Biomedical subjects

X Q Pan

Publications and source records attributed to X Q Pan.

At least 19 recordsLinked to original sources

PubMed2006

Probing nanoscale ferroelectricity by ultraviolet Raman spectroscopy.

We demonstrated that ultraviolet Raman spectroscopy is an effective technique to measure the transition temperature (Tc) in ferroelectric ultrathin films and superlattices. We showed that one-unit-cell-thick BaTiO3 layers in BaTiO3/SrTiO3 superlattices are not only ferroelectric (with Tc as high as 250 kelvin) but also polarize the quantum paraelectric SrTiO3 layers adjacent to them. Tc was tuned by approximately 500 kelvin by varying the thicknesses of the BaTiO3 and SrTiO3 layers, revealing the essential roles of electrical and mechanical boundary conditions for nanoscale ferroelectricity.

Journal Article↗

PubMed2006

Nano-alpha-Al2O3 by liquid-feed flame spray pyrolysis.

Nanometre-sized particles of transition (t)-aluminas are important for the fabrication of high-quality alumina ceramics. Multiple tons are produced each year using a variety of gas-phase processes. The nanoparticles produced by these methods consist mainly of the undesired delta phase with some gamma- and theta-Al(2)O(3). Nano-t-aluminas should provide access to dense nano/submicrometre-grained alpha-Al(2)O(3) shapes offering significant advantages over micrometre-grained shapes. Unfortunately, polymorphism coupled with the high activation energy for nucleating alpha-Al(2)O(3) greatly impedes efforts to process dense alpha-Al(2)O(3) with controlled grain sizes, especially for submicrometre materials. Typically alpha-Al(2)O(3) nucleation within t-aluminas is sporadic rather than uniform, leading to exaggerated grain growth and vermicular microstructures without full densification (5). Thus, production of quantities of nano-alpha-Al(2)O(3) from multiple nano-t-aluminas for seeding or direct processing of alpha-Al(2)O(3) monoliths could greatly change how alpha-Al(2)O(3) components are processed. We report here that liquid-feed flame spray pyrolysis of nano-t-aluminas converts them to dispersible 30-80 nm alpha-Al(2)O(3) powders (50-85% phase transformed). Surprisingly, the powder surfaces are fully dehydrated. These powders pressureless sinter to more than 99.5% dense alpha-Al(2)O(3) with final grain sizes < or =500 nm without sintering aids.

Journal Article↗

PubMed2004

Enhancement of ferroelectricity in strained BaTiO3 thin films.

Biaxial compressive strain has been used to markedly enhance the ferroelectric properties of BaTiO3 thin films. This strain, imposed by coherent epitaxy, can result in a ferroelectric transition temperature nearly 500 degrees C higher and a remanent polarization at least 250% higher than bulk BaTiO3 single crystals. This work demonstrates a route to a lead-free ferroelectric for nonvolatile memories and electro-optic devices.

Journal Article↗

PubMed2004

Room-temperature ferroelectricity in strained SrTiO3.

Systems with a ferroelectric to paraelectric transition in the vicinity of room temperature are useful for devices. Adjusting the ferroelectric transition temperature (T(c)) is traditionally accomplished by chemical substitution-as in Ba(x)Sr(1-x)TiO(3), the material widely investigated for microwave devices in which the dielectric constant (epsilon(r)) at GHz frequencies is tuned by applying a quasi-static electric field. Heterogeneity associated with chemical substitution in such films, however, can broaden this phase transition by hundreds of degrees, which is detrimental to tunability and microwave device performance. An alternative way to adjust T(c) in ferroelectric films is strain. Here we show that epitaxial strain from a newly developed substrate can be harnessed to increase T(c) by hundreds of degrees and produce room-temperature ferroelectricity in strontium titanate, a material that is not normally ferroelectric at any temperature. This strain-induced enhancement in T(c) is the largest ever reported. Spatially resolved images of the local polarization state reveal a uniformity that far exceeds films tailored by chemical substitution. The high epsilon(r) at room temperature in these films (nearly 7,000 at 10 GHz) and its sharp dependence on electric field are promising for device applications.

Journal Article↗

PubMed2001

Fc gamma receptors differ in their structural requirements for interaction with the tyrosine kinase Syk in the initial steps of signaling for phagocytosis.

Receptors for the constant region of IgG, Fc gamma receptors, are expressed on the surface of hematopoietic cells, where they mediate signaling events, such as phagocytosis, essential for host defense. Fc gamma receptors also play a role in the pathophysiology of autoimmune diseases. We have demonstrated that members of each of the three classes of human Fc gamma receptors, Fc gamma RI, Fc gamma RII, and Fc gamma RIII, mediate phagocytosis, but that important differences exist in their requirements for phagocytic signaling. For example, the Fc gamma receptors Fc gamma RI and Fc gamma RIIIA induce signaling largely by association with a gamma subunit containing a conserved cytoplasmic motif (ITAM) whose tyrosines are phosphorylated following receptor stimulation. Fc gamma RIIA contains a similar motif in its own cytoplasmic domain and does not require the gamma chain for phagocytic signaling. The tyrosine kinase Syk associates with the cytoplasmic domain of both the Fc gamma receptor gamma chain and Fc gamma RIIA and is required for phagocytosis by both Fc gamma receptor systems. To elucidate the differences in phagocytic signaling by the gamma chain and Fc gamma RIIA, we investigated the requirements for Fc gamma receptor/Syk co-immunoprecipitation, tyrosine phosphorylation, and phagocytosis. Both Fc gamma RIIA and the human gamma chain contain a tyrosine seven amino acids upstream of the ITAM motif. We observed that the upstream tyrosine plays a role in Fc gamma RIIA phagocytic signaling but is not involved in phagocytic signaling by the human gamma chain. Our data also indicate that the two ITAM tyrosines of the human gamma chain and Fc gamma RIIA do not contribute equally to Fc gamma receptor association with Syk kinase and phagocytic signaling. The data indicate that the carboxy-terminal tyrosine of the receptor cytoplasmic domain is especially important both for the interaction with Syk kinase and for phagocytosis. Elucidating such differences in gamma chain and Fc gamma RIIA signaling may be valuable in designing strategies for therapeutic intervention in hematopoietic and immunological disorders.

Animals↗

PubMed1999

Activation of three classes of nonreceptor tyrosine kinases following Fc gamma receptor crosslinking in human monocytes.

Fc gamma receptors on monocytes/macrophages play an important role in both host defense and autoimmune disorders. Fc gamma receptor signaling can lead to such downstream events as phagocytosis and the release of intracellular cytokines and reactive oxygen species. Freshly isolated human monocytes express two major classes of Fc gamma receptor proteins, Fc gamma RI (CD64) and Fc gamma RII (CD32). Crosslinking of Fc gamma RI and Fc gamma RII gives rise to rapid and transient phosphorylation of multiple monocyte intracellular proteins including proteins of 40, 68-72, 75-85, 95, and 115-165 kDa. A 72-kDa protein was earlier identified as the tyrosine kinase Syk. Here we identify one of the proteins in the 115- to 165-kDa cluster as FAK, a protein tyrosine kinase localized to focal adhesions. A 68-kDa phosphoprotein was identified as paxillin, a cytoskeleton associated substrate for tyrosine kinases, and a 95-kDa protein was found to be the proto-oncogene product Vav. The Src family protein tyrosine kinase Fgr (p58) also displayed enhanced tyrosine phosphorylation after Fc gamma RI and Fc gamma RII crosslinking. Although Fc gamma RIIA utilizes tyrosines within its own cytoplasmic domain for signaling while Fc gamma RI utilizes the cytoplasmic tyrosines of its associated gamma subunit, our results indicate sharing of several proteins for signaling in monocytes by these Fc receptors. These molecules include three distinct classes of tyrosine kinases, Syk, FAK, and Fgr, and the functionally diverse proteins Vav and paxillin.

Cell Adhesion Molecules↗

PubMed1998

The Plasmodium falciparum translationally controlled tumor protein homolog and its reaction with the antimalarial drug artemisinin.

Artemisinin and its derivatives are important new antimalarial drugs. When Plasmodium falciparum-infected erythrocytes are incubated with [10-3H]dihydroartemisinin, several malaria-specific proteins become labeled. One of these proteins is the P. falciparum translationally controlled tumor protein (TCTP) homolog. In vitro, dihydroartemisinin reacts covalently with recombinant TCTP in the presence of hemin. The association between drug and protein increases with increasing drug concentration, plateauing at approximately 1 drug/TCTP molecule. By Scatchard analysis, there appear to be 2 hemin binding sites on TCTP with dissociation constants of approximately 18 microM. When the single cysteine moiety is blocked by pretreatment with iodoacetamide, hemin binding is not affected, whereas drug binding is reduced by two-thirds. Thus, TCTP reacts with artemisinin in situ and in vitro in the presence of hemin and appears to bind to hemin. The function of the malarial TCTP and the role of this reaction in the mechanism of action of artemisinin await elucidation.

Amino Acid Sequence↗

PubMed1997

Overexpression of a 40-kDa protein in human multidrug resistant cells.

The use of anticancer drugs in the chemotherapeutic treatment of cancer patients frequently results in the emergence of drug resistant tumors. Selection of tumor cell lines in vitro has led to the identification of several proteins that mediate drug resistance to anticancer drugs. In this study, an immuno-dot blot method was used to isolate a monoclonal antibody (IPM96) which recognized a 40 kDa protein (or P-40) co-expressed with P-glycoprotein and MRP in several multidrug resistant cell lines (MCF-7/Adr, SKOV/VLB1.0, H69/Adr, and HL60/AR). Furthermore, P-40 levels dropped significantly in one revertant cell line (H69/PR) derived from H69/AR cells. Interestingly, the expression of P-40 was also higher in two tumor cell lines (SKTax6a and A2780CP) that were selected with paclitaxel or cisplatin but do not express P-gp or MRP. Immuno-fluorescence staining of cells with IPM96 showed both membrane and cytoplasmic staining. These results were confirmed by Western blot analysis of different subcellular fractions from MCF-7/Adr cells. The membrane bound P-40 was resistant to extraction with high salt, chelating agents, and denaturing agents, but was solubilized with 10 mM CHAPS. Taken together, the overexpression of P-40 in multidrug resistant cells has not been previously determined and therefore could be important in the expression of the drug resistance phenotype.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1995

Syntheses and antimalarial activities of N-substituted 11-azaartemisinins.

A two-step reaction sequence between artemisinin and methanolic ammonia followed by treatment with Amberlyst 15 yielded 11-azaartemisinin in 65% yield. Substituting a variety of primary alkyl- and heteroaromatic amines for ammonia in the reaction sequence yields N-substituted 11-azaartemisinins in similar or greater yield. When Amberlyst 15 is replaced by a mixture of sulfuric acid/silica gel, both 11-azaartemisinin and the expected metabolite, 10-azadesoxyartemisinin, are formed in 45% and 15% yields, respectively. In vitro and in vivo test data for a number of novel N-substituted 11-azaartemisinins, against drug-resistant strains of Plasmodium falciparum, show they possess antimalarial activities equal to or greater than that of artemisinin. The most active derivative, N-(2'-acetaldehydo)-11-azaartemisinin, 17, was 26 times more active in vitro and 4 times more active in vivo than artemisinin.

Animals↗

PubMed1995

Synthesis and antimalarial activities of several fluorinated artemisinin derivatives.

The carbonyl groups in several artemisinin derivatives were converted into geminal difluorinated compounds on treatment with diethylaminosulfur trifluoride. A number of other mono- and polyfluorinated artemisinin derivatives were prepared. Their in vitro antimalarial activities were all equal to or greater than the nonfluorinated analogs or precursors.

Animals↗

PubMed1995

Induction of phagocytosis by a protein tyrosine kinase.

The transmission of extracellular signals to cellular targets by many noncatalytic surface receptors is dependent on interaction between cytoplasmic protein tyrosine kinases (PTKs) and tyrosine-containing sequences in the cytoplasmic domain of the receptor or an associated subunit. Isoforms of each of the three classes of the noncatalytic Fc gamma receptors, Fc gamma RI, Fc gamma RII, and Fc gamma RIII, are able to transmit a phagocytic signal in transfected COS-1 cells. Both Fc gamma RI and Fc gamma RIIIA require the gamma subunit for this signaling event. The protein tyrosine kinase Syk dramatically enhances phagocytosis mediated by both these receptors and increases the number of cells able to mediate phagocytosis. Two gamma chain cytoplasmic YXXL sequences are required for this effect. The action of Syk is less pronounced on the phagocytic Fc gamma RII receptor, Fc gamma RIIA, which does not require the gamma chain for phagocytosis. However, Syk allows phagocytosis by the nonphagocytic Fc gamma RII receptor Fc gamma RIIB2, which contains only a single YXXL sequence, when an additional tyrosine-containing sequence, YMTL, is introduced. These studies indicate that the efficiency of phagocytosis is markedly enhanced by the presence of a specific protein tyrosine kinase.

Amino Acid Sequence↗

PubMed1995

The functional hepatic volume assessed by 99mTc-GSA hepatic scintigraphy.

The accuracy of measurement of the functional hepatic volume by single photon emission computed tomography (SPECT) with 99mTc-galactosyl serum albumin (99mTc-GAS) was evaluated. 99mTc-GSA planar scintigraphic images were obtained dynamically and the hepatic SPECT imaging was then performed in 25 patients with hepatobiliary tumors. The patients were divided into 4 groups with normal hepatic function, and mild, moderate and severe hepatic dysfunction. The functional hepatic volume determined by SPECT was compared with the morphological hepatic volume determined by compute tomography. The ratio of the hepatic volumes obtained by the two methods was calculated. The mean hepatic volume ratio was 96.6 +/- 2.3% in the normal hepatic function group and 95.9 +/- 2.2% in the mild dysfunction group (n.s.). In both the moderate and severe hepatic dysfunction groups, the hepatic volume ratio was smaller than that in the normal group (87.9 +/- 5.2%, p < 0.0001, and 71.9 +/- 7.6%, p < 0.0001, respectively). There was a linear correlation between the hepatic volume ration and various indices of reserve hepatic function, such as LHL15 (r = 0.83, p < 0.0001), HH15(r = 0.74, p < 0.0001), and ICG15 (r = 0.75, p < 0.0005). These results indicate that the hepatic volume ratio is proportional to the severity of hepatic dysfunction, and suggest that the functional hepatic volume measured with 99mTc-GSA faithfully reflects the functioning hepatocyte mass. 99mTc-GSA scintigraphy and hepatic SPECT therefore provide information regarding global and regional reserve hepatic function.

Adult↗

PubMed1995

Methionine recycling pathways and antimalarial drug design.

5'-Deoxy-5'-(methylthio)adenosine (MTA) is an S-adenosylmethionine metabolite that is generated as a by-product of polyamine biosynthesis. In mammalian cells, MTA undergoes a phosphorolytic cleavage catalyzed by MTA phosphorylase to produce adenine and 5-deoxy-5-(methylthio)ribose-1-phosphate (MTRP). Adenine is utilized in purine salvage pathways, and MTRP is subsequently recycled to methionine. Whereas some microorganisms metabolize MTA to MTRP via MTA phosphorylase, others metabolize MTA to MTRP in two steps via initial cleavage by MTA nucleosidase to adenine and 5-deoxy-5-(methylthio)ribose (MTR) followed by conversion of MTR to MTRP by MTR kinase. In order to assess the extent to which these pathways may be operative in Plasmodium falciparum, we have examined a series of 5'-alkyl-substituted analogs of MTA and the related MTR analogs and compared their abilities to inhibit in vitro growth of this malarial parasite. The MTR analogs 5-deoxy-5-(ethylthio)ribose and 5-deoxy-5-(hydroxyethylthio)ribose were inactive at concentrations up to 1 mM, and 5-deoxy-5-(monofluoroethylthio)ribose was weakly active (50% inhibitory concentration = 700 microM). In comparison, the MTA analogs, 5'-deoxy-5'-(ethylthio)adenosine,5'-deoxy-5'-(hydroxyethylthio)ade nosine (HETA), and 5'-deoxy-5'-(monofluoroethylthio)adenosine, had 50% inhibitory concentrations of 80, 46, and 61 microM, respectively. Extracts of P. falciparum were found to have substantial MTA phosphorylase activity. Coadministration of MTA with HETA partially protected the parasites against the growth-inhibitory effects of HETA. Results of this study indicate that P. falciparum has an active MTA phosphorylase that can be targeted by analogs of MTA.

Animals↗

PubMed1994

Substitutions and deletions in the cytoplasmic domain of the phagocytic receptor Fc gamma RIIA: effect on receptor tyrosine phosphorylation and phagocytosis.

Fc gamma RIIA in the absence of other Fc receptors or receptor subunits induces the ingestion of IgG-coated cells. The cytoplasmic domain of Fc gamma RIIA contains two Y-x-x-L sequences similar to those in other Ig gene family receptors plus an additional tyrosine residue not in a Y-x-x-L motif. Upon cross-linking, Fc gamma RIIA is phosphorylated on tyrosine and the cytoplasmic tyrosines, Y275 (Y1), Y282 (Y2), and Y298 (Y3), may be important for its phagocytic activity. Because COS-1 cells can serve as a model for examining molecular structures involved in phagocytosis, substitutions and deletions were introduced into the cytoplasmic domain of Fc gamma RIIA and examined in COS-1 cell transfectants for their effects on phagocytosis and tyrosine phosphorylation. Disruption of a single cytoplasmic Y-x-x-L motif by substitution of tyrosine Y2 or Y3 by phenylalanine or by removing the threonine and leucine residues within the motif inhibited phagocytosis 50% to 65%. Tyrosine phosphorylation of Fc gamma RIIA also was inhibited, although to a greater extent by the substitution of Y3 than of Y2. Replacement of the N-terminal first cytoplasmic domain tyrosine, Y1, which is not within a typical Y-x-x-L, by itself did not inhibit phagocytosis, but replacement of Y1 in mutants lacking Y2 or Y3 virtually eliminated phagocytic activity and receptor tyrosine phosphorylation. Thus, at least two cytoplasmic tyrosines, including at least one typical single Y-x-x-L motif, are required for phagocytosis by Fc gamma RIIA. The data suggest that there is a close but not a simple relationship between phosphorylation of the Fc gamma RIIA cytoplasmic tyrosines and Fc gamma RIIA-mediated phagocytosis. Y3 appears to be particularly important because its removal by truncation or replacement with phenylalanine inhibits both tyrosine phosphorylation and phagocytosis in parallel. Alterations in the 12 residue proline-containing sequence between the two Y-x-x-L motifs also reduced phagocytic activity and tyrosine phosphorylation. Thus, the specific structure of the Fc gamma RIIA cytoplasmic domain accounts for its ability to stimulate phagocytosis in the absence of other subunits.

Amino Acid Sequence↗

PubMed1994

Insertion of cytoplasmic tyrosine sequences into the nonphagocytic receptor Fc gamma RIIB establishes phagocytic function.

Receptors for the Fc domain of IgG on cells of hematopoietic lineage perform important functions, including stimulation of the ingestion of IgG-coated cells. In examining the function of Fc gamma receptor isoforms by transfection into COS-1 cells, we have observed that Fc gamma RIIA induces the binding and phagocytosis of IgG-sensitized RBCs (EA) and that transfected COS-1 cells can serve as a model for examining the molecular structures involved in mediating a phagocytic signal. We now report that COS-1 cell transfectants expressing the isoforms Fc gamma RIIB1 and Fc gamma RIIB2 and a Fc gamma RIIA mutant without a cytoplasmic tail efficiently bind EA but do not mediate their phagocytosis. Furthermore, wild-type Fc gamma RIIA, but not Fc gamma RIIB1 or Fc gamma RBII2, was phosphorylated on tyrosine upon receptor activation. Tyrphostin 23, which alters tyrosine kinase activity, inhibited the phagocytosis of EA and reduced the phosphorylation of Fc gamma RIIA on tyrosine. Fc gamma RIIB1 and Fc gamma RIIB2 contain one copy of the cytoplasmic sequence YXXL/I implicated in signal transduction, whereas Fc gamma RIIA contains two copies. We therefore inserted YXXL/I sequences at different sites in Fc gamma RIIB2. Low levels of phagocytosis were observed in a Fc gamma RIIB2 mutant bearing the Fc gamma RIIA sequence YMTL and higher levels of phagocytosis were observed in a second Fc gamma RIIB2 mutant that contained both the upstream YMTL and an additional downstream tyrosine-containing motif. Activation of this mutant receptor also induced receptor tyrosine phosphorylation. Thus, these studies indicate that both the number and placement of YXXL sequences in the cytoplasmic domain of the Fc gamma RII receptor family affect both receptor tyrosine phosphorylation and phagocytic competence.

Amino Acid Sequence↗

PubMed1994

The high affinity Fc gamma receptor (CD64) induces phagocytosis in the absence of its cytoplasmic domain: the gamma subunit of Fc gamma RIIIA imparts phagocytic function to Fc gamma RI.

The high affinity Fc gamma receptor, Fc gamma RI, is unique among the three classes of macrophage Fc gamma receptors not only in its affinity for IgG, but also in the structure of its cytoplasmic domain. Fc gamma RIIA and the gamma subunit of Fc gamma RIIIA have tyrosine-containing motifs within their cytoplasmic domains that are phosphorylated when crosslinked and that are required for phagocytosis by COS-1 cell transfectants. In contrast to these other Fc gamma receptors, Fc gamma RI does not contain cytoplasmic tyrosines and does not induce phagocytosis in COS-1 transfectants. We transfected wild-type (WT) and mutant (MT) Fc gamma RI lacking the cytoplasmic domain into COS-1 cells and murine macrophages and assessed phagocytosis using IgG-coated red blood cells (RBCs) and RBCs conjugated with Fab anti-human Fc gamma RI monoclonal antibody (mAb). Fc gamma RI, in contrast to Fc gamma RIIA, did not induce phagocytosis in COS cells. However, both WT and MT Fc gamma RI induced phagocytosis in murine macrophages, and phagocytosis was inhibited by the tyrosine kinase inhibitor tyrphostin 23. Human monocytes also phagocytosed Fc gamma RI-targeted RBCs, and activation of Fc gamma RI on monocytes with Fab anti-Fc gamma RI induced phosphorylation of Fc gamma RII on tyrosine residues. However, Fc gamma RI activation of Fc gamma RI-Fc gamma RIIA COS-1 cotransfectants did not induce tyrosine phosphorylation of Fc gamma RIIA, and coexpression of Fc gamma RI and Fc gamma RIIA in COS cells did not confer Fc gamma RI phagocytic capability. In contrast, coexpression in COS-1 cells of Fc gamma RI with the gamma subunit of Fc gamma RIIIA conferred phagocytic function to both Fc gamma RI and the MT Fc gamma RI lacking the cytoplasmic domain. Thus, Fc gamma RI does not require its cytoplasmic domain to mediate a phagocytic signal and interacts with the gamma subunit of Fc gamma RIIIA to induce phagocytosis.

Animals↗

PubMed1993

[Cardioprotection of 2-[p-(dimethylamino)styryl]pyridine methiodide against ischemic damage and myocardial lipid peroxidation].

Mice were injected ip DSPM 1 or 3 mg.kg-1 3 h prior to a subcutaneous injection of isoproterenol (Iso) 20 mg.kg-1 once daily for 2 d. Iso induced reductions of Se-glutathione peroxidase (Se-GSH-PX), superoxide dismutase (SOD) activities, and an increase of malondialdehyde (MDA) content in myocardium. DSPM 1 or 3 mg.kg-1 significantly abated reduction of Se-GSH-PX activity and decreased MDA production and DSPM 3 mg.kg-1 also abated reduction of SOD activity in the hearts from Iso-treated mice. The changes of above indices were in accordance with those of myocardial ultrastructure and creatine phosphokinase (CPK) concentration in serum. The results indicate that DSPM has a protective effect on myocardial ischemic injury probably by inhibiting oxygen free radicals and subsequent lipid peroxidation.

Animals↗

PubMed1990

The chemotherapy of rodent malaria. XLV. Reversal of chloroquine resistance in rodent and human Plasmodium by antihistaminic agents.

The inherent blood schizontocidal activities of five antihistaminic compounds, cyproheptadine hydrochloride (CYP), ketotifen hydrogen fumarate (KET), pizotyline hydrogen maleate (PIZ), azatadine maleate (AZAT) and loratadine (LOR) were examined against the following organisms: chloroquine-sensitive (CS) Plasmodium berghei and chloroquine-resistant (CR) P. yoelii ssp. NS in mice; and CS Tak 9 clone 96 and CR K1 strain of P. falciparum in vitro. Chloroquine, verapamil and desipramine were used as comparison standards. CYP, KET, PIZ were active against the CS strain in vivo with ED90 levels between 20 and 30 mg kg-1 (given sc daily for four days). They were slightly more active against the CR strain. AZA was active, but much less so than the other compounds. LOR, verapamil and desipramine were inactive in vivo at the doses tested. Against CS P. falciparum in vitro, all five antihistaminics and desipramine were active at EC50 concentrations ranging from about 50-80 mumol l-1, while verapamil was only active at 175 mumol l-1. Against the CR strain of this parasite, CYP, PIZ and LOR were slightly more active than against the CS strain, but KET, AZAT, desipramine and verapamil were significantly less active. The action of all these compounds in combination with chloroquine was then examined both in vivo and in vitro. The ability of verapamil and desipramine to reverse chloroquine resistance in vitro was confirmed, but only a low level of reversal was seen with these compounds in vivo. However, CYP, KET, PIZ and AZAT produced a marked reversal of chloroquine resistance both in vivo and in vitro. The implications of these observations in relation to further laboratory and clinical research are discussed.

Animals↗