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PubMed1976

Spirometric comparison of carbuterol and isoproterenol aerosol therapy in bronchial asthma. A double blind, matched-pair study of 28 adults and a double blind crossover study of 18 children.

Two adrenergic aerosols were compared in a double blind, matched-pair study of 6 months' duration in 28 adult patients with chronic bronchial asthma, and in a double blind, crossover, short-term study in 18 children with severe asthma. In the adult study, one member of each pair was given either 150 mug of isoproterenol or 200 mug of carbuterol 4 times per day, by inhalation, for 6 months. In the childhood study, 18 children, 6 to 12 years of age, with moderate to severe asthma were studied in a double blind, crossover therapeutic trial in which high or low doses of aerosolized carbuterol or isoproterenol were given 4 times daily for 5 days each. Treatment results were evaluated by measuring forced vital capacity, 1-sec forced expiratory volume, and maximal mid-expiratory flow (FEF25-75%) at regulat intervals before and after administration of the respective test drugs. In the adult study, there was a significant difference between carbuterol and isoproterenol for forced vital capacity (P less than 0.02), for 1-sec forced expiratory volume (P less than 0.02), and for FEF25-75% (P less than 0.01) in favor of carbuterol. In the pediatric study, the difference between carbuterol and isoproterenol was significant (P less than 0.05) only for the FEF25-75% on the fifth day of treatment with the high dose administration of carbuterol. There was no associated toxicity of either drug with respect to electrocardiogram, blood chemistry, or subjective complaints. Tachyphylaxis (tolerance with time) to isoproterenol appeared to develop in one patient.

Adrenergic beta-Agonists↗
PubMed1985

The effect of procaterol treatment on beta-adrenergic bronchodilation and polymorphonuclear leukocyte responsiveness.

Procaterol is a new and effective beta-adrenergic bronchodilator. To determine if procaterol administration could cause tachyphylaxis, airway and leukocyte beta-adrenergic function were monitored in 10 patients with asthma during two 4-wk, double-blind treatment periods, each preceded by a 2-wk beta-agonist washout. Treatment periods were randomized to placebo or procaterol (2 wk, 0.1 mg/day; 2 wk, 0.2 mg/day). At each 7 biweekly evaluations, the patient's cumulative bronchodilator dose-response to inhaled isoproterenol (0.1 to 0.64%) was measured, and venous blood was collected to quantitate, in vitro, the polymorphonuclear leukocyte (PMN) beta-adrenergic receptor's 125Iodo-cyanopindolol (125I-CYP) ligand binding and the PMN cyclic AMP response to isoproterenol and procaterol. Neither the airway nor leukocyte beta-adrenergic characteristics were changed during placebo treatment. Procaterol treatment reduced (p less than 0.05) the maximal 125I-CYP binding to PMN membranes but only during the initial 2 wk at low dosage. The percent PMN cyclic AMP increase to procaterol (10(-5) M) was also significantly (p less than 0.05) less during active treatment (141 +/- 40%) than during washout (256 +/- 24%) or placebo (257 +/- 32%). In contrast, procaterol treatment did not alter the acute isoproterenol bronchodilation response as measured by either the percent improvement in FEV1 or the dose required to produce 50% maximal bronchodilation. The duration of bronchodilation was not measured. Therefore, although procaterol therapy of asthma is associated with decreased PMN beta-adrenergic function, airway smooth muscle function appears not to be altered.

Adult↗
PubMed1986

Comparison of tremor responses to orally administered albuterol and terbutaline.

This study was designed to compare the initial tremor response to 4.0 mg albuterol and 5.0 mg terbutaline orally administered and to study the question of tachyphylaxis by rechallenge after 3 wk of maintenance dosing. Twenty fasting patients with severe COPD in whom orally administered sympathomimetics were withheld for 2 wk were challenged with single doses of each drug in a crossover, randomized fashion 1 wk apart. Then after a further 3 wk of dosing 3 times a day of the second medication (10 patients received each medication), they were challenged once more 16 h after the last dose. Rest and postural tremor were measured at zero and 2 h using an accelerometer affixed to the finger, and measurements of subjective tremor, tremor power spectrum, plasma cyclic AMP and lactate, and forced vital capacity were also made. Postural tremor increased from 25.05 to 36.20 relative units for albuterol, an increase of 11.15 units, and from 24.90 to 57.70 units for terbutaline, an increase of 32.80 units (difference significant at p = 0.01). Plasma cyclic AMP (p less than 0.01) and lactate (p = 0.05) increases were also less for albuterol, and the FEV1 and FVC responses, though about one third less, did not differ significantly. After 3 wk, mean baseline tremor for both drugs was elevated even 16 h after the last 3 times a day dosing (38.00 and 33.10) for albuterol and terbutaline (difference, NS), and responses were much less to the single tablet (3.40 and 9.10, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1977

Effects of 5-hydroxytryptamine on the lower esophageal sphincter in vivo: evidence for multiple sites of action.

Intravenous administration of 5-hydroxytryptamine (5-HT) caused a dose-dependent contraction in the lower esophageal sphincter in the opossum. The smallest dose of 5-HT which caused a detectable contraction of the sphincter was 0.5 mug/kg, and a maximal sphincter contraction was produced by a dose of 40 mug/kg. Methysergide converted the contractile effect of 5-HT to a dose-dependent fall in the sphincter pressure; maximal inhibition of 77.2 +/- 7.2% of the resting pressure occurred with a dose of 40 mug/kg. The inhibitory effect of 5-HT was antagonized by tetrodotoxin, 5 MeO-DMT, and 5-HT tachyphylaxis. 5 MeO-DMT enhanced 5-HT-induced contraction of the sphincter. In the presence of 5 MeO-DMT and methysergide, 5-HT still caused a brief contraction of the sphincter; this contraction appeared to be due to stimulation of postganglionic cholinergic neurons as it was antagonized by tetrodotoxin or atropine. Reserpinization caused enhancement of the sphincter contraction by 5-HT. In the reserpinized animals in the presence of methysergide, 5-HT caused a small initial contraction followed by prolonged inhibition; atropine antagonized the initial contraction, while inhibition was antagonized by 5 MeO-DMT. These studies are consistent with the view that 5-HT exerts several different effects on the sphincter. 5-HT causes contraction of the sphincter by its direct action on the muscle and also by stimulation of cholinergic excitatory neurons. In addition, 5-HT inhibits the sphincter by stimulation of nonadrenergic inhibitory neurons.

5-Methoxytryptamine↗
PubMed1983

Neural control of the sphincter of Oddi. A physiological role of 5-hydroxytryptamine in the regulation of basal sphincter of Oddi motor activity in the cat.

The effect of 5-hydroxytryptamine (5-HT) on the sphincter of Oddi (SO) was studied in the cat. The SO had two motor responses to 5-HT: the most common was an initial contraction followed by a more prolonged relaxation, and the other was an exclusive relaxation. Tetrodotoxin did not impair the magnitude of the net contraction induced by 5-HT, but it completely blocked the relaxation. Methysergide partially inhibited the SO contraction in response to submaximal doses of 5-HT (5-20 micrograms/kg). Atropine decreased the SO excitatory response to all doses of 5-HT. The combination of atropine and methysergide completely antagonized the 5-HT excitatory effect, which changed the SO biphasic response to an exclusive relaxation. After tetrodotoxin, the effect of 5-HT was almost completely antagonized by methysergide alone. The SO contraction and relaxation caused by 5-HT were almost completely blocked by 5-HT tachyphylaxis. In contrast, a 5-HT depletion with reserpine enhanced the sensitivity of the SO to 5-HT, responding to doses a thousand times smaller than in control animals. Hexamethonium, phentolamine, propranolol, and 5-methoxy-N,N-dimethyltryptamine did not antagonize the 5-HT-induced contraction or relaxation. These findings indicate that 5-HT caused SO contraction by stimulating postganglionic cholinergic neurons and the smooth muscle directly and caused relaxation by stimulating postganglionic, noncholinergic, nonadrenergic inhibitory neurons. 5-HT blockade or depletion resulted in a significant reduction in basal tonic pressures and in the amplitude of phasic contractions, which suggested that serotonergic neurons may play a physiologic role in the regulation of basal SO motor activity.

Ampulla of Vater↗
PubMed1985

Terbutaline-induced desensitization of human lymphocyte beta 2-adrenoceptors. Accelerated restoration of beta-adrenoceptor responsiveness by prednisone and ketotifen.

We investigated, in 36 healthy volunteers, the effects of prednisone and ketotifen on recovery of lymphocyte beta 2-adrenoceptor density (determined by (-)-125iodocyanopindolol binding) and responsiveness (assessed by lymphocyte cyclic AMP [cAMP] responses to 10 microM (-)-isoprenaline) after desensitization by the beta 2-agonist terbutaline. Terbutaline (3 X 5 mg/d) decreased lymphocyte beta 2-adrenoceptor density by approximately 40-50%; concomitantly, lymphocyte cAMP responses to 10 microM (-)-isoprenaline were significantly reduced. After withdrawal of terbutaline beta 2-adrenoceptor, density and responsiveness gradually increased, reaching predrug levels after 4 d. Prednisone (1 X 100 mg orally) accelerated beta 2-adrenoceptor recovery; only 8-10 h after administration of the steroid beta 2-adrenoceptor density and cAMP responses to (-)-isoprenaline had reached values not significantly different from pretreatment levels. Similar effects were obtained with ketotifen (2 mg; thereafter 2 X 1 mg/d for 4 d): 24 h after application of the drug beta 2-adrenoceptor density and cAMP responses to (-)-isoprenaline had reached pretreatment levels. Furthermore, ketotifen simultaneously applied with terbutaline completely prevented terbutaline-induced decrease in lymphocyte beta 2-adrenoceptor density and responsiveness. Prednisone (1 X 100 mg orally) or ketotifen (2 mg; thereafter 2 X 1 mg/d for 2 d) had no significant influence on lymphocyte beta 2-adrenoceptor density in healthy volunteers not pretreated with terbutaline, but shifted the ratio high-to-low affinity state of the lymphocyte beta 2-adrenoceptor toward high affinity state. We conclude that glucocorticoids as well as ketotifen can accelerate recovery of density and responsiveness of lymphocyte beta 2-adrenoceptors desensitized by long-term treatment with beta 2-agonists. Such an effect may have clinical implications for preventing tachyphylaxis of asthmatic patients against therapy with beta 2-agonists.

Adult↗
PubMed1986

[Pharmacological studies on ginger. V. Pharmacological comparison between (6)-shogaol and capsaicin].

Pharmacological actions of (6)-shogaol and capsaicin were studied. Both (6)-shogaol (0.5 mg/kg, i.v.) and capsaicin (0.1 mg/kg, i.v.) caused a triad such as a rapid fall in blood pressure, bradycardia and aponea in rats. Both drugs-induced marked pressor responses in blood pressure, which occurred after the rapid fall, were markedly reduced by a spinal destruction. In pithed rats, both drugs-induced peripheral pressor responses were markedly reduced with the combined treatment of [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-substance P (0.5 mg/kg, i.v.), phentolamine (10 mg/kg, i.v.) and the section of sciatic nerves. In isolated guinea-pig trachea, (6)-shogaol (100 microM) and capsaicin (10 microM) induced contractile responses which were slightly inhibited by substance P antagonist (10 microM), but exhibited also a tachyphylaxis. Furthermore, although (6)-shogaol (3.6 microM) showed positive inotropic and chronotropic actions on isolated atria in rats, this effect of (6)-shogaol disappeared by repeated injections or pretreatment (100 mg/kg, s.c.) of (6)-shogaol. These results suggest that (6)-shogaol and capsaicin have similar actions, and that both drugs may cause a peripheral action by releasing an unknown active substance from nerve ends.

Animals↗
PubMed1979

Pharmacological studies of lycorenine, an alkaloid of Lycoris radiata Herb.: Vasodepressor mechanism in rats.

Vasodepressor mechanism of lycorenine (an alkaloid of Lycoris radiata Herb.) was investigated in anesthetized rats. Lycorenine (1--10 mg/kg i.v.) produced dose-related decreases in blood pressure and heart rate and tachyphylaxis developed with repeated injections. In the blood-perfused rat hindquarters, lycorenine (62.5--500 micrograms i.a.) produced dose-related decreases both in mean blood pressure and in perfusion pressure, and the lycorenine-induced decrease in perfusion pressure was abolished by phenoxybenzamine or hexamethonium. Lycorenine (more than 1 mg/kg i.v.) blocked the pressor response to sympathetic nerve stimulation, but failed to block the tachycardia induced by sympathetic nerve stimulation. Lycorenine (7.5 or 15 mg/kg i.v.) reduced the spontaneous splanchnic nerve activity. Lycorenine when given intracerebroventricularly produced decreases in blood pressure and heart rate only in large doses (over 500 micrograms). The maximal bradycardia induced by lycorenine was abolished by bilateral vagotomy. It is suggested that lycorenine may produce a decrease in blood pressure as the result of alpha-adrenergic blockade in conjunction with the reduction of the spontaneous sympathetic nerve activity, and produce bradycardia by modifying vagal activity.

Action Potentials↗
PubMed1986

Antidiuretic effects of dibutyryl-cyclic AMP microinjected into the hypothalamic paraventricular nucleus in a water-loaded and ethanol-anesthetized rat.

Effects of dibutyryl-cyclic AMP (db-cAMP) and cyclic AMP (cAMP) when microinjected into the hypothalamic paraventricular nucleus (PVN) in a water-loaded and ethanol-anesthetized rat on the rate of urine outflow, urine osmotic pressure and other visceral functions were investigated. The microinjection of db-cAMP decreased the rate of urine outflow with concomitant increase in the urine osmotic pressure, but did not change mean blood pressure, heart rate, respiration rate and rectal temperature. The antidiuretic effect of db-cAMP was more potent than the effect of cAMP, the median effective doses (ED50) being approx. 40 nmol for db-cAMP and more than 300 nmol for cAMP, respectively. The time-courses for the antidiuretic effects and for the increase in the urine osmotic pressure showed a similar pattern, with the maximal effect at approx. 30 to 40 min and the duration of approx. one hour or longer. The effect of db-cAMP was potentiated by pretreatment with methylxanthines and inhibited by pretreatment with atropine. A second microinjection of db-cAMP induced a less potent antidiuretic effect than the first microinjection (tachyphylaxis). The results indicated the antidiuretic effects of microinjection of db-cAMP and cAMP into the PVN, and a possible mechanism for this was discussed.

1-Methyl-3-isobutylxanthine↗
PubMed1987

Potentiating effect of tyramine on acetaldehyde-induced vasoconstriction in isolated dog mesenteric arteries.

The stainless steel cannula inserting method was used to investigate the effects of acetaldehyde on isolated and perfused dog mesenteric arteries. Acetaldehyde when intraluminally administered induced a marked vasoconstriction, but repetitive injections of acetaldehyde caused tachyphylaxis. Acetaldehyde-induced vasoconstrictions were blocked by bunazosin, an alpha-1 adrenoceptor antagonist. After tyramine treatment, the acetaldehyde-induced constriction was consistently restored temporarily. It is suggested that tyramine may induce a release of norepinephrine mostly from the vesicle to the neuronal cytosol, and acetaldehyde may cause a release of norepinephrine from the cytosol to the extracellular space in the isolated canine mesenteric artery.

Acetaldehyde↗
PubMed2002

Vasoconstricting effect of angiotensin II in human hand veins: influence of aging, diabetes mellitus and hypertension.

We examined human hand veins to determine whether venoconstricting response to angiotensin II (Ang II) and noradrenaline (NA) was influenced by aging or such diseases as diabetes mellitus (DM) and hypertension (HT). Twenty healthy male subjects (20-73 years), and 8 male patients with non-insulin-dependent DM and 8 male patients with essential HT were included in this study. A constant dose (50 ng/min) of Ang II or increasing dose (2-256 ng/min) of NA was infused into the dorsal hand vein and its diameter was measured using a linear variable differential transformer. The constant infusion of Ang II caused rapid desensitization or tachyphylaxis. The venoconstriction by Ang II in the 8 elderly subjects (58 to 73 years) was significantly (p<0.05) larger than that in the 8 young subjects (20 to 36 years) from 6 to 18 min after the start of the infusion (after 6 min: 63.6+/-11.6 (mean+/-SD)% vs. 39.9+/-20.8%, 12 min: 34.0+/-11.9% vs. 12.0+/-12.0%). However, the venoconstriction by Ang II in the patients with DM or HT was not significantly different from that in the 9 age-matched control subjects. No significant difference in venoconstrictor response to NA was observed between the young and elderly subjects, nor between the control subjects and the patients with DM or HT. These findings indicated that venoconstrictor response to Ang II might be greater in the elderly but might not be influenced by DM nor HT.

Adult↗
PubMed1997

Ecabapide, a novel gastroprokinetic agent, ameliorates gastric emptying of stroke-prone spontaneously hypertensive rats (SHRSP).

The effect of ecabapide, a novel gastroprokinetic agent, on gastric emptying was examined in stroke-prone spontaneously hypertensive rats (SHRSP), which are known to exhibit gastric malfunctions as a result of autonomic nervous system disorder. Ecabapide was administered orally to SHRSP in various dose-regimens. Gastric emptying was evaluated by the acetaminophen (APAP) method using semi-solid meal under the conscious conditions. Ecabapide significantly enhanced gastric emptying of SHRSP at 1 mg/kg in single administration, 0.3 and 1 mg/kg in 2-week treatment and 7.7 mg/kg in 4-week (diet) exposure. These results suggest that the effect of ecabapide is exerted without showing tachyphylaxis.

Acetaminophen↗
PubMed1998

Concomitant administration of low-dose prednisolone protects against in vivo beta2-adrenoceptor subsensitivity induced by regular formoterol.

STUDY OBJECTIVES: To assess whether concomitant administration of low-dose prednisolone (PRED) with regular inhaled formoterol (FM) might prevent the occurrence of beta2-adrenoceptor (beta2-AR) tachyphylaxis. DESIGN: Eleven healthy male subjects (mean age, 29 years) were randomized to receive 1 week with either inhaled FM, 24 microg bid, and placebo tablets (PL), or inhaled FM, 24 microg bid, and oral PRED, 15 mg daily, in double-blind, crossover fashion, with a 2-week washout between treatments. A dose-response curve (DRC) for systemic beta2-responses to inhaled salbutamol (800 to 3,200 microg) was constructed before and after each treatment period (ie, FM + PL or FM + PRED). Lymphocyte beta2-AR density (Bmax) and maximal cyclic adenosine monophosphate response to isoproterenol (isoprenaline) (Emax) were evaluated ex vivo at each visit; 8 AM serum cortisol level was also evaluated as a marker of systemic glucocorticoid activity. Comparisons for DRC were made as peak responses and area under curve (AUC). RESULTS: There was significant (p < 0.05) subsensitivity of systemic beta2-AR responses (as AUC) following FM + PL: for heart rate (before vs after), 760 vs 340 beats (95% confidence interval [CI], 160 to 680), for tremor 0.39 vs 0.19 log units/h (95% CI, 0.01 to 0.41), and for potassium, -0.34 vs -0.19 mmol x h/L (95% CI, -0.04 to -0.28). With PRED, there was protection against subsensitivity induced by FM with no significant difference in values before vs after FM: heart rate, 740 vs 640; tremor, 0.35 vs 0.34; and potassium, -0.30 vs -0.25. FM + PL induced significant downregulation of lymphocyte beta2-AR density (log Bmax; fmol/10(6) cells) (before vs after): 0.25 vs 0.11 (95% CI, 0 to 0.22; p < 0.05) and this was not altered by PRED (before vs after): 0.21 vs 0.10 (95% CI, 0.01 to 0.27; p < 0.05). FM + PL also caused desensitization of Emax (pmol/10(6) cells) (before vs after): 6.21 vs 2.29 (95% CI, 1.19 to 6.64; p < 0.05) and this was attenuated by PRED with no significant difference between before and after values: 4.60 vs 3.28. CONCLUSIONS: Concomitant administration of a low dose of PRED produced protection against FM-induced subsensitivity of systemic beta2-AR, as assessed by the response to inhaled salbutamol. In contrast, prednisolone did not prevent ex vivo beta2-AR downregulation despite causing significant cortisol suppression. This, in turn, suggests that there is a dissociation in the dose of PRED required to protect against beta2-AR downregulation and subsensitivity, following continuous exposure to long-acting beta2-agonist.

Administration, Inhalation↗
PubMed1982

Effects of cadmium on the tension of isolated rat aorta (a possible mechanism for cadmium-induced hypertension).

A possible mechanism for the pressor effect of cadmium was investigated in isolated rat thoracic aorta. Cadmium produced contractions at low concentrations, but relaxations at high concentrations. Phentolamine, a sympathetic alpha blocking agent did not inhibit the cadmium-induced contractions. These contractions were reduced in accordance with the decrease in Ca content in medium and were abolished in Ca-free medium, rather inducing a small degree of relaxation. When low concentrations of cadmium were applied repeatedly for a short period of time, the contractions were remarkably reduced and finally abolished. Noradrenaline-induced contractions were not affected after the completion of cadmium-tachyphylaxis. Low concentrations of cadmium potentiated K-, Ba- and noradrenaline-induced contractions, while high concentrations suppressed them. These results suggest that cadmium-induced contractions are dependent on external Ca and that they are produced by direct stimulation on the cell membrane. In addition, low concentrations of cadmium accelerate Ca availability, while high concentrations inhibit it.

Animals↗
PubMed1994

The beta 2-agonist controversy. Observations, explanations and relationship to asthma epidemiology.

Links between frequent use of inhaled beta 2-agonists and morbidity and mortality from asthma appear probable. Two mortality epidemics followed the marketing of potent inhaled adrenergic agents. Case-control studies in New Zealand linked mortality with prescription of fenoterol, especially in severe asthma. A Saskatchewan case-control study confirmed an association of mortality with fenoterol, and also with frequent use of salbutamol (albuterol). Cardiac effects of beta 2-agonists do not cause mortality, but frequent use of these agents may increase the chronic severity of asthma, hence increasing the number of asthmatic patients at risk of death in an acute attack. Frequent use of beta 2-agonists may reduce lung function, increasing airway responsiveness, and impair control of asthma, despite use of inhaled corticosteroids. Mechanisms for this effect may include tachyphylaxis to nonbronchodilator effects, increased responsiveness to allergen, interaction with corticosteroid receptors, altered mucociliary function, differential effects of enantiomers, and masking of symptoms by beta 2-agonist use. The withdrawal of fenoterol from New Zealand in 1990 was associated with a substantial decline in morbidity and mortality. Overall, the evidence suggests that frequent use of inhaled beta 2-agonists has a deleterious effect on the control of asthma. Epidemics of mortality are explained by an increase in chronic severity of asthma following introduction of more potent beta 2-agonists. While beta 2-agonists remain essential for relief of breakthrough symptoms, long term use, particularly with high doses of potent agents, appears to be detrimental.

Adrenergic beta-Agonists↗
PubMed1996

Causes and problems of nonresponse or poor response to drugs.

The lack of (or poor) response to drugs has very important medical, social and economic consequences today. An unsatisfactory response to treatment implies not only a worsening or prolongation of the pathological state, but also prolonged hospitalisation, longer withdrawal from social and active life, and waste of community resources. Poor response to drugs has many and varied causes, among which 4 major categories can be identified: pharmacokinetic, cellular, genetic and medical. After a brief description of the terminology, the phenomena of tachyphylaxis, tolerance and drug resistance are analysed and critically described on the basis of the available evidence. Whenever possible, alternative or operative behaviours aimed at reducing the incidence of the above phenomena are commented on. On the question of medical causes, irrational prescriptions and poor compliance with the prescribed regimen stand as two major issues whose prevalence is worrying. In order to limit the waste of professional responsibility and economic resources, efforts aimed at reducing the present insufficiencies are needed at organisational and educational levels.

Down-Regulation↗
PubMed1979

Continuous mini-infusion of bupivacaine into the epidural space during labor. Part II: Blood concentration of bupivacaine.

Mini-infusion of 0.25 per cent bupivacaine plain into the epidural space was used in 16 healthy women for pain relief during labor. After a loading dose, continuous administration was ensured by using an automatic pump at an infusion rate of 5 or 8 ml per hour. Maternal venous blood concentrations of bupivacaine were determined 20, 40, and 60 minutes after the loading dose. Further samples were taken hourly until delivery. Fetal blood concentrations were determined from fetal scalp blood during mini-infusion, and from umbilical venous blood at delivery. Maternal blood levels averaged 206 ng/ml. The maximum concentration (604 ng/ml) did not exceed 30 per cent of the toxic level. The blood concentration of bupivacaine did not tend to increase during the course of continuous infusion. Tachyphylaxis could not be detected statistically. The fetal blood concentration during blockade averaged 58 ng/ml, giving a feto-maternal ratio of 0.28. The neonatal-maternal ratio, calculated from the umbilical venous blood, was 0.32. With a shift of the acid-base status towards acidosis in the neonate, the ration of bupivacaine slightly increased. Absence of maternal hypotension as well as absence of fetal heart irregularities during infusion may be attributed to the low and stable blood concentration of bupivacaine. The mean Apgar score was 9.5 at one minute and 9.9 at five minutes. The maternal arterial acid-base balance at delivery was normal. The fetal acid-base status at delivery showed wide variation, without any relation to the Apgar score or the total dose of bupivacaine. It is concluded that continuous mini-infusion of bupivacaine by means of an automatic pump has advantages over intermittent administration.

Anesthesia, Epidural↗
PubMed1981

Ocular and systemic responses to water soluble material derived from Cannabis sativa (marihuana).

A water soluble material, isolated from Cannabis sativa, has been tested in albino and pigmented rabbits and rhesus monkeys for both ocular and systemic effects. Intravenous administration produced a dose-related fall in intraocular pressure in both albino and pigmented rabbits with concentrations as low as 0.005 mg/animal being effective, but no response was found in monkeys. High concentrations (0.2 to 1 mg/animal) induced a hypertensive phase in intraocular pressure prior to the ocular hypotension; higher concentrations (2 or 5 mg/animal) also induced antidiuresis and general relaxation. Tachyphylaxis was found to repeated daily injections. Alpha and beta-adrenergic antagonists caused some reduction of the hypertensive phase but had no effect on the hypotensive phase. Superior cervical ganglionectomy did not influence the time course of the intraocular pressure response. Indomethacin inhibited the hypertensive intraocular pressure phase but was ineffective against the hypotensive phase. Systemic blood pressure was unchanged following intravenous administration of 0.2 mg material/animal. Aqueous tumor protein concentration was increased at both 1 and 6 hours after intravenous administration, becoming greater at the later time. Aqueous humor turnover rate was substantially reduced reaching a minimum 8.75 hours after administration. Topical administration was ineffective in eyes when the epithelium was removed in rabbits with and without pretreatment with aspirin. Neither gastric nor suppository administration of large quantities (10 mg or greater) of material had any influence on intraocular pressure.

Adrenergic alpha-Antagonists↗