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In a double-blind crossover study, the pharmacokinetics and effects on night-time respiration and body movements of midazolam 7.5 mg, flunitrazepam 1 mg, and placebo were studied in 5 elderly insomniac patients with the static charge sensitive bed-method (SCSB). In a supine position, the gastrointestinal absorption rate of flunitrazepam (tmax 0.6 h) was faster than that of midazolam (tmax 0.95 h). The elimination phase half-life of midazolam was about twice as long as reported earlier in healthy adult volunteers, but ageing did not affect the elimination of flunitrazepam. The shape of the serum concentration-time curve of both benzodiazepine derivatives was quite similar. The sleep of these five insomniacs became more peaceful and the respiration more regular during midazolam and flunitrazepam, compared with placebo. Both benzodiazepines significantly decreased body movements and the cumulative movement time remained shorter throughout the night, compared with placebo. Total variability (VI) was clearly decreased with flurazepam, and a similar but not statistically significant tendency was seen with midazolam, compared with placebo. Accordingly, the proportion of quiet sleep (QS) increased (p = 0.014) and the proportion of active sleep (AS) decreased (p = 0.019) with both benzodiazepines, compared with placebo. This reflects the changed control of respiration by higher brain structures. No signs of increased respiratory resistance (i.e. ballistocardiographic respiratory amplitude variation BRV < 60%) were seen with either of the drugs or placebo. There were no differences in the subjects' own estimation of their sleep during medication with these drugs. Only the sleep onset latency was shorter with flunitrazepam compared with midazolam and placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

The metabolism of scopolamine and glycopyrrolate was studied in 11 healthy parturients undergoing cesarean section. After a single intramuscular injection of scopolamine (5 micrograms/kg, n = 7) or glycopyrrolate (6 micrograms/kg, n = 4), the concentrations of the drugs in the urine were determined up to 8-12 h using a radioreceptor assay. This assay measures scopolamine and glycopyrrolate with their possible active metabolites. The effect of beta-glucuronidase and sulfatase incubation on the drug concentrations was also studied. The concentrations of scopolamine and/or its active metabolites were on the average 7 times higher after incubation indicating that beta-glucuronide or sulfate conjugation is an important metabolic pathway for scopolamine. On the contrary, the glycopyrrolate concentrations increased only slightly between 1 and 3 hours after the drug injection. Thus, beta-glucuronide or sulfate conjugation plays only a minor part in the metabolism of glycopyrrolate.

In a randomized, double-blind, placebo controlled crossover study, the pharmacokinetics and some clinically important pharmacodynamic effects of intramuscular atropine (dl-hyoscyamine) were studied in 6 healthy male volunteers. The plasma concentrations of l-hyoscyamine were analyzed by radioreceptor assay (RRA) and the plasma concentrations of dl-hyoscyamine by radioimmunoassay (RIA). The absorption rate and the elimination rate of dl-hyoscyamine and l-hyoscyamine were comparable (tmax = 8.40 vs 8.67 min, t1/2el = 2.95 vs 2.43 h, dose 0.02 mg/kg) but the mean maximum plasma concentration of dl-hyoscyamine was 2.9 times and the mean AUC value 6.0 times higher than that of l-hyoscyamine which indicates a kinetic difference between the enantiomers. The concentrations of d-hyoscyamine calculated from the dl- and l-hyoscyamine concentrations reached maximum between 1 and 2 h after drug injection. The renal excretion of l-hyoscyamine occurred mostly in 6 h (34% of the dose) and no conjugated drug forms were detected. The increase in heart rate was observed only after the higher dose (0.02 mg/kg) and it was significant between 30 min and 2 h. The plasma concentrations of l-hyoscyamine and the change in heart rate expressed as percentages showed a linear correlation: concentrations under 0.5 micrograms/l caused slowing of rate, higher concentrations caused acceleration. Also, the antisialagogue effect (30 min-3 h) correlated with plasma concentrations.

The clinical significance of intramuscular premedication with 0.01 mg/kg of atropine in a procedure involving oral benzodiazepine premedication (15 mg midazolam the evening before surgery and on the morning of surgery) was investigated in a double-blind study. As far as sedation, apprehension, excitement, dizziness, emesis, and headache were concerned, there were no significant differences between group 1 (atropine) and group 2 (placebo) patients; however, both during and after anesthesia patients in group 1 had less excessive salivary secretion (especially during extubation). As a result of sympathetic overactivity, patients in group 1 had an increased heart rate and an increased incidence of supraventricular tachycardia. In group 1 intravenous infusion proved more difficult, and in addition, the patients complained more of subjective side effects (dry mouth). There was no significant correlation between the radioimmunologically measured serum concentrations and the clinical effects of atropine measured just before the induction of anesthesia. Substantial interindividual differences were found in these serum levels. From the anesthetist's viewpoint, atropine has both beneficial effects (antisecretory) and unwanted effects (cardiovascular effects). For the patient atropine caused only subjective unwanted effects. Midazolam, a new short-acting, sedative benzodiazepine derivatives, can be used without atropine as an oral premedicant.

The pharmacokinetics of dihydroergotamine (DHE) was studied in healthy volunteers (n = 6) and in neurological patients (n = 12). After a single 1.0 mg intravenous injection (n = 5) DHE quickly disappeared (T 1/2 beta = 32.9 min, Vdss = 0.33 liter/kg, Cltot = 1055.7 ml/min). In saliva (dose 1.0 mg, n =6) and cerebrospinal fluid (dose 0.5 mg, n =12) there were no measurable amounts of DHE after a single i.v. dose. The 32-h cumulative urinary excretion was 0.02-0.04% of the 1.0 mg intravenous dose. In one subject renal (0.18 ml/min) and extrarenal (692.9 ml/min) clearance of DHE was calculated. According to our results DHe is probably eliminated mainly by hepatic metabolism. The pharmacokinetic properties of DHE indicate a fast clinical response without a cumulative action.

The present review shows that labetalol has many advantageous properties in the treatment of patients suffering from angina pectoris with or without hypertension. These patients respond with vasoconstriction to a variety of internal and external influences. The selective alpha 1-blocking component in addition to the non-selective beta-blockade of labetalol attenuates the increased coronary vascular resistance and improves coronary haemodynamics especially under stress in a manner which should be favourable in myocardial ischaemia. In addition, the alpha 1-blocking component may prevent different kinds of arrhythmias generated by alpha-adrenoceptor stimulation. Labetalol has no effect on renal blood flow, glomerular filtration rate, plasma electrolyte concentrations, glucose tolerance, lipoprotein cholesterol ratio, renin-angiotensin-aldosterone system, uric acid levels, or on platelet aggregation. Intravenously administrated labetalol has proved to be effective in patients with acute myocardial infarction, especially if associated with hypertension. In order to avoid postural hypotension, oral treatment should be started with a low dose of 100 mg twice daily. The usual dosage in patients without hypertension is 200 mg twice daily, but in patients with hypertension doses up to 1200 mg or even more have been used. In low doses up to 400 mg daily, the unwanted effects are few and often self-limited. High doses can cause side effects related to both beta- and alpha-blocking properties of labetalol. As an antianginal agent labetalol has proved to be at least as effective as selective or non-selective beta-blockers.

In a double-blind randomized study 40 patients received 1 mg flunitrazepam, 40 patients received 10 mg medazepam, and 40 patients received placebo p.o. the night before surgery. On the morning of surgery each patient received another identical oral dose of the product or placebo taken the previous night. On the average, the flunitrazepam group slept better, was better sedated, and was less anxious than the medazepam or placebo groups. Similarly, as a reflection of diminished autonomic reactions, the patients receiving flunitrazepam had fewer cardiovascular changes. Flunitrazepam significantly decreased the amounts of thiopentone needed for induction of anesthesia. Medazepam did not. The pronounced sedative, sleep-inducing, and anxiolytic effects of flunitrazepam appear to be of great clinical importance for its use in anesthesiology. Repeated administrations of medazepam seem to be required to produce an evident clinical effect of the drug, possibly via the slow accumulation of metabolites. The main difference between these two benzodiazepine derivatives as regards clinical response therefore seems to be pharmacokinetic in origin.

In healthy volunteers plasma antidiuretic hormone level, renin activity, and human growth hormone level remained unchanged during successive CPPV, CPAP, and control periods. The plasma level of insulin C-peptide was higher during CPPV than during the control period. Urine flow, glomerular filtration rate, free water clearance, and sodium excretion rate were lower during CPPV than during the successive CPAP and control periods. The renal function changes during CPPV may be a consequence of diminished cardiac output.

The hemodynamic effects of intravenous injection of 1 mg/kg of labetalol were measured in eight healthy volunteers, using impedance cardiography and systolic time intervals. The mean systolic blood pressure was reduced by 10% (p less than 0.01) and diastolic by 6% (p less than 0.05) 30 min after the injection, and they had returned to pre-drug level 2 h after administration. Heart rate declined consistently throughout the observation period. Cardiac index was reduced by 16% (p less than 0.05), but the changes in stroke volume (- 6%) and peripheral resistance (+ 23%) were not statistically significant. Left ventricular ejection time index increased by 2% (p less than 0.05), and nonsignificant changes were found for pre-ejection period index (- 3%), total electromechanical time index (+ 1%), and PEP/LVET ratio (+ 5%). In healthy subjects resting supine the intravenous dose of 1 mg/kg of labetalol had predominantly beta-blocking effects.

The clinical pharmacokinetics of ergotamine, dihydroergotamine, ergotoxine, bromocriptine, methysergide, and lergotrile are reviewed. Generally the new radioimmunoassay methods have partially resolved the problems involved in determining some of these ergot derivatives in biologic fluids after the low doses used clinically. However, our present knowledge of their pharmacokinetics is limited and much work remains to be done in this area. Many cases show a great difference between results produced with a radioactive drug and with radioimmunoassay. The longer half-lives measured by using a radioactive derivative are apparently due to the many metabolites of ergot alkaloids. However, we still do not know the clinical importance of these metabolites. For instance, the amount of dihydroergotamine reaching the systemic circulation remains below 1% (radioimmunoassay), but according to studies performed with a radioactive derivative the absorption quotient is about 30%. Further studies are needed to resolve the problem of an apparently high "first-pas" metabolism of this and other ergot alkaloids in the liver or gastrointestinal mucosa.

Dioxonium (30, 40, and 60 microgram/kg i.v.), a new depolarizing agent, weas compared with pancuronium (0.05 and 0.1 mg/kg i.v.) as a muscle relaxant in combination anesthesia during general surgical operations in small children. Generally, the conditions during intubation, maintenance of anesthesia, and in the recovery room were comparable after both drugs. There were no differences in the cardiovascular responses either. However, a wider intra- and interindividual variation in the drug response was observed after dioxonium, especially after repeated administrations.

Pharmacokinetic studies carried out on methylergometrine (methylergonovine) by a radioimmunoassay are reviewed. After intravenous injection the half-life of the distribution phase was only 1-3 min, explaining the fast and strong oxytocic response in puerperal mothers. The fast tissue uptake was also obtained in the rabbit uterus in situ with a steep dose-response curve. The rate of gastrointestinal absorption appeared to be slower in patients during puerperium (Tmax 3 h) in comparison with healthy male volunteers (Tmax 0.5 h). The bioavailability after administration was about 60%. After intramuscular injection the rate of absorption was rapid (Tmax 0.5 h). The short half-life of the elimination phase (about 0.5-2 h), low apparent volume of distribution (about that of extracellular water of the body), and the relatively high total plasma clearance value (about 120-240 ml/min) were direct evidence of the rapid elimination of the drug from the body. After repeated oral administrations no accumulation was found. Only about 3% of the single oral dose was excreted into urine, indicating hepatic metabolism and elimination. Although methylergometrine had a good penetration into breast milk in dogs, in postpartum women the mild concentrations were hardly measurable and clinically nonsignificant. Apparently there is no correlation between the plasma level and clinical effect of methylergometrine.

The effect of spinal anesthesia, dilatation and curettage plus the first intracavitary radiotherapy or only that of intracavitary radiotherapy on growth hormone (HGH = the response of anterior pituitary) and arginine vasopressin (AVP = the response of posterior pituitary) levels was studied in 10 patients suffering from cervical or endometrial uterine cancer. Differing from earlier animal studies, irradiation had no effect on GH or AVP secretion, nor was there any change in the hormone levels following spinal anesthesia and dilatation and curettage. The neurosecretory response of hypothalamic-hypophyseal axis to spinal anesthesia and minor gynecological surgery appears to be minimal.

The pharmacodynamics of midazolam was studied in 27 children undergoing elective surgery at five different dose levels (0.075-0.6 mg/kg) in attempting to find a suitable induction dose for general anesthesia. A comparison of the highest dose was made to thiopentone 5 mg/kg. Even an induction dose of 0.6 mg/kg of midazolam was found to be unreliable in children, but effective enough to cause significant fall in systolic blood pressure after induction (p less than 0.05). In the children premedicated with atropine and pethidine thiopentone resulted in a more rapid closure of the eyes (p less than 0.01) and disappearance of the eye-lid reflex (p less than 0.01) than the high dose of 0.6 mg/kg of midazolam. Moreover, midazolam failed to induce sleep in a considerable fraction of the children even at the highest dose employed. The thiopentone group was more alert in the recovery room at 30 min after wake-up. The amnestic effect of thiopentone and midazolam were equal.

Low dosage epidural morphine (4 mg) provided adequate postoperative pain relief in patients undergoing elective cesarean section under epidural analgesia. In the control group (n = 11), all but one patient needed opiates postoperatively, but 9 patients out of the 11 receiving epidural morphine needed only mild analgesics or no analgesics at all, postoperatively. Slight nausea and facial itching were the most common unwanted effects in the epidural morphine group. Low dosage epidural morphine is a useful tool in postoperative pain treatment following cesarean section.

The serum concentration of atropine was determined both by radioreceptor assay (RRA) and by radioimmunoassay (RIA) following a single 0.02 mg/kg i.v. injection of 7 girls (age 6-15 years) and 16 boys (age 4-15 years) at the beginning of a combination anesthesia. RIA appeared to be useful in the clinical kinetic studies of this alkaloid, but RRA determined the whole antimuscarinic activity produced by atropine plus glycopyrrolate when the latter agent was used as an anticurarizing component together with neostigmine at the end of anesthesia. A biexponential serum decay curve of atropine was demonstrated by RIA with a very rapid distribution phase (t1/2 = 1-2 min) and a quite high tissue distribution (mean Vd beta = 2.6 l/kg), but due to the effective clearance of the drug (mean Cl total = 0.310-0.384 l/kg/h) the mean elimination phase half-life was around 6.5 hours. No age or gender dependency was found in the pharmacokinetics of atropine.

The usefulness of radioreceptor assay (RRA) in the pharmacokinetic studies on midazolam - the first benzodiazepine with water-soluble salts - was compared with that of gas liquid chromatography (GLC) in 18 patients operated on under local anesthesia in supine position. There were no significant differences observed in the serum levels determined with these two methods after a single i.v. injection of midazolam 0.075 mg/kg although considerable variability was manifest. Similarly, the pharmacokinetic parameters did not differ from each other in view of the concentrations determined by RRA or GLC. The pharmacokinetics of midazolam were compared in three patient groups on the basis of the GLC determined concentrations: a) in pregnant patients operated on at term under epidural analgesia (group 1, n = 6), b) in nonpregnant women operated on under epidural analgesia (group 2, n = 6), and c) in 3 male and female subjects operated on under brachial plexus blockade (group 3). The total serum clearance, the most important pharmacokinetic parameter, was highest in group 1 patients and lowest in group 3. However, these significant differences were not reflected so clearly in the elimination half-life of midazolam. There were no differences in tissue distribution (Vd alpha, Vd beta) between the three patient groups. A highly significant correlation was observed between the serum concentrations and sedative effects of midazolam. Midazolam is a short-acting sedative-anxiolytic agent with a rapid onset of action especially useful for patients operated on under local anesthesia. Apparently, the pharmacokinetic differences observed in this study are of no great clinical significance in single dose administration.

Labetalol is a unique antihypertensive agent which is a competitive peripheral antagonist at both alpha- and beta-adrenoceptor sites. Clinically, it possesses about one fourth of the beta-adrenoceptor blocking activity of propranolol and one half of the alpha-adrenoceptor blocking activity of phentolamine with a beta- to alpha-blocking ratio of approximately 7:1. Nowadays, the clinical profile of labetalol is clearly defined. Perorally, it has often been used in the treatment of mild, moderate and severe hypertension and intravenously in the management of hypertensive emergencies. It offers many advantages over beta-blockers with no prominent side-effects. Hemodynamically, labetalol reduces blood pressure, heart rate and, first of all, peripheral resistance with almost no change in resting cardiac output or stroke volume. Labetalol appears to be useful particularly in patients whose blood pressure is not adequately controlled by beta-blockers alone or combined with a diuretic, but sometimes at the expense of postural hypotensive side-effects. It has proved to be safe in patients with coronary artery disease or after acute myocardial infarction and in pregnant patients, but in phaechromocytoma further clinical experience is needed. In induced hypotension during anesthesia and surgery no invasive blood pressure measurements are needed. The most frequent adverse effects include fatigue, postural hypotension, headache and gastrointestinal complaints. On the whole, labetalol expands the armamentarium of the practising physician in the treatment of hypertension of different origin.

Aminophylline (3 mg/kg i.v.) was injected in six patients with colicky pain caused by a ureter stone. In all but one this theophylline derivative caused a prompt and subjectively clear decrease in pain lasting from 30 min to 2 h. Serum levels over 12 microgram/ml were associated with good pain relief. A controlled study with an intravenous aminophylline infusion is warranted, because the pain-decreasing effect was too short-lasting after a single injection.

The oropharyngeal absorption of atropine was studied following 0.02, 0.04, 0.06 and 0.07 mg/kg doses of the drug to pregnant patients at term and compared with a 0.02 mg/kg dose given either intramuscularly or subcutaneously. The rate of systemic drug absorption was comparable following the two parenteral drug injections, but oropharyngeal atropine administration is of minor clinical significance.

The bioavailability and effect on the systolic and diastolic blood pressure, heart rate, salivary flow, skin temperature, and subjective sedation of three brands of clonidine were studied in nine healthy volunteers after a single 300-micrograms oral dose. In the gas chromatographically determined plasma concentrations there was no significant difference, nor was there any difference in the clinical effects studied. Highly significant correlations between the plasma concentrations and drug effects were found.

In order to test the possible differences in the clinical effects between benzodiazepines and barbiturates, 5 mg of diazepam and 60 mg of pentobarbital were used in a double-blind study as rectal premedication in 75 small children before major surgery. There were no significant differences between the two groups in the six parameters tested (demeanour in the anaesthetic room, preoperative emetic effect, response to venepuncture, degree of salivary suppression, postoperative state in the recovery room, postoperative emetic effect). The concentrations of pentobarbital and diazepam (and its 3 active metabolites) in the plasma were determined by gas chromatography and correlated with the clinical effects. No significant correlation was found between the total active benzodiazepine concentrations and the clinical effects of rectal diazepam. In contrast to diazepam, a weak but significantly positive correlation between the plasma concentrations of pentobarbital and the total score was found. Similarly, the plasma level of pentobarbital and the response to venepuncture and the degree of salivary secretion were in correlation with each other. In the plasma concentrations of both pentobarbital and total benzodiazepines, a wide interindividual variation was observed, indicating irregular rectal drug absorption.

The usefulness of labetalol, a combined alpha and beta adrenoceptor antagonist, as a moderate hypotensive agent during combination anaesthesia in otological operations was studied. These preliminary results show that an intravenous dose of 2.0 mg/kg of body weight of labetalol causes a moderate decrease in blood pressure without a concomitant increase in heart rate or excessive hypotension. The half-life of the elimination phase of labetalol in plasma varied between 3.9 and 6.3 hours. A direct relationship between the intravenous dose of the drug (0.5, 1.0 and 2.0 mg/kg i.v.) and the increase in the AUC value was observed. No correlation was found between the decrease in either the systolic or diastolic blood pressure and the plasma level of labetalol. This new type of antagonist may possess advantages over other current hypotensive drugs, i.e lack of tachycardia and excessive hypotension.

The clinical effects of flunitrazepam and lorazepam as oral premedicants were tested in a double-blind study in 81 gynaecological patients. Flunitrazepam showed a higher sedative effect (p < 0.05), but in regard to other parameters tested, no significant differences were found (sleep, apprehension, excitement, dizziness, emetic effect, headache, increase or decrease in systolic blood pressure, increase in pulse rate, venipuncture). In 9 per cent of the patients treated with lorazepam, a prominent muscular relaxation with slurred speech was observed, but in none of the cases treated with flunitrazepam. Our results support the earlier claims of flunitrazepam's relatively specific sedative property, but on the whole the difference in the clinical effects of these benzodiazepine derivatives is not marked.

Saccadic eye movements and the volunteers' subjective assessments were used in the determination of the residual effects of a single high evening dose of flunitrazepam 2 mg, midazolam 30 mg, and lorazepam 2.5 mg as well as in that of placebo. Sleep inducing and maintaining effects were subjectively assessed, too. Both flunitrazepam 2 mg, midazolam 30 mg, and lorazepam 2.5 mg possessed sleep inducing and increasing effects (n = 9), but in the number of nocturnal awakenings and quality of sleep no significant differences between placebo and the active medications were reported. Flunitrazepam 2 mg and lorazepam 2.5 mg produced distinct subjective residual effects thus differing from placebo and midazolam 30 mg. Despite this, saccadic eye movement recording could further differentiate midazolam 30 mg from placebo in this respect 10 hours after drug intake. After three repeated 2 mg evening doses, flunitrazepam accumulated in the serum of the volunteers (n = 6), but the effect on saccadic eye movements as well as subjective side effects began to decrease already after one day's treatment. Thus, saccadic eye movement recording proved to be a useful tool in determining the residual effects and development of tolerance of benzodiazepines. No correlation was detected between the serum levels (radioreceptor assay) and saccadic eye movement recordings or subjective residual sequelae.

By random allocation 41 patients received 1 mg flunitrazepam orally the night before operation and 1 mg on the morning of operation (group 1), and another 41 received 100 mg pentobarbital orally the night before operation, followed by intramuscular scopolamine (0.006 mg/kg) + morphine (0.02 mg/kg) on the morning of operation (group 2). All patients received 0.5 mg atropine intravenously just before the induction of anesthesia. The patients in group 2 were better sedated and had less salivary secretion than those in group 1, but otherwise both were comparable. In group 2 the induction requirements of thiopentone were significantly decreased in comparison with group 1, again indicating a more potent sedative effect. Because even in the total scoring of the results there was no significant difference between the two groups, the easy oral route of administration of flunitrazepam offers a clinically relevant alternative to the conventional premedication. In some of these E.N.T. patients who received flunitrazepam, intravenous atropine given just before the induction of anesthesia was unable to prevent salivary secretion. Oral benzodiazepine derivatives (flunitrazepam) appear to be useful before surgery as the old type of premedication (oral pentobarbital + i.m. scopolamine and morphine).

Several new factors have recently been shown to influence the pharmacokinetics of atropine. Age appears to have a clear effect on the elimination of atropine: for example, prolonged elimination has been found in children under 2 years of age and in the elderly. The higher sensitivity of these patients to the effects of atropine can be explained, at least partly, by this phenomenon. Due to the fast placental transfer of atropine, i.v. administration before cesarean section can have strong effects on the newborn. Most important, however, it decreases the barrier pressure of the lower cardioesophageal sphincter (pulmonary aspiration). Thus, routine atropine premedication is contraindicated before cesarean section. On the other hand, children appear to need a routine anticholinergic premedicant. Without it profuse salivary secretion may interfere with anesthesia. The use of atropine in premedication of healthy adult patients is controversial. Because peroral premedication (benzodiazepines) is nowadays increasing in the adult patient, especially in the elderly, routine use of atropine should be avoided.

We measured plasma arginine vasopressin (AVP), plasma renin activity (PRA), human growth hormone (HGH), immunoreactive insulin (IRI), and blood glucose in 25 gynecologic inpatients. Six were undergoing dilatation and curettage (Group 1), nine were undergoing hysterectomy (Myomata uteri) and receiving acetated Ringer's lactate without glucose (Group 2), and ten were undergoing hysterectomy and receiving acetated Ringer's lactate in 5% glucose (Group 3). The measurements were made the night before the operation, during the operation, and postoperatively. Plasma AVP did not change significantly in Group 1, but it increased in both Groups 2 and 3. PRA showed no significant changes in any group studied. HGH decreased slightly at the end of the operation in Groups 1 and 2, but it increased significantly in Group 3 in the recovery room 1 h after surgery. Blood glucose and insulin remained at normal levels in Groups 1 and 2, but they increased significantly in Group 3. We believe that stress was caused more by greater surgical trauma than by the depth of anesthesia and anesthetic agents in Groups 2 and 3, when compared to Group 1; this is a possible mechanism of the increased AVP secretion. Acetated Ringer's lactate without glucose appeared to cause a more physiologic response during gynecologic surgery than did acetated Ringer's lactate in 5% glucose.

One ampule of Palerol and one of Litalgin (combination preparations with vagolytic, smooth-muscle relaxing, and analgesic effects) were injected intravenously in a double-blind study in random order to 19 patients having a routine oral cholecystography. Palerol had a significant dilatation effect on the smooth muscle of the contracted gallbladder, but Litalgin only prevented further contraction caused by fatty meals. Side effects were minimal. Palerol seems to be useful in acute gallstone attacks.

Salbutamol increased significantly the bronchodilating effect of proxyphylline both in experimental animals and in asthmatic patients. In guinea pigs (modified Konzett-Rössler method) the reduction in response to metacholine caused by increasing doses of proxyphylline and salbutamol significantly exceeded that of either drug alone. In a double-blind, randomized cross-over study conducted on 3 consecutive days, asthmatic patients received 500 mg proxyphylline orally three times daily. On the 2nd or 3rd day a significantly greater improvement in the peak expiratory flow was found after the combination of proxyphylline and salbutamol (3 mg p.o.) in comparison with proxyphylline and placebo. Salbutamol had no significant effect on the plasma concentrations of proxyphylline, which varied between 14 and 22 microgram/ml. The combination of oral proxyphylline and salbutamol is clinically useful in increasing drug response without increased adverse effects.

The pharmacokinetics of labetalol, a combined alpha- and beta-receptor blocking agent, were studied in eight healthy volunteers. After intravenous injections (n = 4) of 1.5 mg/kg, the drug was rapidly distributed (mean T 1/2 = 4.9 min) and quite rapidly eliminated (mean T 1/2 = 4.9 hrs). The mean total plasma clearance value was 24.80 ml/min/kg. The values for Vdc (mean 1.1 l/kg) and Vdss (mean 9.41 l/kg) indicate extensive extravascular distribution of labetalol. The systemic availability was about 18%. There was a significant correlation between the calculated drug concentrations in the hypothetical compartment 2 and the percentage decreases in blood pressure after the intravenous injection. After a single 200 mg oral dose (solution, non-coated and coated tablets), the tablet formulation had no significant effect on the gastrointestinal absorption. After repeated oral doses of 200 mg twice daily (n = 4), no accumulation in plasma was observed.

Flunitrazepam (0.015 mg/kg) was injected i.v. into 20 patients, ages 19-79 years, as a sedative agent prior to epidural anesthesia. The concentrations of unchanged flunitrazepam in sea were determined by 63Ni-EC-GLC, and the pharmacokinetic parameters were calculated using the two-compartment open model. Age as such had no effect on the kinetics of flunitrazepam, but its sedative effect was clearly increased in the group over 60. No correlation between the serum level or elimination half-life and sedation was found. Generally, flunitrazepam's strong and rapid sedative effect renders it a useful adjuvant in connection with epidural anesthesia.

The pharmacokinetics and their relation to the pharmacodynamic properties of midazolam, the first water-soluble benzodiazepine derivative, are reviewed. Pharmacokinetically, midazolam is a unique derivative among the benzodiazepines. After both oral and parenteral routes of administration, it has a fast absorption rate, and differing from older derivatives it is very rapidly excreted with a half-life of only about 2 h. A reasonably good correlation has been found with the plasma levels and clinical effects, indicating a fast but short clinical response. Midazolam appears to be a useful short-acting hypnotic having almost no residual effects the following morning. In anesthesiology both oral and parenteral drug forms can be used for premedication. In addition, it is a new alternative for inducing anesthesia when a slow induction time is chosen or its advantageous properties: good cardiovascular stability, transient and mild respiratory depression, low frequency of venous irritation, production of anterograde amnesia, and short duration of action (last-mentioned property in comparison with other benzodiazepines).

Lidocaine dosage recommendations vary widely. Severe heart failure adds to risk factors when attempting to reach the optimal therapeutic blood level. Fifty-two coronary care unit (CCU) patients, who were treated with lidocaine infusion after an initial bolus injection of 100 mg, were randomly selected for the study. Blood samples were drawn at 2, 6 and 18 h. The material was divided into four groups according to infusion rates: Group A (n = 15) 4 mg/min for 3 h and then 3 mg/min for 15 h, Group B (n = 10) 4 mg/min for 3 h and then 2 mg/min for 15 h, Group C (n = 9) 2 mg/min for 18 h and Group D (n = 18) according to clinical situation by a mean rate of 3.3 mg/min for 2 h, 2.5 mg/min for 4 h and 2.15 mg/min for 12 h. The mean serum lidocaine concentrations were in optimum therapeutic range of 2-4 mg/l in Groups A, B and D at every sampling time point. Percentage of the patients whose lidocaine concentrations at each sampling time were within the optimum range as follows: Group A 72, 67 and 52, Group B 70, 70 and 56%, Group C 0, 38 and 63% and Group D 38, 38 and 30%. Our material indicates that the optimal lidocaine infusion rate for CCU patients should be as in Group B.

The pharmacokinetics of disopyramide and its metabolite mono-N-dealkyl-disopyramide (MND) were studied after a single oral and intramuscular dose and at steady state in healthy volunteers, after an intravenous dose in post-surgery patients, and after a single oral dose in two patients with renal insufficiency. After an oral dose in healthy volunteers the plasma elimination half-life of total disopyramide was 8.65 +/- 1.37 h, and that of the non protein-bound disopyramide, 4.74 +/- 1.20 h. The protein binding of disopyramide varied from 0.58 to nearly 1.0, and was concentration dependent. All subjects had detectable amounts of MND in plasma. Its elimination half-life was 12.9 +/- 6.43 h. The ratio of MND to disopyramide was 0.23 +/- 0.09 in plasma and 0.46 +/- 0.11 in urine. There was a close correlation (r = 0.868) between the renal clearances of free disopyramide and creatinine. The renal clearances of disopyramide (both free and total), MND, and creatinine varied with time; this resembled variation in the urine flow. The kinetics of one dose at steady state did not differ markedly from that of a single dose. The elimination half-lives of total disopyramide varied from 4.4 to 17.1 in post-surgery patients, and those of the renal patients were 10.6 and 8.7 h.

Flunitrazepam was given as an induction agent i.v. to 12 patients undergoing otologic operations. Pharmacokinetics were evaluated from serum samples at 5 min-72 h by 63Ni-EC-GLC. Pharmacodynamic characteristics were estimated subjectively by simple questionnaire and objectively by the anesthetist during and after anesthesia. The dose of flunitrazepam required for anesthesia varied from 14 to 33 (mean 21) micrograms/kg and was not related to age. The mean distribution volumes of flunitrazepam, calculated by the three-compartment open model, were Vd1 0.61 (SD = 0.36) l/kg, Vd2 1.4 (SD = 0.70) l/kg, and Vd3 3.6 (SD = 1.39) l/kg. The mean elimination half-life was 25 h and serum clearance was 94 ml/min. The maximum decreases in blood pressure during anesthesia correlated with the age of the patients. The general assessment of the anesthetist about this form of anesthesia was positive in 75% of the 12 cases. A clear anterograde amnesia was found.

Propofol is a rapidly acting intravenous anesthetic agent which has many advantageous kinetic properties explaining its usefulness by bolus dose for induction of anesthesia or for administration by continuous intravenous infusion. It is rapidly distributed in the body with a half-life of only around 2 min and has an efficient hepatic and extrahepatic clearance (total body clearance may exceed liver blood flow). Premedication has little effect on the already good induction characteristics of propofol. The incidence of cardiorespiratory depression appears to be higher than that of other induction agents, but, on the other hand, the absence of tachycardiac response prevents the increase in cardiac oxygen demands. In patients with cardiac disease, especially after high or repeated doses, propofol may be more depressant to the cardiovascular system than thiopentone resulting in imbalance of regional myocardial oxygen demand and supply. Recovery from propofol is rapid and clear-headed with almost no hangover effect. This makes it very suitable for out-patient anesthesia and for cardioversion. However, even with the new emulsion formulation of the drug, pain on injection is still a problem. With regard to a longer lasting combination anesthesia propofol remains an alternative to older induction agents. When given as a continuous intravenous infusion for total intravenous anesthesia or for sedation in intensive care unit propofol has shown little accumulation. Its clinical effects are predictable, consistent and recovery is rapid, independent of the dose given. Propofol has proved to be a useful induction agent regardless of the age of patients, but in the elderly there appears to exist a marked sensitivity to it. Up to now there is no evidence that propofol in emulsion drug form can produce allergic or anaphylactoid reaction more often than other induction agents in use and no severe hematological nor visceral toxicity have been reported. In the present situation, when althesin is not marketed any more due to a high frequency of anaphylactoid reactions and etomidate will have a limited use in clinical practice because of its blocking effect on adrenocortical function, propofol offers an important alternative anesthetic agent to thiopentone.

In a single-blind randomized study 47 patients received 100 mg tofizopam orally as a premedication before minor surgery, 50 patients received placebo, an 50 patients no premedication. Both tofizopam and placebo significantly increased the subjective sedative effect of the patients, but there was no significant difference in any of the measured parameters between tofizopam and placebo. In another double-blind randomized study, 49 patients received 100 mg tofizopam three times orally before gynecologic operations and 49 patients received placebo. Compared with placebo, tofizopam had a stimulant action and decreased the excitement of the patients. The effect of tofizopam on apprehension + excitement was significantly better than that of placebo. According to these results, the active component seems to be an unknown metabolite of tofizopam causing a clear drug effect only after repeated oral doses of the parent drug. A slow accumulation in the central nervous system is also possible. In the drug response a wide interindividual variation was found.

The clinical effects of flunitrazepam and oxazepam as oral premedicants were tested in a double-blind study of 69 otorhinolaryngologic patients. Flunitrazepam had a somewhat higher sedative effect (p less than 0.10) and moderated the increase in systolic blood pressure significantly (p less than 0.005) more than did oxazepam, but as regards the other parameters tested no significant differences were found (sleep, apprehension, excitement, dizziness, emetic effect, headache, increase in heart rate, venepuncture). In some patients a profuse salivary secretion was observed despite intravenous injection of atropine just before the induction of anesthesia. Our results support earlier claims of flunitrazepam's relatively strong sedative and anxiolytic properties, but on the whole the difference in clinical effects of these benzodiazepine derivatives was not marked.

The use of epidural and intrathecal opiates in obstetrics is reviewed. Opiate receptors in the substantia gelatinosa of the spinal cord appear to be the main site of drug action after both epidural and intrathecal modes of drug administration. However, an additional systemic effect for this selective spinal analgesia cannot be excluded, especially after epidural drug administration. Contrary to that of general surgery patients, the response of pregnant women at term to epidural opiates is unpredictable. The action of the opiates is of short duration. There are at least three anatomical reasons for this phenomenon: an extensive epidural venous blood flow during pregnancy, visceral fibers (uterine contraction pain) located deeper in the substantia gelatinosa than somatic fibers (skin and peritoneal pain), and A delta fibers (uterine pain) which bypass opiate receptors in the substantia gelatinosa. After intrathecal injection of opiates, there was a strong analgesic action during delivery, but an unacceptable amount of side effects prevents their routine use. In post-cesarean patients, epidurally administered opiates are quite effective analgesics, but they still have one serious unwanted effect: respiratory depression of delayed onset. Thus, in routine obstetric practice, epidural or intrathecal opiates play only a limited role.

The effects of drugs with different mechanisms of action on the human gallbladder smooth muscle are reviewed. Sincalide, the C-terminal octapeptide fragment of cholecystokinin, caused a clinically important contraction of the gallbladder during oral cholecystography in 72% of the patients. Within 8-12 min cystic duct visualization occurred in 44% and common bile duct visualization, in 17%. On the other hand, the standard concentration meal (200 ml cream) caused a more reliable gallbladder contraction in 30 min. One tablet of Baralgin, i.v. proxyphylline (300 mg), and i.v. glycopyrrolate (0.2 mg) had no relaxing effect on the contracted gallbladder during oral cholecystography. Similarly, i.v. metoclopramide (20 mg) and i.v. prostaglandin E2 (25, 50, and 75 micrograms) were ineffective, whereas 1 ampule of Baralgin and 1 ampule of Palerol i.v. caused a significant dilatation. Litalgin i.v. 1 ampule, i.v. papaverine (40 mg), and sublingual nitroglycerin (0.5 mg) had a slight relaxing effect on the smooth muscle of the gallbladder. In an acute attack of pain in a patient with gallstones, i.v. administered Baralgin and Palerol seem to be effective; i.v. Litalgin, i.v. papaverine, and sublingual nitroglycerin may be of value in milder biliary tract disorders, but the benefit of i.v. proxyphylline, i.v. glycopyrrolate, and oral Baralgin is questionable. Metoclopramide can be used as an antiemetic drug in patients with gallstones.

Isosorbide-5-mononitrate is a longer acting active metabolite than the parent drug, isosorbide dinitrate (ISDN), with a half-life of around 4 hours. In coronary heart disease, myocardial infarction and in heart failure it causes a typical nitrate action on the central hemodynamics, but due to a complete systemic availability with high and predictable systemic drug levels, a drug action with a lower interindividual variability than with ISDN is to be expected. There is a close correlation between serum level and effect. The antianginal exercise tolerance increasing and unwanted effects as well as the development of tolerance to the drug action are comparable with those of ISDN. This naturally long-acting metabolite in ISDN works usually with a standard dosage of 20 mg twice daily.