The intrinsic effects of sarmazenil on sleep propensity and performance level of sleep-deprived subjects

The effect of two dosages of sarmazenil (RO 15-3505) on sleep propensity and performance was investigated in a double-blind, placebo-controlled paradigm. The design included three 24-h testing periods, separated by at least one 7-day rest period, commencing after 24-h of sleep deprivation. Twelve normal, healthy, adult males (mean age 27±2.8 years) were paid to participate. During the experimental periods, they came to the sleep laboratory at 2100 hours and spent the night awake under close supervision. At 0700 hours, a schedule of 7 min attempting sleep in bed, 13 min awake outside the bedroom, began. This schedule was maintained for 24 h. Repeated administrations of 1 mg and 2 mg sarmazenil significantly reduced the 24-h levels of total sleep. This was particularly evident during the period 0700–2300 hours. Sarmazenil also significantly improved reaction time and tended to increase the number of correct responses in the categories search task. Sarmazenil tended to improve reaction time in the Stroop test but this was significant only for the easy version of the test during the night.     

Compressed Donut-Shaped Tablets with Zero-Order Release Kinetics

Purpose. Simple uncoated compressed tablets with a central hole (donut-shape) are proposed to provide a constant drug release over a long period of time (>20 hrs). The effect of hole size and drug solubility on the release kinetics is investigated. Methods. The donut-shaped polyethylene oxide (PEO, Mw = 4 × l0⁶) tablets (600 mg and 12 mm diameter) are bored with a drill bit (3/32, 7/64, 1/8, and 5/32). Results. The release of theophylline from the donut-shaped tablets is zero order (80 – 90% release) before rapidly decreasing. As the hole size is increased from 7/64 to 5/32, the release rate increases and the release time is shortened. However, the release of theophylline from the donut-shaped tablet with a hole size of 3/32 follows the same anomalous release profile from a tablet without a hole. As drug solubility increases, the duration of linear drug release is shortened to 65 – 70% release followed by a severe tailing at the later stage of the release. Conclusions. Donut-shaped PEO tablets with a hole provide zero-order release kinetics because the effect of the releasing surface area on the release kinetics is reduced.     

Differential effects of α-β-methylene ATP on responses to nerve stimulation in SHR and WKY tail arteries

Summary The effects of ,-methylene-adenosine triphosphate, (,-methylene ATP, a P₂-receptor desensitising agent) have been evaluated on vasoconstrictor responses elicited by exogenous agonists or electrical field stimulation in isolated perfused SHR or WKY tail arteries and on tritium release elicited by electrical field stimulation in SHR-tail arteries pre-labeled with ³H-noradrenaline.Exposure to ,-methylene ATP (0.1 mol/l) significantly inhibited vasoconstrictor responses to electrical field stimulation in SHR tail arteries. These inhibitory effects were not further increased at a higher concentration of ,-methylene ATP (1 mol/l). In WKY tail arteries, ,-methylene ATP (1 mol/l) failed to significantly inhibit vasoconstrictor responses to electrical stimulation.In SHR tail arteries prelabelled with ³H-noradrenaline, ,-methyleneATP (1 mol/l) did not inhibit the stimulation evoked release of tritium. However, at this concentration, ,-methylene ATP significantly antagonized the vasoconstrictor responses of SHR tail arteries induced by exogenous ATP (1 mol/l), ,-methylene ATP (30 mol/l), a stable agonist at P₂-receptors, or 60 mmol/l KCl. These effects of ,-methylene ATP on contractile responses to KCl were not observed in WKY-tail arteries.In tail arteries obtained from reserpine pretreated SHR, despite a 85–95% decrease in endogenous noradrenaline tissue content, the vasoconstrictor responses induced by periarterial field stimulation were greatly diminished, but not abolished. These residual responses to periarterial field stimulation were not antagonized by prazosin (0.1 mol/l), but were practically abolished by the addition of ,-methylene ATP (1 mol/l).In tail arteries from WKY rats pretreated with reserpine, exposure to prazosin (0.1 mol/l) further reduced the residual responses elicited by electrical field stimulation. In these WKY-tail arteries, addition of ,-methylene ATP (1 mol/l) did not further inhibit the remaining vasoconstrictor response obtained in the presence of prazosin.While our results suggest a significantly greater cotransmitter role for ATP with noradrenaline in tail arteries of SHR compared with control normotensive WKY rats, additional effects of ,-methylene ATP not involving P₂ receptors cannot be entirely excluded.     

Dopaminergic modulation of hippocampal noradrenaline release

Summary ³H-Noradrenaline release in the rabbit hippocampus and its possible modulation via presynaptic dopamine receptors was studied. Hippocampal slices were preincubated with ³H-noradrenaline, continuously superfused in the presence of cocaine (30 mol/l) and subjected to electrical field stimulation. The electrically evoked tritium over-flow from the slices was reduced by 0.1 and 1 mol/l dopamine and apomorphine, but significantly enhanced by 10 mol/l apomorphine or by 0.1 and 1 mol/l bromocriptine. If the ₂-adrenoceptor antagonist yohimbine (0.1 mol/l) was present throughout superfusion, the inhibitory effects of dopamine and apomorphine were more pronounced and even 10 mol/l apomorphine and 1 mol/l bromocriptine inhibited noradrenaline release. Qualitatively similar observations were made in the presence of another ₂-antagonist, idazoxane (0.1 mol/l). In the presence of the D2-receptor antagonist domperidone (0.1 mol/l) the inhibitory effects of dopamine were almost abolished, whereas both apomorphine (>1 mol/l) and bromocriptine (>0.01 mol/l) greatly facilitated noradrenaline release. The D2-receptor agonist LY 171555 (0.1 and 1 mol/l) significantly reduced the evoked noradrenaline release whereas the D1-selective agonist SK & F 38393 was ineffective at similar concentrations. The effects of LY 171555 were abolished in the presence of domperidone (0.1 mol/l) but remained unchanged in the presence of yohimbine or idazoxane (0.1 mol/l, each).At 1 mol/l the D2-receptor antagonists domperidone and (-)sulpiride significantly increased the evoked noradrenaline release by about 10%. However, at this concentration, domperidone (but not (-)sulpiride) affected also basal tritium outflow. Bulbocapnine and the preferential D1-receptor antagonists SCH 23390 enhanced the evoked noradrenaline release already at 0.1 mol/l. Their marked facilitatory effects (50 to 60% increase at 1 mol/l) were reduced in the presence of idazoxane (0.1 mol/l) and almost abolished in the presence of 0.1 mol/l yohimbine, whereas the increase due to 1 mol/l (-)sulpiride persisted under these conditions.The evoked tritium efflux from rabbit hippocampal slices preincubated with ³H-serotonin was not affected by dopamine receptor agonists.From our results we conclude that hippocampal noradrenaline, but not serotonin release, is modulated via D2-dopamine receptors. In addition, our results provide evidence for more or less pronounced ₂-adrenoceptor agonistic properties of dopamine and ₂-adrenoceptor antagonistic properties of apomorphine, bromocriptine, SCH 23390 and bulbocapnine in this noradrenaline release model from CNS tissue.     

A Novel,Self-Correcting Membrane Coating Technique

A novel coating process, leading to formation of uniform, defect-free coating on solid dosage forms, is proposed. The coating process, termed diffusion-controlled interfacial complexation, involves a chemical reaction between a reactant incorporated in the solid unit to be coated and a polymer solution, forming the coating medium. The reaction results in the formation of an insoluble reactant–polymer film around the solid. The rate of film/membrane formation is controlled by the rate of diffusion of reactant through the reactant–polymer film. In the model system, calcium acetate was selected as the reactant and algin as the polymer. The coating process was mathematically characterized in terms of rate of increase in film thickness, film weight, and depletion of reactant. Compressed tablets coated using the above process provided zero-order release in distilled water.     

Understanding and Predicting Drug Delivery from Hydrophilic Matrix Tablets Using the “Sequential Layer” Model

Purpose. The objectives of this work were (i) to study and understand the physicochemical phenomena which are involved in the swelling and drug release from hydrophilic matrix tablets using the sequential layer model; and (ii) to predict the effect of the initial radius, height and size of the tablets on the resulting drug release profiles. Methods. Tablets were prepared by direct compression, using hydroxypropyl methylcellulose (HPMC) grades with different average molecular weights as matrix-forming polymers. The in vitro release of chlorpheniramine maleate, propranolol HCl, acetaminophen, theophylline and diclofenac sodium was studied in phosphate buffer (pH 7.4) and 0.1 M HCl, respectively. The initial drug loading varied from 1 to 70%, while the radius and height of the tablets varied from 1 to 8 mm. Results. The sequential layer model considers water and drug diffusion with non-constant diffusivities and moving boundary conditions, non-homogeneous polymer swelling, drug dissolution, and polymer dissolution. We showed that this model was able to predict the resulting drug release kinetics accurately in all cases. Conclusions. The sequential layer model can be used to elucidate the swelling and drug release behavior from hydrophilic matrix tablets and to simulate the effect of the device geometry on the drug release patterns. Hence, it can facilitate the development of new pharmaceutical products.     

Enhancement of the Antiinflammatory Effect of Ethyl 4-Biphenylyl Acetate in Ointment by β-Cyclodextrin Derivatives: Increased Absorption and Localized Activation of the Prodrug in Rats

Ethyl 4-biphenylyl acetate (EBA) is a prodrug of the antiinflammatory 4-biphenylyl acetic acid (BPAA). The inclusion complexes of EBA with -cyclodextrin (-CyD), heptakis(2,6-di-O-methyl)--cyclodextrin (DM--CyD), and 2-hydroxypropyl--cyclodextrin (HP--CyD) at a molar ratio of 1:2 (EBA:cyclodextrin) were prepared and used to make hydrophilic antiinflammatory ointments. The in vitro release of EBA from the ointments was enhanced by complexation in the order of -CyD < DM--CyD HP--CyD. The improvement correlated with the improved solubility and not with the decreased diffusibility observed to occur upon the complexation of EBA. In vivo the complexation with cyclodextrin derivatives increased both the release of EBA from the vehicle and its conversion in the underlying tissue to BPAA, but the total of EBA and BPAA in the tissue was decreased. In vitro studies confirmed that the effects of cyclodextrin derivatives on the conversion were exerted indirectly. The combination of the enhanced release and of the enhanced prodrug hydrolysis by esterases in the site where the antiinflammatory action is required resulted in increased therapeutic effects. In the model of carrageenan-induced acute edema in rat paw, the complexation improved the therapeutic effects over those of EBA alone in the order of -CyD < DM--CyD < HP--CyD. HP--CyD may be a particularly useful cyclodextrin derivative since it improves the topical availability and does not irritate tissues.     

Cyclodextrin-Mediated Drug Release from Liposomes Dispersed Within a Bioadhesive Gel

Purpose The aim of the present study was to design a new mucosal drug delivery system composed of liposomes dispersed within a bioadhesive hydrogel containing methyl--cyclodextrin (MeCD) for controlled drug release.Methods A hydrophilic model molecule, inulin, was encapsulated within positively charged and PEG-ylated liposomes and its release was measured in the presence of MeCD after vesicle dispersion within the bioadhesive Carbopol® 974P gel. Freeze-fracture electron microscopy (FFEM) was used to follow liposome morphological changes when dispersed within the hydrogel. Liposome-MeCD interactions were investigated by turbidity monitoring during continuous addition of MeCD to liposomes and by FFEM.Results Inulin diffusion within the gel was influenced by Carbopol® 974P concentration since no gel erosion occurred. When dispersed within the gel, positively charged liposomes displayed a higher stability than PEG-ylated vesicles. In the presence of MeCD, higher amounts of free inulin were released from liposomes, especially in Carbopol®-free system. MeCD appeared to diffuse towards lipid vesicles and permeabilized their bilayer allowing inulin leakage. Indeed, freeze-fracture experiments and liposome turbidity monitoring have shown that MeCD behaved as a detergent behavior, resulting in lipid vesicle solubilization.Conclusion MeCD is able to mediate, within a bioadhesive hydrogel, the release of a liposome-encapsulated molecule allowing further application of this delivery system for mucosal administration.Equal Contribution.     

Processing Considerations for an EC Latex Coating System: Influence of Curing Time and Temperature

The influence of curing time and curing temperature for a commercially available ethylcellulose latex coating dispersion (Aquacoat^®) were evaluated using response surface methodology. Levels for the factor curing time ranged from 30 to 300 minutes while levels for curing temperature ranged from 45° to 75°C. Responses, A, , and , were derived from regression analysis of the dissolution profiles and correspond to the maximum amount of drug released over the 12 hour sampling period, the rate of release, and the inflection point of the dissolution profile, respectively. The nature of the response surface was dramatically influenced by the plasticizer incorporated into the coating formula. When dibutyl sebacate was employed as the plasticizer, faster release resulted (higher A and values, lower values) when samples were exposed to higher curing temperatures or were stored for longer periods of time. Paradoxically, when tributyl citrate was used as the plasticizer, slower release resulted when samples were exposed to more rigorous conditions. Overall, curing temperature had a more dramatic effect than curing time.     

Cyclodextrins as Nasal Absorption Promoters of Insulin: Mechanistic Evaluations

The safety and effectiveness of cyclodextrins (CD) as nasal absorption promoters of peptide-like macromolecules have been investigated. The relative effectiveness of the cyclodextrins in enhancing insulin nasal absorption was found to be in the descending order of dimethyl--cyclodextrin (DMCD) > -cyclodextrin (-CD) > -cyclodextrin (-CD), hydroxypropyl--cyclodextrin (HPCD) > -cyclodextrin (-CD). A direct relationship linking absorption promotion to nasal membrane protein release is evident, which in turn correlates well with nasal membrane phospholipid release. The magnitude of the membrane damaging effects determined by the membrane protein or phospholipid release may provide an accurate, simple, and useful marker for predicting safety of the absorption enhancers. In order to estimate further the magnitude of damage and specificity of cyclodextrin derivatives in solubilizing nasal membrane components, the enzymatic activities of membrane-bound 5-nucleotidase (5-ND) and intracellular lactate dehydrogenase (LDH) in the perfusates were also measured. HPCD at a 5% concentration was found to result in only minimal removal of epithelial membrane proteins as evidenced by a slight increase in 5-ND and total absence of LDH activity. On the other hand, 5% DMCD caused extensive removal of the membrane-bound 5-ND. Moreover, intracellular LDH activity in the perfusate increased almost linearly with time. The cyclodextrins are also capable of dissociating insulin hexamers into smaller aggregates, and this dissociation depends on cyclodextrin structure and concentration. Enhancement of insulin diffusivity across nasal membrane through dissociation may provide an additional mechanism for cyclodextrin promotion of nasal insulin absorption.     

Different effects of vinblastine on the polymerization of isotypically purified tubulins from bovine brain

Vinblastine, a highly successful antitumor drug, targets the tubulin molecule. Tubulin, the subunit protein of microtubules, consists of an - and a -subunit, both of which consist of isotypes encoded by different genes. We have purified three isotypes of bovine brain tubulin, namely, _II, _III and _IV. Microtubule associated protein-2 (MAP2) and Tau-induced assembly of these isotypes were compared in the presence and absence of vinblastine. MAP2-induced assembly of unfractionated tubulin and all the isotypes except _II tubulin was resistant to 1M vinblastine. Vinblastine at low concentrations (<10M) progressively inhibited the assembly of all of the isotypes but the vinblastine concentration required for inhibition of MAP2-induced microtubule assembly was minimal for _II. The tau-induced assembly of unfractionated tubulin and _III were equally sensitive to 1M vinblastine whereas _II and _IV were much more sensitive to vinblastine. The microtubules obtained in the presence of tau from unfractionated tubulin, _II and _IV could be easily aggregated by 20M vinblastine whereas such as aggregation of microtubules obtained from _III and tau required approximatedly 40M vinblastine. Our results suggest that among the tubulin isotypes, _II is the most sensitive to vinblastine in the presence of MAPs while _III is the most resistant and this intrinsic resistance of _III dimers persists in the polymeric form of _III tubulin as well. These results may be relevant to the therapeutic and toxic actions of vinblastine.     

A dispersion model of hepatic elimination: 2. Steady-state considerations-influence of hepatic blood flow,binding within blood,and hepatocellular enzyme activity

The dispersion model of hepatic elimination is based on the distribution of residence times of blood elements within the liver. The model has two asymptotic solutions corresponding to the wellstirred model (complete mixing of blood elements) and the parallel-tube model (no variation in residence times of blood elements). The steady-state form of the dispersion model relevant to pharmacokinetic analysis is developed and explored with respect to changes in blood flow, in binding within blood, and in hepatocellular enzyme activity. Literature data are used to evaluate discrepancies among the predictions of the dispersion, well-stirred, and tube models. It is concluded that the dispersion model is consistent-with the data. The limitations of steady-state perfusion experiments to estimate the residence time distribution of blood elements within the liver are considered.     

Neural ATP release and its α2-adrenoceptor-mediated modulation in guinea-pig vas deferens

Summary Contractions, release of previously stored [³H]-noradrenaline (measured as overflow of total tritiated compounds) and release of ATP elicited by electrical field stimulation (210 pulses, 7 Hz) were studied in the superfused vas deferens of the guinea pig. Prazosin and suramin were used to suppress non-neural ATP release, and effects of bromoxidine and rauwolscine on the neural release thus isolated were examined.Electrical stimulation elicited reproducible contraction, tritium overflow and ATP overflow. Both prazosin (0.03–3 M) and suramin (30–300 M) reduced contractions as well as the evoked overflow of ATP. No visible contraction remained in 21 of 28 tissues exposed to prazosin 0.3 M combined with suramin 300 M. The evoked overflow of ATP under these conditions was about 17% of that observed in the absence of drugs. In the presence of prazosin 0.3 M and suramin 300 M, bromoxidine (0.01–1 M) decreased and rauwolscine (0.1–10 M) increased the evoked overflow of both tritium and ATP. Rauwolscine increased the evoked overflow of tritium to a significantly greater extent than the overflow of ATP.It is concluded that the overflow of ATP elicited by electrical (neural) stimulation in the presence of prazosin 0.3 M and suramin 300 M reflects purely neural release of ATP. This release of ATP, like the release of noradrenaline, is modulated through prejunctional ₂-adrenoceptors. The ₂-adrenoceptor modulation of the release of noradrenaline seems to be more marked than the modulation of the release of ATP. Correspondence to B. Driessen at the above address     

Sex differences in the medication choice for hypertension in general practice. A study with written case simulations

The objective of this study was to explore explanations for the preference of physicians to prescribe blockers to hypertensive men and diuretics to hypertensive women.A qualitative study among 12 family physicians was conducted with a combination of written case simulations, semistructured interviews and statements on attitudes of physicians towards antihypertensive drug choice.Among the male hypertensive cases the most frequently prescribed drugs were blockers, whereas among the female hypertensive cases diuretics were more often prescribed. Physician characteristics associated with a preferred prescribing of blockers to hypertensive men and diuretics to hypertensive women were: older age (no residency in family medicine), the believe that blockers are more effective in men with regard to lowering blood pressure and that diuretics are more effective in women, a nonevidence based attitude and a sexrelated attitude towards the choice of blockers and diuretics in general, and in particular towards the prescribing of blockers to hypertensive men because men have a higher absolute risk of coronary heart disease than women. An additional explanation for these findings may be the higher prevalence of ankle oedema among women. Patient characteristics associated with more prescribing of blockers to hypertensive men and diuretics to hypertensive women were: current employment and a "highrisk" profile in terms of blood pressure level and additional cardiovascular risk factors.Although, most considerations underlying a preferred prescribing of blockers to hypertensive men and diuretics to hypertensive women were not evidencebased, the actual choice of antihypertensive drug (diuretic or blocker) was evidencebased. These considerations may also play a role in the sex difference in the choice of calcium antagonists and angiotensin converting enzyme inhibitors and require further investigation.     

Propagation of impulses in the guinea-pig ureter and its blockade by calcitonin gene-related peptide (CGRP)

The guinea-pig ureter was placed in a three-compartment organ bath to enable the application of electrical stimuli or drugs to its renal end (R site), the middle region (M-site) or the bladder end (B-site) while recording mechanical activity at the R- and B-sites. All experiments were performed in ureters pre-exposed to capsaicin (10 M for 15 min) to prevent the release of sensory neuropeptides from afferent nerves. Electrical field stimulation (EFS, 5–25 ms pulse width, 20 V) produced a phasic contraction at the site of stimulation (direct response to EFS) which propagated to the other end of the ureter. Section of the ureter at the M-site abolished the propagated response to EFS; after section, EFS applied at the M-site induced a phasic contraction at both the R-and B-sites. Likewise, the application of KCl at the M-site produced phasic contractions at both the R- and B-sites. Tetrodotoxin (1 M), nifedipine (1 M) or Bay K 8644 (1 M) applied at the M-site had no influence on the direct or propagated responses to EFS; nifedipine (10 M) applied at the M-site abolished the propagated responses without affecting the direct responses to EFS. Bay K 8644 (1 M) applied at the R-site produced a marked enhancement of the direct response (EFS applied at R-site) while having no effect on the amplitude of the propagated response to EFS. Nifedipine (1 M), applied at the R-site, produced a graded, time-dependent, inhibition of the direct response (EFS applied at R-site) and eventually suppressed it; the propagated response was unaffected until suppression of the direct response, when an allor-none blockade of the propagated response was observed. When applied at the B-site (EFS at Rsite), 1 M nifedipine produced a graded, time-dependent, inhibition of the propagated response and eventually suppressed it, without affecting the direct response to EFS. For further pharmacological analysis of drug action on the propagated activity, EFS was applied at the R-site and drugs were applied at the M-site. Human CGRP (CGRP, 0.1 M) or cromakalim (1-3 M) were applied in superfusion at the M-site in the absence or presence of glibenclamide (1 M). Neither drug affected the direct response to EFS; both CGRP and cromakalim produced a reversible suppression of the propagated response. Glibenclamide suppressed the inhibitory activity of 1 M cromakalim and partly antagonized the effect of CGRP; the blockade by glibenclamide was partly overcome by 3 M cromakalim. The present findings are consistent with the idea that propagation of excitation occurs because of the spread of electrical activity between smooth muscle cells of the ureter and that conduction of impulses is independent of local changes in contractility. The present results also demonstrate that CGRP induced a conduction block along the ureter and that this effect involves activation of glibenclamide-sensitive K channels. Therefore, a local release of CGRP in response to pathophysiological stimuli is, in principle, capable of suppressing ureteral peristalsis and antiperistalsis.     

Viscoelasticity of Anionic Polymers and Their Mucociliary Transport on the Frog Palate

The influence of formulation variables on the rheology of polyanionic formulations and the relationships between viscoelastic properties and mucociliary transport rate were investigated. Polymeric samples were oscillated from 0.001 to 5 Hz using either a "cone and plate or a "coaxial cylinder measuring system. The mucociliary transport rates of polymeric samples were determined and compared movement of charcoal powder on the frog palate. For the linear polymeric solutions, sodium carboxymethylcellulose and sodium alginate, the elastic modulus (G) increased with increasing amplitudes during frequency scan. However, the G or viscous modulus (G) of partially cross-linked polyacrylic acid (cPAA) samples did not change significantly under oscillation. Both G and G of cPAA samples were significantly influenced by the amount of salt present in the formulation. The rheology of 2% (w/w) cPAA in 90:10 (w/w) propylene glycol:alcohol changed from a viscous fluid to a coarse suspension after neutralization. The pH increased gradually when the nonaqueous formulation reacted with water and the maximum dynamic moduli were obtained after incorporating 20% (w/w) water in the formulation. A negative correlation was found between the G of linear polyanionic samples and the relative transport rate. However, the lowest mucociliary transport rate was observed when the loss tangent (G/G) was around 0.4–0.5.     

Methoxamine enhances the release of endogenous noradrenaline from rabbit ear artery: possible involvement of ATP

Summary The effect of methoxamine, an ₁-adrenoceptor agonist, on the electrically-evoked release of endogenous noradrenaline was examined in the isolated rabbit ear artery. Noradrenaline was quantified by high performance liquid chromatography-electrochemical detection. The release of adenine nucleotides and nucleosides by methoxamine was examined using high performance liquid chromatography-fluorescence detection.The release of noradrenaline evoked by electrical field stimulation (EFS) at 4 Hz was reduced by tetrodotoxin 0.3 mol/l and clonidine 1 mol/l by approximately 80% and 50%, respectively. On the other hand, methoxamine at 10 but not 1 mol/l enhanced the release of noradrenaline to approximately twice the control, and the enhancement was prevented by prazosin 1 mol/l. The facilitatory action of methoxamine was also abolished after desensitization of P₂-purinoceptors by ,-methylene ATP 30 mol/l as well as by the presumed P₂-purinoceptor antagonist suramin given at 10 mol/l. Exogenous ATP 10 mol/l significantly enhanced the EFS-evoked release of noradrenaline, and the enhancement was abolished by ,-methylene ATP and suramin. None of the drugs changed the spontaneous outflow of noradrenaline. These results indicate that endogenous ATP, acting at prejunctional purinoceptors, may participate in the facilitatory effect of methoxamine. Indeed, methoxamine 10 mol/l significantly enhanced the spontaneous outflow of ATP and, less so, ADP. The methoxamine evoked release of ATP and ADP was antagonized by prazosin 1 mol/l.It is concluded that methoxamine releases endogenous ATP from postjunctional sites which then, via prejunctional purinoceptors, facilitates action potential-evoked release of noradrenaline in rabbit ear artery.Supported by grants from the Mita Research Foundation, Matsue, Japan and Kanae Research Foundation, Osaka, JapanCorrespondence to K. Takeuchi at the above address     

A new technique for the investigation of some analgesic drugs on a reflexive behavior in the rat

Summary The analgetic action of a series of analgesic and psychotropic agents was tested in a situation in which variable intensities of electric shock to a rat's feet were used to elicit two distinguishable reflexive responses: a flinching response at low shock values, and a jumping response at higher shock values,By using a modified method of limits, reliable threshold for the two responses were obtained.Chlorpromazine, perphenazine, morphine, codeine, nalorphine and acetylsalicylate were found to raise the threshold to jump, but had little or no effect on the threshold to flinch.PIH, JB 835, iproniazid, reserpine, tetrabenazine, and amphetamine were found to have no effect on either the jump or the flinch thresholds.A combination of amphetamine and codeine was found to produce a synergistic potentiation. A combination of morphine and nalorphine was found to produce an antagonism.The results were discussed in terms of Beecher's hypothesis that the analgetic action of drugs is due to a diminution of the emotional components of an animal's reaction to pain and in terms of the relationship of brain amine change to analgetic action.     

Drug,doctor warmth,and clinic setting in the symptomatic response to minor tranquilizers

An NIMH-PRB collaborative double-blind clinical trial, concerned with the importance of the doctor variable for drug treatment outcome, was conducted with 485 anxious neurotic outpatients receiving either chlordiazepoxide, meprobamate, or placebo. The participating clinics were located at the Johns Hopkins Hospital, Philadelphia General Hospital, and the Hospital of the University of Pennsylvania. The doctor variable selected for presentation was doctor warmth. Data on the 169 patients completing the 4 week study according to protocol were analyzed using a factorial analysis of covariance procedure, and the main findings were as follows: 1. several main drug effects, present only at 2 weeks, indicated chlordiazepoxide to produce significantly more improvement than either meprobamate or placebo; 2. several main warmth effects, present only at 4 weeks, showed patients rating their physicians at the initial visit as warm to improve significantly more than patients rating their physicians as non-warm; and 3. several significant drug X clinic interaction effects at 4 weeks reflected the fact that while hardly any drug differences were seen in 2 clinics, at Philadelphia General Hospital, patients strongly favored chlordiazepoxide. Drug and warmth effects were particularly marked in initially sicker patients, and warmth appeared especially important in the improvement of initially sicker placebo patients.     

Viscoelastic Properties of Polyacrylic Acid Gels in Mixed Solvents

The objective of this study is to investigate the viscoelastic properties of Carbopol 934P polymeric systems in a variety of mixtures of pharmaceutical solvents. Carbopol 934P neutralized with a 1:1 equivalent ratio of triethanolamine was dissolved in various binary or ternary solvent mixtures consisting of propylene glycol, glycerol formal, and water. Dynamic moduli G and G, complex viscosities, and , and loss tangent, tan, were examined over a frequency range of 10-3 to 10 Hz using an oscillatory viscoelastic rheometer at 30°C. The results indicated that for 0.5-1.5 wt% neutralized Carbopol in ternary mixtures, G and G increased by 3-4 orders of magnitude and the phase angle decreased from 80 to 25° when the water content in the solvent mixture increased from 10 to 80 wt%. These studies also indicated that the addition of water to nonaqueous Carbopol 934P polymer systems transforms them from low-viscosity solutions to gels with significant elastic behavior involving physical interaction and entanglement of polymer segments with solvents.