Dynamics of malaria vector composition and Plasmodium falciparum infection in mainland Tanzania: 2017-2021 data from the national malaria vector entomological surveillance.

BACKGROUND: In 2015, Tanzania National Malaria Control Programme (NMCP) established a longitudinal malaria vector entomological surveillance (MVES). The MVES is aimed at a periodical assessment of malaria vector composition and abundance, feeding and resting behaviours, and Plasmodium falciparum infection in different malaria epidemiological strata to guide the NMCP on the deployment of appropriate malaria vector interventions. This work details the dynamics of malaria vector composition and transmission in different malaria epidemiological strata. METHODS: The MVES was conducted from 32 sentinel district councils across the country. Mosquitoes were collected by the trained community members and supervised by the NMCP and research institutions. Three consecutive night catches (indoor collection with CDC light trap and indoor/outdoor collection using bucket traps) were conducted monthly in three different households selected randomly from two to three wards within each district council. Collected mosquitoes were sorted and morphologically identified in the field. Thereafter, the samples were sent to the laboratory for molecular characterization using qPCR for species identification and detection of P. falciparum infections (sporozoites). ELISA technique was deployed for blood meal analysis from samples of blood-fed mosquitoes to determine the blood meal indices (BMI). RESULTS: A total of 63,226 mosquitoes were collected in 32 district councils from January 2017 to December 2021. Out of which, 39,279 (62%), 20,983 (33%) and 2964 (5%) were morphologically identified as Anopheles gambiae sensu lato (s.l.), Anopheles funestus s.l., and as other Anopheles species, respectively. Out of 28,795 laboratory amplified mosquitoes, 13,645 (47%) were confirmed to be Anopheles arabiensis, 9904 (34%) as An. funestus sensu stricto (s.s.), and 5193 (19%) as An. gambiae s.s. The combined average entomological inoculation rates (EIR) were 0.46 (95% CI 0.028-0.928) for An. gambiae s.s., 0.836 (95% CI 0.138-1.559) for An. arabiensis, and 0.58 (95% CI 0.165-0.971) for An. funestus s.s. with variations across different malaria transmission strata. Anopheles funestus s.s. and An. arabiensis were predominant in the Lake and South-Eastern zones, respectively, mostly in high malaria transmission areas. Monthly mosquito densities displayed seasonal patterns, with two peaks following the rainy seasons, varying slightly across species and district councils. CONCLUSION: Anopheles arabiensis remains the predominant vector species followed by An. funestus s.s. in the country. Therefore, strengthening integrated vector management including larval source management is recommended to address outdoor transmission by An. arabiensis to interrupt transmission particularly where EIR is greater than the required elimination threshold of less than one (< 1) to substantially reduce the prevalence of malaria infection.

Multi-country review of ITN routine distribution data: are ANC and EPI channels achieving their potential?

BACKGROUND: Routine continuous distribution (CD) of insecticide-treated nets (ITNs) has been an important part of an overall ITN strategy to complement mass campaigns since the early 2000s. The backbone of CD implementation for many sub-Saharan African countries is distribution through antenatal care (ANC) and Expanded Programme for Immunizations (EPI) channels. Performance of these channels is often not monitored closely at the national level, nor is it reviewed globally, unlike the oversight provided to mass campaigns. The question as to why every eligible pregnant woman and child attending these services does not get an ITN remains important and yet, unanswered. METHODS: ANC and EPI issuing rates from seven countries were reviewed with the aim of conducting a blinded multi-country analysis. Monthly data from January to December 2021 was extracted from each country's health management information system and analysed jointly with a National Malaria Control Programme (NMCP) focal point. VectorLink CD assessment reports were also reviewed to glean key findings. RESULTS: ITN issuing rates varied across countries at ANC (31% to 93%) and EPI (39% to 92%). Across the seven countries, the median ITN issuing rate was 64% at ANC and 78% at EPI. Results varied greatly across months per country at both ANC and EPI. NMCP focal points are aware that mass campaigns often negatively affect implementation of ITN distribution through ANC and EPI, even though global and national guidelines emphasize sustaining CD during campaigns. Concerns were also raised about the standard ITN issuing rate indicator at ANC and even more so at EPI due to the denominator. Findings from CD assessments were similar across countries: ITN stock was inconsistent and sometimes inadequate, and updated guidelines on ITN distribution and utilization and funding for social behaviour change activities were lacking at the facility level. CONCLUSION: The importance of optimizing ANC and EPI routine channels cannot be underscored enough. They are at the frontline to protect the most biologically vulnerable populations, i.e., pregnant women and unborn and young children. Although there are encouraging signs of improvement in issuing rates with some countries reaching optimal rates, further improvements are needed to ensure that every pregnant woman and young child receives the ITN to which they are entitled.

The West Africa ICEMR Partnerships for Guiding Policy to Improve the Malaria Prevention and Control.

The Mali National Malaria Control Program (NMCP) recently established a phased set of goals for eliminating malaria in Mali by 2030. Over the past decade, the scale-up of NMCP-led malaria control interventions has led to considerable progress, as evidenced by multiple malariometric indicators. The West Africa International Center of Excellence in Malaria Research (WA-ICEMR) is a multidisciplinary research program that works closely with the NMCP and its partners to address critical research needs for malaria control. This coordinated effort includes assessing the effectiveness of control interventions based on key malaria research topics, including immune status, parasite genetic diversity, insecticide and drug resistance, diagnostic accuracy, malaria vector populations and biting behaviors, and vectorial capacity. Several signature accomplishments of the WA-ICEMR include identifying changing malaria age demographic profiles, testing innovative approaches to improve control strategies, and providing regular reporting on drug and insecticide resistance status. The NMCP and WA-ICEMR partnership between the WA-ICEMR and the NMCP offers a comprehensive research platform that informs the design and implementation of malaria prevention and control research programs. These efforts build local expertise and capacity for the next generation of malaria researchers and guide local policy, which is crucial in sustaining efforts toward eliminating malaria in West Africa.

Curiosities in drug metabolism.

1. It is inevitable that during some xenobiotic biotransformation studies, a certain metabolite or degradation product arises of which the identity is uncertain, the route of formation is ambiguous, or it is just a plain mystery. 2. The following communication draws attention to three drugs reported in the literature, chlorphentermine, phenothiazine and aminopyrine, where after many years of investigation there still exists uncertainty over some of their metabolites. Noticeably, these three examples probably involve (potential) interaction of a nitrogen centre within the drug molecule. 3. It is hoped that the resurrection and assemblage of these data will offer interesting reading and that these examples may prove sufficiently intriguing to motivate further exploration and some resolution of these lingering concerns.

Effects of phentermine and fenfluramine on extracellular dopamine and serotonin in rat nucleus accumbens: therapeutic implications.

Combined administration of the amphetamine analogs phentermine and fenfluramine (PHEN/FEN) has been used in the treatment of obesity. While these medications are thought to modulate monoamine transmission, the precise neurochemical effects of the PHEN/FEN mixture have not been extensively studied. To assess the mechanism of PHEN/FEN action, in vivo microdialysis studies were performed in the nucleus accumbens of conscious freely moving rats. A series of amphetamine derivatives including phentermine, chlorphentermine, fenfluramine, and PHEN/FEN (1:1 ratio), were infused locally into the accumbens via reverse-dialysis (1, 10, 100 microM) or injected systemically (1 mg/kg, ip). Dialysate samples were assayed for dopamine (DA) and serotonin (5-HT) by high-performance liquid chromatography with electrochemical detection. When infused locally, phentermine preferentially increased extracellular DA, whereas fenfluramine selectively increased extracellular 5-HT. Local administration of chlorphentermine or the PHEN/FEN mixture caused parallel elevations of both transmitters. Analogous results were obtained when the drugs were injected systemically. Phentermine stimulated robust locomotor activity in mice, whereas chlorphentermine and fenfluramine did not. PHEN/FEN caused modest locomotor stimulation after a low dose, but had no effect at the highest dose. Accumulating evidence suggests that chronic drug and alcohol abuse is associated with deficits in both DA and 5-HT neuronal function. Thus, dual activation of DA and 5-HT neurotransmission with monoamine releasing agents may be an effective treatment strategy for substance use disorders, as well as for obesity. Synapse 36:102-113, 2000. Published 2000 Wiley-Liss, Inc.

The effect of fenfluramine on the pulmonary disposition of 5-hydroxytryptamine in the isolated perfused rat lung: a comparison with chlorphentermine.

A possible mechanism for fenfluramine-induced pulmonary hypertension has been investigated. Fenfluramine, like chlorphentermine, may inhibit the pulmonary uptake and/or metabolism of 5-hydroxytryptamine (5-HT). This allows more 5-HT to remain in the pulmonary circulation, where it may exert a greater vasoconstrictor action resulting in pulmonary hypertension. Chlorphentermine has been shown to inhibit the uptake and metabolism of 5-HT. The effect of fenfluramine on the pulmonary disposition of [14C]5-HT has been investigated, in comparison with chlorphentermine, using a recirculating isolated perfused rat lung system. The pulmonary disposition of [14C]5-HT was assessed by measuring the change in [14C]5-HT concentration in the perfusion medium during the experiment and at the end, and the concentration in the lung at the end of the experiment. The concentration of 5-hydroxyindoleacetic acid, a metabolite of 5-HT, was measured in perfusate and lung samples. Mean pulmonary clearance of 5-HT for the control lung and lungs challenged with either fenfluramine (2.5 microM) or chlorphentermine (25 microM) was 4.514, 1.316 and 1.007 mL min(-1), respectively (n = 5). The concentration of 5-HT found in the lungs at the end of the experiment for the control and the lungs preloaded with fenfluramine or chlorphentermine was 695.05+/-9.69, 638.65+/-10.27 and 617.3+/-14.38 ng g(-1), respectively. Fenfluramine, like chlorphentermine, inhibited the pulmonary disposition of 5-HT resulting in an elevated perfusate level of 5-HT. This is a possible contributing mechanism for fenfluramine-induced pulmonary hypertension. The effect of fenfluramine was less pronounced than chlorphentermine.

[The role of pharmacotherapy for treatment of obesity in adults]. / Znaczenie farmakoterapii w leczeniu otylosci u osób doroslych.

Obesity is one of the pathologies with ever-increasing prevalence in modern societies. Its occurrence is strongly associated with increased risk of developing diabetes mellitus, atherosclerosis, hypertension, stroke, heart and respiratory failure, breast, prostate and gut cancer, gall stones, arthropathy. Obesity is common in Polish population. Obesity treatment is difficult and frustrating. It consists of several parts like diet, increased physical activity, lifestyle changes, drug therapy and surgery. However, obesity treatment is very often a failure, mostly because of discouraging long-term results and the necessity of intensive patient's involvement in the therapy. For many patients and doctors weight-decreasing agents look promising. The groups of anti-obesity drugs are presented in the article, with special reference to serotoninergic agents and intestinal lipase inhibitors. The prospects for new anti-obesity agents are discussed. Nevertheless, despite intensive research on obesity, we are still waiting for the development of an effective and safe drugs helping lose weight.

Aminorex, fenfluramine, and chlorphentermine are serotonin transporter substrates. Implications for primary pulmonary hypertension.

BACKGROUND: Coadministration of phentermine and fenfluramine (phen/fen) effectively treats obesity and possibly addictive disorders. The association of fenfluramine and certain other anorexic agents with serious side effects, such as cardiac valvulopathy and primary pulmonary hypertension (PPH), limits the clinical utility of these drugs. Development of new medications that produce neurochemical effects like phen/fen without causing unwanted side effects would be a significant therapeutic breakthrough. METHODS AND RESULTS: We tested the hypothesis that fenfluramine (and other anorexic agents) might increase the risk of PPH through interactions with serotonin (5-HT) transporters. Because 5-HT transporter proteins in the lung and brain are identical, we examined, in rat brain, the effects of selected drugs on 5-HT efflux in vivo and monoamine transporters in vitro as a generalized index of transporter function. Our data show that drugs known or suspected to increase the risk of PPH (eg, aminorex, fenfluramine, and chlorphentermine) are 5-HT transporter substrates, whereas drugs that have not been shown to increase the risk of PPH are less potent in this regard. CONCLUSIONS: We speculate that medications that are 5-HT transporter substrates get translocated into pulmonary cells where, depending on the degree of drug retention, their intrinsic drug toxicity, and individual susceptibility, PPH could develop as a response to high levels of these drugs or metabolites. Emerging evidence suggests that it is possible to develop transporter substrates devoid of adverse side effects. Such medications could have therapeutic application in the management of obesity, drug dependence, depression, and other disorders.

[Chloroquine- and chlorphentermin-induced lipidosis in rat retina]. / Chloroquin und Chlorphentermin induzierte Lipidose der Rattenretina.

BACKGROUND: The amphiphilic drugs chloroquine and chlorphentermine are known to cause lipidosis in the human and rat retina. METHODS: We treated femal albino Wistar rats orally with chloroquine for 12 weeks, followed by a period of 4 months with normal feed and another group with chlorphentermine for 4-16 weeks. The animals were submitted to electroretinography, and the retinae were prepared for histological investigations. RESULTS: Chloroquine caused severe lipidosis in the neuroretina and slight photoreceptor cell degeneration after 12 weeks of treatment. The b-wave was reduced to 30% of initial values. After withdrawal the lipidosis remitted, but the degeneration of the photoreceptor cell layer continued to progress. The a-wave and b-wave amplitudes were reduced to 25% and 16% of initial values, respectively. Chlorphentermine caused pronounced lipidosis in the pigment epithelium and less numerous in the neuroretina after 16 weeks; no photoreceptor cell degeneration was found. The b-wave was reduced to 80% of initial values, the a-wave appeared unaffected. CONCLUSION: Whether lipidosis is the primary cause of changes in the electroretinogram and of receptor cell degeneration is doubtful. Excessive lipid storage may be the cause of secondary changes. It is unlikely that lipidosis in pigment epithelium played a role.

Exposure to crystalline silica or treatment with chlorphentermine increases vitamin E levels in rat alveolar lavage materials.

Previous studies have shown that vitamin E may be an integral part of lung surfactant and may function to protect this material from oxidant damage. Therefore, we measured the vitamin E levels in alveolar lavage materials from rats exposed to crystalline silica or treated with chlorphentermine (CP), two treatments that are known to increase surfactant phospholipids (PL) by different mechanisms. Silica exposure leads to increased PL synthesis, and CP treatment causes a reduction in PL degradation. Two different silica preparations, HCL-washed and unwashed silica, were used because exposure to each of them leads to different degrees of phospholipidosis. Exposure to HCL-washed silica results in a more than 17-fold increase in lavage PL and protein levels and a 12.2-fold increase in the amount of vitamin E. Exposure to unwashed silica leads to an approximately 7-fold increase in PL and proteins and a 5.8-fold increase in lavage vitamin E. Following treatment of rats with CP, there is a 15- to 19-fold increase in lavage PL and proteins and a 13.6-fold increase in vitamin E. When the results are expressed as micrograms vitamin E per milligram of lavage PL or protein, there is not much difference between controls and each treatment group. Because surfactant synthesis occurs in the endoplasmic reticulum, we also measured vitamin E in lung microsomes. Both silica exposure and CP treatment also lead to 1.8- to 2.5-fold increases, respectively, in the lung microsomal levels of vitamin E. These results demonstrate that alveolar lavage vitamin E levels are elevated along with lavage PL and proteins, and lung microsomal vitamin E levels are increased following exposure of rats to silica or treatment of the animals with CP.

Biochemical and functional analysis of rat bronchoalveolar macrophages containing chemically induced phospholipid inclusions.

Cationic amphiphilic drugs (CADs) are structurally characterized by hydrophobic ring structures and hydrophilic side chains. Studies have demonstrated that repeated administration of CADs to experimental animals and humans may induce phospholipid (PL) accumulation within the cells of various tissues. The immunomodulatory azaspiranes are novel CADs with beneficial effects in a number of animal models of autoimmune disease and transplantation. Although the mechanism of action of these compounds is unclear, efficacy in all of the disease models is accompanied by the generation of suppressor cell (SC) activity in various lymphoid organs. SK&F 105685 (N,N-dimethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2-propanamine+ ++ hydrochloride) and two analogs, SK&F 106615 and SK&F 103811, were compared with chlorphentermine and chloroquine for their ability to induce PL accumulation and SC activity. Oral administration of SK&F 105685 and SK&F 106615 caused PL accumulation in bronchoalveolar lavage macrophages (AM) but to a far lesser extent (three- to fivefold) than chlorphentermine. Neither the immunologically unreactive azaspirane SK&F 103811 nor chloroquine affected PL levels. AM from rats treated with SK&F 105685 or SK&F 106615 expressed more potent SC activity than chlorphentermine. Thus, SC activity did not correlate with the extent of PL accumulation. Neither SK&F 103811 nor chloroquine induced SC activity. AM from SK&F 105685-treated rats had an enhanced ability to kill the opportunistic pathogen Candida albicans in vitro indicating that there was no impairment of macrophage-dependent host defense mechanisms.

In vivo and in vitro reversibility of chlorphentermine-induced phospholipidosis in rat alveolar macrophages.

Chlorphentermine (CP) is a cationic, amphiphilic drug (CAD) that has been studied widely for its ability to induce phospholipidosis, a disorder characterized by excessive accumulation of cellular phospholipid and ultrastructural development of lysosomal lamellar bodies (LLBs) in the cell. The accumulation of inducing drug correlates with increasing phospholipids. In the present study, we examined the reversibility of this disorder in rat alveolar macrophages (AMs) following a 7-day treatment (30 mg/kg/day, ip). The reversibility of phospholipidosis was examined under in vivo conditions and under in vitro conditions in cell cultures for a period of up to 12 days. There was a marked reduction in cellular CP levels and phospholipid content after 4 days of recovery, both in vivo and in vitro; however, there was no indication of significant loss of LLBs. Beyond this time point, ultrastructural recovery from phospholipidosis lagged behind the biochemical recovery temporally and was somewhat less rapid in vitro than in vivo. By 12 days of recovery, AMs from both groups had recovered biochemically, but a moderate level of LLBs was still present in some AMs in the in vitro recovery group. The results of this study indicate that there are more similarities than differences when comparing the recovery of phospholipidotic cells in vitro to that occurring in vivo. We conclude that the use of cell cultures may prove valuable in studying the reversibility of CAD-induced phospholipidosis.

Chlorphentermine-induced lipidosis in the rat retina: a functional and morphological study.

Chronic administration of the cationic amphiphilic anorexigenic drug chlorphentermine to rats has previously been shown to induce extraocular and ocular lipidosis: large numbers of lipidosis-related cytoplasmic inclusions can be found in the pigment epithelium and smaller numbers in the neuroretina. In the present study, female albino Wistar rats were treated orally with chlorphentermine (30-45 mg/kg body weight) for 4-16 weeks. The animals were submitted to electroretinography, and the retinae were prepared for histological investigations. Our histological findings corresponded to previous reports. The changes in electroretinographic parameters were low. The clearest change was a reduction of the b-wave amplitude of 20% after 12 and 16 weeks of treatment compared with the values before drug treatment. The a-wave amplitude did not differ from that in the control group. Lipidosis in the neuroretina may be the reason for functional influences on the b-wave amplitude. The function of the receptor cells, which is represented by the a-wave, appeared unaffected by chlorphentermine.

Experimentally induced lipidosis in uterine and vaginal epithelium of rats.

The purpose of this study was to investigate the effects of two lipidosis-inducing drugs (the anorectic drug chlorphentermine and the tricyclic antidepressant-imipramine) upon the estrous cycle of rats and upon the morphology of the vaginal and uterine epithelia. After two weeks of continuous administration of high daily drug doses, the estrous cycle became stagnant. Ultrastructurally, the vaginal and uterine epithelia contained storage lysosomes which were filled with undigested polar lipids appearing as multilamellated material. The uterine luminal epithelium was most severely affected. The estrous cycle was abolished also by treatment with the anorexigenic drug phentermine, although this compound does not cause lipidosis. Therefore, the cessation of the estrous cycle cannot be attributed to the lipidosis as induced by chlorphentermine and imipramine; probably it is a consequence of the main actions of these psychotropic drugs. The biological basis for the exceedingly severe lipidosis in the uterine luminal epithelium is suggested to be the heavy load of polar lipids physiologically delivered to the lysosomal apparatus as long as the cycle-dependent apoptotic and autophagic processes were going on during the early period of drug treatment.

X-ray microanalysis of cultured alveolar macrophages with phospholipidosis.

When administered to humans and animals, the iodine-containing drug amiodarone can cause pulmonary toxicity. As part of the pulmonary response to amiodarone, the drug and its principal metabolite, desethylamiodarone, accumulate in alveolar macrophages. Little is known about the susceptibility of lungs with preexisting damage to amiodarone administration. A number of chemicals can cause pulmonary phospholipidosis in humans and animals. To study the effect of a preexisting phospholipidosis on the intracellular accumulation of amiodarone and desethylamiodarone, rats were treated with chlorphentermine to induce a phospholipidosis in alveolar macrophages. The cells were recovered from the lungs by pulmonary lavage and placed in cell culture. They were then exposed to the same concentration of either amiodarone or desethylamiodarone. The intracellular distribution of each drug was quantified by measuring the associated iodine signal using X-ray microanalysis of freeze-dried cryosections of cells. Both drugs accumulated in lipid-rich amorphous bodies which correspond to lysosomally derived lamellar structures observed in conventional plastic sections. The level of desethylamiodarone exceeded that of amiodarone in the amorphous bodies. With both drugs, a higher concentration of iodine was present at the outer edges of the amorphous bodies compared to that in the center core. This suggests that the drugs are unable to freely penetrate the performed structures. By monitoring the concentrations of sodium and potassium ions within the nucleus, it was determined that chlorphentermine treatment disrupted the ionic distribution in the cells. Exposure to amiodarone, but not desethylamiodarone, resulted in further changes in sodium and potassium levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Selective monomethylation of the primary amine function using [11C]CH3I and the N-trifluoroacetyl derivative: preparation of N-[11C-methyl]chlorphentermine.

A simple, rapid and efficient method for the preparation of a potential brain blood-flow agent, N-[11C-methyl]-chlorphentermine ([11C]NMCP), is described. Optimization of the radiochemical yield of [11C]NMCP was accomplished by a Gabriel-like reaction which permits the transformation of a primary amine to a secondary amine through a sequence of acylation, deprotonation, monomethylation and saponification. This method precludes the formation of polymethylated by-products which can reduce radiochemical yields, particularly with low specific activity 11CO2.

Experimental chlorphentermine lipidosis of the retina in albino rats.

Chronic administration of chlorphentermine leads to an accumulation of lysosomal inclusions in the retina of young rats. The cells of the pigment epithelium, the perikeratic part of the ganglial cells and their axones are filled with inclusions, whereas other parts of the retina remain free. As soon as the treatment is discontinued, the alterations recede completely. The experiment can be considered to be a model for the lysosomal capacity of those parts of the retina concerned; in addition, it supplies information on the metabolism of phospholipids in these structures.

Influence of a pre-existing phospholipidosis on the accumulation of amiodarone and desethylamiodarone in rat alveolar macrophages.

Amiodarone is an antiarrhythmic drug that concentrates in the lungs and can cause pulmonary damage in humans. The purpose of the present study was to examine the influence of a pre-existing lung pathology on the pulmonary accumulation of amiodarone and its primary metabolite, desethylamiodarone. To study this problem, male Fischer 344 rats were administered chlorphentermine to induce a phospholipidosis in the alveolar macrophages of the lungs. The accumulation of amiodarone and desethylamiodarone in phospholipidotic alveolar macrophages was measured following 5 weeks of amiodarone administration. When calculated on a per cell basis, the levels of both drugs were increased over 10-fold in phospholipid-laden macrophages compared to cells from control rats in which a phospholipidosis was not present. When phospholipidotic macrophages were exposed to amiodarone and desethylamiodarone in vitro, both drugs were accumulated to a higher level than occurred in cells from control rats. The results of this study demonstrate that the presence of a pre-existing phospholipidosis results in an enhanced accumulation of amiodarone and desethylamiodarone in rat alveolar macrophages.

Differential influence of anionic and cationic charge on the ability of amphiphilic drugs to interact with DPPC-liposomes.

The compounds clofibric acid and chlorphentermine have identical aromatic ring systems, but when charged their side chains are anionic or cationic, respectively. The drugs were applied as tools to investigate whether the interaction of amphiphilic drugs with the zwitterionic dipalmitoyl-phosphatidylcholine (DPPC) depends on the charge of the polar side chain. In suspensions of DPPC-liposomes, the drug-effect on the phase-transition temperature (Tt) was evaluated by means of differential scanning calorimetry. The drug-binding was determined spectrophotometrically. The clofibric acid anion had a much weaker depressing effect on Tt than the chlorphentermine-cation and a considerably lower ability to bind to the DPPC-liposomes. Furthermore, a plot of the effect versus the binding suggested that the clofibric acid-anion had a lower intrinsic activity to reduce Tt compared with the chlorphentermine-cation. In contrast, when the dissociation-equilibrium was shifted towards the uncharged state both drugs were indistinguishable with respect to effect and binding, suggesting that the differences observed with the charged forms could indeed be attributed to the opposite charges. The findings are tentatively explained to result from a different ability of the anionic and the cationic form to reach the hydrophobic interior of the DPPC-bilayer.

Pharmacokinetics of amiodarone in the isolated rat lung.

In these studies we examined the kinetics of amiodarone (Am) uptake and efflux in/from the lung, and the influence of other amphiphilics on these processes. We used single-pass perfused isolated lungs from rats. Medium containing Am (30 microM + 1 microCi of [14C]Am) was perfused through the lung for 20 min (uptake), followed by 20 min of perfusion with drug-free medium (efflux). Lack of metabolism enabled us to follow Am by measuring the amount of radioactivity in perfusate and lung. Other concentrations of Am (3, 60 and 120 microM; n = 2-4 each) were also examined. Inhibited uptake and accelerated efflux of Am were attempted with the pneumophilic amphiphilics chlorimipramine, chlorphentermine, chlorpromazine, verapamil and with the main metabolite of Am: desethylamiodarone (60 and/or 240 microM; n = 3-4 lungs each). Lung extracted Am extensively during uptake. The amount of Am accumulated at 20 min (inflowing concentration: 30 microM) averaged 1307 +/- 109 (S.E.) nmol/g, corresponding to a tissue to medium ratio of 43.3 +/- 1.6. Spontaneous efflux of Am was incomplete. At 40 min, 862 +/- 105 nmol of Am remained bound per g of lung, suggesting sequestration of Am in a slowly effluxable pool in which calculations show that more than 50% of the drug will ultimately persist. Uptake and efflux rates obey biexponential kinetics, indicating storage into two pools. Uptake rate and the amount of Am accumulated in lung at 20 min increased in proportion to inflowing concentration up to 60 microM. At 120 microM the increase was less. Neither amphiphilic was capable of inhibiting Am uptake, whereas only chlorphentermine significantly accelerated Am efflux.(ABSTRACT TRUNCATED AT 250 WORDS)