Changes In Drug Distribution Research Articles

Are Polish Hospital Pharmacies Ready for Changes in Drug Distribution?

All tasks performed by hospital pharmacies concern the management of medicinal products. The aim of this work is to analyze the functioning and implemen-tation costs of unit-dose and multi-dose automatic drug distribution systems in comparison with the classical mode of so-called ward medicine cabinets. The study was conducted from January 2020 to October 2021. It included quantitative study, conducted to verify the functioning of hospital phar-macies based on an original questionnaire, which was completed by 26 masters of pharmacy em-ployed in pharmacies hospitals, of which 92.4% were pharmacy head, and in-depth face-to-face interviews conducted in 4 facilities with unit-dose systems and one center that uses the multi-dose system. The work presents the functioning of hospital pharmacies, and the advantages and disadvantages of classical distri-bution model. Opinions on the operation of unit-dose and multi-dose systems as well as experiences related to their implementation in the hospital, including the necessary changes in the structure and organization of the hospital, were also presented. In conclusion, despite high purchase costs, auto-mated drug distribution systems bring many benefits in the field of hospital functioning, mainly in relation to patient care, improving the effectiveness, safety and individualization of pharmacothera-py. The main barriers to implementation of these systems are high costs, lack of IT infrastructure adaptation, the need to change the organization of staff work and the lack of factory-prepared col-lective packaging. In the opinion of pharmacists, changes in the distribution of drugs are necessary and beneficial from proper pharmacotherapy perspective.

Clozapine-loaded nanocapsules improve antipsychotic activity in rats: building a sequential PopPK/PD model to discriminate nanocarriers in the preformulation step.

We investigated the impact of nanoformulations on the dose-exposure-response relationship of clozapine (CZP), a low-solubility antipsychotic with serious adverse effects, using a popPK/PD approach. We evaluated the pharmacokinetics and PK/PD profiles of three coated polymeric CZP-loaded nanocapsules functionalized with polysorbate 80 (NCP80), polyethylene glycol (NCPEG), and chitosan (NCCS). Data on in vitro CZP release by dialysis bag, plasma pharmacokinetic profiles in male Wistar rats (n = 7/group, 5 mg kg-1, i.v.), and percentage of head movements in a stereotyped model (n = 7/group, 5 mg kg-1, i.p.) were integrated using a sequential model building approach (MonolixSuiteTM-2020R1-Simulation Plus). A base popPK model developed with CZP solution data collected after the i.v. administration of CZP was expanded to describe the changes in drug distribution caused by nanoencapsulation. Two additional compartments were inserted into the NCP80 and NCPEG models, and a third compartment was included in the NCCS model. The nanoencapsulation showed a decrease in the central volume of distribution for NCCS (V1NCpop = 0.21 mL), while for FCZP, NCP80, and NCPEG, it was ~1 mL. The peripheral distribution volume was higher for the nanoencapsulated groups (19.1 and 129.45 mL for NCCS and NCP80, respectively) than for FCZP. The popPK/PD model showed a formulation-dependent plasma IC50, with 20-, 50-, and 80-fold reductions compared to the CZP solution (NCP80, NCPEG, and NCCS, respectively). Our model discriminates the coatings and describes the peculiar PK and PD behavior of nanoencapsulated CZP, especially NCCS, making it an exciting tool for evaluating the preclinical performance of nanoparticles.

Mechanistic basis for multidrug resistance and collateral drug sensitivity conferred to the malaria parasite by polymorphisms in PfMDR1 and PfCRT.

Polymorphisms in the Plasmodium falciparum multidrug resistance protein 1 (pfmdr1) gene and the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene alter the malaria parasite’s susceptibility to most of the current antimalarial drugs. However, the precise mechanisms by which PfMDR1 contributes to multidrug resistance have not yet been fully elucidated, nor is it understood why polymorphisms in pfmdr1 and pfcrt that cause chloroquine resistance simultaneously increase the parasite’s susceptibility to lumefantrine and mefloquine—a phenomenon known as collateral drug sensitivity. Here, we present a robust expression system for PfMDR1 in Xenopus oocytes that enables direct and high-resolution biochemical characterizations of the protein. We show that wild-type PfMDR1 transports diverse pharmacons, including lumefantrine, mefloquine, dihydroartemisinin, piperaquine, amodiaquine, methylene blue, and chloroquine (but not the antiviral drug amantadine). Field-derived mutant isoforms of PfMDR1 differ from the wild-type protein, and each other, in their capacities to transport these drugs, indicating that PfMDR1-induced changes in the distribution of drugs between the parasite’s digestive vacuole (DV) and the cytosol are a key driver of both antimalarial resistance and the variability between multidrug resistance phenotypes. Of note, the PfMDR1 isoforms prevalent in chloroquine-resistant isolates exhibit reduced capacities for chloroquine, lumefantrine, and mefloquine transport. We observe the opposite relationship between chloroquine resistance-conferring mutations in PfCRT and drug transport activity. Using our established assays for characterizing PfCRT in the Xenopus oocyte system and in live parasite assays, we demonstrate that these PfCRT isoforms transport all 3 drugs, whereas wild-type PfCRT does not. We present a mechanistic model for collateral drug sensitivity in which mutant isoforms of PfMDR1 and PfCRT cause chloroquine, lumefantrine, and mefloquine to remain in the cytosol instead of sequestering within the DV. This change in drug distribution increases the access of lumefantrine and mefloquine to their primary targets (thought to be located outside of the DV), while simultaneously decreasing chloroquine’s access to its target within the DV. The mechanistic insights presented here provide a basis for developing approaches that extend the useful life span of antimalarials by exploiting the opposing selection forces they exert upon PfCRT and PfMDR1.

Incorporation of Methoxyphenamine into Hair in Early Stage after Intake.

In order to investigate the incorporation behavior of drugs into hair in early stage (within 24 h) after intake, time-course changes in drug distribution in black hair were carefully analyzed after a single oral administration of methoxyphenamine (MOP), a non-regulated analog of methamphetamine. Single-hair specimens collected by plucking with the roots intact at appropriate intervals post-intake were each divided into 1-mm segments from the proximal end, and MOP in each segment was determined by a validated liquid chromatography-tandem mass spectrometry procedure. At 10 min after intake, MOP was not detected in any of the segments. MOP became detectable 30 min after intake in the hair bulb (0-1-mm segment from the proximal end) and 1 h after intake in the upper dermis zone (1-2-mm to 4-5-mm segments). The amount of MOP in the hair bulb increased rapidly over 3 h after intake and reached a maximum concentration of ∼100-900 pg/1-mm single hair (11-95 ng/mg) around 3-10 h after intake, whereas that in the upper dermis zone increased at a more gradual pace over 24 h and reached a plateau at ∼30-100 pg/1-mm hair (3-11 ng/mg). These differences can be attributed to the different incorporation mechanisms of the drug. Results from this study can further elucidate the drug incorporation mechanism, which is crucial for accurately interpreting results in hair analyses. Our findings also suggest that hair drug analysis with special attention to the hair root can serve as a useful complementary approach to urine- and blood-based testing in the field of forensic toxicology.

Drug-Induced Resistance in Micrometastases: Analysis of Spatio-Temporal Cell Lineages

Resistance to anti-cancer drugs is a major cause of treatment failure. While several intracellular mechanisms of resistance have been postulated, the role of extrinsic factors in the development of resistance in individual tumor cells is still not fully understood. Here we used a hybrid agent-based model to investigate how sensitive tumor cells develop drug resistance in the heterogeneous tumor microenvironment. We characterized the spatio-temporal evolution of lineages of the resistant cells and examined how resistance at the single-cell level contributes to the overall tumor resistance. We also developed new methods to track tumor cell adaptation, to trace cell viability trajectories and to examine the three-dimensional spatio-temporal lineage trees. Our findings indicate that drug-induced resistance can result from cells adaptation to the changes in drug distribution. Two modes of cell adaptation were identified that coincide with microenvironmental niches—areas sheltered by cell micro-communities (protectorates) or regions with limited drug penetration (refuga or sanctuaries). We also recognized that certain cells gave rise to lineages of resistant cells (precursors of resistance) and pinpointed three temporal periods and spatial locations at which such cells emerged. This supports the hypothesis that tumor micrometastases do not need to harbor cell populations with pre-existing resistance, but that individual tumor cells can adapt and develop resistance induced by the drug during the treatment.

Incorporation of zolpidem and methoxyphenamine into white hair strands after single administrations: Influence of hair pigmentation on drug incorporation

In order to investigate the influence of pigmentation on the incorporation of drugs into hair, time-course changes in drug distribution along non-pigmented (white) hairs as well as pigmented (black) hairs plucked from the same subject was observed following single administrations of two basic drugs with different properties, zolpidem and methoxyphenamine. These drugs in 1-mm sections of single hair specimens were each determined by a liquid chromatography–tandem mass spectrometric procedure. During the early stage (12–36 h) after intake, for black hairs, both drugs were detected over the entire area of hair root (4–5 mm in length), in which notable concentration of these drugs in the hair bulb (0–1-mm segment from the bottom of hair root, Region 1) and lower concentrations in the upper dermis zone (1–2-mm to 3–4-mm or to 4–5-mm segments, Region 2) were commonly observed. Meanwhile, for white hairs, high drug concentrations in Region 1 as detected in black hairs were not observed although only small amounts of these drugs were detected over Region 2. Subsequent time-course changes in the concentration of drugs in hair demonstrated that the drugs once incorporated into white hair via Region 2 decreased gradually over the period from 24 h to 35 days after intake, but those of black hairs remained almost unchanged. These findings revealed here suggest that hair pigments have two important roles in the distribution of drugs: (1) incorporation of drugs into hair via Region 1, and (2) retention of already incorporated drugs in the hair tissue. These findings would be useful for discussing individual drug-use history based on hair analysis in the forensic fields.

Hair Testing for Drugs in the Field of Forensics

Hair testing for drugs has been used extensively in the field of forensics since the 1990s as a means of obtaining firm evidence of drug ingestion. In addition to its longer detection windows, hair is the only specimen that can provide chronological information on individual drug use. Illicit drugs and hypnotics account for the majority of substances involved in crimes; they are usually analyzed to prove an addictive use or an exposure to drugs in drug-facilitated crimes. The mechanism of drug incorporation into hair has been intensively investigated to properly interpret the results of hair analysis. However, the exact mechanism remains under much discussion, despite the growing application of hair tests. Recently, the authors have applied matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) imaging and sectional hair analysis of 1-mm segments using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for single-strand hair, to investigate the incorporation pathways of drugs into hair. Time-course changes in drug distribution along single-strand hair suggest that the incorporation of drugs occurs in two regions of the hair root, the hair bulb and the upper part of hair root, and suggest that incorporation from the hair bulb continues for about 2 weeks. Distribution profiles of different drugs in hair additionally revealed that the main incorporation pathway varies (i.e., via the hair bulb or the upper part of hair root) depending on the properties of the drug/metabolite. These findings should be taken into account upon discussing individual drug-use history based on the results of hair analysis.

Incorporation of Zolpidem into Hair and Its Distribution after a Single Administration.

To obtain fundamental information on the drug incorporation into hair, time-course changes in drug distribution along single-strand hair were observed after a single oral administration of zolpidem (ZP), one of the most frequently used hypnotic agents. Quantitative sectional hair analyses of 1-mm segments were performed for each single-strand hair using a validated LC-MS/MS procedure. ZP was detected in all specimens plucked at 10 and 24 hours after a single dose, and the distribution ranged over the whole hair root (4-5 mm in length). A significantly high concentration of ZP was detected in the hair bulb region, whereas much lower concentrations were widely observed in the upper part of the hair root of those samples; this suggested that the incorporation of ZP occurred in two regions, mainly in the hair bulb and to a lesser extent in the upper dermis zone. The ZP-positive area formed lengths of up to 10-12 mm after a single administration, indicating that its incorporation from the hair bulb would continue for about 2 weeks. Time-course changes in the ZP concentration in the hair root additionally revealed that only a small portion of ZP that initially concentrated in the bulb was successively incorporated into the hair matrix and moved toward the keratinized region as hair grew. These findings should be taken into account upon discussing individual drug-use history based on hair analysis. The matrix-assisted laser desorption/ionization mass spectrometry imaging of ZP in the same kinds of hair specimens was also successfully achieved.

Pharmacologie des antalgiques chez le sujet obèse

The excess of body-weight, by its prevalence and its associated complications, explain that more and more obese patients are treated, encouraging a reflection about dosing consideration. In this review, we focus on the physiological changes linked with obesity and the associated changes in drug pharmacokinetics, especially as changes in drug distribution and metabolism occur. We will discuss the pharmacokinetic studies on analgesics in obese subjects and the potential cautions that need to be taken.

Adaptation posologique chez le sujet obèse

The excess of body-weight, by its prevalence and its associated-complications, explain that more and more obese patients are treated, encouraging a reflexion about dosing consideration. In this review, we focus on the physiological changes linked with obesity and the associated changes in drug pharmacokinetics, especially as changes in drug distribution and metabolism occur. In many situations, no recommendation exists for adjusting drug dosage in obese subjects. An “off-label” prescription, when dosage recommendations are lacking, is possible if sufficiently documented. However it must remain careful, as physiological changes linked to obesity are not necessarily associated with a risk of drug under-dosing.

Network Relations and Boundary Spanning: Understanding the Evolution of E-Ordering in the Chinese Drug Distribution Industry

The application of e-ordering systems has brought significant changes to the drug distribution industry in China, but the effects of these changes have remained unclear. Adopting a practice perspective and based on longitudinal data collection using multiple methods, we reveal that the Chinese drug distribution practice has passed through the following three stages: the stage before e-ordering, the transitional stage in which the government attempted to impose a centralised platform, and the current fragmented systems stage. We draw upon the theoretical foundations of the network relations model and the boundary spanning theory developed by Schultze and Orlikowski and Levina and Vaast, respectively, to formulate a taxonomic framework for understanding inter-firm network practices. Applying the framework to explain long-term changes in drug distribution in China, we discover that the practice in the field has evolved from traditional, socially embedded relations to information systems-based, socially embedded relations, while the centralised platform deployed by the government was unable to establish a practice with arm's length relations. Our theoretical work contributes an integrated framework for studying inter-firm practices that explicitly incorporates the presence of inter-organisational information systems. Our empirical findings offer helpful practical insights for facilitating collective efforts toward the innovative use of novel IT in the drug distribution industry in China and in other contexts that are similar.

Intratumoral Modeling of Gefitinib Pharmacokinetics and Pharmacodynamics in an Orthotopic Mouse Model of Glioblastoma

Like many solid tumors, glioblastomas are characterized by intratumoral biologic heterogeneity that may contribute to a variable distribution of drugs and their associated pharmacodynamic responses, such that the standard pharmacokinetic approaches based on analysis of whole-tumor homogenates may be inaccurate. To address this aspect of tumor pharmacology, we analyzed intratumoral pharmacokinetic/pharmacodynamic characteristics of the EGFR inhibitor gefitinib in mice with intracerebral tumors and developed corresponding mathematical models. Following a single oral dose of gefitinib (50 or 150 mg/kg), tumors were processed at selected times according to a novel brain tumor sectioning protocol that generated serial samples to measure gefitinib concentrations, phosphorylated extracellular signal-regulated kinase (pERK), and immunohistochemistry in 4 different regions of tumors. Notably, we observed up to 3-fold variations in intratumoral concentrations of gefitinib, but only up to half this variability in pERK levels. As we observed a similar degree of variation in the immunohistochemical index termed the microvessel pericyte index (MPI), a measure of permeability in the blood-brain barrier, we used MPI in a hybrid physiologically-based pharmacokinetic (PBPK) model to account for regional changes in drug distribution that were observed. Subsequently, the PBPK models were linked to a pharmacodynamic model that could account for the variability observed in pERK levels. Together, our tumor sectioning protocol enabled integration of the intratumoral pharmacokinetic/pharmacodynamic variability of gefitinib and immunohistochemical indices followed by the construction of a predictive PBPK/pharmacodynamic model. These types of models offer a mechanistic basis to understand tumor heterogeneity as it impacts the activity of anticancer drugs.

Diffusion of Macromolecules in the Brain: Implications for Drug Delivery

Therapeutics must diffuse through the brain extracellular space (ECS) in order to distribute within the central nervous system (CNS) compartment; this requirement holds both for drugs that are directly placed within the CNS (i.e., central input) and for drugs that cross the barriers separating blood and brain following systemic administration. The diffusion of any substance within the CNS may be affected by a number of properties associated with the brain microenvironment, e.g., the volume fraction, geometry, width, and local viscosity of the ECS, as well as interactions with cell surfaces, the extracellular matrix, and components of the interstitial fluid. Here, we discuss ECS properties important in governing the distribution of macromolecules (e.g., antibodies and other protein therapeutics), nanoparticles and viral vectors within the CNS. We also provide an introduction to some of the methods commonly applied to measure diffusion of molecules in the brain ECS, with a particular emphasis on those used for determining the diffusion properties of macromolecules. Finally, we discuss how quantitative diffusion measurements can be used to better understand and potentially even improve upon CNS drug delivery by modeling delivery within and across species, screening drugs and drug conjugates, evaluating methods for altering drug distribution, and appreciating important changes in drug distribution that may occur with CNS disease or injury.

The Effect of Critical Illness on Drug Distribution

The complexity of managing critically ill patients has increased since the early establishment of intensive care units in the 1950s. Despite of the fact that the number of drugs available to clinicians has increased, the understanding of the pharmacokinetics of individual drugs in specific disease states is still a matter of concern. Among the pharmacokinetic processes which may be affected in this patient population, drug distribution is a very important one. Changes in drug distribution may cause inadequate drug exposure at the infection site and consequently influence clinical outcome. Since drug distribution is dependent on a plethora of factors, including the physicochemical characteristics of the drug, we will focus on the most common mechanisms responsible for altered tissue distribution. These include changes in protein binding, fluid shifts, and pH changes. Although less common, alterations in organ perfusion may also play a role, particularly in heart failure patients. Despite great advances in understanding the distribution of antibacterial drugs, further studies are needed to define the consequences of changed drug distribution in critically ill patients on dosing regimens and clinical outcome.

Implementation and evaluation of carousel dispensing technology in a university medical center pharmacy

The implementation of carousel dispensing technology (CDT) at a university medical center pharmacy and the associated changes in drug distribution are described. An evaluation of CDT was conducted in three phases: before implementation, during implementation, and after implementation. The preimplementation phase consisted of data collection and facility planning leading up to the physical installation. The implementation phase included the physical installation, carousel medication assignment, and user training. The postimplementation phase included data collection and analysis. The data collected were used to compare preimplementation and postimplementation time studies, labor requirements, inventory turns, and accuracy rates. The estimated labor savings comparing the preimplementation and postimplementation time studies for automated dispensing cabinet (ADC) refills, first-dose requests, supplemental cart fill, and medication procurement totaled 2.6 full-time equivalents (FTEs). After departmental reorganization, a net reduction of 2.0 technician FTEs was achieved. The average turnaround time for stat medication requests using CDT was 7.19 minutes, and the percentage of doses filled in less than 20 minutes was 95.1%. After implementing CDT, the average accuracy rate for all dispense requests increased from 99.02% to 99.48%. The inventory carrying cost was reduced by $25,059. CDT improved the overall efficiency and accuracy of medication dispensing in a university medical center pharmacy. Workflow efficiencies achieved in ADC refill, first-dose dispensing, supplemental cart fill, and the medication procurement process allowed the department to reduce the amount of technician labor required to support the medication distribution process, as well as reallocate technician labor to other areas in need.

ARV Medication Errors: Experience of a Community-Based HIV Specialty Clinic and Review of the Literature

ObjectiveTo describe antiretroviral (ARV) medication errors reported within a community Human Immunodeficiency Virus (HIV) clinic, identify potential strategies to prevent errors, and review the literature pertaining to ARV medication errors.DesignReview of voluntarily reported ARV errors. Errors were classified using the National Coordinating Council for Medication Error Reporting and Prevention (NCC-MERP) Index. The clinic's medication distribution process was also analyzed.SettingCommunity-based clinic with HIV-experienced clinicians in an urban setting.ResultsThirty-seven errors were reported over 3 years; 81.1% of these were classified as NCC-MERP category C. Most errors resulted from lapses in clinic and pharmacy systems of care (n = 21). Pharmacy and clinic prescribing errors were less (n = 11).ConclusionARV medication errors were notable. Changes in drug distribution and prescribing processes may reduce future ARV medication errors.

Mutation in an Adaptor Protein PDZKI Affects Transport Activity of Organic Cation Transporter OCTNs and Oligopeptide Transporter PEPT2

Genetic polymorphisms in xenobiotic transporters have recently been clarified to be associated with change in drug distribution and disposition. To expand on recent identification of direct interaction and functional regulation of several transporters by a PDZ (PSD95, Dlg and ZO1) domain containing protein PDZK1, the effect of mutation in PDZK1 on transport activity and subcellular localization of organic cation/carnitine transporters OCTN1 and OCTN2, and oligopeptide transporter PEPT2 was examined in the present study. HEK293 cells stably expressing a mutant transcript PDZK1-E195K (HEK293/PDZK1-E195K) were constructed, followed by transient transfection of cDNA for each transporter. Uptake of tetraethylammonium by OCTN1 was much higher in HEK293/PDZK1 cells, compared with that in the parent HEK293 cells, the uptake in HEK293/PDZK1-E195K cells showing middle range between the two values. Such difference in transport activity was accounted for the difference in transport capacity, with minimal change in affinity of OCTN1 to the substrate or other compounds. The similar difference among HEK293/PDZK1, HEK293/PDZK1-E195K and HEK293 cells was also observed in transport property of OCTN2 and PEPT2, whereas the difference was not so remarkable in each transporter with the last four amino acids deleted, that has much lower interaction potential with PDZK1. Immunohistochemical analysis indicated that OCTN1 was colocalized with PDZK1 on cell-surface, whereas colocalization with PDZK1-E195K was partially observed in cytoplasmic region. These results suggest a novel hypothesis that mutation in PDZK1 potentially changes transport property of various types of xenobiotic transporters by affecting their subcellular localization, possibly leading to change in disposition of various types of substrate drugs.

The Ontogeny of Human Kidney Development

After completing this article, readers should be able to: 1. Explain the changes in renal blood flow after birth. 2. Describe the changes in plasma creatinine concentration relative to infant age. 3. List the factors that can affect the altered pharmacokinetic characteristics of furosemide in preterm infants. Diuretics are administered routinely to sick neonates for the treatment of multiple clinical disorders, including edema, hypertension, congestive heart failure/cardiovascular disease, bronchopulmonary dysplasia, and renal dysfunction. Unfortunately, much of the available research data about diuretic use in pediatrics and, in particular, neonates are derived from studies conducted in adults. The well-documented age-related changes in drug distribution, metabolism, and clearance across the age spectrum in pediatrics (1)(2) can alter diuretic pharmacokinetics substantially and, thus, their pharmacodynamics, limiting the direct applicability of such data. (3)(4) Because diuretic effectiveness ultimately is guided by the functional capacity of the kidney, it is important to appreciate the ontogeny of renal function across a wide range of postconceptional ages. The establishment and maturation of renal blood flow (RBF), glomerular filtration rate (GFR), and renal tubular secretory capacity all affect the delivery of diuretics to their sites of action and, thus, the infant’s response. Consequently, it is essential to understand the pharmacokinetic and pharmacodynamic characteristics of diuretic drugs integrated with the effects that gestational age, birthweight, and other factors impart on therapeutic efficacy. In this article, we provide a succinct overview of the ontogenic characteristics of human kidney development. In an accompanying article in this issue (Pharmacology Reviews), we discuss the various diuretics of clinical value in infant therapeutics, focusing on their pharmacokinetic/pharmacodynamic characteristics as related to their clinical utility. Human kidney development appears to be under the control of a complex association of growth factors, regulatory genes, and renal innervation. (5)(6)(7)(8). Renal …

The dynamics of pulmonary tuberculosis in Colima, Mexico (1999–2002)

Tuberculosis is a public health problem in Mexico. From 1999 to 2002, we assessed retrospectively the epidemiological, clinical, and treatment characteristics of pulmonary tuberculosis in the hospitals of the Mexican Institute of Public Health in the state of Colima (Mexico). We included 184 cases diagnosed with pulmonary tuberculosis. A database containing demographic, epidemiological, and clinical information was constructed and analyzed. We estimate a median patient delay of 83 d and a mean treatment delay of 2.3 d. Of 14 cases suspected for multiresistance and microbiologically assayed, 5 were found to carry a multi-drug-resistant strain. We also found a significant association between a short patient delay and the presence of hemoptysis (p = 0.002) or dyspnea (p<0.001). 86 patients (46.8%) were sputum smear microscopy negative at the end of treatment and 40 (21.7%) completed treatment giving an overall success rate of 68.5%, which compares unfavorably with the World Health Organization target success rate of 85%. Five (2.7%) patients failed treatment, 10 (5.4%) died, 39 (21.2%) interrupted treatment, and 4 (2.2%) transferred to another reporting unit. A 2002 strategic change in drug distribution seemed to prove successful.

Evaluation of the impact of altered lipoprotein binding conditions on halofantrine induced QTc interval prolongation in an anaesthetized rabbit model.

Halofantrine has been observed to cause QT interval prolongation in susceptible patients and the effect has most commonly been observed after post-prandial administration. Halofantrine-induced QT prolongation occurs in conjunction with a significant increase in plasma halofantrine concentrations and an increase in halofantrine association with post-prandial plasma lipoproteins. The increased association of halofantrine with post-prandial lipoproteins is accompanied by a marked change in drug distribution between the different plasma lipoprotein fractions. This study was designed to evaluate the putative role of myocardium-based lipoprotein receptor-mediated uptake of lipoproteins as a possible contributing factor to the observed effect of halofantrine on QT intervals. The extent of QT interval prolongation following intravenous halofantrine administration (10 mg kg(-1)) to normolipidaemic (fasted) or hyperlipidaemic (induced with Intralipid infusion) anaesthetized New Zealand White rabbits (n = 6) was determined, as was the distribution of halofantrine between the plasma lipoprotein classes. The results, however, were in contrast to the suggested hypothesis since the QT interval was reduced (and not increased) after halofantrine administration to hyperlipidaemic rabbits relative to fasted rabbits. Therefore, it is unlikely that lipoprotein-based uptake of halofantrine into the myocardium is a major contributor to the previously observed increase in QT prolongation after post-prandial administration of halofantrine.