Gatifloxacin 400 mg as a single shot or 200 mg once daily for 3 days is as effective as ciprofloxacin 250 mg twice daily for the treatment of patients with uncomplicated urinary tract infections.

The efficacy and safety of two oral dosing regimens of gatifloxacin compared with ciprofloxacin for the treatment of acute uncomplicated lower urinary tract infection was investigated in a double-blind, randomised study, in adult female patients who received either gatifloxacin (400 mg as a single shot or 3 days of 200 mg once daily) or ciprofloxacin (250 mg given twice daily for 3 days). Bacteriological and clinical responses were assessed 7-9 days after the end of treatment (EOT), and 4-6 weeks post-treatment (end of study, EOS). One thousand one hundred and two women were treated, 741 (248 in the gatifloxacin 400 mg group, 252 in the gatifloxacin 200 mg group, and 241 in the ciprofloxacin group) presented with bacteriological proof of infection and entered the efficacy analysis. The bacteriological response per patient at EOT in the three groups were 80% (177/220) [95% CI to ciprofloxacin -8.4%; 6.4%], 83% (184/222) [95% CI to ciprofloxacin -5.9%; 8.7%] and 81% (176/216), respectively. At the follow-up assessment they were slightly lower, 75% (167/224), 79% (169/213) and 79% (171/217), respectively. The clinical responses at EOT were 81% (197/243) [95% CI to ciprofloxacin -10.2%; 3.4%], 85% (213/250) [95% CI to ciprofloxacin -5.7%; 7.2%] and 85% (201/238), respectively. At EOS they were 82% (195/239), 88% (212/241) and 86% (200/233), respectively. The eradication rates for all initial pathogens at the EOT were 90.3% in the gatifloxacin 400 mg S.D. group, 90.6% in the gatifloxacin 200 mg group, and 88.3% in the ciprofloxacin group. All treatment groups showed a similar safety profile. The incidence of treatment-related adverse events was comparable, the majority of adverse events were of mild or moderate intensity and the medications were well tolerated. Both the administration of gatifloxacin 200 mg once daily for 3 days, and gatifloxacin 400 mg as a single shot were shown to be equivalent to ciprofloxacin 250 mg twice daily for 3 days for the treatment of acute uncomplicated lower urinary tract infections.

Potent cyclic peptide inhibitors of VLA-4 (alpha4beta1 integrin)-mediated cell adhesion. Discovery of compounds like cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg) (ZD7349) compatible with depot formulation.

Additional structure-activity relationship studies on potent cyclic peptide inhibitors of very late antigen-4 (VLA-4) are reported. The new N- to C-terminal cyclic hexa-, hepta- and octapeptide inhibitors like cyclo(MeIle/MePhe-Leu-Asp-Val-X) (X = 2-4 amino acids containing hydrophobic and/or basic side chains) were synthesized using solid phase peptide synthesis methods. The peptides were evaluated in in vitro cell adhesion assays and in in vivo inflammation models. Many of the peptides like cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg) (ZD7349) (17), cyclo(MeIle-Leu-Asp-Val-D-Arg-D-Arg-D-Phe) (20), cyclo(MeIle-Leu-Asp-Val-D-Arg-D-Arg-MePhe) (21) and cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg-D-Ala-D-Ala) (23) were potent inhibitors of VLA-4-mediated cell adhesion and inhibited ovalbumin-induced delayed type hypersensitivity (DTH) response in mice. The more potent compounds were highly selective and did not affect U937 cell adhesion to fibronectin (VLA-5), phorbolmyristate acetate or PMA-differentiated U937 cell adhesion to intercellular cell adhesion molecule-1 (ICAM-1)-expressing Chinese hamster ovary cells (LFA-1) and adenosine diphosphate (ADP)-induced platelet aggregation (GPIIb/IIIa). In contrast to the inhibitors like Ac-cyclo(D-Lys-D-Ile-Leu-Asp-Val) and cyclo(CH2CO-Ile-Leu-Asp-Val-Pip-CH2CO-Ile-Leu-Asp-Val-Pip) described earlier, the new compounds were much more compatible with the depot formulations based on poly(DL-lactide-co-glycolide) polymers. The hexapeptide cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg) (ZD7349) (17) inhibited MOLT-4 cell adhesion to fibronectin and vascular cell adhesion molecule-1 (VCAM-1) with IC50 values of 260 and 330 nM, respectively, and did not show any significant effect against other integrins (IC50 > 300 microM). ZD7349 inhibited ovalbumin-induced DTH response in mice when administered continuously using a mini-pump (ED50 0.01 mg/kg/day) or when given as an s.c. or i.v. bolus injection at a dose of 1-10 mg/kg. ZD7349 was also active in type II collagen-induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE) tests at a dose of 3-10 mg/kg. The peptide was released from some formulations over a period of 10-20 days. ZD7349 is currently undergoing pre-clinical investigation.

Potent cyclic monomeric and dimeric peptide inhibitors of VLA-4 (alpha4beta1 integrin)-mediated cell adhesion based on the Ile-Leu-Asp-Val tetrapeptide.

Potent monomeric and dimeric cyclic peptide very late antigen-4 (VLA-4) inhibitors have been designed based on a tetrapeptide (Ile-Leu-Asp-Val) sequence present in a 25-amino acid peptide (CS-1) reported in the literature. The peptides, synthesized by the SPPS techniques, were evaluated in the in vitro cell adhesion assays and in the in vivo inflammation models. The N- to C-terminal cyclic peptides such as cyclo(Ile-Leu-Asp-Val-NH-(CH2)2-S-(CH2)2-CO) (28) and cyclo(MeIle-Leu-Asp-Val-D-Ala-D-Ala) (31), monomeric and dimeric peptides containing piperazine (Pip) or homopiperazine (hPip) residues as linking groups, e.g. cyclo(MeIle-Leu-Asp-Val-Pip-CH2CO-NH-(CH2)2-S-CH2-CO) (49) and cyclo(MeIle-Leu-Asp-Val hPip-CH2CO-MeIle-Leu-Asp-Val-hPip-CH2CO) (58) and cyclic peptides containing an amide bond between the side chain amino group of an amino acid such as Lys and the C-terminal Val carboxyl group, e.g. Ac-cyclo(D-Lys-D-Ile-Leu-Asp-Val) (62) and beta-Ala-cyclo(D-Lys-D-Leu-Leu-Asp-Val) (68) were more potent than CS-1 in inhibiting the adhesion of the VLA-4-expressing MOLT-4 cells to fibronectin. The more potent compounds were highly selective and did not affect U937 cell adhesion to fibronectin (VLA-5), PMA-differentiated U937 cell adhesion to intercellular cell adhesion molecule- 1-expressing Chinese hamster ovary cells (LFA-1) and ADP-induced platelet aggregation (GPIIb/IIIa). A number of the more potent compounds inhibited ovalbumin-induced delayed type hypersensitivity in mice and some were 100-300 times more potent (ED50 = 0.003-0.009 mg/kg/day, s.c.) than CS-1. Two peptides, Ac-cyclo(D-Lys D-Ile-Leu-Asp-Val) (62) and cyclo(CH2CO-Ile-Leu-Asp-Val-Pip-CH2CO-Ile-Leu-Asp-Val-Pip) (55), were formulated in poly(DL-lactide-co-glycolide) depots and the release profile was investigated in vitro over a 30-day period.

Comparison of a fixed combination of domperidone and paracetamol (Domperamol) with sumatriptan 50 mg in moderate to severe migraine: a randomised UK primary care study.

Migraine is a common and debilitating condition routinely managed in primary care. A number of treatment options--both acute and prophylactic--are currently available but may differ in terms of efficacy, tolerability and cost. The aim of this study was to compare the effectiveness and tolerability of a fixed combination of domperidone and paracetamol (Domperamol; Servier), which has anti-nauseant and anti-emetic activity, with sumatriptan 50 mg in moderate to severe migraine. To do this, 120 patients were recruited from 23 primary care practices throughout the UK and were enrolled into the six-month trial. Patients were randomised at entry to one of the comparator regimens (used to treat their first migraine attack) and then crossed over to the alternative treatment for their second attack. Detailed diary cards were completed for each attack using a scale of pain severity. At two hours and four hours post-dose, the two treatments showed comparable efficacy (< or = 15% difference) in relieving headache and reducing nausea and vomiting. Both were well tolerated and there were no serious adverse effects. In the management of migraine patients typically seen in routine general practice, this trial showed that the effects of Domperamol and sumatriptan 50 mg were broadly comparable. Since Domperamol is considerably less expensive than sumatriptan (and other triptans), a first-line role for this agent appears appropriate.

Anti-inflammatory activity of c(ILDV-NH(CH2)5CO), a novel, selective, cyclic peptide inhibitor of VLA-4-mediated cell adhesion.

1. Small, N- to C-terminal cyclized peptides containing the leucyl-aspartyl-valine (LDV) motif from fibronectin connecting segment-1 (CS-1) have been investigated for their effects on the adhesion of human T-lymphoblastic leukaemia cells (MOLT-4) to human plasma fibronectin in vitro mediated by the integrin Very Late Antigen (VLA)-4 (alpha4beta1, CD49d/CD29). 2. Cyclo(-isoleucyl-leucyl-aspartyl-valyl-aminohexanoyl-) (c(ILDV-NH(CH2)5CO)) was approximately 5 fold more potent (IC50 3.6+/-0.44 microM) than the 25-amino acid linear CS-1 peptide. Cyclic peptides containing two more or one less methylene groups had similar potency to c(ILDV-NH(CH2)5CO) while a compound containing three less methylene groups, c(ILDV-NH(CH2)2CO), was inactive at 100 microM. 3. c(ILDV-NH(CH2)5CO) had little effect on cell adhesion mediated by two other integrins, VLA-5 (alpha5,beta1, CD49e/CD29) (K562 cell adhesion to fibronectin) or Leukocyte Function Associated molecule-1 (LFA-1, alphabeta2, CD11a/CD18) (U937 cell adhesion to Chinese hamster ovary cells transfected with intercellular adhesion molecule-1) at concentrations up to 300 microM. 4. c(ILDV-NH(CH2)5CO) inhibited ovalbumin delayed-type hypersensitivity or oxazolone contact hypersensitivity in Balb/c mice when dosed continuously from subcutaneous osmotic mini-pumps (0.1-10 mg kg(-1) day(-1)). Maximum inhibition (approximately 40%) was similar to that caused by the monoclonal antibody PS/2 (7.5 mg kg(-1) i.v.) directed against the alpha4 integrin subunit. 5. c(ILDV-NH(CH2)5CO) also inhibited oxazolone contact hypersensitivity when dosed intravenously 20 h after oxazolone challenge (1-10 mg kg(-1)). Ear swelling was reduced at 3 h and 4 h but not at 1 h and 2 h post-dose (10 mg kg(-1)). 6. Small molecule VLA-4 inhibitors derived from c(ILDV-NH(CH2)5CO) may be useful as anti-inflammatory agents.

Comparison of the angiotensin II receptor antagonist irbesartan with atenolol for treatment of hypertension.

In this multicenter, double-blind study, the antihypertensive efficacy and safety of irbesartan were compared with those of atenolol in patients with mild-to-moderate hypertension. Following a 4- to 5-week placebo lead-in period, 231 patients with seated diastolic blood pressure (SeDBP) 95-110 mmHg were randomized to irbesartan 75 mg or atenolol 50 mg once daily for 24 weeks. Doses were doubled at Week 6 for SeDBP > or = 90 mmHg. At Week 12, or anytime thereafter, doses were doubled for SeDBP > or = 90 mmHg if not done at Week 6, and hydrochlorothiazide and then nifedipine were added. Efficacy was determined by change from baseline in blood pressure and by therapeutic response rates. Safety was assessed by monitoring adverse events (AEs). Both treatments significantly lowered blood pressure from baseline. There were no significant differences between treatment groups with respect to blood pressure changes or therapeutic response. Atenolol significantly reduced seated heart rate compared with irbesartan at Week 12. The incidences of serious AEs and discontinuations due to AEs were approximately twice as high in the atenolol group compared with the irbesartan group. Thus, in comparison to atenolol, irbesartan < or = 150 mg provided at least equivalent blood pressure control while demonstrating an excellent safety and tolerability profile.

Comparison of the effects of xamoterol and isoprenaline on rat cardiac beta-adrenoceptors: studies of function and regulation.

1. The effects of the beta 1-selective partial agonist xamoterol and the full agonist isoprenaline on rat cardiac beta-adrenoceptors were compared in functional studies of heart rate response in vivo and in vitro. In addition, the ability of both agents to cause receptor down-regulation in the rat heart following chronic (6 days) subcutaneous infusions was assessed by radioligand binding with [125I]-pindolol. 2. In the functional studies, xamoterol produced a maximal effect equivalent to approximately 65% of that of isoprenaline and was overall less potent than the full agonist. 3. Compared to saline control, the density of beta-adrenoceptors was reduced approximately 39% in ventricular membranes prepared from animals after 6 days of isoprenaline infusion but was unaffected by xamoterol. The relative proportions of the beta-adrenoceptor subtypes were unchanged by either active treatment. 4. Plasma xamoterol level at the end of the infusion period was equivalent to that associated with maximum tachycardia in vivo and to the concentration producing maximal stimulation of the rat isolated atrium in vitro. Thus suggesting 100% beta-adrenoceptor occupancy during the period of xamoterol infusion. 5. These results indicate that in this animal model xamoterol does not induce cardiac beta-adrenoceptor down-regulation during chronic treatment, with doses that produce a maximal functional response both in vitro and in vivo.

Analysis of piezoelectric bulk-acoustic-wave resonators as detectors in viscous conductive liquids.

An analytical solution for the resonance condition of a piezoelectric quartz resonator with one surface in contact with a viscous conductive liquid is presented. The characteristic equation that describes the resonance condition and accounts for all interactions including acoustoelectric interactions with ions and dipoles in the solution is obtained in terms of the crystal and liquid parameters. A simple expression for the change in the resonance frequency is obtained. For viscous nonconductive solutions, the frequency change is reduced to a relationship in terms of the liquid density and viscosity. For dilute conductive liquid, the change in frequency is derived in terms of the solution conductivity and dielectric constant. The boundary conditions for the problem are defined with and without the electrical effects of electrodes. Experiments were conducted with various viscous and conductive chemical liquids using a fabricated miniature liquid flow cell containing an AT-cut quartz crystal resonator. The results, which show good agreement with the theory, on the use of quartz crystal resonators as conductivity and/or viscosity sensors are reported.

Radioimmunoassay of LTB4 in plasma from different species: a cautionary note.

In clinical and pre-clinical research the pharmacodynamics of selective 5-lipoxygenase and dual 5-lipoxygenase/cyclo-oxygenase inhibitors may be studied by direct RIA of plasma LTB4. Although immunoreactive LTB4 in plasma from A23187 stimulated human blood has the characteristics of authentic LTB4 our results show, particularly in mice and rats, that exposure to A23187 produces large quantities of 12-HETE. Since in different species the levels of 12-HETE increase with platelet concentration we suggest that the 12(S)-HETE is produced by platelet lipoxygenase. However, we do not rule out the possibility that a proportion of 12-HETE may exist as the (R)-stereoisomer. The latter has greater potential for interference in the direct RIA of LTB4. Biosynthesis of 12-HETE may be measured either by RPHPLC/U.V. abs. (8) or by RIA (9) and LTB4 by a more specific antibody described in this report. We conclude that the combined ex vivo RIA of plasma TXB2, LTB4 and 12-HETE has utility in determining the selectivity of inhibitors of arachidonate metabolism and in distinguishing between selective 5-lipoxygenase inhibitors which interact directly with the enzyme and anti-oxidant or free radical scavenging types which may be less specific.

Simple procedure for measuring the pharmacodynamics and analgesic potential of lipoxygenase inhibitors.

A model is described for determining the pharmacodynamics of inhibitors of arachidonate metabolism in mice. Bioavailability and selectivity were assessed by ex vivo RIA of TXB2, LTB4, and 12-HETE from ionophore-challenged blood. Inhibition of LTB4 and 12-HETE was measured using a single LTB4 RIA, following extraction and separation of these eicosanoids from plasma. Separation on cyanopropyl mini-columns yielded hexane/ether and methanol fractions, which contained 12-HETE and LTB4, respectively. Analgesic efficacy was measured by inhibition of phenylbenzoquinone-induced abdominal constriction. The NSAIDs, indomethacin ibuprofen, flurbiprofen, and benoxaprofen, were analgesic and selective cyclo-oxygenase inhibitors. BW775C was also analgesic, but inhibited cyclo-oxygenase, 5-lipoxygenase and 12-HETE formation. Other in vitro 5-lipoxygenase inhibitors, NDGA, quercetin, and nafazatrom, were inactive in vivo, although NDGA reduced abdominal constrictions. The results indicate that this model has utility in determining the mechanism/selectivity of action and analgesic potential of 5-lipoxygenase inhibitors.

Pro-inflammatory effects of bradykinin, sigma-cyclo[Lys1,Gly6]bradykinin and sigma-cyclo-kallidin in the rat.

A comparison of the effects of bradykinin (BK), sigma-cyclo-BK and sigma-cyclo-kallidin (sigma-cyclo-KD) to induce oedema, hyperalgesia and blood flow in the rat paw was made. BK produced dose-dependent increases in oedema and blood flow and a reduction in the nociceptive pressure threshold. Sigma-Cyclo-BK and sigma-cyclo-KD were more potent than BK at inducing oedema and increasing blood flow but had no effect on nociceptive pressure threshold at the doses used. The relative lack of hyperalgesic activity of sigma-cyclo-BK and sigma-cyclo-KD compared with BK raises the possibility of differences between kinin receptors mediating permeability and blood flow changes and those involved in nociception in this model.

Speech amplitude statistics and the gamma density function as a theoretical approximation.

Knowledge of the speech amplitude density provides basic data concerning the statistics of the continuous speech waveform. The objective of this paper is to present data which characterize the longtime speech amplitude density utilizing a data base of sufficient size to describe the distribution. The data base consists of approximately 45 min of recorded speech for each of the 25 speakers. Two parameters of a theoretical gamma density function are estimated from the experimental data to provide the best curve fit between the experimental data and the gamma density function. Overall results presented in this paper substantiate three main conclusions: There is a significant difference between the speech amplitude density for male and female speakers; the speech amplitude density for positive speech amplitudes differs from that for negative speech amplitudes; and the gamma probability density function is a better approximation for full-wave rectified speech than it is when considering just positive or just negative amplitudes.

Thromboxane synthase inhibition: implications for prostaglandin endoperoxide metabolism. I. Characterisation of an acute intravenous challenge model to measure prostaglandin endoperoxide metabolism.

It has been proposed that thromboxane synthase inhibition (TXSI) may be a useful form of anti-thrombotic therapy and that this is due, in part, to redirection of PGH2 metabolism in favour of PGI2, a potent vasodilator and anti-platelet agent. While redirection has been observed ex vivo there are conflicting reports of its occurrence in vivo. We now describe the characterisation of an acute intravenous challenge model using thrombin, collagen, arachidonic acid (AA) and PGH2 for the study of PGH2 metabolism. Following challenge, plasma concentrations of TXB2, 6-oxo-PGF1 alpha, alleged metabolites of PGI2 (PGI2m) and PGE2 were measured by radioimmunoassay (RIA). Thrombin and collagen challenge resulted in a dose-related increase in plasma TXB2 while AA and PGH2, in addition, elevated 6-oxo-PGF1 alpha and PGI2m. Injection of PGH2 elevated 6-oxo-PGF1 alpha, PGI2m, TXB2 and PGE2 levels. Experimental conditions were defined such that challenge with thrombin (40 NIH units kg-1), collagen (100 micrograms kg-1), AA (1 mg kg-1) and PGH2 (5 micrograms kg-1) and measurement of eicosanoids 0.5 min following challenge were optimal for detection of redirection of PGH2 metabolism in vivo. The identity of immunoreactive TXB2 and 6-oxo-PGF1 alpha was further supported by experiments in which the extracted immunoreactive eicosanoids co-eluted with authentic [3H]standards when subject to reverse phase high performance liquid chromatography (RPHPLC). Evidence is also presented that the levels of plasma eicosanoids measured in this model reflect in vivo biosynthesis.

Thromboxane synthase inhibition: implications for prostaglandin endoperoxide metabolism. II. Testing the 'redirection hypothesis' in an acute intravenous challenge model.

In the preceding paper we described the characterisation of an acute intravenous challenge model for the evaluation of the effects of thromboxane synthase inhibition (TXSI) on eicosanoid metabolism. Herein we describe the biochemical pharmacology of two TXSI and aspirin in this model. Both TXSI caused significant inhibition of plasma TXB2 in vivo without elevation of 6-oxo-PGF1 alpha levels. Similar results were obtained when combined levels of 6-oxo-PGF1 alpha,13,14 dihydro 6-oxo-PGF1 alpha,13,14 dihydro 6,15-dioxo-PGF1 alpha and 6-oxo-PGE1 were measured as an index of PGI2 biosynthesis (PGI2m). Thus no evidence of in vivo redirection of PGH2 to PGI2 was found. Ex vivo experiments performed in serum gave an apparent stimulation of immunoreactive 6-oxo-PGF1 alpha following TXSI but RPHPLC analysis of extracted serum showed that this stimulation was accounted for by increase in a product co-eluting with [3H]PGF2 alpha. The implications of these findings in relation to TXSI and receptor antagonists are discussed.

Prostacyclin and thromboxane in non-insulin dependent diabetes: the chlorpropamide alcohol flush reaction revisited.

Levels of immunoreactive 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha) and thromboxane B2 (TXB2) were measured in peripheral venous plasma in a group of volunteers and non-insulin dependent diabetic patients (NIDDS). Levels of these eicosanoids were close to the limit of sensitivity of the radioimmunoassays and consequently data are reported as maximal values. Basal plasma levels of 6-oxo-PGF1 alpha did not exceed 5 pg/ml in either group and maximal levels of immunoreactive TXB2 were 125 +/- 14 and 128 +/- 8 pg/ml for volunteers and NIDDS respectively. Attempts to elicit peripheral vascular prostacyclin biosynthesis in volunteers by using forearm ischaemia produced no increase in plasma 6-oxo-PGF1 alpha levels. Measurement of the combined plasma levels of 6-oxo-PGF1 alpha, 13,14-dihydro-6-oxo-PGF1 alpha, 13,14-dihydro-6,15-dioxo-PGF1 alpha and 6-oxo-PGE1 indicated that these were also low (less than 5 pg/ml) and that failure to demonstrate increased 6-oxo-PGF1 alpha levels was unlikely to have arisen from metabolism of prostacyclin to one or more of these metabolites. Measurement of 6-oxo-PGF1 alpha and TXB2 in peripheral venous plasma before and during chloropropamide alcohol flushing (CPAF) did not provide evidence for a role for these eicosanoids in the etiology of this phenomenon. These findings point to the need for a reappraisal of studies that have described altered plasma levels of 6-oxo-PGF1 alpha and TXB2 in CPAF and other pathophysiological conditions in man.

Effects of vascular trauma and transient myocardial ischaemia on coronary venous prostaglandin levels in the dog.

The plasma concentrations of immunoreactive thromboxane B2 and 6-keto-prostaglandin-F1 alpha were determined in coronary venous blood sampled from open-chested, anaesthetised beagle dogs by local vein catheterisation. Thromboxane levels were high immediately following catheterisation (2.08 +/- 0.75 ng X ml-1, mean +/- SEM, n = 6) and fell over 25 min to 0.48 +/- 0.07 ng X ml-1. Initial trauma of the coronary veins (agitation of the catheter) produced a large but variable increase to 5.13 +/- 2.27 ng X ml-1 (0.1 greater than P greater than 0.05) within 2 min, but arterial trauma (repeated momentary occlusions) produced 0.4 +/- 0.03 ng X ml-1, a value not significantly different from control. After 7 min ischaemia an increase to 0.98 +/- 0.26 ng X ml-1 was detected (P less than 0.05). Reperfusion after 15 min ischaemia caused a fall to 0.43 +/- 0.09 ng X ml-1 at 2 min. In contrast, 6-keto-prostaglandin-F1 alpha levels varied little with trauma but increased to 0.64 +/- 0.14 ng X ml-1 (P less than 0.01) within 2 min ischaemia, remaining elevated. On reperfusion, levels fell to 0.27 +/- 0.06 ng X ml-1 (P less than 0.05) at 2 min, progressively increasing to 0.35 +/- 0.05 ng X ml-1 at 30 min. We conclude that intimal trauma of coronary veins induced thromboxane release and that the physical effects of venous sampling may contribute to apparent thromboxane release from ischaemic muscle. Although transient arterial and venous trauma had no significant effect on 6-keto-prostaglandin-F1 alpha, it is still possible that its release during ischaemia may follow prolonged arterial clamping.

The evaluation of the effect of the venous tonic 263-E on capillary permeability in the rabbit after administration by intradermal and intravenous routes.

The effects of 2,5-dihydroxybenzene-1,4-disulphonic acid-bisdiethylamine salt (263-E) and trihydroxyethylrutoside (Vitamin P4) on capillary permeability have been compared in the rabbit. Both drugs were administered by intradermal and intravenous routes. Histamine and bradykinin were injected intradermally to increase permeability. 263-E was sown to be a potent inhibitor of permeability changes induced by histamine and bradykinin intravenous routes. Vitamin P4 maximally inhibited permeability at the lowest intravenous dose level but with increasing dose the inhibition became negligible. After intradernal administration, vitamin P4 did not inhibit permeability but potentiated the permeability response induced by histamine and bradykinin.

Hyperbaric system for oxygen toxicity studies in the toad urinary bladder.

A hyperbaric research system to study the effects on membrane function of oxygen at pressures as high as 20 ATA has been designed. The system includes a pressure chamber capable of holding eight isolated toad bladder short-circuit current apparatuses and unique experimental gassing, diluent addition, and sampling systems which are monitored by a control panel mounted on the side of the pressure chamber. These externally controlled gassing, diluent, and sampling systems permit experimental manipulations at any ambient pressure and are a significant addition to the methodology of hyperbaric research.