ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Altretamine (hexamethylmelamine) is an antitumour drug with demonstrated antitumour activity in refractory ovarian cancer. Due to its poor water solubility, the drug has been given by the oral route. In all animal species, including humans, altretamine undergoes oxidativeN-demethylation with the formation of hydroxymethyl derivatives as intermediates. Hydroxymethylmelamines are believed to be responsible for the cytotoxic and antitumour activity of the drug.The inter- and intrapatient variability of the bioavailability of altretamine after oral administration represents an important drawback for effective clinical use of this drug. The variability appears to be mostly related to the first-pass effect and therefore may be overcome by intravenous administration of the drug. Although attempts to administer the drug intravenously have not been successful in the past, some investigations on the use of the new parental formulation of altretamine are in progress.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Tacrine is currently the only treatment approved for use in Alzheimer's disease. There is, however, considerable debate over its effectiveness due to conflicting clinical trial results. Most investigators agree, nevertheless, that a definite sub-population of patients do benefit from therapy with tacrine.Tacrine is associated with large pharmacokinetic interindividual variation within both patient and control groups. This is thought to influence both the efficacy and incidence of symptomatic adverse effects in individual patients.Following oral administration of tacrine the drug is rapidly and well absorbed with peak plasma concentrations (Cmax) achieved within 0.5 to 3 hours (after a single dose of 20 to 50mg). Tacrine appears to have a wide tissue distribution, which is reflected by its large volume of distribution. High concentrations of the drug were found in the kidney, liver, adrenal gland and brain tissue in animal models. It has a low bioavailability following oral intake, thought to result from extensive first-pass metabolism. Bioavailability can be increased upon rectal administration. The drug is rapidly and extensively metabolised in humans.In vitrometabolism studies have demonstrated the importance of cytochrome P450 (CYP1A2) in the biotransformation of tacrine to 1-, 2-, 4- and 7-hydroxylated metabolites. In humans, mono- and dihydroxylated tacrine and glucuronide conjugates were identified in the urine, which was the primary route of excretion. The elimination half-life of tacrine was short, 1.5 to 2.5 hours after single oral and intravenous doses and 2.9 to 3.6 hours after multiple oral doses.At low doses (10mg) of tacrine, the pharmacokinetic profile was nonlinear and the oral bioavailability of the drug was disproportionately low in comparison to higher doses of tacrine (20mg). This may reflect saturable hepatic uptake of the parent compound.Both symptomatic and asymptomatic adverse effects occur frequently with tacrine therapy (32 to 80% of patients). These adverse reactions, ranging from predictable cholinergic effects to nonpredictable elevations in serum transaminase levels, can however be reversed by dosage withdrawal and/or adjustment. It has been postulated that the elevated levels of transaminase associated with tacrine therapyin vivoare dependent upon bioactivation of tacrine, mediated by hepatic CYP1A2, to form a toxic compound.Limited data are available regarding the propensity of tacrine to interact with other drugs. In one study, concomitant administration of theophylline led to an alteration of the pharmacokinetics of theophylline, whereas an elevation of plasma tacrine concentrations results from coadministration of cimetidine. Both of these effects are thought to be due to the interaction of the agents with CYP1A2. Therefore, the potential for tacrine to be subject to interactions with other drugs that are substrates of this enzyme should be recognised.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Lansoprazole, a benzimidazole derivative with antisecretory and antiulcer activities, inhibits the acid pump activity at the final stage of the enzyme process and therefore reduces the acid secretion of parietal cells. Lansoprazole is converted to active metabolites in the acid environment of these cells. It is rapidly absorbed from a gastric acid-resistant formulation and is approximately 97% bound in human plasma.Single dose pharmacokinetics of lansoprazole appear to be linear over the range from 15 to 60mg. Food and time of dose influence absorption after single doses, but do not modify the antisecretory effect of multiple doses. Lansoprazole is extensively metabolised following oral administration into sulphone and 5-hydroxylated metabolites by the cytochrome P450 enzymes CYP3A4 and CYP2C18. Two other metabolites have been identified in plasma: sulphide and hydroxylated sulphone.Mean plasma elimination half-life (t½) is between 1.3 and 2.1 hours in healthy volunteers. 15 to 23% of the total dose is found in urine as free and conjugated hydroxylated metabolites, while unchanged lansoprazole is not detected. The pharmacokinetic profile of the drug is not modified by multiple administration. In healthy elderly volunteers, area under the plasma concentration-time curve (AUC) and t½are significantly greater after single administration than that in young volunteers; accumulation from repeated daily administration occurs to the same extent as in young volunteers.Renal failure has no influence on the pharmacokinetics of lansoprazole, but severe hepatic failure causes a significant decrease in clearance and an increase in the AUC and t½of lansoprazole. This is accompanied by modifications in the AUC of metabolites, but severe hepatic failure has minimal effect on accumulation of the drug after multiple administration. The pharmacokinetics of lansoprazole in patients with acid-related disorders do not differ from those in healthy volunteers. Studies of interactions of lansoprazole with warfarin, prednisone, theophylline, phenazone (antipyrine), diazepam, phenytoin and oral contraceptives suggest minimal risk of any clinically significant interaction.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Immune protective devices containing pancreatic islets are designed to treat insulin-dependent diabetes mellitus by providing glycaemic control without immunosuppression. The immune protection is achieved by separating allogeneic or xenogeneic islets from the host by semipermeable membranes that allow only small molecules such as glucose, insulin and nutrients to pass through. Lymphocytes and immunoglobulins are excluded by the membrane and unable to cause rejection of the islets.Three types of immune protective devices, i.e. microcapsules, diffusion chambers and perfusion devices (vascularised artificial pancreas), have been studied. Microcapsules injected into the abdominal cavity in a large quantity achieved glycaemic control, but required a small amount of immunosuppression to prevent fibrosis around the capsules. A clinical attempt to use microcapsulated human islets in a diabetic patient who has maintained functional kidney allografts has been reported. Intra-abdominal placement of diffusion chambers containing allogeneic islets achieved excellent glycaemic control without immunosuppression in diabetic dogs. However, their use was limited by the eventual breakage of tubular chambers. We have extensively used the vascularised artificial pancreas for treatment of experimental diabetes mellitus. Excellent biocompatibility of the device was evidenced by the extraordinary longevity of the patency of the device in healthy dogs. Long term control of severe diabetes mellitus was achieved in totally pancreatectomised dogs without immunosuppression by devices seeded with allogeneic (canine) and xenogeneic (porcine) islets. The vascularised artificial pancreas could be an excellent alternative to Diabetes Control and Complication Trial (DCCT)-type intensive insulin therapy or pancreatic transplantation by providing tight glycaemic control with minimal exogenous insulin therapy without immunosuppression.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Digoxin intoxication occurs frequently and may require treatment with digoxin-specific Fab therapy. Little is known, however, regarding the biological fate of this compound. Pharmacokinetic studies have not been performed in healthy volunteers, but there are limited kinetic data from patients who have received therapy for the treatment of digoxin toxicity. Digoxin-specific Fab is eliminated via renal and nonrenal routes, having a volume of distribution slightly exceeding extracellular volume (0.40 L/kg) and an elimination half-life of 16 to 20 hours. Patients with renal impairment and end-stage renal disease have elimination half-life values that are prolonged up to 10-fold in magnitude, while volume of distribution is unaffected. Systemic clearance of digoxin-specific Fab is approximately 0.32 ml/min/kg in digoxin-toxic patients with preserved renal function. Renal failure also decreases Fab clearance by up to 75%. Therefore, Fab may reside in the serum of anephric patients for 2 to 3 weeks after administration.More important is the effect of Fab on the disposition of digoxin. Because digoxin-specific Fab has a stronger digoxin-binding affinity than do biological membranes, it can sequester tissue-bound and intracellular digoxin into the extracellular spaces. This results in a rapid increase in digoxin serum concentrations in the central compartment. Since the majority of digoxin is bound by Fab, it cannot interact with its biological receptor and thus reverses digoxin toxicity.The pharmacokinetic fate of total digoxin after administration of digoxin-specific Fab follows that of Fab. However, it appears that the elimination half-life of Fab is slightly shorter than that of total digoxin in patients with end-stage renal disease, suggesting that the clearance of Fab is slightly faster than that of total digoxin. Free digoxin concentrations fall rapidly after Fab administration and then rebound upwards within 12 to 24 hours. This rebound in free digoxin concentrations, however, is delayed by 12 to 130 hours in patients with renal dysfunction and end-stage renal disease. Rebound in free digoxin concentrations occurs during the initial phase of the biexponential decline of the serum concentration-time profile for digoxin-specific Fab, suggesting that distribution from the vascular spaces is the likely cause. Following the increase, free digoxin concentrations decline in a manner that is dependent on renal and nonrenal routes of elimination. During this time period it is evident that Fab retains its capability of binding digoxin while it resides in plasma.There is no evidence to support a dissociation between the Fab-digoxin complex over extended periods of time. This was demonstrated in a report where the free fraction of digoxin, in the presence of Fab remained less than the free fraction in the absence of Fab. Recent evidence also supports the role of monitoring free digoxin concentrations in certain patients who received digoxin-specific Fab therapy as they are more predictive of the pharmacological activity of digoxin than either total or bound digoxin concentrations. Indeed, free digoxin concentrations correlate with recurrences of digoxin toxicity, the need for supplemental Fab doses, and the efficacy of digoxin therapy initiated during Fab therapy.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS

摘要:

Psychotic symptoms related to mental and medical disorders can pose a medical emergency. Selecting an appropriate antipsychotic medication to treat this emergency is based on the clinical situation, preferred route of administration, pharmacokinetic profile of the antipsychotic and the medications currently being taken by the patient. Intramuscular preparations are usually preferred over oral medication when the patients are not co-operative and require drugs with a faster onset of action and good bioavailability.High potency antipsychotics such as haloperidol and fluphenazine are effective in stabilising patients with psychotic symptoms quickly. Loxapine is an alternative when sedation is necessary and molindone is useful if a short-acting antipsychotic is required. Rapid neuroleptisation with intramuscular preparations of antipsychotic achieves therapeutic drug concentrations more rapidly, and also provides optimal control of psychotic symptoms. If the patient is cooperative, liquid oral preparations can be used; they are as effective as intramuscular formulations.If long term treatment with an antipsychotic is necessary and the patients are stabilised, they can be switched from intramuscular to oral preparations. The oral dose is usually 1.5 to 5 times the total intramuscular dose per day, based on the bioavailability of the antipsychotic medication. If the patient is currently taking antipsychotic medication when the emergency situation occurs, it is usually adequate to increase the dose of antipsychotic drug.Appropriate dose adjustment or antipsychotic selection is necessary when drug interactions are expected. An in-depth knowledge of the pharmacokinetic profile and drug interaction profile of antipsychotic is necessary for the selection of the appropriate antipsychotic for any given emergency situation.

ISSN:0312-5963    

出版商:ADIS    

年代:1995

数据来源: ADIS