Lipid, sugar and liposaccharide based delivery systems

Although there are formidable barriers to the oral delivery of biologically active drugs, considerable progress in the field has been made, using both physical and chemical strategies of absorption enhancement. A possible method to enhance oral absorption is to exploit the phenomenon of lipophilic modification and mono and oligosaccharide conjugation. Depending on the uptake mechanism targeted, different modifications can be employed. To target passive diffusion, lipid modification has been used, whereas the targeting of sugar transport systems has been achieved through drugs conjugated with sugars. These drug delivery units can be specifically tailored to transport a wide variety of poorly absorbed drugs through the skin, and across the barriers that normally inhibit absorption from the gut or into the brain. The delivery system can be conjugated to the drug in such a way as to release the active compound after it has been absorbed (i.e. the drug becomes a prodrug), or to form a biologically stable and active molecule (i.e. the conjugate becomes a new drug moiety). Examples where lipid, sugar and lipid-sugar conjugates have resulted in enhanced drug delivery will be highlighted in this review.

Drug use evaluation of ipratropium bromide at two tertiary referral hospitals in Brisbane.

Objective: To assess the appropriateness of ipratropium bromide prescribing in two tertiary referral hospitals. Method: Criteria for optimal use were developed based on current literature and modified after consultation with respiratory physicians and clinical pharmacists. A prospective review of prescribing was performed over a 2-month period to assess conformity to these criteria. Results: Information was collected from 84 patients; 5% were receiving inhalers and 96% nebuliser therapy (one patient used both). 77% of patients (n = 65) had a principal diagnosis of chronic obstructive pulmonary disease, 14% (n = 12) asthma and 8% (n = 7) had neither diagnosis. 75% of patients were using ipratropium outside the guidelines. The major areas where the guidelines were not met were a lack of therapeutic justification, use of inappropriate doses, and use of an inappropriate delivery device. Feedback and educational interventions were designed and delivered based on the data obtained. Conclusions: There was widespread use of ipratropium outside the developed guidelines. Interventions in specific areas could lead to significant improvements in the use of this high cost drug

Population pharmacokinetics of magnesium in preeclampsia

OBJECTIVE: The purpose of this study was to determine the population pharmacokinetics of magnesium from sparse observational data in patients with preeclampsia. STUDY DESIGN: Serum magnesium concentrations (1-11 per patient) were obtained retrospectively from the records of 116 patients with preeclampsia who had a loading dose of magnesium sulfate (16 or 20 mmol), followed by a maintenance dose (1 mmol/h) over an average of 28 hours. Population clearance, volume of distribution, and the baseline magnesium concentration were estimated using the NONMEM program. RESULTS: The following population typical values, together with the interpatient variability (expressed as coefficient of variation) were obtained with the use of a 1-compartment model: systemic clearance, 4.28 L/h (37.3%); volume of distribution, 32.3 L (32.1%); baseline concentration, 0.811 mmol/L (18.5%). The average half-life was 5.2 hours. Clonus was not obtunded in 4 patients whose serum magnesium concentrations were similar to the average concentration of 1.7 mmol/L. The variability remaining unexplained after the population model was fitted to the data was 6.5% to 10.8%. CONCLUSION: This study extended knowledge of the pharmacokinetic disposition of magnesium in preeclampsia. The results are potentially useful for the calculation of loading and maintenance doses, particularly when the relationship between serum concentration and effect in preeclampsia is clarified.

Species and regional variations in the effectiveness of antivenom against the in Vitro neurotoxicity of death adder (Acanthophis) venoms

Although viperlike in appearance and habit, death adders belong to the Elapidae family of snakes. Systemic envenomation represents a serious medical problem with antivenom, which is raised against Acanthophis antarcticus venom, representing the primary treatment. This study focused on the major Acanthophis variants from Australia and islands in the Indo-Pacific region. Venoms were profiled using liquid chromatography-mass spectrometry, and analyzed for in vitro neurotoxicity (0.3-10 mug/ml), as well as the effectiveness of antivenom. (1-5 units/ml; 10 min prior to the addition of 10 mug/ml venom). The following death adder venoms were examined: A. antarcticus (from separate populations in New South Wales, Queensland, South Australia, and Western Australia), A. hawkei, A. praelongus, A. pyrrhus, A. rugosus, A. wellsi, and venom from an unnamed species from the Indonesian island of Seram. All venoms abolished indirect twitches of the chick isolated biventer cervicis nerve-muscle preparation in a dose-dependent manner. In addition, all venoms blocked responses to exogenous acetylcholine (1 m-M) and carbachol (20 muM), but not KCl (40 mM), suggesting postsynaptic neurotoxicity. Death adder antivenom (1 unit/ml) prevented the neurotoxic effects of A. pyrrhus, A. praelongus, and A. hawkei venoms, although it was markedly less effective against venoms from A. antarcticus (NSW, SA, WA), A. rugosus, A. wellsi, and A. sp. Scram. However, at 5 units/ml, antivenom was effective against all venoms tested. Death adder venoms, including those from A. antarcticus geographic variants, differed not only in their venom composition but also in their neurotoxic activity and susceptibility to antivenom. For the first time toxicological aspects of A. hawkei, A. wellsi, A. rugosus, and A. sp. Seram venoms were studied. (C) 2001 Academic Press.

Hepatocyte [H-3]-palmitate uptake: effect of albumin surface charge modification

The role of plasma proteins on the cellular uptake of lipophilic substrates has perplexed investigators for many years. We tested the hypothesis that an ionic interaction between the protein-ligand complex and hepatocyte surface may be responsible for supplying more ligand to the cell for uptake. The surface-charged groups on albumin were modified to yield proteins having a range of isoelectric points (ALB, ALBs, ALBm, ALBe had values of 4.8-5.0, 4.5-4.7, 3.0-3.5, 8.4-8.6, respectively). [H-3]-Palmitate uptake studies were performed with adult rat hepatocyte suspensions using similar unbound ligand fractions in the presence of the different binding proteins. Mass spectrometry, isoelectric focusing (pI), and heptane : water partitioning were used to determine protein molecular weight, pI, and protein-palmitate equilibrium binding constant, respectively. Hepatocyte [H-3]-palmitate clearance in the presence of ALBs and ALBm were significantly lower (p < 0.05) than ALB, whereas [H-3]-palmitate clearance in the presence of ALBe was significantly higher (p < 0.05) than ALB. The data were consistent with the notion that ionic interactions between extracellular protein-ligand complexes and the hepatocyte surface facilitate the uptake of long-chain fatty acids.

Hydromorphone-3-glucuronide - A more potent neuro-excitant than its structural analogue, morphine-3-glucuronide

In humans, hydromorphone (HMOR) is metabolised principally by conjugation with glucuronic acid to form hydromorphone-3-glucuronide (H3G), a close structural analogue of morphine-3-glucuronide (M3G), the major metabolite of morphine. In a previous study we described the biochemical synthesis of H3G together with a preliminary evaluation of its pharmacology which revealed that it is a neuro-excitant in rats in a manner analogous to M3G. Thus the aims of the current study were to quantify the neuro-excitatory behaviours evoked by intracerebroventricular (icv) H3G in the rat and to define its potency relative to M3G. Groups of adult male Sprague-Dawley rats received icy injections (1 muL) of H3G (1 - 3 mug), M3G (2 - 7 mug) or vehicle via a stainless steel guide cannula that had been implanted stereotaxically seven days prior to drug administration. Behavioural excitation was monitored by scoring fifteen different behaviours (myoclonic jerks, chewing, wet-dog-shakes, rearing, tonic-clonic-convulsions, explosive motor behaviour, grooming, exploring, general activity, eating, staring, ataxia, righting reflex, body posture, touch evoked agitation) immediately prior to icy injection and at the following post-dosing times: 5, 15, 25, 35, 50, 65 and 80 min. H3G produced dose-dependent behavioural excitation in a manner analogous to that reported previously for M3G by our laboratory and reproduced herein. H3G was found to be approximately 2.5-fold more potent than M3G, such that the mean (+/- S.D.) ED50 values were 2.3 (+/- 0.1) mug and 6.1 (+/- 0.6) mug respectively. Thus, our data clearly imply that if H3G crosses the BBB with equivalent efficiency to M3G, then the myoclonus, allodynia and seizures observed in some patients dosed chronically with large systemic doses of HMOR, are almost certainly due to the accumulation of sufficient H3G in the central nervous system, to evoke behavioural excitation. (C) 2001 Elsevier Science Inc. All rights reserved.

Clinically significant drug interactions with agents specific for migraine attacks

The drugs which provide specific relief from migraine attacks, the ergopeptides (ergotamine and dihydroergotamine) and the various 'triptans' (notably sumatriptan), are often prescribed for persons already taking various migraine preventative agents, and sometimes drugs for other indications. As a result, migraine-specific drugs may become involved in drug-drug interactions. The migraine-specific drugs all act as agonists at certain subclasses of serotonin (5-hydroxytryptamine; 5-MT) receptor, particularly those of the 5-HT1D subtype, and produce vasoconstriction through these receptor-mediated mechanisms. The oral bioavailabilities of these drugs, particularly those of the ergopeptides, are often incomplete, due to extensive presystemic metabolism. As a result, if migraine-specific agents are coadministered with drugs with vasoconstrictive properties, or with drugs which inhibit the metabolism of the migraine-specific agents, there is a risk of interactions occurring which produce manifestations of excessive vasoconstriction. This can also occur through pharmacodynamic mechanisms, as when ergopeptides or triptans are coadministered with methysergide or propranolol (although a pharmacokinetic element may apply in relation to the latter interaction), or if one migraine-specific agent is used shortly after another. When egopeptide metabolism is inhibited by the presence of macrolide antibacterials, particularly troleandomycin and erythromycin, the resultant interaction can produce ergotism, sometimes leading to gangrene. Similar pharmacokinetic mechanisms, with their vasoconstrictive consequences, probably apply to combination of the ergopeptides with HIV protease inhibitors (indinavir and ritonavir), heparin, cyclosporin or tacrolimus. Inhibition of triptan metabolism by monoamine oxidase A inhibitors, e.g. moclobemide, may raise circulating triptan concentrations, although this does not yet seem to have led to reported clinical problems. Caffeine may cause increased plasma ergotamine concentrations through an as yet inadequately defined pharmacokinetic interaction. However, a direct antimigraine effect of caffeine may contribute to the claimed increased efficacy of ergotamine-caffeine combinations in relieving migraine attacks. Serotonin syndromes have been reported as probable pharmacodynamic consequences of the use of ergots or triptans in persons taking serotonin reuptake inhibitors. There have been two reports of involuntary movement disorders when sumatriptan has been used by patients already taking loxapine. Nearly all the clinically important interactions between the ergopeptide antimigraine agents and currently marketed drugs are likely to have already come to notice. In contrast, new interactions involving the triptans are likely to be recognised as additional members of this family of drugs, with their different patterns of metabolism and pharmacokinetics, are marketed.

Can anticonvulsant drug therapy 'cure' epilepsy?

There is now evidence to show that, as time passes, epilepsy, even if untreated, tends to undergo spontaneous remission in a significant proportion of patients. The question therefore arises as to whether anticonvulsant drug therapy increases this chance of the patient with epilepsy ultimately entering a terminal remission which continues after the treatment is withdrawn, Le. whether anticonvulsant drug therapy itself may sometimes cure epilepsy. There are no well-designed studies available in the literature that provide a clear answer to this question. However, data from a number of investigations carried out for other purposes can be used to see whether contemporary anticonvulsant drug therapy is associated with higher rates of expected untreated terminal remission than those that apply for never-treated patients with epilepsy, or for those whose anticonvulsant treatment has probably been inadequate for various social or historical reasons. Despite the admitted uncertainties inherent in drawing conclusions from such material, there appears to be a reasonably consistent tendency for contemporary anticonvulsant drug treatment to be associated with a greater chance of achieving probable cure of epilepsy. Therefore it would appear premature to take the view that contemporary anticonvulsant drug therapy does no more than suppress epileptic seizures until epilepsy remits spontaneously, or fails to remit, with the passing of time.

Valproic acid has temporal variability in urinary clearance of metabolites

The reasons for the intra- and interindividual variability in the clearance of valproic acid (VPA) have not been completely characterized. The aim of this study was to examine day-night changes in the clearance of 3-oxo-valproate (3-oxo-VPA), 4-hydroxy-valproate (4-OH-VPA), and valproic acid glucuronides under steady state. Six diurnally active healthy male volunteers ingested 200 mg sodium valproate 12 hourly, at 0800 and 2000, for 28 days. On the last study day, two sequential 12-h urine samples were collected commencing at 2000 the evening before. Plasma samples were obtained at the end of each collection. Following alkaline hydrolysis, urine was analyzed for concentrations of VPA, 3-oxo-VPA, and 4-OH-VPA. A separate aliquot was assayed for creatinine (CR). The plasma concentrations of VPA, 3-oxo-VPA, 2-en-VPA, and CR were determined. The analysis of VPA and its metabolites was performed by CC-MS. There was an increase in plasma 3-oxo-VPA concentration at 0800, sampling as compared to 2000 sampling (p < .05). The urinary excretion of 3-oxo-VPA and VPA glucuronides were decreased between 2000 and 0800, compared to between 0800, and 2000, by 30% and 50% respectively (p < .05). These results indicate a nocturnal decrease in renal clearance of 3-oxo-VPA rather than a decrease in the beta -oxidation of VPA at night. These differences were not explained by differences between the sampling periods in CR excretion. These results indicate the importance of collecting samples of 24-h duration when studying metabolic profiles of VPA.