunteers, followed by pilot studies and large-scale clinical trials. Regulations that control how these trials are performed are considered. The licensing of drugs in the UK, USA and Europe is compared.

Limitations of dose tolerance studies on predictability for phase III.

Phases I, II and III of the development of a new drug are briefly described. The limitations of dose tolerance studies in Phase I are considered in relation to their predictive value for Phase III. Limitations on predictability may arise because of differences between Phase I and Phase III in both study population and study design. The study population in Phase I, in contrast with Phase III, is usually numerically small, male, young, of average size, healthy, asymptomatic and free from other medication. The Phase III population may be of different nationality or race. Phase I studies are always of short duration. Drug administration is usually in the morning and may be accompanied by more restrictions on diet, smoking and alcohol intake than in Phase III trials. The implications of these differences in study population and design are discussed. The predictive value of dose tolerance studies for Phase III can be substantial, provided that the results are interpreted sensibly. However, the tolerance studies should perhaps be regarded mainly as an essential preliminary to single and multiple dose kinetic, dynamic and interaction studies; the combined experience of these trials should have much greater predictive power for Phase III than dose tolerance studies alone.

Consumption rates and utilization efficiencies of four species of polyphagous Lepidoptera feeding on sycamore leaves.

Four species of Geometridae showed similar consumption rates and approximate digestibilities (100 x ingestion-egestion/ingestion) of sycamore leaves (Acer pseudoplatanus L.). A significant decline in E.C.I. (100 x growth/ingestion) and E.C.D. (100x growth/ingestion-egestion) with increasing larval weight is reported. The earlier descent from the sycamore canopy ofErannis defoliaria Cl. andOperophtera brumata L. larvae, to pupate in the soil, in comparison withAlsophila aescularia D. and S. andAgriopis aurantiaria Hb. larvae is discussed in relation to small differences in the utilization efficiencies of final instar larvae. Later descending species suffered greater predation by wood-ants in the field site studied.

Effects of intravenous epoprostenol on platelets and the cardiovascular system are not potentiated by dipyridamole.

Normal subjects received infusions of epoprostenol (prostacyclin, PGI2) at doses of 2, 4, 6, and 8 ng/kg/min on each of two occasions after pretreatment with dipyridamole (400 mg/day for 3 days) or placebo. Baseline headache and bleeding time were increased and preejection period (PEP) shortened after dipyridamole. The baseline heart rate was increased on dipyridamole by an amount that correlated to the blood dipyridamole level. PGI2 infusion increased heart rate, systolic blood pressure (BP), pulse pressure, left ventricular ejection time index, and degree of flushing and severity of headache, and reduced diastolic BP, PEP, and T wave height. There was no apparent interaction between PGI2 and dipyridamole on these variables. PGI2 inhibited adenosine diphosphate-induced platelet aggregation and increased bleeding time. We conclude that, despite the synergism between dipyridamole and PGI2 that might be predicted and has been demonstrated in some animal experiments, no such interaction is apparent in normal humans after standard doses.