Search PubMed⌕ Search

Biomedical subjects

G Storm

Publications and source records attributed to G Storm.

At least 109 records · Page 6Linked to original sources
PubMed1992

Prolonged systemic delivery of peptide drugs by long-circulating liposomes: illustration with vasopressin in the Brattleboro rat.

The value of novel systemically long-circulating liposomes to prolong the duration of an antidiuretic hormone, arg8-vasopressin (VP), was investigated as a representative of low molecular weight peptides with rapid clearance. Cholesterol content was found to have a controlling effect on VP release in serum. Three types of liposomes were selected for urine production measurements in VP deficient Brattleboro rats. One contained phosphatidylserine (PS), which was rapidly cleared from the circulation. In the other two liposomes, the PS component was replaced by either phosphatidylglycerol or a novel phospholipid derivatized with polyethylene glycol (PEG); both showing prolonged circulation. Free VP (up to 8 micrograms/kg) gave reduced urine production for less than 24 hr. The PG formulation exhibited a dose-dependent prolonged duration of bioactivity of up to 4 days. Substitution of PEG-PE resulted in a 2-day delay followed by a prolonged duration of bioactivity for over 4 days. The duration of the prolonged bioactivity was not dose dependent but the amplitude was. This is attributed to VP release from liposomes which have distributed intact to another compartment without having been taken up by the RES. By balancing liposome circulation time, release rate, and dose, long-circulating liposomes can be applied to prolong the biological activity of a therapeutic peptide.

Animals↗
PubMed1992

[Duplex sonographic monitoring of infra-inguinal arterial reconstructions: can a threatened bypass occlusion be detected by this method?].

In our institution, 95 infrainguinal arterial reconstructions were prospectively entered into a graft surveillance programme which consisted of a postoperative i.a. DSA and routine assessment of graft flow velocity (GFV) and ankle pressure indices (ABI) during the first postoperative year. An average of 4.1 GFV measurements was obtained during a mean follow-up period of 8.2 months. Abnormal GFV led to arteriography in 29 bypasses identifying--aside from three false positive findings--two graft occlusions and 24 severe (> 70%) graft stenoses. Of the latter, in only 7 cases a significant decrease in ABI was found. Unheralded graft occlusion occurred in 6 patients. Including the corrections of the above mentioned lesions, secondary patency rates were 97% at 30 days and 89% at one year.

Aged↗
PubMed1992

[Determination of vascular resistance in bypass operations with infragenual anastomosis: is prediction of early occlusion possible with this value?].

Peripheral outflow resistance (OR) was assessed intraoperatively in 75 infrainguinal bypass procedures to the below knee popliteal artery (20) or a single crural artery (55). OR measurement was done after completion of the distal anastomosis. For that purpose, the graft was perfused with Ringer solution at constant flow rates of 100 and 150 ml/min using a roller pump. During infusion, arterial pressure was recorded. In this way distal (DOR) and total (TOR) outflow resistance in E/S anastomoses was calculated before and after vasodilatation with papaverine. DOR at a flow rate of 100 ml/min was found to be most discriminant as a predictor of early graft thrombosis: 1. In the limbs with a thrombosed graft at 30 days OR was significantly higher than in the limbs with a patent graft (1828 +/- 418 vs. 1472 +/- 221 mPRU; p less than 0.01, Mann-Whitney U-Test). 2. The cut-off value of 1700 mPRU, which was determined by ROC curves, was 100% sensitive and 81% specific in the group of femoro-crural grafts to predict early graft failure. A better discrimination by the application of papaverine could not be achieved. We concluded from our results that OR might be an important factor in early graft thrombosis. But still there is more experience required to select patients for primary amputation or adjunctive procedures (av-fistula, sequential graft) on the basis of the present available data.

Arterial Occlusive Diseases↗
PubMed1991

A combined single and multiple dose pharmacokinetic study of oral isosorbide-5-mononitrate in healthy volunteers.

Pharmacokinetics of 20 mg isosorbide-5-mononitrate (IS-5-MN) after single and multiple administration of two different tablet formulations were investigated in twelve healthy human subjects using an open, randomized, two-way crossover experimental design. Pentacard 20 mg tablets were compared with Ismo 20 mg tablets. After single-dose administration, both preparations caused a rapid increase in IS-5-MN plasma levels with the peak plasma concentration occurring between 0.5 and 1.5 h. For both formulations, the mean plasma half-life was found to be approximately 5 h after a single dose. In steady state during multiple dosing (t.i.d. at 8 h dosing intervals), a reduced elimination rate was observed. In line with this observation, the area under the plasma concentration-time curve (AUC) for one 8 h dosing interval during multiple dosing was higher than the extrapolated AUC after a single dose. Based on statistical evaluation of the various relevant pharmacokinetic parameters calculated from the plasma concentrations occurring after single and multiple dosing, the tablet formulations are judged to be bioequivalent.

Administration, Oral↗
PubMed1991

Liposomes and biotherapeutics.

Application of liposomes as delivery system for biotherapeutic peptides and proteins may offer important therapeutic advantages over existing delivery methods. Several approaches towards achieving improved delivery of biotherapeutics with liposomes are outlined. Although the literature on this topic is sporadic and frequently incomplete, enough of a research foundation exists to justify the conclusion that liposomes can play an important role in the formulation and delivery of biotherapeutics. However, it will be necessary to understand more fully the mechanisms of action before optimum liposomal dosage forms can be designed.

Animals↗
PubMed1989

A comparative study on the antitumor effect, cardiotoxicity and nephrotoxicity of doxorubicin given as a bolus, continuous infusion or entrapped in liposomes in the Lou/M Wsl rat.

Liposome encapsulation of doxorubicin (DXR) has been shown to increase the therapeutic index of the drug in several animal systems. The prevention of peak plasma concentrations of free drug might be a major factor contributing to the beneficial effects resulting from liposome encapsulation. If so, the administration of DXR as a continuous infusion should also lead to an improved therapeutic index. In the present paper, the administration of liposome-encapsulated DXR is compared with the infusion of DXR with regard to their potential to preserve antitumor activity, enhance survival and reduce cardiomyo- and nephropathy in IgM immunocytoma-bearing Lou/M Wsl rats. Plasma concentrations of DXR were determined to correlate the biological results with pharmacokinetic parameters. Liposomes containing phosphatidylcholine, phosphatidylserine and cholesterol (extrusion-multilamellar vesicles) were used. Bolus injections of free DXR (free DXR) and DXR liposomes (lip-DXR) in a multiple-dose regimen were compared with 24-h infusions of the same cumulative doses of DXR (inf-DXR). The antitumor activity of inf-DXR equalled that of free DXR as well as that of lip-DXR at doses of greater than 0.25 mg/kg. The overall survival of tumor-bearing animals treated with 2.0 mg/kg lip-DXR was significantly prolonged (P less than 0.01) in comparison with that of animals treated with 2.0 mg/kg free DXR; however, treatment with 2.0 mg/kg inf-DXR did not induce a significant prolongation of survival. At a cumulative dose of 12 mg/kg, inf-DXR appeared to be as effective as lip-DXR in reducing the severity of cardiomyopathy induced by free DXR. However, for the reduction of nephropathy, only therapy with lip-DXR was effective. Inf-DXR induced high nephropathy scores comparable with those obtained with free DXR. For the first 24 h after an injection of 2.0 mg/kg or after the start of a continuous infusion of 2.0 mg/kg given over 24 h, similar areas under the plasma concentration-time curves (AUC) were calculated for free DXR and inf-DXR. However, for lip-DXR a much higher value was calculated. The higher plasma levels of lip-DXR did not result in higher cardiac levels. After five daily doses of 2.0 mg/kg, a much lower DXR concentration was found in cardiac tissue after the administration of lip-DXR than after the administration of free DXR or inf-DXR. This suggests that an important parameter to be determined and correlated with biological results is the free (i.e. not bound to liposomes) circulating fraction of DXR in lip-DXR-injected animals.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Release of doxorubicin from peritoneal macrophages exposed in vivo to doxorubicin-containing liposomes.

Intracellular depot formation may be an important component of the mode of action of doxorubicin (DXR)-containing liposomes. In this paper it was investigated whether it is possible that DXR is released from macrophages which have taken up DXR-containing liposomes in vivo. Macrophages were harvested from the peritoneal cavity of LOU/M rats after i.p. administration of DXR-liposomes. Two different liposome types were used for this investigation. The amount of DXR associated with macrophages was determined by high performance liquid chromatography. In order to monitor DXR release from the macrophages, an in vitro tumor cell growth inhibition assay was applied. Peritoneal macrophages collected 24 h after an i.p. injection of DXR-liposomes (10 mg/kg body weight) caused considerable growth inhibition of tumor cells in culture. The cytostatic potential of macrophage monolayers in vitro depended on the type of injected DXR-liposomes and was directly related to the amount of macrophage-associated DXR. The DXR content of the macrophage monolayers was completely released from the cells into the culture medium during the cocultivation with tumor cells. Supernatants obtained from monolayers, which were cultivated in the absence of tumor cells, showed a high growth-inhibitory activity. DXR either free or in liposomal form was chemically stable for up to 26 h during incubation with lysosomal fractions isolated from rat liver homogenates. The results indicate that release of DXR from macrophages which have phagocytosed DXR-liposomes in vivo is a real possibility.

Animals↗
PubMed1988

Potential pitfalls in in vitro antitumor activity testing of free and liposome-entrapped doxorubicin.

This paper addresses several potential problems which may play a critical role in the outcome of in vitro studies designed to investigate the antitumor activity of drugs. These problems were demonstrated to exist in in vitro assays developed for the evaluation of antitumor activity of free and liposome-entrapped doxorubicin (DXR). The stability of DXR-containing liposomes against drug leakage into the culture medium, as well as the chemical stability and extent of adsorption to tissue culture plastics of both free and liposomal DXR during the liposome-tumor cell incubation, were investigated. It is concluded that a full understanding of these processes is required for a reliable interpretation of the experimental results.

Animals↗
PubMed1988

Liposomes as drug carrier system for cis-diamminedichloroplatinum (II). II. Antitumor activity in vivo, induction of drug resistance, nephrotoxicity and Pt distribution.

In this study we have investigated the use of liposomes as a drug carrier system for cis-diamminedichloroplatinum(II) (cis-DDP) in order to reduce the nephrotoxicity with preservation of antitumor activity. Liposomes (PC/PS/Chol 10:1:4) were prepared using hydration media containing no or a relatively low concentration of NaCl. It was found that cis-DDP containing liposomes (lip cis-DDP) injected i.v. to IgM immunocytoma-bearing LOU/M rats at a dose of 1 mg cis-DDP/kg (cumulative dose 7 mg cis-DDP/kg) showed less antitumor activity than the free drug. The optimal cumulative dose of free cis-DDP for induction of antitumor activity in this tumor system is 7 mg/kg (7 X 1 mg/kg). At a dose of 2 mg lip cis-DDP/kg (cumulative dose 14 mg cis-DDP/kg) the antitumor activity could not be increased by choosing another phospholipid composition of the liposomes [DPPC/DPPG/Chol (10:1:10)]. cis-DDP incorporated in DPPC/DPPG/Chol liposomes showed a similar antitumor activity to cis-DDP incorporated in PC/PS/Chol liposomes. After an i.v. dose of 2 mg lip cis-DDP/kg (PC/PS/Chol) kidney damage was less compared to the treatment with free cis-DDP (1 mg/kg). However, after a single dose of 2 mg cis-DDP/kg or a cumulative dose of 8 or 16 mg cis-DDP/kg, kidneys of rats treated with lip cis-DDP contained twice as much Pt as after treatment with free cis-DDP. Moreover, after treatment with lip cis-DDP, a twofold increase of the amount of Pt in tumor tissue was measured. In vitro studies with Pt recovered from spleens obtained from rats treated with lip cis-DDP i.v. showed that based on the equal amounts of Pt recovered the antitumor activity of the recovered Pt was reduced, indicating inactivation of cis-DDP in vivo. As during treatment with free cis-DDP, recurrence of the tumor was observed during the continued treatment with lip cis-DDP. It was found that these recurrent tumors were resistant to further therapy with cis-DDP. In conclusion, cis-DDP encapsulation into liposomes decreased the nephrotoxicity. The antitumor activity of cis-DDP is preserved by liposome encapsulation when it was used at a dose of 2 mg/kg, but it was reduced in terms of earlier onset of regrowth.

Animals↗
PubMed1988

High-performance liquid chromatographic determination of doxorubicin in tissues after solid phase extraction.

A method is described for the determination of doxorubicin in tissues. The drug was selectively extracted from the biological matrix by solid phase extraction using 1-ml octadecyl silane extraction columns. Prior to extraction, tissue samples were digested by an enzymic digestion procedure. Daunorubicin was used as an internal standard. Quantitation was by high-performance liquid chromatography (HPLC) using ion-pair chromatography on a reversed-phase column. Detection was by fluorescence. Recovery of doxorubicin from tissue was 81.7 +/- 2.1% mean +/-SD. Doxorubicin concentrations as low as 0.01 mg kg(-1) could be determined. A typical value of the relative standard error of measurement was 3.7% at 2.1 mg kg(-1).

Journal Article↗
PubMed1987

Influence of lipid composition on the antitumor activity exerted by doxorubicin-containing liposomes in a rat solid tumor model.

The effect of changes in lipid composition on the antitumor activity of doxorubicin (DXR)-containing liposomes was studied in immunoglobulin solid immunocytoma-bearing Lou/M Wsl rats. Rats bearing a tumor with a diameter between 20 and 30 mm were treated i.v. with 2 mg/kg free DXR or different DXR-containing liposome types for 5 consecutive days followed by one injection more at day 11 after start of therapy. A similar pattern of tumor regression was observed for free DXR and DXR entrapped in "fluid" liposome types. However, DXR entrapped in "solid" liposome types expressed an antitumor activity which was significantly delayed; during the first 3 days after start of therapy solid DXR-containing liposomes were less effective in inducing antitumor activity than fluid DXR-containing liposomes. In order to gain more insight into the mode of action of DXR-containing liposomes, one of the solid liposome types [composed of distearoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, and cholesterol (chol)] was compared with one of the fluid liposome types [composed of egg phosphatidylcholine, phosphatidylserine, and chol] with respect to distribution and integrity in vivo. Results obtained after i.v. administration of [3H]inulin-labeled vesicles to tumor-bearing animals suggested that a differential liposome uptake by the tumor was not relevant for the explanation of the delayed antitumor effect. To monitor the structural integrity of liposomes after i.v. injection, the liposomes were double radiolabeled with [3H]inulin as a marker of the aqueous phase and cholesteryl [14C]oleate as a marker of the lipid phase. The bilayer structure of both liposome types remained intact during their presence in the blood compartment. Intact liposomes were taken up primarily by liver and spleen with subsequent degradation of the liposome structure. The degradation rate appeared to be dependent on the lipid composition of the liposomal membranes; phosphatidylcholine/phosphatidylserine/chol liposomes were degraded much faster than distearoylphosphatidylcholine/dipalmitoylphosphatidylglycerol/chol liposomes. The difference in degradation rate was manifested more clearly in the spleen than in the liver. In vitro investigations on uptake and processing of liposomes by liver macrophages indicated that the difference in degradation rate between liver and spleen was caused by intrahepatic reutilization of [14C]oleate liberated from the liposome structures.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Liposomes in treatment of infectious diseases.

In reviewing the literature about the potential of liposomes in the therapy of infections caused by protozoa, bacteria, fungi and viruses, it can be concluded that liposomal encapsulation may improve the therapeutic index of anti-infectious drugs. The improved therapeutic index may be a result of a reduction in drug toxicity and/or an enhanced drug delivery at the intracellular site of infection. Furthermore, attention is paid to the therapeutic utility of liposome-encapsulated immunomodulators in treatment of infections.

Adjuvants, Immunologic↗
PubMed1987

Investigation of the role of mononuclear phagocytes in the transportation of doxorubicin-containing liposomes into a solid tumor.

The present paper is concerned with the question whether cells of the mononuclear phagocyte system (MPS) function as a transport system for doxorubicin (DXR)-containing liposomes into solid tumors. The investigations were performed in solid IgM immunocytoma bearing Lou/M Wsl rats. In this tumor system macrophage accumulation was observed during DXR and cisplatin induced tumor regression. Tumor-bearing rats were treated i.v. with 1 mg/kg DXR (either free or entrapped in liposomes) for 4 consecutive days. Changes in the cellular composition of the tumor were studied by histology and cytology comparing free and liposomal DXR treatment. Therapy with DXR-liposomes (lip DXR) induced macrophage accumulation similar to free DXR. No differences in cellular changes in the tumor between both types of treatment were found. The DXR-content of tumor-associated cells was measured at various times during treatment with free or lip DXR by means of flow cytometry. Most DXR-fluorescence was associated with dead cells and cellular debris. No clear-cut differences in DXR-content were found between macrophages isolated from tumors of free DXR treated animals and those isolated from lip DXR treated animals. In order to investigate whether DXR-liposomes are taken up by tumor tissue (either via macrophages or directly by the tissue itself), [3H]inulin-labeled DXR-liposomes were administered to tumor-bearing rats. The distribution of radiolabeled lip DXR in non-treated rats was compared with that in rats which were pretreated with non-radiolabeled lip DXR to induce macrophage accumulation. In both untreated and pretreated animals most of the administered 3H-dose was recovered in liver and spleen. Only a minor fraction was recovered from the tumor and other tissues. This fraction was not higher than that obtained when a comparable amount of free [3H]inulin was injected. In conclusion, this study suggests that DXR-liposomes do not enter the solid IgM immunocytoma, even when during therapy macrophages pass the endothelial barrier. Therefore, it is unlikely that macrophage-mediated transportation of DXR-liposomes into the tumor is involved in the mechanism of tumor regression induced by liposome-entrapped DXR.

Animals↗
PubMed1985

The interaction of cytostatic drugs with adsorbents in aqueous media. The potential implications for liposome preparation.

A new method that involves the use of the cation exchange resin Dowex 50W-X4 to remove non-encapsulated drugs from liposome dispersions was investigated. Cytostatic drugs widely varying in their molecular structure can be removed from aqueous solutions by Dowex 50W-X4. The applicability of the resin to separate free from liposome-bound drugs was illustrated for a number of cytostatic drugs (cisplatin, doxorubicin, vincristine). The technique presented allows for a rapid, efficient and convenient procedure for the free drug removal from liposome dispersions without dilution of the liposomal preparation. Studies with liposome-encapsulated drugs will be facilitated by the use of this method, since it avoids many of the problems introduced by conventional methods as dialysis, gel filtration and centrifugation/washing. To elucidate the interaction mechanism of doxorubicin with Dowex 50W-X4, alternative adsorbents were studied for their doxorubicin binding properties. In the adsorption process of doxorubicin onto Dowex 50W-X4 both electrostatic (ion exchange) and hydrophobic effects play a role. The results indicate that hydrophobic contributions to the interaction are responsible for the high resistance offered by the binding forces against desorption of adsorbed doxorubicin. For other adsorbents the interactions are either mainly of an electrostatic or a hydrophobic nature.

Adsorption↗
PubMed1980

Ophthalmodynamic studies in kinking of the internal carotid artery. Surgical implications.

In 6 patients with kinking of the internal carotid artery and 10 healthy volunteers ophthalmodynamographic studies were performed. Sideward head bending in the patients caused major ipsilateral decrease of internal carotid flow as did forward flexion on both sides. This effect was minimal in healthy humans. Intraoperative monitoring by the same method showed instant improvement of flow dynamics after kink resection and end-to-end anastomosis.

Adult↗
PubMedDate not supplied

Comparative transfection studies of human ovarian carcinoma cells in vitro, ex vivo and in vivo with poly(2-(dimethylamino)ethyl methacrylate)-based polyplexes.

BACKGROUND: Poly(2-(dimethylamino)ethyl methacrylate) (p(DMAEMA)) can be used successfully for in vitro transfection of different cell lines, including the OVCAR-3 human ovarian carcinoma cell line. The aim of this study was to investigate whether it is possible to transfect OVCAR-3 cells in vivo with polyplexes containing p(DMAEMA). METHODS: In order to understand the generally observed gap between in vitro and in vivo transfection, we gradually went from in vitro to in vivo transfection of OVCAR-3 cells, while keeping the exposure conditions the same, as far as possible. To find the reason for the negligible degree of in vivo transfection, in vitro cultured OVCAR-3 cells were transfected in the presence of peritoneal ascites fluid. Next, the influence of hyaluronic acid, one of the ascites components, on the transfection efficiency was studied. RESULTS: P(DMAEMA)-containing polyplexes can transfect OVCAR-3 cells in vitro with an overall transfection efficiency of 10%. Cells grown in vivo can be transfected ex vivo with p(DMAEMA)/plasmid complexes with an overall transfection efficiency of approximately 1-2%. When transfection complexes are injected i.p. into nude mice bearing OVCAR-3 cells in the peritoneal cavity, the degree of in vivo transfection efficiency achieved is negligible. In vitro cultured OVCAR-3 cells were also transfected with polyplexes in the presence of peritoneal ascites fluid. The results indicate that one or more components of ascites had a negative effect on the transfection efficiency of p(DMAEMA)-containing polyplexes. To elucidate which component(s) of ascites may have interfered, the influence of hyaluronic acid, one of the ascites components, on the transfection efficiency was studied. The outcome suggests that hyaluronic acid may have induced a negative effect on the transfection capability of p(DMAEMA)-containing polyplexes. CONCLUSION: P(DMAEMA) is an efficient transfectant in vitro and ex vivo. However, transfected cells were not detected in vivo which may be caused by a negative influence of components of the ascites fluid.

Animals↗