Simultaneous determination of pancuronium, vecuronium and their related compounds using LC-ESI-MS.

A simultaneous determination method of quaternary amino steroidal muscle relaxants, pancuronium (PAN), vecuronium (VEC), and 17-monodesacetyl pancuronium (17-OH-PAN), 3,17-bisdesacetyl pancuronium (3,17-OH-PAN), 3-monodesacetyl vecuronium (3-OH-VEC), 3,17-bisdesacetyl vecuronium (3,17-OH-VEC) in human serum was developed using liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS). The weak cation exchange cartridge was useful for the extraction of these compounds. Under optimized LC-ESI-MS conditions, these compounds were almost fully separated within 6.5 min. Linear responses over the concentration range 0.25-50.0 ng/mL were demonstrated for each compound. The developed method successfully detected VEC, 3-OH-VEC and 3,17-OH-VEC in serum intravenously administered with VEC. The level of 3-OH-VEC was higher than other compounds. This suggested that 3-OH-VEC was useful as a forensic probe in VEC administration.

Vecuronium kinetics and dynamics in anesthetized infants and children.

Vecuronium kinetics and dynamics were determined in five infants (3 to 11 months old) and five children (1 to 5 years old) during anesthesia with 70% nitrous oxide and 0.9 MAC halothane. Vecuronium was infused intravenously at a rate of 2.5 micrograms/kg/min while twitch tension of the adductor pollicis muscle was recorded and venous blood samples were drawn for determination of vecuronium concentrations by mass spectrometry. The elimination t1/2 was determined by linear regression of the log postdistribution concentration-time data; these values and noncompartmental techniques were used to calculate total plasma clearance (Cl), volume of distribution at steady state (Vdss), and mean residence time. The steady-state plasma concentration resulting in 50% depression of twitch tension (Cpss50) was determined by an effect compartment and a sigmoid concentration vs. paralysis model. Vdss was larger in infants (357 +/- 70 ml/kg; mean +/- SD) than in children (204 +/- 116 ml/kg), and Cl was of the same order for infants and children (5.6 +/- 1.0 and 5.9 +/- 2.4 ml/kg/min). Mean residence time was longer in infants (66.3 +/- 22.9 minutes) than in children (34.3 +/- 8.0 minutes). Cpss50 was lower in infants (57 +/- 18 ng/ml) than in children (110 +/- 28 ng/ml). The quantity of vecuronium in the body at steady state at 50% depression of twitch tension (Vdss X Cpss50) was similar in infants and children (21.2 +/- 9.9 and 19.0 +/- 3.3 micrograms/kg). During comparable nitrous oxide-halothane anesthesia, age-related changes in Vdss, Cl, and Cpss50 were much like those found for d-tubocurarine.(ABSTRACT TRUNCATED AT 250 WORDS)

A new method for studying the relationship between hepatic uptake of drugs and their pharmacodynamic effects in anaesthetized cats.

1 A new in vivo experimental method is described whereby the liver can be temporarily excluded from the general circulation by means of a portocaval shunt operation. The influence of this manoeuvre upon the effects of pancuronium and Org 6368 was investigated using the tibialis muscle preparation of anaesthetized cats. 2 The procedure also allowed intraportal injections of the drugs to be made so that the effect of first-passage uptake by the liver could be compared with hapatic exclusion in the same animal. 3 Hepatic exclusion greatly increased the duration of action of both drugs. Whereas intraportal injection did not significantly alter the effect of pancuronium on the tibialis muscle, the effect of Org 6368 was greatly diminished when given by this route. 4 The liver appears to tolerate short periods of hepatic exclusion and it is concluded that this technique may become a useful tool for studying the handling of drugs by this organ.

A comparison of the effects of pancuronium bromide and its monoquaternary analogue, ORG NC 45, on autonomic and somatic neurotransmission in the rat.

1 Potentiation by pancuronium of the effects of adrenergic nerve stimulation, previously shown in cardiovascular tissues, was also found in rat anococcygeus and vas deferens, in vitro or in vivo. 2 In the pithed rat, in the presence of pancuronium, pre-junctional alpha-adrenoceptor-mediated feedback inhibition of cardiac sympathetic transmission was uncovered at relatively low stimulation frequencies by phentolamine or yohimbine. 3 The effects of pancuronium and its mono-quaternary analogue Org NC 45 on autonomic and somatic neuromuscular transmission were compared, in the pithed rat. Org NC 45 was less potent than pancuronium at blocking somatic neuromuscular transmission by a factor of 2.1, at blocking cardiac, parasympathetic transmission by a factor of 538 and at potentiating sympathetic transmission by a factor of 33.

A novel class of antitumour agents. I. Chemistry and animal experiments.

Newly synthesized tertiary amino steroids, among them 2 beta,16 beta-dipiperidino-5 alpha-androstane-3 alpha,17 beta-diol dipivalate (DAP), were tested in three animal species as to their antitumour activity against transplantable tumours. The acute toxicity of DAP was similar to that of cyclophosphamide and considerably lower than vinblastine. Rats with Walker ascites, treated intraperitoneally with DAP, survived up to one year without ascites; untreated animals died within 10 days of transplantation. Intragastric and intraperitoneal application of DAP caused side effects suggesting a local toxicity.

A novel class of antitumour agents. II. In vitro testing.

Suspensions of Walker and HeLa cells, rat fibroblasts and human stimulated lymphocytes were incubated over various periods with the synthetic amino steroid, 2 beta,16 beta-dipiperidino-5 alpha-androstane-3 alpha,17 beta-diol dipivalate (DAP). The acute cell destroying effect was found to be exponentially time and dose dependent within a certain range. With lower nontoxic doses, decreases in the mitotic and labelling indices were observed, and clotted mitotic figures occurred. The effects were essentially the same for all experimental cell types; chromosome alterations were not seen.

A novel class of antitumour agents. III. Morphological findings in treated cells.

The findings of intracellular light-reflecting droplets and clotted mitoses after incubation of Walker and HeLa cells, human lymphocytes and rat fibroblasts with the synthetic amino steroid, 2beta, 16beta-dipiperidino-5alpha-androstane-3-alpha,17beta-diol dipivalate (DAP) were examined in detail. An interaction of DAP with the cellular membranes in all stages of cell life, with the exception of the Go-phase, is postulated.

Hepatic transport mechanisms for bivalent organic cations. Subcellular distribution and hepato-biliary concentration gradients of some steroidal muscle relaxants.

In order to characterize the hepato-biliary transport of bivalent cations in more detail, the subcellular distribution of three steroidal muscle relaxants, that differ physicochemically and kinetically, was studied by differential centrifugation of liver homogenates. Binding of the muscle relaxants to macromolecular compounds was measured in Krebs-albumin solution, in cytosolic fraction of liver homogenate and in bile, to estimate the unbound concentrations in the particular fluids. Cytosol/plasma concentration ratios increased in the order pancuronium less than Org 6368 less than vecuronium, but for all of the compounds did not exceed the value that would be attained by passive equilibration according to the membrane potential. The subcellular distribution patterns of the three substances indicated that the mitochondrial fraction is a major storage compartment in the liver. Yet Org 6368 was bound to the particulate fraction of liver homogenate to a larger extent than pancuronium and vecuronium. The high bile/cytosol concentration ratios indicate that for all of these cations an active transport system is involved in the biliary excretion process. For Org 6368 and vecuronium the bile/cytosol concentration ratios are in the same range (about 30) and substantially higher than for pancuronium (about 6). This suggests that for Org 6368 and vecuronium the transport across the canalicular membrane is more efficient than for pancuronium. The combined data indicate that the extensive binding of Org 6368 to particles within the cell is a major factor in the relative efficient hepatic uptake and the modest biliary excretion of this agent. The limited hepato-biliary transport of pancuronium appears to be due to a relatively small net transport, both at the sinusoidal land at the canalicular membrane.

Pharmacokinetics of steroidal muscle relaxants in isolated perfused rat liver.

Both in humans and animals hepatic elimination is an important factor determining the duration of action of non-depolarizing neuromuscular blocking drugs. To elucidate the hepato-biliary disposition of muscle relaxants the pharmacokinetics of several structurally related but physicochemically distinct steroidal neuromuscular blocking drugs were studied in isolated perfused rat livers. Pharmacokinetics analysis with the DIFFIT computer program enabled the simultaneous fitting of independently measured perfusate disappearance and biliary excretion rate curves using a numerical approach. The hepatic disposition of the steroidal muscle relaxants could be adequately described by a three compartment model with elimination from the peripheral compartment V2 (biliary excretion) and storage in a deep compartment (V3) connected to V2. In addition, for vecuronium only slow ester hydrolysis occurring in V2 and V3 was included in the model. The lipophilicity rather than the relative mobility of the muscle relaxants showed a positive relationship with biliary clearance (Cl20) and the initial hepatic uptake (Cl12), indicating that hepato-biliary transport of these organic cations is highly dependent on the hydrophobic character of the compounds. In addition, net hepatic uptake of the steroidal cations was influenced markedly by transport from the liver to perfusate (hepatic efflux). This hepatic efflux (k21) decreased with increasing lipophilicity. In contrast, the extent of intracellular sequestration into deep compartments, indicated by high k23/k32 ratios, seemed to be inversely related to the lipophilicity of the muscle relaxants and might explain the observed prolonged hepatic storage of some of these compounds. In combination with data from subfractionation studies the results indicate that the pharmacokinetic analysis of the hepatic disposition of steroidal muscle relaxants may be used to evaluate actual transport phenomena participating in the hepatic disposition of these drugs.

Inhibition of the plasma cholinesterase variants by pancuronium bromide and some of its analogues.

Pancuronium bromide, a 3,17-diacetoxy-5 alpha-androstane, and three of its analogues, the 17-desoxy, the 3,17-dibutyryloxy and the 16-N-monoquaternary ammonium derivatives have been used as inhibitors of the usual and atypical plasma cholinesterase variants. In all cases the usual enzyme is more sensitive to inhibition by the substituted steroids than the dibucaine resistant enzyme. The relative affinities of the bis-quaternary ammonium compounds for either enzyme is in the order dibutyryloxy derivative > 17-desoxy derivative greater than or equal to pancuronium bromide. The monoquaternary compound has the least affinity of all the inhibitors for the usual enzyme but the greater affinity for the atypical enzyme. These observations show that the bis-quaternary compounds are very powerful differentiators of the variants. The monoquaternary derivative shows less differential inhibition, but provides additional evidence that the usual and dibucaine resistant variants differ in structure at or near their esteratic active site.

Vecuronium: a new nondepolarizing neuromuscular-blocking agent. Clinical pharmacology, pharmacokinetics, cardiovascular effects and use in special clinical situations.

Vecuronium provides additional flexibility to the clinician using neuromuscular-blocking drugs. Its shorter duration of action, lack of significant cardiovascular effects and lack of dependence on the kidney for elimination provide clinical advantages over, or alternatives to, currently available, nondepolarizing neuromuscular-blocking drugs.

Clinical comparison of two low-dose oral contraceptives, Minulet and Mercilon, in women over 30 years of age.

A comparative study of two low-dose oral contraceptives, gestodene (GES) 75 mcg/ethinyl oestradiol (EE) 30 mcg and desogestrel (DES) 150 mcg/EE 20 mcg, was conducted in women over 30 years of age. This randomised, open-label study was organised in Denmark, Italy, New Zealand and United Kingdom. A total of 505 women received GES/EE and 501 received DES/EE for 6 consecutive menstrual cycles. The two groups were comparable in terms of demographic and gynaecologic characteristics at baseline. However, the menstrual flow length was slightly longer in the GES/EE group before the start of the treatment. The mean age (+/- SD) was 35 +/- 4 years in the GES/EE group and 35 +/- 5 years in the DES/EE group. The subjects in the GES/EE group contributed data for a total of 2800 cycles and those in the DES/EE group, data for 2796 cycles. There were no pregnancies on medication with either preparation. The results showed that there were significantly more normal cycles in the GES/EE group for cycles 1 to 6. Irregular bleeding between withdrawal bleeds occurred in 10% of GES/EE and 18.5% of DES/EE cycles. Absence of all bleeding was reported in 29 (1%) and 63 (2%) cycles, respectively. The incidence of missed pills was low in both groups (11% of cycles). No significant differences were observed in cycle length or withdrawal bleeding episode length. Withdrawal bleeding mean intensity was statistically significantly greater with GES/EE. However, for both preparations, the mean intensity was close to light bleeding. No clinically significant differences were noted in weight, blood pressure, Papanicolaou smears or laboratory data. Sixty-eight (13.5%) subjects in the GES/EE group and 64 (12.8%) in the DES/EE group discontinued before the end of the study. Among them, 37 (7%) and 40 (8%) in the respective groups withdrew because of adverse reactions. There was no difference between groups in terms of primary reasons for withdrawal. The most frequently reported complaints that led to discontinuation in both groups were headache, nausea and metrorrhagia. Breast tenderness led to the discontinuation of 1 subject in the GES/EE group and 3 in the DES/EE group. These results show excellent cycle control, efficacy and very low rate of side effects with both GES/EE and DES/EE. These low-dose oral contraceptives could be well suited to healthy nonsmoking women requiring contraception up to the age of menopause.

PIP: At 66 sites in Denmark, Italy, New Zealand, and the UK, clinicians randomly allocated 1006 women 30 years old, some of whom were in their early 50s, into 1 of 2 groups receiving a low-dose oral contraceptive (OC): Minulet containing 75 mcg gestodene (GES)/30 mcg ethinyl estradiol (EE) and Mercilon containing 150 mcg desogestrel (DES)/20 mcg EE. The study aimed to compare these 2 low-dose OCs to help physicians prescribe an OC that could be continued into later years. Before treatment, the 2 groups had similar demographic and gynecologic characteristics. The mean menstrual flow length in the GES/EE group was longer than that of the DES/EE group (4.7 days vs. 4.5 days; p = .035) though. None of the women during 2800 cycles of GES/EE use and 2796 cycles of DES/EE use conceived, even though women forgot to take at least 1 pill in 11% of cycles. The GES/EE OC had significantly better cycle control than did the DES/EE OC. For example, the GES/EE group was more likely to have normal cycles than the DES/EE group (84-93% vs. 73-83%; p .001). The DES/EE group experienced a significantly lower withdrawal bleeding mean intensity than the GES/EE group in all 6 cycles, but the bleeding for both groups was close to light bleeding. The 2 groups were similar in weight, blood pressure, Papanicolaou smears, and laboratory data. Discontinuation rates for the GES/EE and DES/EE groups were 13.5% and 12.8%, respectively. Adverse reactions accounted for discontinuation in 7% of the GES/EE group and 8% of the DES/EE group. The major complaints leading to discontinuation were headache, nausea, and breakthrough bleeding. Both GES/EE and DES/EE had very good cycle control and efficacy and a very low rate of side effects. These results suggest that both these low-dose OCs would be acceptable for healthy nonsmoking women needing contraception up to menopause.

Sister-chromatid exchanges in newborns after normal and progesterone-treated pregnancies.

Two groups of newborns were selected for SCE analyses, one consisting of infants born after progesterone-treatment during pregnancy (PTP) and a control group. A slight, but statistically significant difference in the number of SCEs was found: in the control group 5.55 +/- 0.62, and in the PTP group 7.99 +/- 0.88. This effect also proved to be true in an in vitro system, where various concentrations of progesterone were tested. The authors offer two possible explanations: one involving the biochemical pathways of progesterone and the influence on the level of excretory products; the other involving a direct relationship between progesterone and DNA.

A cross-over study of three oral contraceptives containing ethinyloestradiol and either desogestrel or levonorgestrel.

A randomised cross-over trial was performed to compare the pharmacodynamic actions of three low-dose oral contraceptives (OCs): Marvelon (150 micrograms desogestrel (DSG)+ 30 micrograms ethinyloestradiol (EE)), Mercilon (150 micrograms DSG + 20 micrograms EE) and Microgynon (150 micrograms levonorgestrel (LNG) + 30 micrograms EE). None of the OCs produced any significant changes in serum cholesterol, LDL-C and apoprotein B. Triglycerides were increased by the desogestrel OCs but not by Microgynon. The latter however increased the glucose and insulin responses to a glucose tolerance test whereas Marvelon and Mercilon had no effect. HDL-C increased with Marvelon, was unchanged with Mercilon and was decreased with Microgynon. Apoprotein AII was increased by all three OCs but only the DSG OCs increased apoprotein AI. All OCs produced similar increases in caeruloplasmin but the increase in SHBG was much greater with Marvelon and Mercilon than with Microgynon. Testosterone was reduced more with Microgynon than with the DSG OCs. Many of the changes reflect the strong anti-oestrogenic action of LNG on metabolic parameters compared to DSG. Except for the effect on HDL-C, there was little difference between Marvelon and Mercilon on metabolic parameters and this complements the findings from large-scale clinical trials of the two OCs. Mercilon, therefore provides a very satisfactory alternative to Marvelon.

PIP: 12 healthy volunteers attending the family planning clinic at Shanghai, First Maternity and Infant China, Hospital, enrolled in the study, Oral contraceptives (OCs) were prescribed: Marvelon (150 mcg of desogestrel--DSG), Mercilon (150 mcg of DSG), and Microgynon (150 mcg of levonorgestrel--LNG). The patients were divided into 6 groups of 2 persons each in a randomized cross-over study. OCs were taken on day 6 of the cycle up to day 21, then stopping for 7 days. Each OC was used for 3 months. During the pretreatment cycle between days 6 and 9 of the follicular phase and 21 and 22 of the luteal phase a blood sample was taken after fasting for determination of lipids, sex hormone binding globulin (SHGB), ceruloplasmin, and testosterone. After glucose loading, significant increases of glucose and insulin occurred at 1, 2, and 3 hours during treatment with Microgynon only. The ratio for total areas of insulin to glucose did not change significantly nor did glycosilated hemoglobin A1 levels. Serum triglyceride concentrations increased significantly for both Marvelon (27%-43%) and Mercilon (29-40%). Serum high density lipoprotein (HDL) cholesterol concentrations were significantly elevated with Marvelon but less so with Mercilon, while HDL-C decreased significantly with Microgynon. The serum low density lipoprotein (LDL) cholesterol changes were not significant, but LDL-C concentrations declined with DSG formulations and increased with Microgynon. Apoprotein A1 and A2 increased significantly for both Marvelon and Mercilon. Apoprotein A2 increased with Microgynon. Serum SHBG increased markedly with Marvelon (335-380%). Serum testosterone concentrations decreased significantly (33.2-40.4% with Microgynon) and so did ceruloplasmin values. The antiestrogenic effect of strong LNG in Microgynon produced significant metabolic changes. The effect of 30 mcg EE in Marvelon and 20 mcg EE of Mercilon was equal.

Clinical experience and pharmacological effects of an oral contraceptive containing 20 micrograms oestrogen.

The performance of a new low-dose oral contraceptive (Mercilon) containing only 20 micrograms ethinyloestradiol combined with 150 micrograms desogestrel is reviewed. Eight multicentre clinical trials have been completed and provide information on 10,672 women studied over 73,477 cycles. The high efficacy of Mercilon was indicated by the finding that only 10 pregnancies were reported; nine of these occurred in women who omitted to take Mercilon on a number of days and only one in a woman who took all the tablets according to instructions. Cycle control was good; as with all oral contraceptives, the incidence of breakthrough bleeding and spotting was highest in the first treatment cycle and by the sixth treatment cycle the values were usually < 5% and < 7%. More than 80% of women had regular cycles. Side effects were few, the most common being headache, nausea and breast tenderness with incidences in the sixth treatment cycle of less than 2%, 6% and 6%, respectively. There were no significant changes in body weight or blood pressure. Pharmacodynamic investigations showed no adverse effects. Only 1 of 5 studies found an increased response to a glucose tolerance test compared to the pretreatment test. In 8 of 10 studies, serum HDL-C concentrations increased on treatment and this was associated with increases in apoproteins A1 and A2. Serum triglyceride levels also increased but no change occurred in serum cholesterol or LDL-C levels. Haematological factors were assessed in 8 studies and only minor changes were observed. Serum binding protein (SHBG, CBG, caeruloplasmin) concentrations increased and serum androgen levels decreased. Measurements of blood FSH, LH, oestradiol and progesterone indicated adequate inhibition of ovulation. Mercilon is the only oral contraceptive containing 20 micrograms ethinyloestradiol to have high efficacy, to have no adverse pharmacodynamic effects and, importantly, to produce an acceptable bleeding pattern not significantly different from that of oral contraceptives with a higher content of ethinyloestradiol.

Changes in androgens during treatment with four low-dose contraceptives.

The aim of the present study was to compare changes in the endogenous androgen environment in healthy women while on low-dose oral contraceptives (OCs). One-hundred healthy women were randomized to receive one of four OCs during six months: 21 tablets of Cilest, Femodeen, Marvelon, or Mercilon. During the luteal phase of the pretreatment cycle, body weight and blood pressure were recorded and the following parameters were measured: sex hormone-binding globulin (SHBG), corticosteroid-binding globulin (CBG), testosterone (T), free testosterone (FT), 5 alpha-dihydrotestosterone (DHT), androstenedione (A), dehydroepiandrosterone-sulphate (DHEA-S) and 17 alpha-hydroxyprogesterone (170HP) while also the free androgen index (FAI) was calculated. Measurements were repeated during the 3rd week of pill intake in the 4th and the 6th pill month. There were no differences on body mass and blood pressure with the use of the four OCs. The mean serum DHEA-S decreased significantly in all groups though less in the Mercilon group when compared to Cilest and Marvelon (approximately 20% vs 45%). Mean serum SHBG and CBG increased significantly in all four groups approximately 250% and 100%, respectively. In each group CBG also increased significantly but less in women taking Mercilon (-75%) as compared to the others (-100%). Current low-dose OCs were found to have similar impact on the endogenous androgen metabolism with significant decreases of serum testosterone, DHT, A, and DHEA-S. They may be equally beneficial in women with androgen related syndromes such as acne and hirsutism.

PIP: Health researchers randomly assigned 100 healthy women aged 18-38 from the Netherlands and Saudi Arabia to one of four various oral contraceptive (OC) groups to undergo six cycles of OC therapy so they could evaluate changes in plasma concentrations of sex hormone binding globulin (SHBG), corticosteroid-binding globulin (CBG), albumin (Alb), testosterone (T), free testosterone (FT), dihydrotestosterone (DHT), androstenedione (A), dehydro-epiandrosterone-sulphate (DHEA-S), and 17 alpha-hydroxyprogesterone (17OHP). The four monophasic OCs were Cilest (35 mcg ethinyl estradiol [E2] and 250 mcg norgestimate), Femodeen (30 mcg E2 and 75 mcg gestodene), Marvelon (30 mcg E2 and 150 mcg desogestrel), and Mercilon (20 mcg E2 and 150 mcg desogestrel). There were 12 dropouts. Neither body weight nor blood pressure changed significantly during the study. All steroidal serum parameters (T, FT, DHT, A, DHEA-S, 17OHP, Alb) fell significantly during the six cycles of OC treatment (ratio of decrease, 1.3-3), regardless of OC type. These changes had appeared after cycle 4. The only significant difference between the OC groups was that the mean decrease of DHEA-S for Mercilon was lower than that for the other OC groups (21% vs. 43% for Cilest, 44% for Marvelon, and 34% for Femodeen; p 0.05). SHBG and CBG rose greatly during OC use in all four OC groups (mean increase = 263% and 94%, respectively; p 0.05). The increase in CBG was significantly less in the Mercilon group than in the other OC groups (74% vs. 96% for Cilest, 101% for Femodeen, and 102% for Marvelon; p 0.05). These findings show that OC use changed the endogenous androgen environment in the direction of hypoandrogenism. Thus, all four OCs can equally treat androgen-related syndromes (e.g., acne and hirsutism).

Hemostatic and metabolic effects of lowering the ethinyl-estradiol dose from 30 mcg to 20 mcg in oral contraceptives containing desogestrel.

The metabolic and hemostatic effects of two oral contraceptives containing 150 mcg desogestrel and 20 mcg ethinyl-estradiol (EE) (MERCILON) or 30 mcg EE (MARVELON) were compared in order to examine the effect of reducing the EE dose in contraceptive pills. Forty-nine women participated in this randomized study during 6 cycles. In both groups, there was a significant increase in triglycerides, HDL-cholesterol and apoprotein A1; the same increase was observed for SBP and CBG. Slight and transient variations of fasting blood glucose levels were seen in the 30 mcg EE group and in the two groups for fasting insulin levels. The increase in renin substrate was significantly higher with the 30 mcg EE than with the 20 mcg EE pill. In both groups, plasminogen increased significantly, but antithrombin III, total and free protein S and fibrinogen decreased significantly only in women taking the 30 mcg EE pill, whereas there was no significant change in the 20 mcg EE group. Reducing the dose of EE in oral contraceptives from 30 mcg to 20 mcg minimizes their impact on renin substrate and hemostatic parameters.

Antagonism of non-depolarising neuromuscular blockade by aminopyridines in cats.

The antagonism of pipecuronium- and vecuronium-induced neuromuscular blockade by 4-aminopyridine (4AP), 3,4-diaminopyridine (3,4AP) and 3-[(dimethylamino)-carbonyl] amino-4-aminopyridine (LF14) were studied in anaesthetized cats during constant infusion of the relaxants. Aminopyridines were administered cumulatively at steady state 90% block level. The ED50 values of 4AP, 3,4AP and LF14 were 243, 106 and 254 micrograms kg-1 in pipecuronium, and 232, 195 and 235 micrograms kg-1 in vecuronium blockade. It has been assumed that in cats the anticurare effect of aminopyridines is mainly a result of K+ channel blockade on motor nerve terminals which enhances the evoked release of acetylcholine.

The neuromuscular and autonomic blocking activities of pancuronium, Org NC 45, and other pancuronium analogues, in the cat.

Twenty-six mono- or bis-quaternary salts of 3,17-dioxy-2 beta, 16 beta-dipiperidino-5 alpha-androstanes (including pancuronium) and one 17-desoxy congener were tested for neuromuscular blocking and autonomic blocking activities in the chloralose-anaesthetized cat. The 17 beta-acetoxy series, all the members of which contain an acetylcholine-like fragment in the steroidal D-ring, was most selective for effecting neuromuscular blockade. The salient member of this series is 3 alpha, 17 beta-diacetoxy-2 beta, 16 beta-dipiperidino-5 alpha-androstane 16 beta-N-monomethobromide (Org NC 45) which is highly selective in blocking neuromuscular transmission in that a dose approximately sixty times greater than the neuromuscular blocking dose was required to block responses to vagal stimulation. In contrast, in doses sufficient to produce neuromuscular block, pancuronium simultaneously blocked responses to vagal stimulation. Moreover, pancuronium and Org NC 45 exhibited the same order of neuromuscular blocking activity and therefore the latter potentially represents a useful addition to the armamentarium of neuromuscular blocking agents currently in clinical use.

On the pharmacology of Org 6338 (2beta, 16beta-dipiperidino - 5alpha - androstan - 3alpha - ol acetate dimethobromide), a new steroidal neuromuscular blocking agent.

Org 6368 is a homologue of pancuronium bromide. Its interactions with other agents in the cat sciatic nerve-gastrocnemius muscle preparation revealed that paralysis was of the non-depolarizing type. This was confirmed in experiments using avian muscle. Org 6368 is a potent muscle relaxant being 2-4 times as potent as (+)-tubocurarine in the cat. Paralysis in the cat is rapid in onset and of appreciably shorter duration than that of pancuronium and (+)-tubocurarine. Repeated injections of the same dose of Org 6368 show no cumulative effect. Muscle relaxant doses generally cause a slight increase in both blood pressure and heart rate. Although its histamine-releasing capacity is greater than that of pancuronium it is less than that of (+)-tubocurarine. Org 6368 shares with pancuronium a very weak effect on both the muscarinic receptor and ganglionic transmission. Differences in the muscle relaxant profiles of Org 6368 and pancuronium are discussed.