The effect of a surgery-specific cardiac output-guided haemodynamic algorithm on outcomes in patients undergoing pancreaticoduodenectomy in a high-volume centre: a retrospective comparative study.

In this retrospective observational study performed in a high-volume hepatobiliary-pancreatic unit, we evaluated the effect of a surgery-specific goal-directed therapy (GDT) physiologic algorithm on complications and length of hospital stay. We compared patients who underwent pancreaticoduodenectomy with either a standardised Enhanced Recovery After Surgery program (usual care group), or a standardised Enhanced Recovery After Surgery program in combination with a surgery-specific cardiac output-guided algorithm (GDT group). We included 145 consecutive patients: 47 in the GDT group and 98 in the usual care group. Multivariable associations between GDT and lengths of stay and complications were investigated using negative binomial regression. Postoperative complications were common and occurred at similar frequencies amongst the GDT and usual care groups: 64% versus 68% respectively, P=0.71; odds ratio 0.82; (95% confidence interval 0.39-1.70). There were fewer cardiorespiratory complications in the GDT group. Median (interquartile range) length of hospital stay was ten days (8.0-14.0) in the GDT group compared to 13 days (8.8-21.3) in the usual care group, P=0.01. Median (interquartile range) total intraoperative fluid was 3,000 ml (2,050-4,175) in the GDT group compared to 4,500 ml (3,275-5,325) in the usual care group, P <0.0001; but by day one, the median (interquartile range) fluid balance was similar (1,198 ml [700-1,729] in the GDT group versus 977 ml [419-2,044] in the usual care group, P=0.96). Use of vasoactive medications was higher in the GDT group. In our patients undergoing pancreaticoduodenectomy, GDT was associated with restrictive intraoperative fluid intervention, fewer cardiorespiratory complications and a shorter hospital length of stay compared to usual care. However, we could not exclude an influence of surgical caseload, which we have previously found to be an important variable. We also could not relate the increased hospital length of stay to cardiorespiratory complications in individual patients. Therefore, these observational retrospective findings would require confirmation in a prospective randomised study.

Mechanism of decongestant activity of alpha 2-adrenoceptor agonists.

The vascular bed in nasal mucosa of different species, including human, is highly vascularized and an extensive sinusoidal network of large capacitance vessels is present deep within the submucosa. When this network of venous sinusoids is engorged with blood, the swollen mucosa reduces the size of the airway lumen and congestion ensues. Nasal vasculature tone is strongly influenced by the sympathetic nervous system and the only drugs approved specifically to relieve vascular nasal obstruction are alpha-adrenoceptor sympathomimetic agents. Due to their vasoconstrictor action, the sympathomimetic decongestants oppose vasodilation, reducing nasal airway resistance and thus facilitating nose breathing. However, standard decongestants that are non-selective alpha-adrenoceptor agonists are associated with the potential for side-effect liabilities including hypertension, stroke, insomnia and nervousness. We propose than a selective alpha 2-adrenoceptor agonist, by acting preferentially on nasal venous capacitance vessels, will elicit decongestion with a reduced side-effect liability. In the present study, we evaluated the effects of the selective alpha 2-adrenoceptor agonist BHT-920 in a real-time tissue contractility assay using isolated pig nasal explants and in an in vivo cat model of congestion. The vasoconstrictor and decongestant effects of BHT-920 were compared to the non-selective alpha-adrenoceptor agonist epinephrine and the standard decongestant oxymetazoline. Our results showed that the alpha 2-adrenoceptor agonist BHT-920 preferentially contracts venous sinusoids confirming previous observations [Corboz MR, Varty LM, Rivelli MA, Mutter JC, Mingo G, McLeod R, et al. Effects of an alpha 2-adrenoceptor agonist in nasal mucosa. Arch Physiol Biochem 2003;11: 335-6, Corboz MR, Rivelli MA, Varty LM, Mutter J, Cartwright M, Rizzo CA, et al. Pharmacological characterization of postjunctional alpha-adrenoceptor in human nasal mucosa. Am J Rhinol 2005;19: 495-502] and displays decongestion without affecting blood pressure. Therefore, an alpha 2-adrenoceptor agonist, by causing constriction in the capacitance vessels of nasal mucosa, can produce nasal decongestion without the effects on blood pressure observed with the standard selective alpha 1-adrenoceptor and non-selective alpha-adrenoceptor sympathomimetic decongestants.

Type I and type II fatty acid biosynthesis in Eimeria tenella: enoyl reductase activity and structure.

Apicomplexan parasites of the genus Eimeria are the major causative agent of avian coccidiosis, leading to high economic losses in the poultry industry. Recent results show that Eimeria tenella harbours an apicoplast organelle, and that a key biosynthetic enzyme, enoyl reductase, is located in this organelle. In related parasites, enoyl reductase is one component of a type II fatty acid synthase (FAS) and has proven to be an attractive target for antimicrobial compounds. We cloned and expressed the mature form of E. tenella enoyl reductase (EtENR) for biochemical and structural studies. Recombinant EtENR exhibits NADH-dependent enoyl reductase activity and is inhibited by triclosan with an IC50 value of 60 nm. The crystal structure of EtENR reveals overall similarity with other ENR enzymes; however, the active site of EtENR is unoccupied, a state rarely observed in other ENR structures. Furthermore, the position of the central beta-sheet appears to block NADH binding and would require significant movement to allow NADH binding, a feature not previously seen in the ENR family. We analysed the E. tenella genomic database for orthologues of well-characterized bacterial and apicomplexan FAS enzymes and identified 6 additional genes, suggesting that E. tenella contains a type II FAS capable of synthesizing saturated, but not unsaturated, fatty acids. Interestingly, we also identified sequences that appear to encode multifunctional type I FAS enzymes, a feature also observed in Toxoplasma gondii, highlighting the similarity between these apicomplexan parasites.

alpha2-adrenoceptor agonists as nasal decongestants.

Nasal congestion, one of the major disease features of rhinitis, is induced by the filling of venous sinusoids causing mucosal engorgement with resultant obstruction of nasal airflow. The only available drugs that directly target the underlying vascular features driving nasal obstruction are the sympathomimetic alpha-adrenoceptor agonists due to their vasoconstrictor action. However, standard decongestants are nonselective alpha-adrenoceptor agonists, which have the potential for side-effects liabilities such as hypertension, stroke, insomnia and nervousness. In the present study, the effects of nonsubtype selective alpha(2)-adrenoceptor agonists BHT-920 and PGE-6201204 were evaluated in several isolated nasal mucosa contractile bioassays including dog, pig and monkey, and in a real-time tissue contractility assay using isolated pig nasal explants for BHT-920. The decongestant activity of PGE-6201204 was evaluated in vivo in a cat model of experimental congestion. Our results showed that alpha(2)-adrenoceptor agonists (1) contract nasal mucosa of different species, (2) exert a preferential vasoconstrictor effect on the capacitance vessels (veins and sinusoids), and (3) elicit decongestion. In conclusion, a selective alpha(2)-adrenoceptor agonist causing constriction preferentially in the large venous sinusoids and veins of nasal mucosa and producing nasal decongestion is expected to show efficacy in the treatment of nasal congestion without the characteristic arterio-constrictor action of the standard nonselective sympathomimetic decongestants.

Sulfur-dioxide exposure increases TRPV1-mediated responses in nodose ganglia cells and augments cough in guinea pigs.

The objective of the present experiments was to study the effects of pulmonary inflammation induced by subacute Sulfur-dioxide (SO(2)) exposure on capsaicin-induced responses in isolated primary vagal sensory neurons and cough. Additionally, we examined the effects of SO(2) exposure on respiratory function and lung histology. All experiments were conducted 24 h after 4 days of subacute SO(2) (1000 ppm, 3 h/day for 4 days) exposure. In in vitro experiments, intracellular Ca(2+) concentrations were measured in single nodose ganglia cells isolated from SO(2) treated and control guinea pigs, using a fluorescence-based methodology. In nodose ganglia cells from SO(2)-exposed animals, intracellular Ca(2+) responses evoked by capsaicin (1 x 10(-7) and 1 x 10(-6) M) were significantly augmented (87% and 59%, respectively) compared to nodose ganglia from control animals. In vivo experiments, cough responses induced by a submaximal dose of aerosolized capsaicin (30 microM) were increased approximately 50% in SO(2) exposed animals compared to control animals. The enhanced cough response produced by SO(2) was inhibited by the corticosteroid, dexamethasone (10 mg/kg, p.o. b.i.d for 4 days and 10 mg/kg, p.o. once on day 5). In separate experiments, guinea pigs exposed to SO(2) displayed a decrease in respiratory frequency and minute ventilation and an increase in enhanced pause (PenH), a surrogate measure for pulmonary obstruction. Associated with the SO(2)-induced increase in cough and changes in respiratory parameters was an increase in BAL neutrophils. BAL neutrophil counts were 5+/-4 and 691+/-141 cells x 10(3)/ml for air and SO(2)-exposed animals, respectively. The neutrophillic inflammation induced by SO(2) was attenuated by dexamethasone treatment. Finally, staining for collagen, smooth muscle and goblet cells showed inflammation, remodeling and goblet cell metaphasia in the SO(2)-exposed animals. Our results demonstrate that SO(2) exposure enhances TRPV1 receptor function at the level of the nodose ganglia. This effect occurs in parallel with an increase sensitivity of the cough response to capsaicin.

Antitussive action of nociceptin in the cat.

Experiments were conducted to determine the influence of the specific ORL1 receptor agonist, nociceptin, on the cough reflex in the cat. Cats were anesthetized and allowed to breathe spontaneously. Cough was elicited by mechanical stimulation of the intrathoracic airway. Intravenous administration of nociceptin (0.001-3.0 mg x kg(-1)) inhibited cough number and the magnitude of abdominal muscle electromyogram (EMG) discharge during cough in a dose-dependent manner. Nociceptin had no effect on the magnitude of the inspiratory muscle EMG during cough. These effects of nociceptin were antagonized by pretreatment with the ORL1 receptor antagonist, 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro-2H-benzimidazol-2-one (J-113397, 0.1 mg x kg(-1), i.v.). We conclude that intravenous nociceptin inhibits cough in the cat.

Comparative oral and topical decongestant effects of phenylpropanolamine and d-pseudoephedrine.

Nonselective adrenergic alpha-agonists such as phenylpropanolamine and d-pseudoephedrine are widely used as decongestants to treat nasal congestion associated with a variety of nasal diseases. Although the activity of these drugs is well established in clinical studies, a direct comparison of their nasal decongestant effect as determined by changes in nasal cavity dimensions and nasal architecture has not been studied. Using acoustic rhinometry, we evaluated the effects of these drugs on nasal cavity volume, minimum cross-sectional area (Amin), and the distance from the nosepiece to the Amin (Dmin) in a feline, pharmacological model of nasal congestion. Administration of topical compound 48/80 (1%), a mast cell histamine liberator, into the left nasal passageway decreased nasal volume by 66%, reduced Amin by 51%, and increased Dmin by 116%. The congestive responses to compound 48/80 (1%) were reproducible through six weeks. In a subset of cats, the nasal cavity volume effect of repetitive exposure to compound 48/80, given once every two weeks for six weeks, was not different from the nasal responses after the initial exposure to compound 48/80. Pretreatment with oral phenylpropanolamine (10 mg/kg) or oral d-pseudoephedrine (10 mg/kg) attenuated the nasal effects of compound 48/80, but were associated with a pronounced increase in systolic blood pressure of +51 and +82 mmHg, respectively. A similar decongestant profile was observed with phenylpropanolamine (1%) and d-pseudoephedrine (1%) when given topically. Topical phenylpropanolamine (1%) and d-pseudoephedrine (1%) 45 minutes after dosing increased blood pressure +44 and +17 mmHg, respectively, over control animals. We conclude that oral and topical phenylpropanolamine and d-pseudoephedrine display equieffective nasal decongestant activity and produce similar cardiovascular profiles characterized by significant increases in blood pressure.

Nociceptin inhibits cough in the guinea-pig by activation of ORL(1) receptors.

We studied the central and peripheral antitussive effect of ORL(1) receptor activation with nociceptin/orphanin FQ in conscious guinea-pigs. In guinea-pig cough studies, nociceptin/orphanin FQ (10, 30, and 90 microg) given directly into the CNS by an intracerebroventricular (i.c.v.) route inhibited cough elicited by capsaicin exposure by approximately 23, 29 and 52%, respectively. The antitussive activity of nociceptin/orphanin FQ (90 microg, i.c.v.) was blocked by the selective ORL(1) antagonist [Phe(1)gamma(CH(2)-NH)Gly(2)]nociceptin-(1-13)-NH(2) (180 microg, i.c.v.) and J113397 (10 mg kg(-1), i.p.) but not by the opioid antagonist, naltrexone (3 mg kg(-1), i.p.). Furthermore, intravenous (i.v.) nociceptin/orphanin FQ (1.0 and 3.0 mg kg(-1)) also inhibited cough approximately by 25 and 42%, respectively. These findings indicate that selective ORL(1) agonists display the potential to inhibit cough by both a central and peripheral mechanism, and potentially represent a novel therapeutic approach for the treatment of cough.

Intranasal application of the alpha2-adrenoceptor agonist BHT-920 produces decongestion in the cat.

The effect of alpha2-selective adrenoreceptor activation on nasal cavity dimension in an experimental model of congestion has not been defined. Presently, we used acoustic rhinometry to evaluate the decongestant activity of BHT-920, a selective alpha2-adrenergic agonist against nasal congestion produced by intranasal compound 48/80. Administration of the mast cell liberator compound 48/80 (1%) into a nasal passageway decreased ipsilateral volume and minimum cross-sectional area by 73 +/- 4% and 42 +/- 6%, respectively. The congestant effect of compound 48/80 was blocked by topical BHT-920 (0.3 and 1%) in a dose related manner. In addition, the decrease in minimum cross-sectional area produced by compound 48/80 was attenuated after topical BHT-920 treatment. As a comparison we also evaluated the topical decongestant activity effects of the alpha1-adrenergic agonist phenylephrine, and the nonselective alpha-agonist oxymetazoline. Both phenylephrine (0.1-1.0%) and oxymetazoline (0.01-0.3%) produced decongestion. The blood pressure effects of these three drugs also were evaluated. At doses of 0.3 and 1.0%, BHT-920 did not produce hypertension. In contrast, oxymetaZoline (0.01-0.1%) produced a transient hypertension that peaked at 15 minutes and fully recovered 45 minutes after administration. The hypertensive effect of phenylephrine at 0.3 and 1.0% lasted over 60 minutes. The present findings indicate that selective alpha2-agonists may produce decongestant activity with an improved cardiovascular profile compared with current sympathomimetic drugs such as phenylephrine.

Combined histamine H1 and H3 receptor blockade produces nasal decongestion in an experimental model of nasal congestion.

We studied the pharmacological actions of combined histamine H1/H3 receptor blockade on the increase in nasal airway resistance (NAR) and decrease in nasal cavity volume produced by nasal exposure to compound 48/80, a mast cell degranulator. In the anesthetized cat compound 48/80 (1%) produced a maximum increase in NAR of 9.1 +/- 0.7 cmH20.L/minute. The increase in NAR in animals pretreated with a combination of the H1 antagonist, chlorpheniramine (CTM; 0.8 mg/kg i.v.) and increasing doses of the H3 antagonist, thioperamide (THIO; 1.0, 3.0, and 10.0 mg/kg i.v.) were 6.1 +/- 2.1, 4.2 +/- 1.0 and 2.2 +/- 0.7 cmH20.L/minute, respectively. A second H3 antagonist, clobenpropit (CLOB; 0.03, 0.3, and 1.0 mg/kg i.v.) combined with CTM (0.8 mg/kg i.v.) also inhibited the nasal effects of compound 48/80. When the nonsedating H1 antihistamine, loratadine (3.0 mg/kg i.v.), was substituted for CTM, it also reduced nasal congestion when given in combination with THIO (10 mg/kg i.v.). In contrast, treatment with CTM (1.0 mg/kg i.v.) and the H2 antagonist, ranitidine (RAN; 1.0 mg/kg i.v.) were without activity. Loratadine, CTM, CLOB, RAN, or THIO administered alone were inactive. The alpha-adrenergic agonist, phenylpropanolamine (PPA; 1.0 mg/kg i.v.) demonstrated decongestant effects, but in contrast to H1/H3 blockade, PPA produced a significant hypertensive effect. Using acoustic rhinometry (AcR) we found that combined i.v. CTM (1.0 mg/kg) and THIO (10 mg/kg) and combined oral CTM (10 mg/kg) and THIO (30 mg/kg) blocked the decrease in nasal cavity volume produced by intranasal compound 48/80 (1%, 50 microL). We conclude that combined H1/H3 histamine receptor blockade enhances the efficacy of an H1 antagonist by conferring decongestant activity to the H1 antihistamine. We propose that the decongestant activity of combined H1/H3 blockade may provide a novel approach for the treatment of allergic nasal congestion without the hypertensive liability of current therapies.

Changes in nasal resistance and nasal geometry using pressure and acoustic rhinometry in a feline model of nasal congestion.

This is the first report describing the use and pharmacological characterization of nasal patency by both pressure rhinometry and acoustic rhinometry (AcR) in an experimental cat model of nasal congestion. In pressure rhinometry studies, aerosolized compound 48/80 (0.1-3.0%), a mast cell liberator, increased nasal airway resistance (NAR) 1.2 +/- 0.6, 5.8 +/- 0.5, 8.6 +/- 1.1 and 7.9 +/- 1.5 cmH2O.L/minute, respectively. Increases in NAR produced by compound 48/80 were associated with a 395% increase in histamine concentration found in the nasal lavage fluid. Pretreatment with the alpha-adrenoreceptor agonist, phenylpropanolamine (PPA; 0.1-3.0 mg/kg, i.v.), and the NO synthetase inhibitor, NG-nitro-L-arginine (L-NAME; 10 mg/kg, i.v.) attenuated the increases in NAR produced by compound 48/80. The histamine H1 antagonist chlorpheniramine (1.0 mg/kg, i.v.) and the H2 antagonist, ranitidine (1.0 mg/kg, i.v.) had no decongestant activity. Also without decongestant activity were the muscarinic antagonist atropine, the cyclooxygenase inhibitor indomethacin, and the 5-HT blocker methysergide. Aerosolized histamine (0.1-1.0%) also produced a dose dependent increase in NAR. In studies using acoustic rhinometry (AcR), intranasal application of compound 48/80 (0.1-1.0%) elicited pronounced decreases in nasal cavity volumes and minimum cross-sectional area (Amin). Pretreatment with PPA (3 mg/kg, i.v. or 10 mg/kg, p.o.) attenuated the decreases in nasal volume and Amin. The effects of topical intranasal histamine (0.1-1.0%) on nasal geometry were similar to compound 48/80. We conclude that the cat is a useful model for evaluating the pharmacological actions of potential nasal decongestants. Furthermore, we also conclude that AcR is a useful method for noninvasive assessment of nasal patency in a preclinical setting.

Sch 50971, an orally active histamine H3 receptor agonist, inhibits central neurogenic vascular inflammation and produces sedation in the guinea pig.

We studied the actions of Sch 50971, a novel histamine H3 receptor agonist, in an experimental neurogenic model of migraine and characterized its sedative and respiratory actions. Sch 50971 (i.v. and p.o) inhibited plasma protein extravasation in the dura mater of guinea pigs after electrical stimulation of the trigeminal ganglia. The minimum effective doses of Sch 50971 were 3.0 mg/kg i.v. and 10 mg/kg p.o., which produced a 40% and 42% decrease in plasma protein extravasation, respectively. The effects of Sch 50971 (3.0 mg/kg i.v. ) were blocked by the histamine H3 antagonist thioperamide (3.0 mg/kg i.v.). The 5-HT1D agonist, sumatriptan (0.3 mg/kg i.v.), and the histamine H3 agonist, (R)-alpha-methylhistamine (0.3 mg/kg), also inhibited plasma extravasation by 40 and 46%. In sedation studies, Sch 50971 (1-100 mg/kg p.o.) potentiated pentobarbital-induced sleep. The ED40 min for Sch 50971, the benzodiazepines triazolam and diazepam, the histamine H1 antagonist diphenhydramine and the H3 receptor agonist (R)-alpha-methylhistamine were 7.0, 0.5, 2.3, 14.1 and 23.4 mg/kg p. o., respectively. The sedative effects of oral Sch 50971 was blocked by thioperamide (10 microgram i.c.v.). The sedative activity of Sch 50971 was also examined using EEG activity, locomotor activity and sleep. In conscious guinea pigs, Sch 50971 (10 mg/kg p.o.) depressed locomotor activity, increased total sleep time and produced EEG patterns consistent with physiological sleep. Sch 50971 decreased beta wave activity but had no effects on delta wave activity, theta activity or alpha wave activity. In contrast, triazolam (1.0 mg/kg p. o.) depressed delta and theta wave activity and produced large increases in alpha and beta wave activity. In conclusion, Sch 50971 is an orally active, potent and selective agonist of histamine H3 receptors that may act to ameliorate the sequelae of migraine headaches, where activation of histamine H3 receptors may be beneficial. Sch 50971 also decreases motor activity and promotes EEG activity consistent with physiological sleep.

Studies on the pharmacology of the novel histamine H3 receptor agonist Sch 50971.

Experiments were performed to characterize the pharmacology of Sch 50971 ((+)-trans-4-(4(R)-methyl-3(R)-pyrolidinyl)-1H-imidazole dihydrochloride, CAS 167610-28-8), a novel histamine H3 receptor agonist. The activity of Sch 50971 was compared with that of (R)-alpha-methylhistamine (CAS 75614-87-8), a potent and moderately selective agonist of histamine H3 receptors, in a series of in vitro and in vivo assays. Sch 50971 is a high affinity, selective H3 receptor agonist in vitro and in vivo. Sch 50971 inhibits [3H]-N-alpha-methylhistamine (CAS 673-50-7) binding to the histamine H3 receptor in human brain (Ki = 5.0 nmol/l) and guinea pig brain (Ki = 2.5 nmol/l). Sch 50971 also inhibits electric field stimulated guinea pig ileum contractions (pD2 = 7.47) and decreases [3H]-norepinephrine (CAS 51-41-2) release (pD2 = 7.48) from guinea pig pulmonary artery by activation of presynaptic inhibitory H3 receptors. The in vitro effects of Sch 50971 are antagonized by low concentrations of a selective H3 antagonist, thioperamide (CAS 106243-16-7). Sch 50971 has low affinity (IC50's > 10 mumol/l) for histamine H1, dopamine D1 and D2, serotonin 5-HT2 and muscarinic cholinergic receptors. It also does not exhibit histamine H2-antagonist activity. In guinea pigs and cats, Sch 50971 exhibits in vivo H3 agonist activity. Sch 50971 inhibits sympathetic hypertension evoked by stimulation of the medulla oblongata in anesthetized guinea pigs (ED30 = 0.3 mg/kg i.v., ED30 = 1.0 mg/kg i.d.). Sch 50971 also inhibits the effects of sympathetic nerve stimulation on nasal resistance in cats. In these assays, Sch 50971 exhibits an efficacy and potency comparable to H3-agonist (R)-alpha-methylhistamine. However, under in vivo conditions, Sch 50971 does not exhibit histamine H1-mediated responses that are seen with (R)-alpha-methylhistamine at doses close to those that produce H3 effects. Therefore, Sch 50971 is a novel, potent and selective agonist of histamine H3 receptors with an improved in vitro and in vivo receptor profile selectivity compared with (R)-alpha-methylhistamine.

Antitussive action of antihistamines is independent of sedative and ventilation activity in the guinea pig.

We studied the oral actions of antihistamines from six chemical classes, namely: the ethanolamines (ENA, diphenhydramine and clemastine); ethylenediamines (EDA, pyrilamine and tripelennamine); piperidines (PPD, terfenadine and astemizole); piperazines (PPZ, hydroxyzine and cetirizine); phenothiazines (PTZ, promethazine), and the alkylamines (ALA, chlorpheniramine and bromopheniramine) on cough reflexes, pentobarbital-induced sedation and minute ventilation in the conscious guinea pig. Antihistamines of the ENA class had minimal effects on capsaicin-induced cough although both diphenhydramine (30 and 100 mg/kg p.o.) and clemastine (30 and 100 mg/kg p.o.) increased sedation time (ST). The PPZ class demonstrated both antitussive and sedating activity. The minimum effective oral antitussive dose (MED) of cetirizine and hydroxyzine was 30 and 10 mg/kg, respectively. The EDA did not exhibit antitussive activity. Tripelennamine (10, 30 and 100 mg/kg p.o.) but not pyrilamine enhanced ST. The MED for the PTZ, promethazine, was 10 mg/kg, and at 100 mg/kg promethazine increased ST. The ALA group displayed antitussive activity but only chlorpheniramine (10 mg/kg p. o.) had any effects on ST. The MED for chlorpheniramine and bromopheniramine was 3 and 10 mg/kg p.o., respectively. The PPD antihistamines, namely terfenadine and astemizole, inhibited cough (MED 30 and 10 mg/kg p.o.) without sedative effects. Of the antihistamines tested only promethazine (100 mg/kg p.o.) depressed ventilation responses; however, this dose of promethazine was associated with adverse behavioral effects. The present findings indicate that the antitussive actions of antihistamines are not directly related to histamine H1-receptor blockade because several antihistamines did not antagonize capsaicin-induced cough. In addition, the antitussive actions of antihistamines are independent of their sedative or ventilation effects.

In vivo metabolism-based discovery of a potent cholesterol absorption inhibitor, SCH58235, in the rat and rhesus monkey through the identification of the active metabolites of SCH48461.

SCH48461 is a selective and highly potent inhibitor of cholesterol absorption. In rats, SCH48461 is rapidly and completely metabolized in the first pass through the body. To compare the activity of the metabolites of SCH48461 with SCH48461 itself, an intestinally cannulated, bile duct-cannulated rat model for cholesterol absorption was developed. SCH48461 inhibited the absorption of cholesterol by 70%, whereas bile containing the metabolites of SCH48461 (henceforth, "metabolite bile") inhibited the absorption by greater than 95%. Very little of the recovered radioactive dose of SCH48461 was located in the intestinal lumen (7%) or wall (4%), whereas 85% appeared in bile. However, in rats treated with metabolite bile, 62% of the dose remained in the lumen, 13% was associated with the wall and only 24% reappeared in bile, which suggests that the activity of the metabolite bile may be related to its higher retention in the intestinal wall. Rats treated with metabolite bile had 64% and 84% less drug-related radioactivity in their plasma and livers, respectively, compared with animals treated with SCH48461, which indicates that the metabolites are systemically less available than SCH48461. The metabolites in bile were separated by high-performance liquid chromatography; the most active fraction in the bile duct-cannulated rat model was identified by mass spectrometry as the glucuronide of the C4-phenol of SCH48461. The other fractions had moderate or no activity. Through the identification of the most active biliary metabolites of SCH48461 in the rat, we have discovered SCH58235, a novel cholesterol absorption inhibitor which is 400 times more potent than SCH48461 in the cholesterol-fed rhesus monkey.

Central antitussive activity of the NK1 and NK2 tachykinin receptor antagonists, CP-99,994 and SR 48968, in the guinea-pig and cat.

1. The purpose of this study was to investigate the antitussive activity and sites of action of the NK1 and NK2 tachykinin receptor antagonists, CP-99,994, SR 48968, and the racemate of SR 48968, SR 48212A in the cat and guinea-pig. 2. Guinea-pigs were dosed subcutaneously (s.c.) with CP-99,994, SR 48212A or SR 48968 one hour before exposure to aerosols of capsaicin (0.3 mM) to elicit coughing. Coughs were detected with a microphone and counted. 3. Intracerebroventricular (i.c.v.) cannulae were placed in the lateral cerebral ventricles of anaesthetized guinea-pigs. Approximately one week later, the animals were dosed with CP-99,994 or SR 48212A (i.c.v.) and exposed to aerosols of capsaicin (0.3 mM) to elicit coughing. 4. Cough was produced in anaesthetized cats by mechanical stimulation of the intrathoracic trachea and was monitored from electromyograms of respiratory muscle activity. Cannulae were placed for intravenous (i.v.) or, in separate groups of animals, intravertebral arterial (i.a.) administration of CP-99,994, SR 48212A or SR 48968. Dose-response relationships for i.v. and i.a. administration of each drug were generated to determine a ratio of i.v. ED50 to i.a. ED50, known as the effective dose ratio (EDR). The EDR will be 20 or greater for a centrally active drug and less than 20 for a peripherally active drug. 5. In the guinea-pig, CP-99,994 (0.1-30 mg kg-1, s.c.), SR 48212A (1.0-30 mg kg-1, s.c.), and SR 48968 (0.3-3.0 mg kg-1, s.c.) inhibited capsaicin-induced cough in a dose-dependent manner. Capsaicin-induced cough was also inhibited by i.c.v. administration of CP-99,994 (10 and 100 micrograms) or SR 48212A (100 micrograms). 6. In the cat, both CP-99,994 (0.0001-0.3 mg kg-1, i.a., n = 5; 0.003-3.0 mg kg-1, i.v., n = 5) and SR 48212A (0.003-1.0 mg kg-1, i.a., n = 5; 0.01-3.0 mg kg-1, i.v., n = 5) inhibited mechanically induced cough by either the i.v. or i.a. routes in a dose-dependent manner. SR 48968 (0.001-0.3 mg kg-1, i.a., n = 5; 0.03-1.0 mg kg-1, i.v., n = 5) inhibited cough when administered by the i.a. route in a dose-dependent manner, but had no effect by the i.v. route up to a dose of 1.0 mg kg-1. Intravenous antitussive potencies (ED50, 95% confidence interval (CI) of these compounds were: CP-99,994 (0.082 mg kg-1, 95% CI 0.047-0.126), SR 48212A (2.3 mg kg-1, 95% CI 0.5-20), and SR 48968 (> 1.0 mg kg-1, 95% CI not determined). The intra-arterial potencies of these compounds were: CP-99,994 (1.0 microgram kg-1, 95% CI 0.4-1.8), SR 48212A (25 micrograms kg-1, 95% CI 13-52), and SR 48968 (8.0 micrograms kg-1, 95% CI 1-32). The derived EDRs for each compound were: CP-99,994, 82; SR 48212A, 92; and SR 48968, > 125. 7. We concluded that CP-99,994 and SR 48968 inhibit cough in the guinea-pig and cat by a central site of action. In the cat, the antitussive action of these compounds appears to be solely by a central site.

Hemodynamic profile of activation of histamine H3 receptors by R-alpha-methylhistamine in the guinea pig.

1. The effect of R-alpha-methylhistamine, a histamine H1 receptor agonist, was studied on cardiovascular hemodynamics in bilateral vagotomized, anesthetized guinea pigs. 2. R-alpha-methylhistamine (100 micrograms/kg, IV) a dose that selectively activates histamine H3 receptors, produced hypotension and bradycardia. Total peripheral resistance (TPR) and rate pressure product (RPP) were also decreased at this dose. 3. Pretreatment with the ganglionic blocker hexamethonium (20 mg/kg, IV) blocked the blood pressure (BP), heart rate (HR), TPR, and RPP effects of R-alpha-methylhistamine (100 micrograms/kg, IV). Hexamethonium did not block the hypotensive and TPR lowering actions of the muscarinic agonist methacholine (1 and 3 micrograms/kg, IV). 4. Pretreatment with the alpha 1-adrenoceptor antagonist prazosin (0.5 mg/kg IV), blocked R-alpha-methylhistamine's (100 micrograms/kg, IV) effects on BP, TPR, and RPP. Prazosin did not antagonize the bradycardia effect of R-alpha-methylhistamine. 5. Pretreatment with the beta-adrenoceptor antagonist atenolol (1 mg/kg, IV) did not alter the BP, TPR, or RPP actions of R-alpha-methylhistamine. The HR effects of R-alpha-methylhistamine were blocked by atenolol. 6. The hemodynamic effects of R-alpha-methylhistamine were compared to the hemodynamic profile of the calcium channel blocker, verapamil (0.5 mg/kg, IV). Verapamil had little effect on TRP and had a greater cardiac depressant effect as evidenced by a significant reduction in HR and cardiac output (CO). 7. In summary, these results show that activation of prejunctional H3 receptors with R-alpha-methylhistamine decreases basal, BP, HR, TPR, and RPP in anesthetized guinea pigs. The fall in BP is mediated by a decrease in TPR. Furthermore, the inhibitory effects of R-alpha-methylhistamine on sympathetic control of the vasculature appears to impart a greater physiologic effect on the H3-histamine mediated hypotension than its inhibitory effects on sympathetic agents to the heart.

Resolution of intracranial calcifications in infants with treated congenital toxoplasmosis.

PURPOSE: To determine the natural history of intracranial calcifications in infants with treated congenital toxoplasmosis. MATERIALS AND METHODS: Between January 1982 and March 1994, cranial computed tomography was performed in 56 infants with treated congenital toxoplasmosis when they were newborns and approximately 1 year old. Locations and sizes of intracranial calcifications were noted. RESULTS: Forty newborns had intracranial calcifications. By 1 year of age, calcifications diminished or resolved in 30 (75%) and remained stable in 10 (25%) of these treated infants. Ten (33%) of the 30 infants whose calcifications diminished versus seven (70%) of the 10 infants with stable calcifications received less intensive antimicrobial treatment than the other treated infants. In contrast, a small number of infants who were untreated or treated 1 month or less had intracranial calcifications that increased or remained stable during their 1st year of life. CONCLUSION: Diminution or resolution of intracranial calcifications was an unexpected and remarkable finding in infants with treated, congenital toxoplasmosis, consonant with their improved neurologic functioning.

Species differences in the cardiovascular responses to histamine H3 receptor activation.

Potential species differences in cardiovascular responses to histamine H3 receptor activation were studied in the conscious guinea pig, rabbit, normotensive rat and the spontaneously hypertensive rat. R-alpha-Methylhistamine (100 micrograms/kg i.v.) decreased blood pressure in both the guinea pig and the rabbit. In the guinea pig, R-alpha-methylhistamine decreased heart rate, whereas in the rabbit it produced a tachycardia. In the normotensive rat and spontaneously hypertensive rat, R-alpha-methylhistamine (100 micrograms/kg i.v.) had no effect on blood pressure and heart rate. The cardiovascular action of R-alpha-methylhistamine in the guinea pig and rabbit was blocked by pretreatment with thioperamide (1.0 mg/kg i.v.) but not by chlorpheniramine (0.3 mg/kg i.v.) or cimetidine (3.0 mg/kg i.v.), respectively. These results indicate species differences in cardiovascular responses to histamine H3 receptor activation.

Production by R-alpha-methylhistamine of a histamine H3 receptor-mediated decrease in basal vascular resistance in guinea-pigs.

1. The effect of the selective histamine H3 receptor agonist, R-alpha-methylhistamine given intravenously (10-100 micrograms kg-1) was examined on baseline total peripheral resistance (TPR), and cardiovascular haemodynamics in bilaterally vagotomized, anaesthetized guinea-pigs. 2. R-alpha-methylhistamine produced a dose-dependent hypotension and fall in TPR at 30 and 100 micrograms kg-1. A decrease in heart rate (HR) was observed at a dose of 100 micrograms kg-1. R-alpha-methylhistamine (10-100 micrograms kg-1) also produced a dose-dependent fall in rate pressure product (RPP). There was no effect on cardiac output (CO) or stroke volume (SV) at these doses. 3. Histamine H1 and H2 blockade in animals pretreated with a combination of chlorpheniramine (0.3 mg kg-1) and cimetidine (3.0 mg kg-1) did not alter the haemodynamic actions of R-alpha-methyl-histamine (100 micrograms kg-1, i.v.). Pretreatment with the selective H3 antagonist, thioperamide (1 mg kg-1), completely blocked the action of R-alpha-methylhistamine on haemodynamic parameters. 4. To study the mechanism of action of R-alpha-methylhistamine, the vasodilator hydralazine (1 mg kg-1, i.v.) was used. Hydralazine lowered BP, TRP and RPP in guinea-pigs pretreated with ipratropium (50 micrograms kg-1, i.v.). Hydralazine had no effect on HR, SV or CO. 5. R-alpha-methylhistamine (100 micrograms kg-1) did not affect the vasopressor action and increases in TPR produced by adrenaline (1 and 3 micrograms kg-1). On the other hand, the vasodilator hydralazine (1 mg kg-1, i.v.) inhibited the effects of adrenaline (3 micrograms kg-1) on TPR and RPP. The effect of both doses of adrenaline on BP were attenuated by hydralazine. Therefore, the inhibitory effects of R-alpha-methylhistamine are not mediated through a direct action on vascular smooth muscle.6. In adrenalectomized guinea-pigs, R-alpha-methylhistamine (100 microg kg-1) produced a drop in BP and HR.There was no difference between the effects of R-alpha-methylhistamine on blood pressure and heart rate in adrenalectomized and non-adrenalectomized guinea-pigs.7. These results show that activation of peripheral H3 receptors lowers basal BP, HR and TPR, most likely by a peripheral prejunctional mechanism. The fall in BP and TPR is probably due to a decrease in noradrenaline release from sympathetic effector nerves innervating the resistance blood vessels.