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P Cullis

Publications and source records attributed to P Cullis.

14 recordsLinked to original sources
PubMed2001

Cervical dystonia severity scale reliability study.

Cervical dystonia (CD) is characterized by sustained contractions of the neck musculature, resulting in abnormal head postures. The Cervical Dystonia Severity Scale (CDSS) was developed to provide a reliable measure of treatment response in patients with CD. The CDSS uses a protractor and wall chart to rate the severity of the head's deviation from neutral in each of three planes of motion (rotation, laterocollis, anterocollis/retrocollis), which is then scored in 5 degree intervals (1 degree to 5 degrees deviation = 1; 86 degree to 90 degrees deviation = 18). To test the reliability of the CDSS, four centers, each with two independent examiners, evaluated 42 patients with CD. At each site, each of the two examiners used the CDSS to evaluate the head position of each patient twice, on the same day, for a total of four evaluations. The kappa value for intra-examiner agreement was 0.94 (95% confidence limit of 0.900-0.972), indicating excellent intra-examiner reliability. The kappa value for interexaminer reliability was 0.79 for the first evaluation and 0.86 for the second evaluation (95% confidence limits of 0.668-0.920 and 0.790-0.920) indicating excellent interexaminer reliability. Thus, the CDSS was highly reliable in both intra-examiner and interexaminer scoring comparisons.

Adult↗
PubMed1999

Progress towards a synthetic virus for systemic gene therapy.

Here we discuss recent progress in non-viral gene therapy with an emphasis on developments which specifically attempt to address the limitations of current systems and their inability to overcome the first barrier to systemic gene delivery, delivery to the disease site and the target cell. Other issues associated with the efficiency of transfection, such as intracellular delivery, the endosomal release of vectors internalized through endocytosis and nuclear delivery are also discussed.

Animals↗
PubMed1994

The comparative toxicity of chlorambucil and chlorambucil-spermidine conjugate to BALB/c mice.

The acute intraperitoneal toxicities of chlorambucil and chlorambucil-spermidine conjugate have been compared, in mice. Both compounds were neurotoxic and also caused a prolonged fall in bodyweight and a depletion of lymphocyte numbers associated with a fall in the total leukocyte count and loss of spleen and thymus weight. Alanine aminotransferase and aspartate aminotransferase activities and blood urea nitrogen concentration were increased at 24 h after conjugate administration, but had returned to normal at 72 h. Chlorambucil significantly decreased blood urea nitrogen concentration for 72 h, but did not affect transferase activity. Tissue concentrations of conjugate were measurable in liver and kidney for 12 days and lung for 5 days after dosing. The toxicity of both compounds was cumulative. In mol/kg, the chlorambucil-spermidine conjugate was 10-fold more toxic than chlorambucil, on the basis of their neurotoxicity, but only 2- to 3-fold more toxic on the basis of their effects on lymphocyte depression. The increased toxicity of the conjugate does not improve its therapeutic index relative to chlorambucil.

Alanine Transaminase↗
PubMed1992

The influence of cholesterol 3-sulphate on phase behaviour and hydrocarbon order in model membrane systems.

Cholesterol 3-sulphate (CS) is a component of the intercellular lipid found in the uppermost layer of human epidermis (the 'stratum corneum') and is thought to play an important role in tissue cohesion. In this investigation we have compared the influence of cholesterol (CH) and CS on the gel-to-liquid crystalline phase behaviour, the polymorphic phase behaviour, and the hydrocarbon order profile in selected model membranes. It is shown that in sphingomyelin (SPM) systems, the presence of equimolar amounts of either CH or CS eliminates the gel-to-liquid crystalline transition as detected by calorimetry. Similarly, in 1-palmitoyl,2-oleoyl-phosphatidylethanolamine (POPE) dispersions containing a perdeuterated palmitoyl chain (POPE-d31), it is shown that both CH and CS exert an ordering effect as determined by 2H-NMR techniques, however, CS is less potent at temperatures both above and below that of the main transition for the native phospholipid. Alternatively, in mixed systems containing dioleoylphosphatidylethanolamine (DOPE) and SPM (DOPE/SPM, 6:1 mol/mol) CH promotes thermotropic L alpha-->HII phase transitions, whereas CS stabilizes the bilayer organization. These bilayer stabilization effects can be diminished by addition of Ca2+. These effects are consistent with a larger area per molecule of CS as compared to CH, presumably related to the presence of the negatively charged sulphate moiety of CS.

Cell Membrane↗
PubMed1992

Uptake and cytotoxicity of novel nitroimidazole-polyamine conjugates in Ehrlich ascites tumour cells.

A number of tumour cells, including Ehrlich ascites tumour cells (EATC), possess a polyamine uptake system which selectively accumulates endogenous polyamines and structurally related compounds by an active energy dependent system(s). We suggest that it may be possible to utilize this uptake system to target certain cytotoxic agents to those tumour cells possessing this system. In an initial attempt to determine the feasibility of this suggestion, we have synthesized a series of 2- and 5-nitroimidazoles linked to polyamines and determined their ability to utilize the polyamine uptake system. Within the limited series of compounds synthesized, 2-nitroimidazole-polyamine conjugates were more potent inhibitors of spermidine uptake into EATC than the 5-nitroimidazole conjugates. It has been assumed partly based on the competitive nature of this inhibition, that the ability of these compounds to inhibit spermidine uptake is also a measure of their ability to be accumulated by EATC. A greater than 700-fold variation was observed in the ability of different analogues to inhibit spermidine uptake. The most potent inhibitors retained certain structural characteristics similar to those of spermidine. Those compounds linked to polyamines were much more potent inhibitors of polyamine uptake than the parent nitroimidazoles i.e. metronidazole and misonidazole. The toxicity of the parent compounds and their polyamine conjugates in control and polyamine-depleted EATC was assessed by measuring inhibition of tritiated thymidine incorporation. Polyamine depletion, by prior exposure to difluoromethylornithine, results in a compensatory increase in the uptake of polyamines and related structures which may result in an increase in toxicity. Whilst many of the novel conjugates showed only little or moderate toxicity to control cells, the toxicity of several of the conjugates but not the parent nitroimidazoles increased in the polyamine-depleted cells. A clear distinction was also observed between the ability to inhibit spermidine uptake (and hence affinity for the uptake system) and toxicity, e.g. compound 430, a dinitroimidazole-polyamine conjugate, was the best inhibitor of spermidine uptake studied but showed no toxicity. These results support the hypothesis that linking polyamines to nitroimidazoles facilitates the entry of the latter into cells, such as EATC, which possess the polyamine uptake system and may therefore have therapeutic application in the delivery of polyamine-linked cytotoxics to certain tumours.

Animals↗
PubMed1989

Detection of surface charge-related properties in model membrane systems by aqueous two-phase partition.

Unilamellar vesicles composed of phosphatidylcholine (PC) and either phosphatidic acid (PA) or phosphatidylglycerol (PG) partition to the upper poly(ethylene glycol) (PEG)-rich phase of a charge-sensitive 5%:5% (w/w) PEG 8000/Dextran T-500 phase system containing 10 mM sodium phosphate at pH 7, consistent with the vesicles bearing a net negative charge. When prepared in the presence of a pH gradient (interior acidic), PC/PA vesicles exhibit an increased partition to the top PEG-rich phase, consistent with a redistribution of the PA from the inner to the outer monolayer of the vesicle bilayer. Conversely, when prepared in the presence of a pH gradient (interior basic), PC/PG vesicles exhibit a decreased top-phase partition, consistent with a redistribution of the PG from the outer to the inner monolayer of the vesicle bilayer. Unilamellar vesicles composed of PC and stearylamine partition to the lower dextran-rich phase of a 5%:5% (w/w) PEG 8000/Dextran T-500 phase system containing 10 mM sodium phosphate at pH 8.5, consistent with the vesicles bearing a net positive charge. When prepared in the presence of a pH gradient (interior acidic), conditions under which the stearylamine is trapped on the inner monolayer of the bilayer, the vesicles now partition predominantly to the interface in a manner similar to vesicles composed of PC alone. These results demonstrate that partitioning in aqueous two-phase polymer systems is a sensitive method for monitoring the asymmetry of charged lipids in model membrane systems and also suggests that partitioning in charge-sensitive systems depends only on the physical nature of the exterior surface of the membrane.

Kinetics↗
PubMed1989

Aqueous two-phase polymer partitioning of lipid vesicles of defined size and composition.

The kinetics of the partitioning of lipid vesicles containing acidic phospholipids in aqueous two-phase polymer systems are dependent upon the vesicle size; the larger the vesicles, the more readily they absorb to the interfaces between the two polymer phases and hence are cleared from the top phase as phase separation proceeds. The partitioning of neutral lipid vesicles is principally to the bulk interface and is the same in phase systems of both low and high electrostatic potential difference between the two phases (delta psi). The incorporation of negatively charged lipids has two effects upon partition. First, vesicles with negatively charged lipids exhibit increased bottom phase partitioning in phases of low delta psi due to an enhanced wetting of the charged lipids by the lower phase. Second, the presence of a negatively charged group on the vesicle surface results in increased partition to the interface and top phase in phase systems of high delta psi. Differences observed in the partition of vesicles containing various species of negatively charged lipid thus reflect a competition between these two opposing factors.

Adsorption↗
PubMed1989

Liposomal Gd-DTPA: preparation and characterization of relaxivity.

Gadolinium diethylenetriaminepentaacetic acid (DTPA) has not proved particularly useful for hepatosplenic magnetic resonance imaging. However, by entrapping the Gd-DTPA within lipid vesicles, one may exploit the ability of the reticuloendothelial system to endocytose particulates, permitting passive delivery of contrast agent to the liver and spleen while decreasing the rate of clearance of Gd-DTPA from the vasculature. Liposomes of 70-400 nm diameter containing Gd-DTPA were prepared by a freeze-thaw extrusion process. These exhibited high trapping efficiencies and excellent stability during storage. For all sizes of liposomes, the relaxivity of the entrapped Gd-DTPA was less than that of free Gd-DTPA. Relaxivity varied linearly with the surface-area-to-volume ratio of the liposomes; the smaller the liposomes, the greater the relaxivity. Liposomes containing cholesterol had a lower relaxivity than liposomes without cholesterol. The authors suggest this reflects the decrease in the water permeability coefficient caused by the presence of cholesterol in the liposome membrane.

Contrast Media↗
PubMed1988

Gadolinium-DTPA liposomes as a potential MRI contrast agent. Work in progress.

To evaluate the use of liposomes containing Gadolinium-DTPA (Gd-DTPA) as potential intravascular contrast agents, we synthesized and tested Gd-DTPA liposomes. A freeze-thaw extrusion process was used to synthesize neutral unilamellar vesicles. Using this technique, we prepared 0.4 micron vesicles with encapsulation efficiency as high as 39% for Gd-DTPA. In vitro dialysis showed that essentially 100% of the Gd-DTPA was retained with the liposomes after 72 hours of dialysis. MR imaging of in vitro samples showed concentration-dependent increase in signal intensity with Gd-DTPA liposomes. Imaging of rats after intravenous injection of Gd-DTPA liposomes showed sustained intravascular contrast enhancement of vascular structures and liver greater than free Gd-DTPA. There was no evidence of acute toxicity in rats during the imaging experiments or on follow-up of two months. Paramagnetic liposomes may be useful to enhance the vasculature, liver, and spleen.

Animals↗
PubMed1987

Cholesteryl ester transfer activity in plasma measured by using solid-phase-bound high-density lipoprotein.

We studied the ability of lipid-transfer factors in plasma to promote transfer, to endogenous lipoproteins, of [3H]cholesteryl ester from high-density lipoprotein (HDL) covalently bound to Sepharose 4B beads. After incubation for 2 h at 37 degrees C, 12 to 14% of the [3H]cholesteryl ester had been transferred to the lipoproteins of the plasma, in the proportions 57% to HDL and 43% to low- and very-low-density lipoproteins. This process was a function of the amount of plasma present and was stimulated by addition of partly purified lipid-transfer protein. Transfer also depended on the concentration of donor HDL but was independent of the amount of acceptor lipoprotein. This simple evaluation of cholesteryl ester transfer does not require removal of lipoproteins from the plasma before incubation.

Cholesterol Esters↗
PubMed1984

Grand mal discharge.

Two hundred nineteen grand mal discharges were reviewed in 50 epileptic patients. It was commonly seen in patients with prenatal and perinatal causes, mental deficiency with neurological deficits, and multiple types of seizures. Eighty-eight percent of the discharges were bilaterally synchronous with 49 percent of bifrontal predominance. Fifty-eight percent were associated with drowsiness or sleep, and 64 percent were associated with clinical accompaniments. The most common clinical signs were tonic movement of arms, legs or neck, eye opening, eye fluttering, head drop, etc. The increased frequency of clinical seizures usually observed during the occurrence of this pattern may provide some clues that the antiepileptic medication should be reassessed to control the oncoming seizure attacks.

Adolescent↗
PubMedDate not supplied

Liposomal Gd-DTPA: effect of encapsulation on enhancement of hepatoma model by MRI.

Liposomes entrapping gadolinium-DTPA (Gd-DTPA) were synthesized from 60 mole percent egg phosphatidylcholine (EPC) and 40 mole percent cholesterol or EPC alone entrapping Gd-DTPA in diameters of 100 and 200 nm. Rats bearing Morris hepatoma in their flanks were imaged by MR pre- and post-contrast with free Gd-DTPA and liposomal Gd-DTPA for up to four hours after IV contrast. Comparison of images after free and liposomal Gd-DTPA showed dramatic differences in tumor and organ enhancement. Liposomal Gd-DTPA enhancement of tumor corresponded more closely to histologically proven vascularized portions of tumor than free Gd-DTPA. Hepatic enhancement was greater with liposomal than free Gd-DTPA and time course of liver, kidney and tumor enhancement was prolonged. The 100-nm EPC Gd-DTPA liposomes caused the greatest enhancement. Gd-DTPA liposomes may be useful as liver and blood pool contrast agents. By varying lipid composition and vesicle size, patterns of enhancement may be selectively modified.

Animals↗