Cannabinoids with a propyl side chain in cannabis: occurrence and chromatographic behavior.

Neutral cannabinoids with a pentyl side chain-for example, cannabidiol, tetrahydrocannabinol, and cannabinol-are generally accompanied by homologs with a propyl side chain, of which at least one has psychotropic activity. Samples of hashish and marihuana from Asia especially sometimes have abundant amounts of propyl cannabinoids, the quantities being of the same order as that of the accompanying pentyl cannabinoids. Detection and identification of the propyl and pentyl cannabinoids in gas chromatography and thin-layer chromatography is discussed.

Continuous monitoring of plasma antiepileptic drug levels.

Quantitative knowledge of the fate of antiepileptic drugs in individual patients is useful in the prevention, explanation, and correction of subtherapeutic and toxicity-causing regimens. Several variables, such as age and co-medication, require adaptation of the regimen. An interactive computer-assisted laboratory reporting service provides a data base with epidemiological options that helps in the daily management of patients and can supply information on pharmacokinetic parameters, local, regional, and national drug utilization, and disease frequency. Some treatment variables are quantitatively predictable, but many others require individual monitoring of clinical, behavioral, and laboratory observations by a multidisciplinary team of experts. Intensive monitoring by an epilepsy team in an institution for mentally retarded patients has allowed conclusions on the value of therapeutic substances, reduction of the number of simultaneously administered drugs, and seizure registration.

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).

Drug-drug interactions affecting fluoroquinolones.

In a three-week study, the metabolism of the bronchodilator theophylline and its major metabolites formed by C-8 oxidation (1,3-dimethyluric acid) and N-demethylation (3-methylxanthine and 1-methyluric acid) was investigated in two healthy volunteers. Metabolic studies were performed following intravenous infusion of a single 6 mg/kg dose of aminophylline. During Week 1, theophylline was given alone (blank period), and during Weeks 2 and 3 it was given during oral coadministration of ofloxacin and enoxacin, respectively. Dosage of each quinolone was 200 mg twice daily for four days, starting three days prior to the theophylline infusion. During enoxacin coadministration, elimination half-lives of theophylline increased from 8.7 to 17.4 hours and from 6.1 to 12.3 hours, respectively. Total body clearance of theophylline decreased in both volunteers, whereas renal clearance did not alter. From this it was concluded that the decreased elimination results from a reduced metabolic clearance. During enoxacin coadministration, the formation of the metabolites 1-methyluric acid and 3-methylxanthine clearly was decreased, whereas the formation of 1,3-dimethyluric acid was less affected compared with the blank period. Interference with theophylline disposition by enoxacin is based predominantly on inhibition of microsomal N-demethylation. Ofloxacin comedication did not cause a change in the plasma parameters or renal excretion of theophylline and its metabolites compared with the blank period.

Pharmacokinetics of sulphamethoxazole in man: effects of urinary pH and urine flow on metabolism and renal excretion of sulphamethoxazole and its metabolite N4-acetylsulphamethoxazole.

A high performance liquid chromatography method for the determination of sulphamethoxazole and its metabolite N4-acetylsulphamethoxazole is described. The renal excretion rate and cumulative renal excretion of sulphamethoxazole is markedly influenced by urinary pH. With constant urinary pH, the renal excretion rate and the renal clearance of sulphamethoxazole is dependent on the urine flow. The renal clearance of the metabolite N4-acetylsulphamethoxazole is not influenced by urinary pH or urine flow. No clear acetylator phenotype could be detected in the group of volunteers studied. The extent of acetylation depends on the amount of sulphamethoxazole available for acetylation, thus indirectly on the urine pH and flow.

Pharmacokinetics of N1-acetyl- and N4-acetylsulphamethoxazole in man.

The pharmacokinetics of N1-acetylsulphamethoxazole and N4-acetylsulphamethoxazole in man are described. N1-Acetylsulphamethoxazole is deacetylated to sulphamethoxazole and acetylated to N4-acetylsulphamethoxazole. N4-Acetylsulphamethoxazole is excreted almost unchanged in the urine. The renal excretion rate is independent of the urine flow and urinary pH. N4-Acetylsulphonamides are less lipid soluble and more acidic than their corresponding parent sulphonamides.

Determination of the acetylator phenotype and pharmacokinetics of some sulphonamides in man.

The pharmacokinetics of sulphamethizole, sulphamethoxazole, sulphadiazine, sulphapyridine and sulphadimidine have been studied in man. Renal clearance values of the metabolite N4-acetylsulphonamide are 6 to 20 times higher than those of the corresponding parent compound. The renal clearance of sulphonamides is dependent on the urine flow. N4-Acetylsulphonamide concentration-time profiles for plasma and urine have been constructed for the sulphonamides. The percentage N4-acetylsulphonamide-time profiles for plasma are excellent tools for establishing the acetylator phenotype, while those constructed from urine samples are less useful. Evidence is obtained that sulphadimidine is metabolically processes by 2 different isoenzymes, while sulphadiazine, sulphapyridine and sulphamethoxazole are processes by 1 acetylating isoenzyme. Sulphamethizole is acetylated to very little extent.

Steady-state kinetics of the quinolone derivatives ofloxacin, enoxacin, ciprofloxacin and pefloxacin during maintenance treatment with theophylline.

Some of the new quinolone derivatives may be of value in the treatment of respiratory tract infections. It has been demonstrated that enoxacin, pefloxacin and ciprofloxacin, but not ofloxacin, decreased the metabolic clearance of the bronchodilator theophylline. This resulted in elevated plasma theophylline concentrations and, in some of the patients, theophylline toxicity. When the pharmacokinetic parameters of enoxacin, pefloxacin, ciprofloxacin and ofloxacin obtained in the present study were compared with those obtained from other studies in healthy volunteers not given concomitant theophylline, there was no evidence of theophylline influencing the clearance of the investigated quinolones.

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.

The effect of multiple-dose oral lomefloxacin on theophylline metabolism in man.

Single-dose plasma pharmacokinetics of theophylline (6 mg/kg intravenously) and renal excretion of theophylline and its metabolites, resulting from 8-oxidation and N-demethylation, were investigated in eight healthy volunteers before and at day 3 of concomitant oral administration of the quinolone derivative lomefloxacin (400 mg twice daily). Plasma samples were collected until 24.5 h, and urine samples were collected until 72 h after theophylline administration. The concentrations of theophylline and the major metabolites, resulting from N-demethylation and 8-oxidation, were measured utilizing a high-pressure liquid chromatography (HPLC) technique. No significant changes in theophylline half-life, volume of distribution, protein binding, total body clearance, or renal clearance were noted. In addition, renal excretion of unchanged theophylline, the products of the N-demethylation, 3-methylxanthine, and 1-methyluric acid, and the product of the 8-oxidation, 1,3-dimethyluric acid, were not altered by simultaneous administration of lomefloxacin. Orally administered lomefloxacin is absorbed quickly and to a high extent. During administration of 400 mg twice daily, plasma concentrations reached are well above minimum inhibitory concentration (MIC) values of pathogens that are frequently isolated in lower respiratory tract infections. This study shows that lomefloxacin in a twice daily dose of 400 mg does not effect theophylline metabolism. Lomefloxacin and theophylline can be coadministered without concern about effects of lomefloxacin on theophylline pharmacokinetics.

Kinetics of L-tryptophan in depressive patients: a possible correlation between the plasma concentrations of L-tryptophan and some psychiatric rating scales.

The plasma concentration and flux of L-tryptophan are abnormal in primary depressive patients, according to the literature. The plasma concentrations of L-tryptophan over a 6-h period after ingestion of 5 g L-tryptophan were investigated and did not differ significantly between depressive patients and controls during the absorption, distribution, and elimination phases. There was no correlation between the plasma concentrations with anxiety or depression scores, or with the excretion in urine of 17-hydroxycorticosteroids and xanthurenic acid during the 24 h after L-tryptophan. Treatment with either 125 mg pyridoxine (three times daily with meals) and L-tryptophan (3 g at 10 PM) or with maprotiline (100 mg at 10 PM) had no influence on the plasma concentrations of L-tryptophan after 2 or 4 weeks of treatment. This excludes L-tryptophan deficiency as a pathogenic factor of depression in the patients studied. No kinetic differences could be demonstrated in the depressive patients, making differences in body compartments or flux of L-tryptophan unlikely to be of pathogenic importance to depression.

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.

Achievement of therapeutic concentrations of cefuroxime in early preterm gestations with premature rupture of the membranes.

OBJECTIVE: To determine whether therapeutic cefuroxime concentrations can be achieved in maternal plasma, amniotic fluid (AF), neonatal plasma, placenta, and membranes in women with premature rupture of the membranes (PROM) at 27-33 weeks' gestation. METHODS: In an open nonrandomized, dose-response study, nine patients with PROM at 27-33 weeks' gestation received 1.5 g of cefuroxime intravenously three times daily. Maternal plasma and AF specimens were collected during pregnancy, and umbilical cord plasma, placenta, and membrane specimens were collected after delivery to assay cefuroxime concentrations using high-performance liquid chromatography. RESULTS: A high rate of placental transfer of cefuroxime was found. Bactericidal concentrations could be demonstrated in maternal plasma and in AF leaking from the vagina. A concentration-time curve in AF could be detected, with a peak concentration 3-4 hours after infusion. Therapeutically active levels were present in the newborns. The resorption of cefuroxime by the fetal membranes was high. CONCLUSIONS: Therapeutic concentrations of cefuroxime were found in all body fluids and tissues studied. Further study to establish the clinical utility of cefuroxime prophylaxis in PROM seems appropriate.

Pharmacokinetics and toxicology of sparsomycin in beagle dogs.

Sparsomycin is a cytotoxic drug exhibiting a broad spectrum of in vitro activity against murine tumors and many tumor cell lines. It also appears to be a potent stimulator of the antitumor activity of cisplatin against L1210 leukemia in vivo. However, because of its toxicity, the antitumor activity of sparsomycin on murine tumors in vivo has been disappointing. The purpose of our study was to investigate the pharmacokinetics of this drug as well as the possible mechanisms that produce sparsomycin toxicity. Tests on beagle dogs revealed that about 60% of the drug is eliminated by metabolic clearance, while 40% is eliminated by the kidneys. After a single bolus injection of 0.1 mg/kg sparsomycin without narcosis, sparsomycin was eliminated with a t beta 1/2 of 0.6-0.7 h, the AUC being 0.32-0.38 mg.h.l-1, and the volume of distribution (Vd) 0.26 l/kg. In addition to being subject to glomerular filtration, sparsomycin is probably also actively excreted and actively reabsorbed by the renal tubuli. Sparsomycin itself may inhibit its active tubular excretion, thus resulting in a decrease in the drug's renal clearance and its accumulation in the plasma. Sparsomycin appeared to be toxic primarily in the liver, disturbing its function and the synthesis of plasma proteins. Two out of five dogs developed hemorrhagic diathesis due to hypofibrinogenemia and deficiency of other blood-coagulation factors. Sparsomycin was not toxic to the bone marrow.

Effects of acute and chronic cocaine administration on EEG and behaviour in intact and castrated male and intact and ovariectomized female rats.

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.

The effect of surgery on the renal excretion of beta 2-microglobulin.

Surgical trauma causes an increase in the renal excretion rate of beta 2-microglobulin whilst creatinine excretion is not influenced. The increase in the renal excretion rate of beta 2-microglobulin is probably the result of an increased release of beta 2-microglobulin by the cells which exceeds a maximum in the active tubular reabsorption of the compound by the proximal tubule cell. The renal excretion of beta 2-microglobulin is proportional to the relative clinical trauma score.

The relationship between the renal clearance of creatinine and the apparent renal clearance of beta-2-microglobulin in patients with normal and impaired kidney function.

The renal clearances of creatinine and beta 2-microglobulin of patients with either normal or impaired kidney function were measured. The renal clearance of beta 2-microglobulin depends on the urinary pH and must be considered as an apparent renal clearance because after tubular reabsorption the compound is metabolized in the kidney. Impaired kidney function reduces the percentage of tubular reabsorption of beta 2-microglobulin.

Interaction between the renal excretion rates of beta 2-microglobulin and tobramycin in man.

The renal excretion rate of beta 2-microglobulin in man is 127 +/- 98 ng/min at alkaline urine pH (pH 7). Tobramycin, up to intravenous doses of 160 mg (2 mg/kg) does not increase the renal excretion rate of beta 2-microglobulin. Tobramycin must have less affinity than gentamicin for the tubular system for active reabsorption of amino groups containing organic compounds. Due to this reduced affinity tobramycin will be absorbed less by the proximal tubular cells, which may be one of the reasons for tobramycin being less toxic than gentamicin. beta 2-Microglobulin excretion can be used as a parameter for the relative binding affinity of aminoglycosides.

Preclinical pharmacokinetics of the antitumor antibiotic deshydroxy-sparsomycin in beagle dogs.

Sparsomycin (Sm) is a well known inhibitor of protein synthesis with anticancer potential. In order to minimize toxicity of this drug and increase its activity, several analogues were synthesized. Deshydroxy-Sm (dSm) appeared to be a good candidate for further investigations because of its lower toxicity and significantly higher antitumor activity in several ascitic tumors in mice. Pharmacokinetic evaluation in beagle dogs was performed using either single iv bolus or continuous infusion administrations. The drug was eliminated with a terminal t1/2 beta of 0.8 +/- 0.08 hours (48 +/- 5 minutes). The mean volume of distribution was 0.4 +/- 0.06 l.kg-1. The mean total body clearance was 6.4 +/- 0.8 ml.min-1.kg-1. The drug is eliminated mainly by the kidneys (54%). Active tubular secretion and active tubular reabsorption of the drug were observed. The pharmacokinetics was linear until the lethal dose. The results of this study provided additional data useful in selection of potentially useful analogues for further preclinical studies.

Clinical pharmacokinetics of drugs used in the treatment of status epilepticus.

Pharmacokinetics as the basis for dosage calculation for acute and subacute treatment of status epilepticus have been discussed. Bolus injection and intravenous infusion are the most common forms of drug administration in these cases. Rectal administration may be a good alternative in certain conditions. Intravenous diazepam and phenytoin are the first-line drugs against status epilepticus. Diazepam and sodium valproate have been reported to be effective by the rectal route. Depending on its pharmacokinetic parameters, each drug effect has a different onset, intensity, and time course.