A new paracetamol/paracetamol-methionine ester combination effects on postoperative course

Summary The SUR 2647 combination is a sachet formulation containing free paracetamol and its N-acetyl-methionate ester (SUR 2647). In a randomized, singel-blind, within-patient study the effect of the SUR 2647 combination on the postoperative course was investigated in 30 out-patients after bilateral oral surgery. On one occasion they received sachets of SUR 2647 combination 2 b.i.d. (equivalent to 2 g paracetamol ×2) on the day of operation, and one sachet b.i.d. (equivalent to 1 g paracetamol ×2) on the following two days. On the other occasion they received placebo caplets. The observed mean reduction in swelling on the third (16%) and seventh (34%) postoperative days after receiving active drug was not significantly different as compared to placebo, nor was there a significant difference between the two treatments with respect to oral temperature, mouth-opening capability or postoperative bleeding. Pain after the SUR 2647 combination regime was significantly lower (P<0.01) than placebo until the second postoperative evening. Complaints were registered in both treatment groups, although reports of mild to moderate drowsiness were more common after the SUR 2647 combination.     

In vivo studies on toxic effects of concurrent administration of paracetamol and its N-acetyl-DL-methionine ester (SUR 2647 combination)

1. Single p.o. doses of paracetamol 400 and 800 mg/kg or SUR 2647 combination (free paracetamol + paracetamol-N-acetyl-DL-methionate, paracetamol/methionine ratio 2:1) equivalent to paracetamol 400 and 800 mg/kg were given to Bom:NMRI mice. Vehicle treated (1% w/v aqueous methylcellulose) mice were established as a control group. 2. All treatment groups irrespective of medication caused an initial GSH depletion. However, SUR 2647 combination 400 mg/kg caused a much earlier hepatic GSH recovery than paracetamol 400 mg/kg. SUR 2647 combination 800 mg/kg caused a higher hepatic GSH level than paracetamol 800 mg/kg. 3. There was no significant difference in the plasma ALAT level after SUR 2647 combination 400 or 800 mg/kg and the control group. Paracetamol 400 and 800 mg/kg caused significant plasma ALAT elevations compared to the control group. 4. The addition of N-acetyl-DL-methionine esterified to paracetamol, as in the SUR 2647 combination, enhances the hepatic GSH synthesizing capacity in Bom:NMRI mice after experimental overdosage and offers protection of hepatic cell integrity as assessed by plasma ALAT level compared to paracetamol alone.     

The cardiovascular effects of intraventricularly administered histamine in the anaesthetised rat

Summary In urethane-anaesthetised rats intraventricular (i.c.v.) injections of histamine (0.1–10.0 g) elicited dose-related rises in both the resting blood pressure and heart rate. These cardiovascular effects of histamine were antagonised in a dose-dependent manner by i.c.v. pretreatments with the histamine H₁-receptor antagonists mepyramine (10, 50 and 100 g) and diphenylpyraline (100 and 200 g). Pretreatment with the histamine H₂-receptor antagonist metiamide (100 and 200 g i.c.v.) failed to modify either of the responses. A dose-related antagonism of the hypertensive response to histamine i.c.v. was elicited by phentolamine (100 and 200 g i.c.v.) but the positive chronotropic effect was not modified by this pretreatment. The cardiovascular responses to histamine i.c.v. were abolished by mecamylamine (5.0 mg/kg i.v.) and greatly reduced by 6-hydroxydopamine (3×250 g i.c.v.), but only the tachycardia was significantly modified by atropine (100 g i.c.v.) and propranolol (1 mg/kg i.v.). Propranolol (100 g i.c.v.), bilateral vagotomy, or acute bilateral adrenal demedullation failed to modify the cardiovascular responses to histamine i.c.v. The results suggest that histamine is able to modify the resting blood pressure and heart rate by independent central modes of action, which involve central adrenergic and cholinergic mechanisms.Preliminary findings of this study were presented at the Autumn meeting of the British Pharmacological Society (Finch and Hicks, 1975).     

Steady-state concentrations of choline and acetylcholine in rat brain parts during a constant rate infusion of deuterated choline

Summary An intravenous infusion of deuterated choline at constant rate for 6 min (5 or 25 moles kg^–1 min^–1) significantly increases the concentration of choline in plasma, occipital cortex and striatum. Both 5 and 25 moles kg^–1 min^–1 increase the concentration of acetylcholine in cortex but only 25 moles kg^–1 min^–1 increases the acetylcholine content in striatum. In contrast, 1 mole kg^–1 min^–1 does not change the choline or acetylcholine content in cortex or striatum. A single pulse injection of choline (200 moles kg^–1) causes a significant increase in the concentration of choline in striatum 30 sec following injection. The choline content returns to normal values within 2 min. These studies show that when a pulse injection of a non-tracer dose of radioactive choline is used to measure brain acetylcholine turnover rate the maintenance of steady state must be verified within seconds after the pulse injection of radioactive choline. When constant infusion of deuterated choline is used to measure turnover rate of acetylcholine in the brain of rats, a dose of 1 mole kg^–1 min^–1 appears to be a maximal infusion rate.     

High versus low dose granisetron,a selective 5HT3 antagonist,for the prevention of chemotherapy-induced nausea and vomiting

Summary Fifty six patients, with histologically confirmed cancer, who received highly emetogenic chemotherapy, were entered on a randomized double blind, low versus high dose, study of granisetron, a 5HT₃ receptor antagonist. A single dose of intravenous granisetron protected the majority of patients from nausea and vomiting, 160 g/kg was more effective than 40 g/kg with no more side effects. Additional doses of granisetron conferred added benefit to patients who experienced breakthrough symptoms. Granisetron at a dose range of 40–240 g/kg over a 24 hour period was well tolerated with the only side effect being mild headache.     

Enhancement of Solubility and Bioavailability of β-Lapachone Using Cyclodextrin Inclusion Complexes

Purpose. To explore the use of cyclodextrins (CD) to form inclusion complexes with -lapachone (-lap) to overcome solubility and bioavailability problems previously noted with this drug. Methods. Inclusion complexes between -lap and four cyclodextrins (-, -, -, and HP-CD) in aqueous solution were investigated by phase solubility studies, fluorescence, and ¹H-NMR spectroscopy. Biologic activity and bioavailability of -lap inclusion complexes were investigated by in vitro cytotoxicity studies with MCF-7 cells and by in vivo lethality studies with C57Blk/6 mice (18-20 g). Results. Phase solubility studies showed that -lap solubility increased in a linear fashion as a function of -, -, or HP-CD concentrations but not -CD. Maximum solubility of -lap was achieved at 16.0 mg/ml or 66.0 mM with HP-CD. Fluorescence and ¹H-NMR spectroscopy proved the formation of 1:1 inclusion complexes between -CD and HP-CD with -lap. Cytotoxicity assays with MCF-7 cells showed similar biologic activities of -lap in -CD or HP-CD inclusion complexes (TD₅₀ = 2.1 M). Animal studies in mice showed that the LD₅₀ value of -lap in an HP-CD inclusion complex is between 50 and 60 mg/kg. Conclusions. Complexation of -lap with HP-CD offers a major improvement in drug solubility and bioavailability.     

Differential modulation by muscimol and baclofen on antinociception induced by morphine, β-endorphin,d-Pen2,5-enkephalin and U50,488H administered intracerebroventricularly in the mouse

The present study was designed to investigate the modulatory effects of stimulation of GABA_A and GABA_B receptors at supraspinal sites on antinociception induced by supraspinally administered -, -, -, and -opioid receptor agonists. The effects of the GABA_A and GABA_B receptor agonists, muscimol and baclofen respectively, on the antinociception induced by morphine (a -receptor agonist), -endorphin (an -receptor agonist), D-Pen^2,5-enkephalin (DPDPE, a -receptor agonist) and U50,488H ({trans-3,4-di-chloroN-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeocetamide}; a -receptor agonist) injected intracerebroventricularly (i.c.v.) were studied. The anti-nociception was assayed using the tail-flick and hot-plate tests. Muscimol at doses of 25–200 ng, administered i.c.v. alone did not affect the latencies of tail-flick and hot-plate thresholds, but attenuated dose-dependently the inhibition of the tail-flick and hot-plate responses induced by i.c.v. administered morphine (2 g), -endorphin (1 g), DPDPE (10 g), and U50,488H (60 g). Baclofen (1.25–10 ng) administered i.c.v. alone did not affect the latencies of the tail-flick and hot-plate responses, but attenuated dose-dependently the inhibition of the tail-flick and hot-plate responses induced by -endorphin and U50,488H, without affecting morphine-or DPDPE-induced responses. Our results indicate that activation of GABA_A receptors at the supraspinal sites by i.c.v. injection of muscimol antagonizes antinociception induced by supraspinally administered -, -, -, and -opioid receptor agonists. On the other hand, activation of GABA_B receptors at supraspinal sites by i.c.v. baclofen antagonizes antinociception induced by i.c.v. administered - and -opioid agonists, but not - or -opioid agonists.     

Is there a need for more precise definitions of bioavailability?

Summary After evaluation of the present definitions in a set of particular cases, it was agreed that there was no need for more precise definitions and that the current ones were adequate in the majority of cases. However, it was felt that the present definitions might be improved, in particular in view of the existence of non-systemically acting drugs and future targeted drugs. Thus, the FDA definition might be modified as follows: Bioavailability means the rate and extent to which the active drug ingredient or therapeutic moiety from a drug product becomes available at the site of drug action or in a biological medium believed to reflect accessibility to a site of action.     

Different types of opioid receptors mediating analgesia induced by morphine,DAMGO, DPDPE,DADLE and β-endorphin in mice

Summary The effects of intracerebroventricular (i.c.v.) administration of d-Phe-Cys-Tyr-d-Try-Orn-Thr-Pen-Thr-NH₂ (CTOP), a selective mu-opioid receptor antagonist, (Allyl)2-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174864) and (N,N-Bisallyl-Tyr-Gly-Gly--(CH₂S)-Phe-Leu-OH (ICI 154129), selective delta-opioid receptor antagonists on blocking analgesia induced by -endorphin, morphine, d-Ala²-NMePhe⁴-Gly-ol-enkephalin (DAMGO), d-Ala²-d-Leu⁵-enkephalin (DADLE) and d-Pen²-enkephalin (DPDPE) administered i.c.v. were studied in male ICR mice. The analgesia was assessed by the tail-flick and paw-licking (hot-plate) tests. The potencies of opioid agonists injected i.c.v. for producing analgesia were DAMGO > DADLE > -endorphin > morphine > DPDPE. Intracerebroventricular administration of CTOP (0.05 g) selectively antagonized inhibition of the tail-flick and paw-licking response induced by morphine, DAMGO or DADLE but not -endorphin or DPDPE. ICI 174864 (5 g) and ICI 154129 (5 g) injected i.c.v. selectively antagonized analgesia induced by DPDPE or DADLE but not -endorphin, morphine or DAMGO injected i.c.v. These results indicate that analgesia induced by morphine and DAMGO is mediated by the stimulation of mu-opioid receptors while analgesia induced by DPDPE is mediated by the stimulation of delta-opioid receptors. DADLE-induced analgesia is mediated by the stimulation of both mu- and delta-opioid receptors. Analgesia induced by -endorphin is mediated by neither munor delta-opioid receptors.Abbreviations i.c.v. intracerebroventricular - i.t. intrathecal - CTOP d-Phe-Cys-Tyr-d-Try-Orn-Thr-Pen-Thr-NHZ - DAMGO d-Ala²-NMePhe²-Gly-ol-enkephalin - DADLE d-Ala²-d-Leus-enke-phalin - DPDPE dd-Pen²-dd-Pen⁵-enkephalin - ICI 174864 (Allyl)2Tyr-Aib-Aib-Phe-Leu-OH - ICI 154129 (N,N-Bisallyl-Tyr-Gly-Gly-(CH₂S)-Phe-Leu-OH     

Plasma insulin levels and β-adrenoceptor antagonists

Summary The effect of -adrenoceptor antagonists on the intravenous glucose tolerance test was investigated in conscious dogs. dl-Celiprolol (cardioselective with ISA=intrinsic sympathomimetic activity) 200 and 1000 g/kg i.v., dl-metoprolol (cardio-selective without ISA) 200 and 1000 g/kg i.v., dl-pindolol (non-selective with ISA) 5 and 25 g i.v. and l-bupranolol (non-selective without ISA) 10 and 50 g/kg i.v. were used in the study. The influence of -adrenoceptor antagonists on the plasma glucose and immunoreactive insulin following the intravenous glucose tolerance test were evaluated by calculating the respective areas under the plasma curve.The present investigtion clearly demonstrates the marked difference between the various -adrenoceptor antagonists on heart rate and, especially on metabolic parameters. dl-Metoprolol, a -adrenoceptor antagonist with cardioselectivity and without ISA can be assumed not to alter plasma insulin level and glucose assimilation. l-Bupranolol, a non-selective -adrenoceptor antagonist without ISA reduces plasma insulin level and probably enhances peripheral glucose uptake, resulting in an unchanged glucose tolerance. dl-Celiprolol or dl-pindolol, -adrenoceptor antagonists with ISA, but cardioselective or non-selective enhance both, basal insulin level and insulin level after glucose stimulation but must be assumed to decrease peripheral glucose uptake since here too glucose tolerance was unchanged.     

Cardiovascular effects of selective agonists and antagonists of histamine H3 receptors in the anaesthetized rat

The cardiovascular responses to a series of selective histamine H₃ receptor agonists, (R) -methylhistamine, imetit and immepip and selective antagonists, thioperamide, clobenpropit and clophenpropit, were studied in anaesthetized rats. At 0.003–1 mol/kg i.v. doses, H₃ agonists failed to produce any significant change in the basal blood pressure and heart rate. Larger doses of (R) -methylhistamine increased the blood pressure and heart rate and higher doses of imetit caused vasodepressor responses and reduced heart rate, whereas immepip proved virtually inactive. While (R) -methylhistamine-induced effects were not blocked by histamine H₁-, H₂- and H₃-receptor antagonists, they were however reduced by idazoxan and propranolol, which indicates that the mechanisms involved are adrenergic. The effects induced by imetit are not related to histamine H₃ receptors but are mediated by indirect (via 5HT₃ receptors) cholinergic mechanisms, since these effects were prevented by 1 mg/kg i.v. atropine and by 0.1 mg/kg i.v. ondansetron. Similarly, the H₃ antagonists per se failed to change basal cardiovascular function up to 10 mol/kg i.v. and only at 30 mol/kg i.v. were marked decreases observed in the blood pressure and heart rate with a significant reduction in the effects of noradrenaline. These data indicate that in anaesthetized rats, histamine H₃ receptor activation or blockade has no effect on basal cardiovascular function. The effects recorded after the administration of large doses of (R) -methylhistamine and imetit are clearly unrelated to histamine H₃ receptors and should be taken into account when using these compounds as H₃ ligands for in vivo experiments.     

Evaluation of P2-purinoceptor antagonists at two relaxation-mediating P2-purinoceptors in guinea-pig taenia coli

The guinea-pig taenia coli possesses two relaxation-mediating receptors for nucleotides: a prototypic P_2Y-purinoceptor, which is activated by adenosine 5-O-(2-thiodiphosphate) (ADPßS), and a separate receptor for ,-methylene ATP (,-MeATP). Effects of several as yet incompletely characterized P₂-purinoceptor antagonists at these receptors were examined.The concentration-relaxation curve of ADPßS was shifted to the right by reactive blue 2, suramin, 8-(3,5-dinitro-phenylenecarbonylimino)-1,3,5-naphthalenetrisulphonic acid (XAMR0721; at 1000 M only), pyridoxalphosphate-6-azophenyl-2,5-disulphonic acid (iso-PPADS), pyridoxal 5-phosphate, trypan blue and Evans blue (at 320 M only). Schild plots for the antagonism of reactive blue 2, suramin, iso-PPADS and pyridoxal 5-phosphate against ADPßS had slopes <1. The concentration-relaxation curve of ,-MeATP was shifted to the right by reactive blue 2, suramin, XAMR0721, iso-PPADS, pyridoxal 5-phosphate and trypan blue but not by Evans blue (320 M). Schild plots for the antagonism of suramin, XAMR0721 and iso-PPADS against ,-MeATP had slopes >1. Only XAMR0721 differed clearly in potency against the two nucleotides: it was considerably more potent against ,-MeATP than against ADPßS. 2-Methylthio ATP (MeSATP; 1 M) and ATP (100 M) were degraded by pieces of taenia coli. All antagonists except trypan blue attenuated the degradation of either or one of the two nucleotides.The selective effect of XAMR0721 against ,-MeATP confirms the existence of two relaxation-mediating P₂-purinoceptors in guinea-pig taenia coli. Comparison of the apparent affinities of the antagonists for the two taenia coli receptors with affinities for the P_2X-purinoceptor of the rat vas deferens shows that reactive blue 2, suramin, iso-PPADS, pyridoxal 5-phosphate and trypan blue have little selectivity for any of the three receptors. XAMR0721, which has been shown to possess relatively high affinity for the P_2Y-purinoceptor in turkey erythrocytes, was very weak at the P_2Y-receptor of the taenia, thus supporting the existence of pharmacologic P_2Y-receptor subtypes. Evans blue, with little effect in the taenia coli but a marked effect in the rat vas deferens, is the most selective P_2X-(versus P_2Y-) purinoceptor antagonist presently known, although its effect on the degradation of nucleotides must be kept in mind.     

The binding spectrum of narcotic analgesic drugs with different agonist and antagonist properties

Summary Four groups of narcotic analgesic drugs have been assessed for their opiate activities by using three binding assays and three pharmacological bioassays. In the binding assays, their inhibition constants (K _I, nM) were determined against the binding of the -ligand, [³H]-[d-Ala ² ,MePhe ⁴ , Gly-ol⁵]enkephalin, of the -ligand, [³H]-[d-Ala ² ,d-Leu ⁵]enkephalin and of the -ligand, [³H]-(±)-ethylketazocine after suppression of - and -binding by 100 nM of the unlabelled -ligand and 100 nM of the unlabelled -ligand. The pharmacological agonist or antagonist activities were assayed on the guinea-pig ileum, mouse vas deferens and rat vas deferens.The first group of compounds were pure agonists in all three pharmacological bioassays. The majority of the compounds showed preference to -binding but phenazocine and particularly etorphine had also high affinities to the - and -binding sites.The second group consisted of N-allyl and N-cyclopropylmethyl homologues of the morphine, 3-hydroxymorphinan and normetazocine series which had agonist and antagonist activities in the guinea-pig ileum and mouse vas deferens but were pure antagonists in the rat vas deferens. In the binding assays, -binding and -binding were prominent.The third group was made up by the ketazocine-like compounds which in the guinea-pig ileum and mouse vas deferens were pure agonists and in the rat vas deferens pure antagonists. The binding spectrum showed particularly high binding to the -binding site.The fourth group was the antagonists which were devoid of agonist activity with the exception of diprenorphine and Mr 2266 which had retained some agonism. The binding spectrum showed considerable variation, naloxone in low concentration being a selective -antagonist, Mr 2266 having high affinities to the - and -binding sites and diprenorphine having considerable affinities to the -, - and -binding sites.Since each of the four groups of compounds, whether pure agonists, agonist-antagonists, ketazocine-like drugs or pure antagonists, shows independent varittions in the affinities to the - and -binding sites, their different pharmacological behaviour cannot be solely due to difference in the binding spectra.     

Development of tolerance to antinociceptive effects of an intrathecal morphine/clonidine combination in rats

Previous animal studies have shown the antinociceptive effects of intrathecal clonidine and intrathecal morphine to be synergistic. This study investigated the intrathecal administration of multiple doses of this drug combination to examine the rate of development of tolerance and to determine whether there was any toxic effect on the spinal cord.Rats with indwelling intrathecal catheters were given saline, morphine (2.5–7.5 g), clonidine (17.5 g), or clonidine (17.5 g) plus morphine (1 g) intrathecally twice daily for 41/2 days (total of 9 doses). Hot plate and tail flick tests were conducted after the first, fifth and ninth doses. After the ninth dose animals were killed and their spinal cords were removed for histological examination.Tolerance developed to the antinociceptive effects of the drug combination, but at a slower rate than to morphine alone. No evidence of toxicity or injury to the spinal cord was observed other than changes which could be ascribed to the presence of the catheter.     

Development of Interferon Suppositories. I. Enhanced Rectal Absorption of Human Fibroblast Interferon by Fusogenic Lipid via Lymphotropic Delivery in Rats

We attempted to enhance the rectal absorption of human fibroblast interferon (HuIFN-) in rats by the administration of suppositories containing fusogenic lipid and a nontoxic surfactant. Suppositories containing either the lipid (linoleic acid) or the surfactant [HCO60; polyoxyethylated (60 mol) hydrogenated castor oil] alone failed to enhance the absorption of HuIFN-. However, suppositories containing both linoleic acid and HCO60 facilitated the rectal absorption of HuIFN-. The absorbed HuIFN- was selectively delivered via the lymph.     

Differential effects of methylxanthines on local cerebral blood flow and glucose utilization in the conscious rat

Summary The aim of this study was to test the effects of the three classical methylxanthines, theophylline, caffeine and theobromine, on local cerebral blood flow and glucose utilization. Equimolar doses (1.6 mol/kg/min i.v.) of theophylline and caffeine produced increases in local cerebral glucose utilization and decreases in local cerebral blood flow. These compounds, therefore, re-set the ratio of cerebral blood flow per unit of glucose utilization at a lower level. These results are interpreted with respect to the known adenosine antagonist properties of caffeine and theophylline. Theobromine, a substance with less significant adenosine antagonist properties, had minimal effects on local cerebral blood flow and glucose utilization at a dose of 1.6 mol/kg/min i.v. These data may provide supportive evidence for the hypothesis that adenosine plays an important role in cerebral blood flow-metabolism coupling.Part of this work has previously been presented at the Deutsche Pharmakologische Gesellschaft March 13–16, 1984 on Mainz     

Short-term effects of herbicides on primary productivity of periphyton in lotic environments

Freshwater algae are quite sensitive to herbicides that enter running water ecosystems through direct application, aerial drift, and/or watershed run-off. However, due to a lack of suitable methodologies, few studies examine the effects of such contamination on naturally occurring attached algal communities under field conditions (i. e., exposure regimes using pulsed doses or brief episodes of peak concentrations to simulate surface run-off during storm events). This paper describes a method for determining the acute short-term effects of four herbicides (hexazinone, atrazine, tebuthiuron and metolachlor) on the net primary productivity (NPP) of periphytic algae in the field using a portable bankside incubator; NPP was measured by monitoring changes in oxygen production (mg O₂ per m²) upper surface of rock substrate per h and mg O₂ h per mg chlorophyll using the light-dark technique. All herbicides with photosynthetic inhibition as a mode of action significantly reduced NPP. The lowest observed effect concentrations (LOECs) for the herbicides were 43 g hexazinone l^–1, 109 g atrazine l^–1 and 137 g tebuthiuron l^–1. The no observed effect concentrations (NOECs) for these chemicals were <43 g hexazinone l^–1, 93 g atrazine l^–1 and 52 g tebuthiuron l^–1. Metolachlor did not significantly reduce NPP at the concentrations that were tested (range 19.6–274 g l^–1). However, community respiration (which included respiration by invertebrates) was significantly reduced at the highest metolachlor concentration (274 g l^–1). Community respiration was not significantly affected by any concentration of the other three herbicides used.     

Influence of N-allyl-normetazocine on acetylcholine release from brain slices: involvement of muscarinic receptors

Summary The effects of (±)N-allyl-normetazocine on the release of acetylcholine from different areas of guinea-pig and rat brain were investigated. 1. The drug did not modify the electrically (2 Hz) evoked tritium efflux from guinea-pig cerebral cortex, thalamus and caudate nucleus slices, preloaded with ³H-choline 0.1 mol/l and superfused with Krebs solution containing hemicholinium-3 10 mol/l. 2. (±)N-allyl-normetazocine 10 mol/l. enhanced the evoked ³H efflux from guinea-pig brain slices superfused with Krebs solution containing physostigmine 30 mol/l or oxotremorine 0.3 -1 gmol/l; the effect was naloxone-insensitive and was abolished by atropine 0.15 mol/l, but not by pirenzepine 1 mol/l. 3. (±)N-allyl-normetazocine 5 mol/l enhanced the electrically evoked release of endogenous acetylcholine as well, in a naloxone-insensitive way. 4. Both (±) and (+)N-allyl-normetazocine were without effect on ³H efflux from rat caudate nucleus slices electrically stimulated at 0.2 Hz frequency, after preloading with ³H-choline and during superfusion with hemicholinium-3. 5. The results are discussed in view of the antimuscarinic properties of the drug. Send offprint requests to A. Siniscalchi     

Hospital pharmacists'' reinforcement of guidelines for switching from parenteral to oral antibiotics: a pilot study

Objective: The cost of antibiotics in hospitals may be reduced by streamlining, and, particularly, by early switching from the intravenous (i.v.) to the oral route of administration. The aim of the study was to evaluate the feasibility and impact of guidelines for switching, reinforced by pharmacists. Method: Patients admitted to internal medicine wards and treated with i.v. antibiotics for various infections were included for six weeks before (group A) and six weeks after (group B) the intervention. Differences in patient characteristics and their outcomes were sought between the two groups.Results: The 26 patients in group B stayed longer in hospital than the 29 in group A (13.3 vs. 9.7 days; P = 0.05). They also tended to need more time to reach the predefined criteria for switching (3.6 vs. 2.4 days; P = 0.09). From that point on, they were switched more rapidly to oral antibiotics (1.5 vs. 3.2 days; P = 0.02), which resulted in a trend toward a lower treatment cost until their discharge (44 vs. 92 euros; P = 0.08). No difference was found between the 2 groups for the duration of the i.v. therapy, or the total inhospital cost of antibiotics. Conclusion: Pharmacists may help implement and reinforce guidelines for switching to oral antibiotics. The evaluation of such interventions implies the choice of appropriate outcomes and the awareness of confounding factors.     

Inhibition by opiate narcotics of rat flexor α-motoneurones

Summary Specific effects of opiate narcotics on rat flexor -motoneurones were studied in ventral roots of laminectomized rats under halothane anaesthesia. The -motoneurones were activated by tetanic stimulation of the cut ipsilateral common peroneal nerve, exciting up to group II- but not group III- and C-afferents. Morphine (0.5–3.0 mg/kg i.v.) reduced or completely suppressed the discharge rate of flexor -motoneurones in a dose-dependent manner. This effect was antagonized by naloxone (0.5 mg/kg i.v.) and mimicked by levorphanol (1.0 mg/kg i.v.), but not by an equal dose of its steroisomer dextrorphan, suggesting that the effect described is a specific one. After spinalization, the inhibitory effect of morphine was abolished. Previous studies had shown that opiates (e.g. morphine, given in a dose of 2 or 4 mg/kg i.v.) excite rat extensor -motoneurones, an effect opposite to the opiate narcotic action on flexor -motoneurones. The action of opiates leading to an inhibition of flexor -motoneurones may contribute to akinesia and catalepsy, and opioid-induced muscular rigidity. From the results presented it appears that morphine produces a reciprocal change in the activity evoked in extensor and flexor reflex pathways.Some of these results were presented at the 18th Spring Meeting of the German Pharmacological Society, Mainz, March 16–18, 1977These studies were supported by a grant (B-3) from the Sonder-forschungsbereich 33 Nervensystem und biologische Information of the Deutsche Forschungsgemeinschaft