T. B. Vree

Ergot alkaloids. Current status and review of clinical pharmacology and therapeutic use compared with other oxytocics in obstetrics and gynaecology.

Ergot alkaloids are well known preparations. Ergot alkaloids used in obstetrics and gynaecology are ergometrine (ergonovine; EM), methylergometrine (methergine; ME) and bromocriptine. The pharmaceutical properties of ME EM) are critical. To guarantee stability, ME and EM ampoules should be stored in a cool, dark place. ME and EM tablets are unstable in all conditions and they show an unpredictable bioavailability, which prevents oral use of the drugs for any purpose.ME and EM are known for their strong uterotonic effect and, compared with other ergot alkaloids, for their relatively slight vasoconstrictive abilities. ME and EM do have a place in the management of the third stage of labour as they are strong uterotonics. They act differently from oxytocin and prostaglandins, and have different adverse effects. Oxytocin should be used as prophylaxis or a the drug of first choice; next, ME or EM should be used, and if none of these drugs produce the desired effects, prostaglandins should be used to control bleeding.Ergot alkaloid use in gynaecology has been limited and today is discouraged even in essential menorrhagia. It is suggested that EM and ME be used (parenterally) only in first trimester abortion curettage, to reduce blood loss. Bromocriptine has been used for lactation suppression. However, alternatives such as cabergoline, which possess fewer adverse effects, are now available and therefore preferred for this indication.In sum, there is no place for the prophylactic use of ME and EM in obstetrics or gynaecology. They can be used for therapeutic purposes in the third stage of labour. During use, the practitioner must be alert for adverse effects.

Decreased plasma albumin concentration results in increased volume of distribution and decreased elimination of midazolam in intensive care patients

The pharmacokinetic parameters of 16 patients in the intensive care unit, sedated with midazolam, were evaluated. A large variation was observed in the plasma concentration of midazolam and between the plasma concentration of midazolam and its metabolite 1‐hydroxymethylmidazolam glucuronide. The plasma albumin concentration governs the volume of distribution of midazolam. Decreased plasma albumin concentration (25 gm/L) results in an increased volume of distribution and a decreased elimination rate of midazolam. The observed plasma concentration ratio between the parent drug and its metabolite 1‐hydroxymethylmidazolam glucuronide is governed by the variables of protein binding, the metabolic rate of midazolam, and the renal clearance of the glucuronide metabolite itself (which can be considered as a measure of the kidney function of the patient).

Pharmacokinetics of antibiotics in critically ill patients.

Differences in pharmacokinetic data of aminoglycosides, ceftazidime and ceftriaxone between intensive care patients and volunteers or patients who are less severely ill, are described. Similar differences are observed for midazolam. In severely ill patients with normal renal function a wide interpatient variability of aminoglycoside half-life (t1/2) and increased distribution volume (Vd) are observed. This results in inadequate serum levels. A pharmacokinetic approach of drug dosing, based on serum concentrations in individual patients, is advised. For ceftazidime and ceftriaxone similar changes of t1/2 and Vd are observed. Since protein binding is frequently reduced in severely ill patients, the influence of altered binding of highly bound drugs on Vd and drug clearance is discussed. As both may be increased by reduced protein binding, the change of t1/2 to be expected is unpredictable. Dosing regimens should be based on pharmacokinetic data derived from patients whose severity of disease is comparable to that of the patients to be treated.

Plasma and urinary excretion kinetics of oral baclofen in healthy subjects

SummaryBaclofen, a centrally acting muscle relaxant, is used in the treatment of spasticity. Its pharmacokinetics has been derived from plasma and urine data in four healthy subjects, whose renal function was simultaneously measured.After oral administration of a single 40 mg dose, baclofen was mainly excreted unchanged by the kidney, 69 (14) %. The half-life, calculated from extended least squares modelling (ELSMOS) both of plasma and urine data was 6.80 (0.68) h, which is longer than reported in most studies based solely on plasma data.The renal excretion rate constant had the high mean value of 0.35 (0.24) h−1, and the apparent renal clearance of baclofen equalled the creatinine clearance. Passive tubular reabsorption is relatively unimportant, since no dependence was observed on variables urine flow or pH.Although active tubular secretion may contribute to its renal clearance, as shown by the effect of coadministration of probenecid, glomerular filtration appears to be the dominant transport mechanism.

Pharmacokinetics, renal clearance and metabolism of ciprofloxacin following intravenous and oral administration to calves and pigs

The pharmacokinetics of ciprofloxacin, a quinoline derivative with marked bactericidal activity against gram-negative bacteria, was studied in calves and pigs following intravenous and oral administration. Ciprofloxacin was rapidly and well distributed in the body, exhibited a short elimination half-life of 2.5 h in both species, and was rapidly absorbed after oral administration (Tmax:2 to 3 h). The oral bioavailability in calves was 53 +/- 14% and for 1 pig 37.3%. The renal clearance of the unbound ciprofloxacin for both species was of the same order, indicated a predominantly tubular secretion pattern, and accounted for about 46% of the total drug elimination. No complete drug mass balance could be demonstrated. Small amounts of two metabolites were detected in the urine of calves, but not in pig urine.

Identification in hashish of tetrahydrocannabinol, cannabidiol and cannabinol analogues with a methyl side-chain

The cannabis constituents Δ1‐tetrahydrocannabinol, cannabidiol and cannabinol are accompanied by their homologues with an n‐propyl and with a methyl side‐chain. The identification procedure by combined gas chromatography‐mass spectrometry in hashish and marihuana is described and the consequences for cannabis use are discussed.

Determination of trimethoprim and sulfamethoxazole (co-trimoxazole) in body fluids of man by means of high-performance liquid chromatography

A high-performance liquid chromatographic method for the determination of trimethoprim, sulfamethoxazole and its metabolite and a series of structurally related sulfonamides is described. The half-life time of elimination of sulfamethoxazole and its metabolite N4-acetylsulfamethoxazole is 9 h for both compounds. The renal excretion rate of sulfamethoxazole depends strongly on the urinary pH. The renal excretion rate of the metabolite N4-acetylsulfamethoxazole is not dependent on the urinary pH.

Direct high-performance liquid chromatography determination of propofol and its metabolite quinol with their glucuronide conjugates and preliminary pharmacokinetics in plasma and urine of man

Propofol (P) is metabolized in humans by oxidation to 1,4-di-isopropylquinol (Q). P and Q are in turn conjugated with glucuronic acid to the respective glucuronides, propofol glucuronide (Pgluc), quinol-1-glucuronide (Q1G) and quinol-4-glucuronide (Q4G). Propofol and quinol with their glucuronide conjugates can be measured directly by gradient high-performance liquid chromatographic analysis without enzymic hydrolysis. The glucuronide conjugates were isolated by preparative HPLC from human urine samples. The glucuronides of P and Q were present in plasma and urine, P and Q were present in plasma, but not in urine. Quinol in plasma was present in the oxidised form, the quinone. Calibration curves of the respective glucuronides were constructed by enzymic deconjugation of isolated samples containing different concentrations of the glucuronides. The limit of quantitation of P and quinone in plasma are respectively 0.119 and 0.138 microg/ml. The limit of quantitation of the glucuronides in plasma are respectively: Pgluc 0.370 microg/ml, Q1G 1.02 microg/ml and Q4G 0.278 microg/ml. The corresponding values in urine are: Pgluc 0.264 microg/ml, Q1G 0.731 microg/ml and Q4G 0.199 microg/ml. A pharmacokinetic profile of P with its metabolites is shown, and some preliminary pharmacokinetic parameters of P and Q glucuronides are given.

Intravenous regional anesthesia with 0.5% articaine, 0.5% lidocaine, or 0.5% prilocaine : a double-blind randomized clinical study

Background and Objectives. The purpose of this study was to compare 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 administered for IVRA were 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 were randomly allocated to receive one of three local anesthetics: articaine, lidocaine, or prilocaine. Patients received 40 mL of a 0.5% solution of the local anesthetic. The onset time of sensory block was assessed by pinprick and the extent of motor block was was scored as 0‐3. Plasma concentrations of local anesthetics were determined in all patients from serial arterial blood samples drawn at predetermined times before and after tourniquet release. Results. The onset time of sensory block was significantly shorter (2.5 minutes) in the articaine group than in the lidocaine group (11.1 minutes) or the prilocaine group (10.9 minutes) (Scheffe, P < .05). Development of motor block was equal in all three groups (score 2). Estimation of plasma concentrations by high performance liquid chromatography showed that the peak level in all 30 patients was reached immediately after release of the tourniquet; plasma concentrations thereafter gradually declined. Maximum concentrations of articaine, lidocaine, and prilocaine were, 1.85, 8.5, and 4.4 μg/mL, respectively. No signs of local anesthetic toxicity of the cardiovascular or central nervous systems were seen. Conclusion. Articaine had the fastest onset of sensory block and the lowest peak plasma concentration of the three local anesthetics when used for intravenous regional anesthesia.

Dose dependent disposition of sulphadimidine and of its N4-acetyl and hydroxy metabolites in plasma and milk of dairy cows.

The disposition of sulphadimidine (SDM) and of its N4-acetyl (N4-SDM) and two hydroxy metabolites, 6-hydroxymethyl-(SCH2OH) and 5-hydroxyasulphadimidine (SOH), was studied in plasma and milk of dairy cows following intramuscular or intravenous administration of sulphadimididine-33.3% at doses of 10, 45, 50, and 100 mg/kg. The main metabolite in plasma as well as in milk was SCH2OH. The metabolite percentages, the final plasma elimination half-lives, and the time of peak SDM concentrations in milk are presented for different dosages. The concentrations of SDM and its metabolites in milk ran parallel to those in plasma beyond 4 hours p.i. The metabolite concentrations in plasma and milk were lower than those of the parent SDM. Sulphate and glucuronide metabolites could not be detected in milk. At high doses (45 mg/kg or more) and SDM plasma concentrations exceeding 20 micrograms/ml, a capacity limited metabolism of SDM to SCH2OH was noticed, viz. a steady state concentration of SCH2OH and a biphasic elimination pattern for SDM and SCH2OH in plasma and milk. The mean ultrafiltrate ratios of the milk to plasma concentrations with respect to SDM, SCH2OH, SOH, and N4-SDM were: 0.69, 0.22, 020, and 0.63, respectively. The total amount of SDM and its metabolites recovered from the milk after milking twice daily over the whole experimental time was less than 2% of the applied dose. A bioassay method allowed of detecting qualitatively SDM concentrations exceeding 0.2 micrograms/ml in plasma or milk. Withholding times for edible tissues and milk are suggested.