Search

SummaryR,S-Oxazepam and R,S-temazepam can be separated in their enantiomers by means of a chiral AGP column. The corresponding R- and S-glucuronide conjugates can be separated on a normal reversed-phase C18 column. Man conjugates the S-enantiomer of oxazepam and temazepam both better than the R-enantiomer. The urinary recovery of the glucuronides following either R,S,-oxazepam or R,S-temazepam almost amounts to 100% of the dose administered.

SUMMARY Objectives. This study is part of a programme on reduction of postpartum haemorrhage. Buccal oxytocin and desamino–oxytocin administration with a favourable effect on both blood loss and maternal morbidity and mortality were regarded as possible treatments for use in tropical countries. The stability of buccal oxytocin and desamino–oxytocin under tropical conditions was unknown and therefore tested in this study. Study methods. The ‘experimental shelf lives’ of buccal oxytocin and desamino–oxytocin were examined by exposing the tablets to seven artificially controlled conditions. Samples were analysed by high performance liquid chromatography to determine the content of oxytocin and desamino–oxytocin at nine different times during the period of 1 year. Results. Oxytocin and desamino–oxytocin are fairly stable under refrigeration. Instability for both drugs was detectable after 20 weeks' storage under humid conditions, independent of temperature. Desamino–oxytocin is more sensitive to light exposure; its concentration declines to 55-6% of the stated amount after 1 year of exposure to light compared to 85% in the case of oxytocin. Oxytocin packaged as supplied by the manufacturer were stable for 21 weeks when exposed to simulated humid (75% relative humidity) conditions. At 40°C and 25% relative humidity there is no difference in stability between tablets in sealed aluminium packs as supplied by the manufacturer and unpackaged tablets. Conclusions. Tropical conditions make oxytocin and desamino–oxytocin tablets unstable, with humidity as the most adverse factor. The oxytocin tablets were partially protected from the harmful effect of humidity by sealed aluminium package.

This study is part of a programme on reduction of postpartum haemorrhage (PPH). Ergometrine and methylergometrine have a favourable effect on both blood loss and maternal morbidity and mortality and oral preparations were regarded as a possible treatment for use in tropical countries. The stability of oral preparations of the two ergometrine compounds under tropical conditions was unknown and was therefore examined in this study.The 'experimental shelf lives' of ergometrine and methylergometrine tablets were examined by exposing the tablets to seven artificially controlled conditions. Samples were analysed by high performance liquid chromatography at nine different sampling times over a period of 1 year to determine the content of ergometrine and methylergometrine.Under refrigeration (test I), less than 90% of the stated amount of active ingredient was found in the tablets after 14 weeks in the case of ergometrine and 21 weeks in the case of methylergometrine. When stored in the dark at 40 degrees C and 75% relative humidity (test VI), the tablets fall outside accepted specification (= 90-110% of state amount of active ingredient) within 3 weeks in the case of ergometrine and 21 weeks in the case of coated methylergometrine tablets. The stability of uncoated ergometrine tablets was far less than that of coated methylergometrine tablets. Instability worsened under extreme humid conditions (test IV and VI), and hot conditions (test V), for both ergometrine and methylergometrine. From week 31 onwards the coating did not seem to protect the compound anymore, irrespective of the condition of exposure.Tropical conditions make the tablets unstable with humidity as the main adverse factor. The sugar-coated methylergometrine tablets are more stable under humid/hot conditions than the non-coated ergometrine tablets. Under all simulated conditions both oral ergometrine and methylergometrine tablets are unstable.

Background and Objectives . The purpose of this study was to com pare the effectiveness of three local anesthetic agents for intravenous regional anesthesia in the upper limb, Side effects and plasma concentrations of the drugs in the doses adm inistered for IVRA w ere also studied. Methods . Thirty patients in ASA groups I and II received intravenous regional anesthesia for surgery of the upper limb. In a double-blind prospective study, they w ere random ly allocated to receive one of three local a n e s­ thetics: articaine, lidocaine, or prilocaine. Patients received 40 mL of a 0.5% solu­ tion of the local anesthetic. The onset lime of sensory block was assessed by p in ­ prick and the extent of m otor block was was scored as 0-3. Plasma concentrations of local anesthetics w ere determ ined in all patients from serial arterial blood sam ­ ples drawn at predeterm ined times before and after tourniquet release. Results. The onset time of sensory block was significantly shorter (2.5 m inutes) in the articaine group than in the lidocaine group (11.1 m inutes) or th e prilocaine group (10.9 m in ­ utes) (Scheffe, P < .05). D evelopm ent of m otor block was equal in all three groups (score 2). Estim ation of plasm a concentrations by high perform ance liquid chro­ matography show ed th at the peak level in all 30 patients was reached im m ediately after release of the tourniquet; plasma concentrations thereafter gradually declined. M aximum concentrations of articaine, lidocaine, and prilocaine were, 1.85, 8.5, and 4.4 pg/mL, respectively. No signs of local anesthetic toxicity of the cardiovascular or central nervous systems w ere seen. Conclusion. Articaine had the fastest onset of sensory block and the lowest peak plasma concentration of the three local a n e sth e t­ ics w hen used for intravenous regional anesthesia. Reg Anesth 1997:22:29-34. K ey w ords: intravenous regional anesthesia, articaine, lidocaine, prilocaine.

Contains fulltext : 28628.pdf (Publisher’s version ) (Open Access) Intact and gonadectomized male and female WAG/Rij rats were used to study the effects of gender and gonadal hormones on the development of sensitization and tolerance to cocaine-induced changes in EEG and behaviour. The four groups of WAG/Rij rats differed in the number of spontaneously occurring spike-wave discharges: ovariectomy decreased and castration increased the number of spike-wave discharges. This confirms that testosterone has antiabsence effects and that female gonadal hormones may promote the occurrence of spike-wave discharges. Cocaine [10 and 20 mg/kg, intraperitoneally (IP)] was administered before and after chronic cocaine administration (9 days, one daily injection with 10 mg/kg) and EEG and behaviour were monitored. Cocaine strongly suppressed the occurrence of spike-wave discharges before and after chronic administration in all four groups, although the decrease was less in the intact males. Sensitization or tolerance induced by cocaine on EEG could not be established. Acute cocaine administration eliminated explorative, automatic, and passive behaviour, whereas various stereotypical activities such as uncoordinated head and body movements and head swaying emerged. Differences between groups were observed as intact males were less likely than subjects in the three other groups to engage in intense stereotyped behaviour. These data suggest that testosterone inhibits EEG and behavioural effects of acute cocaine administration. All four groups displayed less head swaying and more uncoordinated head and body movements after chronic cocaine administration, suggesting that behavioural sensitization had occurred. Differences between the four groups had faded away. Although pharmacokinetic differences in levels of cocaine and benzoylecgonine between the four groups were found, they could not easily be related to the behavioural differences between groups.

A high-performance liquid chromatographic method with fluorometric detection has been developed for the determination of succinylcholine in human plasma. Succinylcholine shows fluorescence at 282 nm with an excitation at 257 nm. The assay is sensitive, reproducible and linear for concentrations ranging from 100 ng/ml to 100 micrograms/ml of succinylcholine. In a pilot study the plasma concentration-time curve showed a triphasic elimination, with half-lives of 0.4, 1.2 and 8 min, respectively. In a clinical setting, drugs commonly administered during anaesthesia did not interfere with the assay. This method provides a simple and time-saving alternative to existing methods.

Biotransformation and elimination of diazepam and four 3-hydroxy-benzodiazepines after i.v. injection in anaesthetized cats were investigated. Decay of plasma concentration of 3-hydroxy-benzodiazepines was slow and plasma concentrations of their glucuronides were lower than of unchanged parent compounds. In the urine, very low excretion rates of all investigated benzodiazepines were found during the first eight hours. It is concluded that cats poorly glucuronidate 3-dydroxy-benzodiazepines.

Growing awareness of problems arising from over-use of antimicrobial agents has led to attempts to develop policies or guidelines for rational treatment. To follow the effects of guidelines, the percentage of patients receiving anti-microbial drug therapy, acquired from patient records, has been a frequently used parameter. In this paper the Defined Daily Dose (DDD) per 100 bed-days has been used instead. This parameter can be calculated by converting the number of units of antimicrobials, delivered to individual wards, to defined daily doses per bed-day. This parameter determines the probability of treating a patient with a particular drug, based on pooled data. The DDD per 100 bed-days has been used to follow changes in prescribing habits arising from the acceptance of and adherence to guidelines over a period of 5 years in a University Hospital.

Studies of the possible interactions between the water-soluble benzodiazepine, midazolam, and two non-depolarizing neuromuscular blocking drugs, vecuronium and tubocurarine, were performed in the rat in vivo sciatic nerve-tibialis anterior muscle preparation. Midazolam 0.5 and 5 mg kg-1 caused 17% and 34% depression of the twitch height, respectively, once a steady-state blockade of the twitch height had been induced by vecuronium. The potentiation of the tubocurarine steady state blockade by midazolam 5 mg kg-1 was quantitatively equal to that of vecuronium, but was slower in onset. The buffer solvent of midazolam 5 mg kg-1 did not change the steady-state blockade of vecuronium. Midazolam 5 mg kg-1 caused a shift to the left of the cumulative dose-response curves of vecuronium.

A survey is given conserving the possibility of gas-chromatographic analysis of drugs. Attention is paid to the plasma concentration curve, biological half-life and multicompartment kinetics.

It is known that the molecular ion of trans-1,6-tetrahydrocannabinol (1,6-THC) with m/e 314 decomposes via a retro Diels-Alder reaction to fragment m/e 246, which then loses a Me radical to give the ion m/e 231 (cf Scheme 1).1 A similar breakdown is found for trans-1,2-tetrahydrocannabinol (1,2-THC), suggesting a shift of the double bond from the 1,2 to the 1,6 position in its molecular ion. Methylation of the phenolic OH group in trans-1,2-tetrahydrocannabinol however, shows that the phenolic proton transfer to the 1,2 double bond (cf Scheme 2) is much more important (∼ 35–80%) than simple double bond migration (∼ 20%; Scheme 3) in the formation of fragment m/e 231.

The renal excretion of fencamfamine and pipradrol after oral administration was followed over several days by measuring the amount of unchanged drug in each urine fraction by gaschromatographic analysis. The biological half-life in man of fencamfamine and pipradrol were approximately 12 and 25 hr respectively. The renal excretion of fencamfamine was completely suppressed over several hours by ingestion of about 10 g sodium bicarbonate. The renal excretion of pipradrol was also suppressed by the same treatment but to a lesser extent. It was concluded that the doping control may lead to false negative results when fencamfamine is used in combination with an alkalising agent. Pharmacokinetics Renal excretion Suppression of elimination Gaschromatography Amphetamines Fencamfamine Biological half-life Doping control Abuse of stimulants

1. Ferrocenylisopropylamine (FIPA) inhibits the elimination of amphetamines in rat. The half-life of isopropylamphetamine was increased from approx. 30 to 85–100 min after administration of FIPA.2. With isolated, perfused, rat liver, the half-lives of isopropylamphetamine, biamphetamine and benzylamphetamine were increased from 5–20 min to about 200 min by equimolar amounts of FIPA, indicating that the prolonging effect of FIPA is due to interference at the metabolic level.3. Experiments with hepatic microsomal suspensions demonstrated that FIPA competitively inhibits the oxidative N-dealkylation of isopropylamphetamine; the Ki of FIPA is 4·1 × 10−6 M.4. Binding of isopropylamphetamine and FIPA to cytochrome P-450 was studied using hepatic microsomes of phenobarbital-treated rats. Isopropylamphetamine caused a type I, and FIPA a type II difference spectrum; FIPA showed a much higher binding affinity (Ks = 1·24 × 10−2 M) than isopropylarnphetamine (Ks = 0·96 × 10−3 M). FIPA acts as a modifier of th...

In vitro studies using the rat phrenic nerve-hemidiaphragm preparation were performed to investigate the effects of diazepam and three of its metabolites on indirectly evoked twitch tension. Diazepam, desmethyl-diazepam and temazepam alone caused an increase in twitch tension in lower concentrations, followed by complete depression in higher concentrations. Oxazepam did not cause an initial increase in twitch tension, but showed an immediate and dose-dependent depression. Cumulative concentration-response curves for pancuronium and suxamethonium in the presence of different concentrations of diazepam or oxazepam showed that small concentrations of diazepam, which did not change twitch tension alone, caused antagonism of the action of pancuronium, but not of suxamethonium. With ozazepam no such antagonism was observed. In liminal and supraliminal concentrations, both diazepam and oxazepam potentiated the action of pancuronium and suxamethonium. Possible implications for in vivo interactions are discussed.

Plasma disposition of sulphadimidine ( sdm ) and its metabolites was studied in laying hens after 100 mg sdm kg−1 doses were administered as a single intravenous dose, a single oral dose and multiple oral doses once daily for five consecutive days. sdm was extensively metabolised by acetylation and hydroxylation. In plasma, the metabolite observed with the highest concentration was N4-acetylsulphadimidine (N4- sdm ) followed by hydroxymethylsulphadimidine (CH2OH) and 5-hydroxysulphadimidine. Following intravenous administration a biphasic elimination (as seen for a capacity limited reaction) pattern for sdm and its metabolites was observed. Multiple (5×) sdm dosing revealed plasma sdm concentrations ranging between 7 and 108 µg ml−1; within 96 hours of termination of the multiple sdm dosing, the plasma sdm concentration was below 0·01 µg ml−1. The renal clearances of N4- sdm and the hydroxy metabolites were approximately 10 times greater than that of sdm. The sdm mass balance (faecal/urinary recovery) showed a loss of 56 per cent after intravenous dosage and of 67 per cent after a single oral dosage; the hydroxy metabolites accounted for the highest percentage in faeces/urine. Thus additional metabolic pathways must exist in laying hens.

The oxytetracycline (OTC) disposition was studied in a group of six calves following the administration of an oxytetracycline-10 per cent formulation (i) intravenously (i.v.), (ii) subcutaneously (s.c.) in the lateral neck, and intramuscularly (i.m.) in (iii) the lateral neck, (iv) the shoulder (M. triceps brachii), and (v) the buttock (M. semitendineus). The dose levels used for the intravenous route and other routes were respectively 17.0 +/- 2.3 and 18.3 +/- 1.25 mg OTC/kg. The peak OTC concentrations (Cmax) were achieved with the s.c. and i.m. routes between 4 and 8 hours after injection, the highest being found after application in the shoulder (Cmax:6.9 +/- 0.82 microgram/ml plasma). The Cmax for the s.c. and other i.m. routes in application was similar to each other, ranging from 5.0 to 5.5 micrograms/ml plasma. For different points in time after injection the partial bioavailability was calculated. At 52 h post injection (p.i.) maximal bioavailability was observed for the i.m. shoulder route, viz. 98.1 +/- 7.0 per cent of the administered dose, while at 76 h p.i. similar bioavailabilities were achieved for the i.m. neck and shoulder route, namely 93.3 +/- 8.9 and 99.4 +/- 4.2 per cent, respectively. The lowest bioavailability (83.1 +/- 13.4 per cent) was obtained following the i.m. buttock route at 76 p.i. An obvious irritating effect was observed after s.c. application in the neck an di.m. injection in the buttock, which had disappeared at 5 days p.i. It is assumed that the longer persistence of OTC in plasma resulting with the latter two routes of administration was due to this irritation effect.