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.

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.

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.

Association of chlorphentermine with phospholipids in rat alveolar lavage materials, alveolar macrophages and type II cells.

Administration of chlorphentermine to rats leads to an increase in the phospholipid content of pulmonary surfactant materials and alveolar macrophages. It is known that this drug binds to pure phospholipids and prevents their degradation by phospholipases. Therefore, experiments were carried out to determine if chlorphentermine binds to surfactant phospholipids in vitro and to measure the in vivo association of drug with phospholipids in alveolar lavage materials from rats injected with [14C]chlorphentermine. The presence of chlorphentermine in alveolar macrophages, type II cells and other small pneumocytes (a population of lung cells which does not include alveolar macrophages or type II cells) from treated animals was also assessed. Binding of the drug to surfactant phospholipids, as measured with the fluorescent probe, 1-anilino-8-naphthalene sulfonate, occurs in vitro and does not differ in various subfractions of alveolar lavage materials isolated by differential centrifugation. Following daily administration of chlorphentermine to rats for 3 days, the drug appears to be associated with surfactant phospholipids such that the molar ratio is 1:100 (chlorphentermine/phospholipid). Chlorphentermine is also associated with alveolar macrophages (molar ratio, 1:18) and type II cells (molar ratio, 1:33). Not much drug is associated with the population of other lung cells (molar ratio, 1:333). In alveolar macrophages, approx. 70% of the drug seems to be bound to phospholipid and/or sequestered in subcellular organelles. However, only 20% of the chlorphentermine is bound and/or sequestered in type II cells. The results of these experiments suggest that following chlorphentermine administration, the drug is associated with phospholipids in acellular pulmonary lavage materials, alveolar macrophages and type II cells. This drug-phospholipid interaction may impair phospholipid degradation and lead to a phospholipidosis in surfactant materials and alveolar macrophages.

Freeze-fracture studies of cytoplasmic inclusions occurring in experimental lipidosis as induced by amphiphilic cationic drugs.

The ultrastructure of cytoplasmic inclusions, which characterize experimental lipidosis as induced by several amphiphilic cationic drugs, was studied by means of freeze-fracturing and thin-sectioning. Retinal and adrenal tissues of rats chronically treated with high oral doses of chlorphentermine were used. In thin sections the cytoplasmic inclusions, which were previously shown to represent lysosomes overloaded with polar lipids, exhibit lamellated or lattice-like internal patterns. The present freeze-fracture observations are interpreted as to indicate that the lamellated inclusions contain polar lipids in the lamellar phase, whereas those with lattice-like patterns contain polar lipids in a hexagonal phase.

Alterations in rat alveolar surfactant phospholipids and proteins induced by administration of chlorphentermine.

Chlorphentermine is a cationic amphiphilic drug which produces a phospholipid storage disorder in rat lungs. Experiments were carried out to characterize changes in the composition of acellular alveolar lavage materials and to study possible mechanisms by which pulmonary surfactant phospholipidosis is produced by administration of the drug. Following ten daily injections of chlorphentermine (25 mg/kg body weight), there are 12.2- and 13.6-fold increases of pulmonary lavage total phospholipids and disaturated phosphatidylcholines (disaturated PC), respectively. In addition, there is a 2.8-fold increase in total protein and a 12.7-fold increase in the surfactant apoprotein group with molecular weights from 28,000 to 32,000. We measured incorporation of labeled palmitate, choline and glycerol into disaturated PC in type II cells and alveolar macrophages isolated from control and chlorphentermine-treated animals. The drug does not affect the incorporation of labeled substrates into disaturated PC in either cell type. However, in alveolar macrophages there is a decrease in the rate of intracellular degradation of recently synthesized disaturated PC in chlorphentermine-treated animals. The drug also inhibits the phospholipase-induced catabolism of rat surfactant disaturated PC which occurs during incubation of alveolar lavage fluid in vitro at 37 degrees C. When the lavage fluid is divided into subfractions by differential centrifugation, a larger percentage of the phospholipid is distributed in the less sedimentable subfractions in chlorphentermine-treated animals relative to controls, suggesting the accumulation of older surfactant materials. These results suggest that chlorphentermine-induced phospholipidosis of pulmonary surfactant materials is due to decreased rates of phospholipid degradation.

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.

The early changes in experimental myopathy induced by chloroquine and chlorphentermine.

In soleus muscles of rats treated for 2 to 11 days with high doses of chloroquine or chlorphentermine, muscle fibres showed autophagocytosis followed by segmental contracture and necrosis. Vascuolar degeneration, "splitting", and internal nuclei were absent. At variance with findings in progressive muscular dystrophy, the incidence of intramembrane particles was unchanged and membrane defects in necrotizing fibres were absent. Autophagic vacuoles were formed by cup-shaped cisternae derived from tubules that often enclosed single mitochondria. Golgi complexes occurred in the centre of the fibres; dilated vesicles of the sarcoplasmic reticulum contained an electrondense substance, possibly lysosomal enzymes. Exocytosis of autophagic vacuoles and of almost undigested mitochondria was observed. The changes in the plasma membrane were as in other cells: a bulge was formed that was cleared of intramembrane particles; the membrane fused with the limiting membrane of the autophagic vacuole, the content of which was expelled through an orifice. Inside autophagic vacuoles, persisting phospholipids arranged themselves into protein-free lipid bilayers, that formed concentric membranes or single-layered vesicles. Both drugs are known to inhibit degradation of phospholipids; the findings indicate that the rate of autophagocytosis and exocytosis were enhanced as well. Fibre necrosis was probably due to the fact that fibres eventually became unable to maintain their integrity.

Relationship between anorectic and reinforcing properties of appetite suppressant drugs: implications for assessment of abuse liability.

A quantitative ratio measure was developed which permitted comparisons between the reinforcing and anorectic potency of eight phenylethylamine anorectics and cocaine in laboratory baboons. The ordering of these compounds based upon this ratio bears a reasonable correspondence to clinical drug evaluations. The measure may provide information for preclinical evaluation of relative abuse potential of anorectic drugs.

Mitochondrial alterations in the brain of the rat caused by chlorphentermine.

The effects of chlorphentermine on the bioenergetics and activity of monoamine oxidase in mitochondria from the brain of the rat were examined. Oxidation rates of glutamate and succinate were investigated in the presence of chlorphentermine (0.1-5.0 mM). In small concentrations (0.1-1.0 mM), chlorphentermine decreased the respiratory control ratio and the adenosine diphosphate oxygen (ADP/O) ratio, and stimulated state four respiration. State three respiration and the uncoupled state were also decreased, but to a lesser degree. In the presence of larger concentrations of chlorphentermine (1.0-5.0 mM), the respiration in states four, three, and in the uncoupled state, as well as the respiratory control ratio and ADP/O ratio, were decreased significantly. These data indicate that chlorphentermine functions as an uncoupler of oxidative phosphorylation. Oxidation of norepinephrine, serotonin, octopamine, tyramine and dopamine by monoamine oxidase (MAO), an enzyme marker of the outer mitochondrial membrane, was inhibited in the presence of 0.01 to 0.1 mM of chlorphentermine. Oxidation of tryptamine and benzylamine was unaffected. A kinetic study of the oxidation of serotonin in the absence and presence of chlorphentermine (0.025-0.1 mM) indicated that both the Vmax and Km were affected. This drug is an inhibitor of monoamine oxidase of mitochondria of the brain with mixed type inhibition. These combined data show that chlorphentermine affects biochemical processes in both inner and outer mitochondrial membranes.

Cytochemical demonstration of increased phospholipid content in cell membranes in chlorphentermine-induced phospholipidosis.

We recently introduced a novel cytochemical approach to high-resolution cytochemistry of phospholipids in biological tissues. The technique consists of adsorption of bee venom phospholipase A2 to colloidal gold particles (PLA2-gold complex) and subsequent application of this complex for localization of the enzyme substrate, i.e., glycerophospholipids. In the present study, this technique was applied at the post-embedding level, in both light (LM) and transmission electron microscopy (TEM), to investigate drug-induced phospholipidosis, an experimental disorder in which the lysosomal catabolism of phospholipids is inhibited. Rats received one week of daily treatment (40 mg IP/kg) with chlorphentermine (CP), a cationic amphiphilic drug known to induce phospholipidosis in several tissues. Glutaraldehyde- and osmium-fixed lung and kidney tissues from both treated and control animals, were embedded in Epon and sections processed for labeling by PLA2-gold. In CP-treated specimens the presence of large osmiophilic inclusions in several cell types of lung parenchyma and kidney cortex confirmed the onset of phospholipidosis. These inclusions were densely labeled by PLA2-gold at both LM and TEM levels. Two general types of abnormal inclusions were distinguished on the basis of their ultrastructure and labeling pattern by PLA2-gold, suggesting different content or configuration of phospholipids. Moreover, quantitative evaluation of labeling density over various membrane compartments in lung alveolar cells evidenced significantly increased phospholipid content after CP treatment. In type II pneumocytes, such increases were measured in membranes of the RER, Golgi complex, outer and inner nuclear envelope, and the basolateral and apical domains of the plasma membrane. In capillary endothelial cells, the basal and luminal domains of the plasma membrane also showed an increase in labeling density. These results further demonstrate the potential usefulness of the PLA2-gold technique for in situ ultrastructural localization of phospholipids in normal and pathological tissues.

N-[11C-Methyl]chlorphentermine and N,N-[11C-dimethyl]chlorphentermine as brain blood-flow agents for positron emission tomography.

N-[11C-methyl]chlorphentermine ([11C]NMCP) and N,N-[11C-dimethyl]chlorphentermine ([11C]NDMCP) were prepared from chlorphentermine and 11CH3I in DMF and evaluated in rats as brain blood-flow agents for positron emission tomography (PET). Tissue distribution of [11C]NMCP showed that brain uptake was 2.70 +/- 0.40% of injected dose per organ at 5 min with no change in radioactivity concentration up to 30 min after i.v. injection. Approximately 80% of the initial brain uptake remained at 60 min. On the other hand, initial brain uptake of [11C] NDMCP (3.66 +/- 0.31 and 3.63 +/- 0.88% injected dose per organ at 5 and 15 min, respectively) was greater than that of [11C]NMCP. The brain activity however, rapidly decreased to 2.38 +/- 0.17 and 1.82 +/- 0.32% at 30 and 60 min, respectively. Because of its longer retention in the brain compared with [11C]NDMCP, [11C]NMCP would be a potential brain blood-flow agent for quantitative PET studies.

Comparative potencies of amphetamine, fenfluramine and related compounds in taste aversion experiments in rats.

1 Rats failed to drink a flavoured solution when its consumption had been followed by injection of amphetamine (conditioned taste aversion).2 There was very little difference between the potencies of (+)- and (-)-amphetamine.3p-Chloromethamphetamine was a more potent aversive agent than methamphetamine.4 Strong taste aversions were also conditioned with other congeners of amphetamine. The rank order of potency was: fenfluramine > chlorphentermine >p-hydroxyamphetamine.5 Cocaine induced only moderate taste aversions, even at high doses.6 Aversive potency did not appear to be correlated with known neurochemical actions of the drugs or with behavioural stimulation, but appeared to be a central action which may have been linked to anorexigenic potency or time course of action.

Influence of cationic amphiphilic drugs on the phosphatidylcholine hydrolysis by phospholipase A2.

On chronic treatment certain amphiphilic drugs induce a generalized phospholipidosis. This drug side effect has been related to an inhibition of the lysosomal phospholipases due to the interaction of the drugs with phospholipids (PL). In the present experiments, the influence of the amphiphilic drugs ambroxol, imipramine, chloroquine and chlorphentermine on the hydrolysis of dipalmitoyl-phosphatidylcholine (DPPC) unilamellar liposomes by bee venom phospholipase A2 (PLase A2) was studied. Special emphasis was laid on the initial phase and temperature dependence. The activity of PLase A2 was measured continuously with a spectrophotometric assay using cresol red as indicator. In most cases a lag-phase of different duration was observed before the enzyme exhibited its full activity. The duration of the lag-phase and the rate of hydrolysis in the second phase are inversely related. The temperature dependence of the hydrolysis reveals a maximum of activity near the phase transition of the bilayer and a gradually decreasing activity at lower and higher temperatures, respectively. The analysis of the influence of amphiphilic drugs reveals three types of interaction. Imipramine and ambroxol shift the temperature activity profile towards lower temperatures without a substantial influence on the shape of the profile and on the maximal rate of hydrolysis. Chloroquine inhibits the enzyme activity without any temperature dependence. Chlorphentermine, the classical lipidosis inducing drug, exhibits a third type of interaction which seems to be a combination of the two former types.

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.

Chlorphentermine-induced alterations in pulmonary phospholipid content in rats.

Daily, intraperitoneal administration of the anorectic drug chlorphentermine (30 mg/kg) for 5 days to rats significantly increased phosphatidylcholine and total phospholipid content after 1 week and reached a maximal level 4 weeks after treatment in whole lung tissue (unlavaged lungs) and in sessile tissue in which alveolar lipids and macrophages were removed by pulmonary lavage (lavaged lungs). In lavaged lung, a significant rise in the content of sphingomyelin, phosphatidylserine plus phosphatidylinositol component, and phosphatidylethanolamine plus phosphatidylglycerol fraction occurred after 2 weeks, remained at this increased level for 4 weeks, and was followed by a return to control amounts after 5 weeks. In unlavaged lung, the chlorphentermine-induced elevation in sphingomyelin content seen after 1 week persisted at this same significant level even 5 weeks after treatment. Regardless of experimental duration, pulmonary glycogen levels were not altered markedly by chlorphentermine in unlavaged or lavaged tissue. Phenobarbital (30 mg/kg) did not markedly alter pulmonary glycogen and phospholipid component levels. Simultaneous phenobarbital and anorectic drug administration prevented the chlorphentermine-induced rise in total phospholipid, sphingomyelin, and phosphatidylcholine in unlavaged lung without a change in glycogen. A 7-day withdrawal from chlorphentermine treatment in rats previously injected with drug for 2 weeks resulted in a return to control in the levels of sphingomyelin, phosphatidylcholine, and total phospholipid in unlavaged lung. Extension of withdrawal from treatment for 2 weeks produced a significant decrease in all phospholipid components below control values, suggesting that a possible imbalance in synthetic and catabolic activity may persist after drug removal. The concentration of lung glycogen was not altered significantly by chlorphentermine treatment or withdrawal from drug administration. Our results indicate that the chlorphentermine-induced rise in phospholipid components was time-dependent in lavaged and unlavaged lungs, and the increase in phosphatidylcholine occurred independently of a change in glycogen. In addition, the present study shows that the chlorphentermine-induced changes in phospholipid levels are reversible and almost completely prevented by phenobarbital.

Alcohol-induced bronchospasm in an asthmatic patient: pharmacologic evaluation of the mechanism.

A 23-year-old Asian with histamine-reactive asthma complained of recurrent chest tightness, nasal congestion and flushing immediately after drinking minimal amounts of alcoholic beverages. He was extensively studied to determine the possible mechanism of his alcohol-induced respiratory symptoms. Drinking of either beer or 95 percent ethanol in apple juice immediately provoked vasomotor signs and moderately severe bronchospasm (54 percent and 73 percent decreases in specific airway conductance, respectively), which spontaneously improved over 30 minutes and two hours, respectively. Intravenous and inhaled ethanol caused less bronchospasm than observed with oral ethanol, and recovery was rapid. Pretreatment with cromolyn sodium (inhaled or oral) and isoproterenol had no inhibitory effect on the alcohol-induced bronchoconstriction, whereas atropine, acetylsalicylic acid, cyproheptadine, and chlorpheniramine appeared to have a partial inhibitory effect. Approximately 70 percent inhibition was observed after chlorpheniramine. Observations in this patient suggest that the bronchoconstriction induced by alcoholic beverages is related to their ethanol content and may be related to formation or release of one or more bronchoconstrictor and vasoactive compounds, including a stimulant of histamine1-receptors. The route of ethanol administration may also influence the bronchospastic response.

Effects of drug-induced pulmonary phospholipidosis on lung mechanics in rats.

Chronic administration of amphiphilic drugs to rats induces pulmonary phospholipidosis (P), a disease characterized by accumulation of phospholipids and large foamy macrophages in alveolar spaces. We investigated whether P induced by chlorphentermine (CPH) causes changes in lung volumes and mechanics in this species. Groups of rats were fed CPH (50 mg.kg-1.day-1) for 1, 2, 3, 5, 9, and 14 wk. After each treatment period, lung volumes and mechanics were studied in the anesthetized, paralyzed, supine rat. Partial pressure-volume (PV) curves were developed at 3 and 6 ml above functional residual capacity (FRC; PV3, PV6), followed by maximal [up to total lung capacity (TLC)] PV curves. FRC was determined by saline displacement. Lungs were then fixed for histopathological examination. A subgroup of animals was allowed a recovery period of 6 wk, after the 9 wk of CPH administration. Pair-fed rats served as controls (CTR) at each time point. Lung weight increased in CPH-treated (CPH-T) rats from 1.5 +/- 0.2 (SD) g at week 1 to 5.8 +/- 1.4 g at week 14, reflecting the development of P. TLC, FRC, transpulmonary pressure at FRC, the shape of maximal PV curves, and static expiratory lung compliance computed from maximal PV data points did not change in CPH-T rats. However, partial PV curves of CPH-T lungs (particularly PV3) were shifted downward and to the right of those of CTR at 2, 3, 5, and 9 wk, indicating increased recoil pressure in phospholipidotic lungs at these time points.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug-induced phospholipidosis. II. Alterations in the phospholipid pattern of organs from mice, rats and guinea-pigs after chronic treatment with chlorphentermine.

In three species chronic treatment with the anorectic drug chlorphentermine causes a profound alteration of the phospholipid/lipid metabolism in the organism, resulting in an increase of the fractions of phospholipids and lipids, e.g. in lungs, livers and adrenals. The results are interpreted as drug-induced generalized phospholipidosis, which is caused by amphiphilic drugs, like chlorphentermine and others. Its extent depends on several factors, like content, pattern and turnover rate of phospholipids in different organs, and on the species.