J. Zuidema

Lymphatic uptake and biodistribution of liposomes after subcutaneous injection.: II. Influence of liposomal size, lipid composition and lipid dose

The present paper reports on the results of a systematic study on liposome variables potentially affecting lymphatic disposition and biodistribution of liposomes after sc injection. Liposomal size was found to be the most important factor influencing lymphatic uptake and lymph node localization of sc administered liposomes. Lymphatic uptake from the s.c. injection site of small liposomes (about 0.04 microm) was relatively high (76% of the injected dose (%ID)) as compared to large, non-sized liposomes, which remained almost completely at the site of injection. Small liposomes were less efficiently retained by regional lymph nodes than larger liposomes. Liposomal lipid composition did not influence lymphatic uptake with one exception: Lymphatic uptake was decreased in case of neutral liposomes composed of (DPPC). Lymph node localization was substantially enhanced by inclusion of phosphatidylserine (PS) into the liposomal bilayers. Saturation of lymphatic uptake and lymph node localization did not occur over a large liposomal lipid dose range, illustrating the efficient performance of lymph nodes in capturing s.c. administered particles.

The pharmacokinetics of artemisinin after oral, intramuscular and rectal administration to volunteers

Abstract— The pharmacokinetics after oral, intramuscular and rectal administration of artemisinin, a new potent antimalarial drug, to healthy volunteers has been examined. The study was set‐up as a four‐way cross‐over design with a wash‐out period of one week between the test days. In ten volunteers artemisinin concentrations in serum were monitored using a reversed phase HPLC assay with UV detection after derivatization. After oral administration, artemisinin was rapidly but incompletely absorbed, the mean absorption time was 0.78 h and the bioavailability relative to the intramuscularly injected suspension in oil 32%. The mean residence time of the latter (10.6 h) was 3 times that of the oral formulation (3.4 h). This seems to enable a twice daily dosage regimen for the intramuscular oil injection, while the oral formulation necessitates a more frequent dosing interval. After intramuscular injection and rectal administration of an aqueous suspension, very low and variable artemisinin concentrations in serum were observed, probably indicating a poor and erratic absorption.

OXIDATIVE STRESS IN MALARIA; IMPLICATIONS FOR PREVENTION AND THERAPY

Malaria affects world-wide more than 200 million people, of which 1–2 million die every year. New drugs and treatment strategies are needed to face the rapidly increasing problems of drug resistance.During a malaria infection, both host and parasite are under oxidative stress. Increased production levels of reactive oxygen species (ROS, e.g. superoxide anion and the hydroxyl radical) are produced by activated neutrophils in the host and during degradation of haemoglobin in the parasite.The effects of ROS in malaria can be both beneficial and pathological, depending on the amount and place of production. Enhanced ROS production after the administration of pro-oxidants, which is directed against the intra-erythrocytic parasite, inhibits the infection bothin vitro andin vivo. However, ROS are also involved in pathological changes in host tissue like damage of the vascular endothelial lining during a malaria infection (cerebral malaria).Pro-oxidants support the host defense against the parasite when working in or near the infected cell but potentially cause vascular damage when working on or near the vascular lining. Examples of pro-oxidants are found among xenobiotics and food components. Important new drugs belonging to the class of pro-oxidants are artemisinin and its derivatives. Anti-oxidants potentially counteract these agents.Treatment with anti-oxidants or chelators of metals to prevent their catalytic function in the generation of ROS may prevent vascular pathology. In addition, the iron chelator desferrioxamine, exhibits an antiparasitic activity, because iron is also essential for the proliferation of the parasite.Cytokines play an important role in ROS-related pathology of malaria, though their mechanism of action is not completely elucidated. This field might bring up new treatment concepts and drugs.Drugs which prevent host pathology, such as the cerebral complications might be life saving.

Release and absorption rates of intramuscularly and subcutaneously injected pharmaceuticals (II)

Abstract The rate and extent of intramuscular (i.m.) and subcutaneous (s.c.) drug absorption are very erratic and variable. The lipophilicity of the compound plays an important role. Aqueous drug solutions and suspensions of the more lipophilic compounds are often absorbed incompletely within the therapeutically relevant time. More hydrophilic compounds are absorbed completely. Injection depth, drug concentration and vehicle volume, pH-p K a relation, vehicle, cosolvents and surfactants have strong influences on the absorption profile of lipophilic drugs. Aqueous solutions of hydrophilic drugs are less sensitive to these factors. Drug solutions in oil and even suspensions in oil are often thought to be sustained release preparations. In fact, rapid absorption has often been observed. Slow release is not a property of the oily vehicle but is achieved by a high lipophilicity of the dissolved or suspended compound. Liposomal preparations are currently under investigation as i.m. and s.c. injectable sustained release preparations. Factors that induce drug release at the injection sites are the proteins and especially lipoproteins in the interstitial fluids, originating from serum filtrate and from turnover of inflammatory cells. Phagocytosis by macrophages and fat cells may play an important role in the local clearance of liposomal material from the injection site. Sustained release of some pharmaceuticals with normal or long half-lives appeared in specific cases preferable to rapid release. In addition, high arterial drug concentrations during the absorption phase may result in undesired effects even when venous drug concentrations are within the safe range.

Preparation and characterisation of Poly (d,l-lactic-co-glycolic acid) microspheres containing desferrioxamine

Abstract The iron chelator desferrioxamine (DFO) demonstrates antimalarial activity upon multiple or continuous parenteral administration. The aim of this study was to develop a controlled release system for the water-soluble drug DFO based on poly ( d , l -lactic-co-glycolic acid) (PLGA). PLGA microspheres containing DFO were prepared using the water-in-oil-in-water (w/o/w) solvent evaporation technique. The influence of formulation parameters (internal phase volume and polymer concentration) on the microsphere characteristics (particle size, porosity, encapsulation efficiency of DFO) and DFO release profile were investigated. An increasing internal phase volume at a fixed polymer concentration resulted in an increasing volume weight mean diameter, an increasing porosity and a decreasing encapsulation efficiency. An increasing PLGA concentration at a fixed internal phase volume resulted in a decreasing porosity of the particles with an increased volume weight mean diameter and encapsulation efficiency of DFO. DFO was released from the microspheres in an initial burst (controlled by formulation parameters) followed by marginal release and a pulse release at the time the microspheres start to dissolve (20–30 days). The release of DFO was incomplete after complete dissolution of the microspheres. This is probably caused by the instability of DFO at low pH, generated upon degradation of the PLGA matrix.

Formulation and pharmacokinetics of artemisinin and its derivatives

Abstract Artemisinin, the leading compound of a completely deviant class of drugs, might be of incredible importance in the combat of malaria. Although the herb from which it is isolated has been known for more than 2000 years, and over 2000 patients have been successfully treated in clinical studies, no pharmacokinetic data are available, and thus empirical formulations are used. In this review the available literature on formulation and kinetic aspects of artemisinin and its derivatives is reinterpreted and discussed in order to determine the kinetic requirements for a rational and optimal design of artemisinin formulations.

Lymphatic Uptake and Biodistribution of Liposomes after Subcutaneous Injection I. Influence of the Anatomical Site of Injection

AbstractLiposomes have been proposed as carriers for the delivery of therapeutic and diagnostic agents to the lymphatic system. Subcutaneous (s.c.) injection is the route of administration most extensively studied for this purpose. To establish the influence of the anatomical site of s.c. injection on lymphatic uptake of liposomes, we have examined the pharmacokinetics and biodistribution of small (0.10 μm) [3H]-labeled liposomes administered at three different s.c. sites of the rat. Lymphatic uptake of liposomes from the s.c. site of injection, lymph node localization and biodistribution in liver, spleen and kidneys were highly dependent on the site of injection. s.c. injection into the dorsal side of the foot or in the footpad resulted in relatively high uptake of liposomes from the site of injection as compared to uptake from the s.c. injection site at the flank. Moreover, injection into the dorsal side of the foot or in the footpad resulted in relatively high levels of radioactivity in regional lymph ...

The Parenteral Controlled Release of Liposome Encapsulated Chloroquine in Mice

Abstract— Free (0.6 mg), and liposome encapsulated chloroquine (0.6, 3 mg), were injected intraperitoneally, intramuscularly and subcutaneously in mice. Intraperitoneal administration of liposome‐encapsulated chloroquine resulted in high and long lasting concentrations of chloroquine in the blood compared with intraperitoneal administration of free chloroquine. After administration of the liposome‐encapsulated chloroquine the concentrations in the spleen were also higher, indicating that chloroquine liposomes reached the blood compartment intact after intraperitoneal administration. After intramuscular and subcutaneous administration the chloroquine liposomes acted as a local depot, giving a slower release from the subcutaneous fat layer than from the muscle depot. After the 0.6 mg dose a burst effect was found at about 7 h in most of the animals; this was not found after the 3 mg dose. This finding and the slower release after the 3 mg dose than after the 0.6 mg dose could be explained by the formation of aggregates after the injection.

Evaluation of the Salivette as sampling device for monitoring β-adrenoceptor blocking drugs in saliva

The Salivette was evaluated with a range of racemic beta-adrenoceptor blocking drugs with different lipophilicity. Recovery from the Salivette appeared to be independent of the stereochemical configuration of the drugs but a significant loss of drug due to the Salivette was observed for all tested drugs. The performance of the method, in terms of accuracy and precision, fitted well within the generally accepted criteria for validation, except near the limit of quantification. The Salivette is successfully used for quantitating salivary beta-blocking drugs.

Pharmacokinetic and Pharmacodynamic Aspects of Artelinic Acid in Rodents

Abstract— The efficacy of artelinic acid and artemisinin, orally administered at 10 and 50 mg kg−1 day−1, was compared in Plasmodium berghei infected mice. Subsequently, the pharmacokinetics of artelinic acid after intravenous, intramuscular, oral and rectal administration of a 20 mg kg−1 aqueous solution to rabbits were studied in a four‐way randomized cross‐over experiment. After intravenous administration, artelinic acid concentrations in blood plasma were high (C0: 76 ± 15 mg L−1), and the drug was rapidly eliminated from the central compartment, showing linear elimination kinetics with an elimination half‐life of 15 ± 3 min. A large inter‐subject variation appeared in the absorption rate and the extent of absorption (2–92%) over the 120 min interval after intramuscular administration. Also, a large inter‐subject variation in individual rectal bioavailability (17–100%) was shown, which was dependent on the site of absorption in the rectum. The estimated oral bioavailability was low (4·6 ± 1·7%), probably due to a high first‐pass effect and possible decomposition in the acidic gastric environment.