Biomedical subjects

R Perez-Soler

Publications and source records attributed to R Perez-Soler.

At least 91 records · Page 5Linked to original sources

PubMed1989

Preclinical toxicity and pharmacology of liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II).

Liposome-entrapped cis-bis-neodecanoate-trans-R,R-1,2-diaminocylohexane platinum(II) (L-NDDP) is a new lipophilic cisplatin derivative formulated in a liposomal carrier currently in phase I clinical trials. The preclinical toxicity and pharmacology of L-NDDP were studied in mice and dogs. At the LD50 dose (i.v. bolus) in mice (60.5 mg/kg or 181.5 mg/m2), a tenfold decrease in the granulocyte and platelet counts was observed in the absence of renal toxic effects. In dogs, the maximum tolerated dose (MTD) of L-NDDP given i.v. over a period of 45-60 min was 150 mg/m2. This dose produced significant vomiting (6-18 episodes), minimal renal dysfunction, a maximal decrease in granulocyte and platelet counts of from 30% to 70%, and acute and transient elevation of liver enzymes. Higher doses (225 and 300 mg/m2) resulted in severe gastrointestinal (GI) toxicity in one animal and the death of two others within 48 h. Autopsy results showed multifocal hemorrhages in the lungs, GI tract, kidney, and liver. Three dogs were treated monthly with the MTD up to a cumulative dose of 637.5-712.5 mg/m2 with excellent tolerance. No cumulative myelosuppression or liver dysfunction was observed, whereas a slight increase in the creatinine baseline level was detected in all three animals. Autopsy results at the end of the study showed mild changes limited to the liver, kidney, and GI tract. Pharmacologic studies showed that the drug was cleared, fitting a two-compartment model with a mean t1/2 alpha of 7.1 min and a t1/2 beta of 87.8 h. These studies show that L-NDDP can safely be given at therapeutic doses to animals and that the dose-limiting toxic effects consists of myelosuppression in mice and a multiorgan hemorrhagic syndrome related to vascular injury in dogs.

Animals↗

PubMed1989

Toxicity and antitumor activity of cis-bis-carboxylato(trans-R,R-1,2-diaminocyclohexane) platinum(II) complexes entrapped in liposomes.

A new series of highly lipid-soluble cis-bis-carboxylato(trans-R,R-1,2-diaminocyclohexane)platinum(II) complexes were synthesized and characterized by their elemental analysis and by various spectroscopic techniques [infrared (IR), 195pt nuclear magnetic resonance (NMR)]. cis-bis-Neopentanoato(trans-R,R-1,2-diaminocyclohexane)platinum(II ) (NPDP), cis-bis-neodecanoato(trans-R,R-1,2-diaminocyclohexane)-platinum(II ) (NDDP), and cis-bis-n-decanoato(trans-R,R-1,2-diaminocyclohexane)-platinum(II) (DEDP) complexes were entrapped in multilamellar vesicles composed of dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidylglycerol (DMPG) at a 7:3 molar ratio and tested for toxicity and antitumor activity. The entrapment efficiency of the liposomal platinum (L-Pt) complexes (L-NPDP, L-NDDP, L-DEDP) was greater than 95%, and the stability in 0.9% NaCl solution at 4 degrees C was greater than 95% at day 14 in each case. The LD50 values of L-NPDP, L-NDDP, and L-DEDP when injected i.v. were 30, 54, and 150 mg/kg, respectively. L-NPDP, L-NDDP, and L-DEDP had no significant nephrotoxicity [as evidenced by a lack of elevated blood urea nitrogen (BUN) levels]. The percentages of T/C obtained after a single i.p. injection of the optimal dose of L-NPDP, L-NDDP, and L-DEDP tested against L1210 leukemia were 175%, 187%, and 212%, respectively [160% for cisplatin (CDDP)]. When a multiple i.p. injection schedule was used (on days 1, 5, and 9), L-NPDP, L-NDDP, and L-DEDP were more active than CDDP (percentage of T/C: 312%, 312%, 277%, and 220%, respectively). When injected i.v., only L-NDDP showed significant activity against L1210 leukemia i.v. (percentage of T/C: 186%). L-NDDP and L-DEDP were markedly active against L1210 leukemia resistant to CDDP (percentage of T/C: 200% and 145% vs 112% for CDDP). L-NPDP, L-NDDP, and L-DEDP also had good activity against i.p. B16 melanoma when they were injected i.p. on days 1, 5, and 9 (percentage of T/C: 206%, 225%, and 306%, respectively). L-NDDP and L-DEDP were more effective than CDDP in inhibiting the growth of liver metastases of murine M5076 reticulosarcoma, whereas L-NPDP was not active. The results obtained to date suggest that L-NDDP is the best L-Pt-complex candidate for further developmental studies.

Animals↗

PubMed1989

Liposomes as carriers of antitumor agents: toward a clinical reality.

For several years, liposomes have been explored as carriers of antitumor agents. Liposomes can be administered intravenously to carry lipid-soluble drugs, to improve drug stability, to target organs with fenestrated capillaries, to achieve an intravascular slow drug-release system, and to reduce drug levels in certain organs sensitive to toxicity. They also have significant potential for local therapy when administered subcutaneously or intraperitoneally. The preclinical development of liposome-entrapped antitumor agents has been, in general, slowed by cumbersome formulation problems. However, during the last few years, new drug loading techniques and a better selection of the drugs for liposome entrapment have resulted in pharmaceutically acceptable liposomal formulations or antitumor agents. Three preparations have been approved by the Federal Drug Administration, two containing doxorubicin, and the other a new lipophilic cisplatin analogue [cis-bis-neodecanoato-trans-R,R-1,2-diamino-cyclohexane platinum (II)]. In preclinical studies, these preparations were shown to be less toxic than the parent compounds and more active in models of liver micrometastases. Clinical Phase I and II studies with these formulations are now in progress. Although liposomal antitumor agents have no established role in the anticancer armamentarium at this stage, the information available suggests that they may improve the therapeutic index or broaden the applications of available antitumor agents and possibly act as carriers for newly designed liposome-dependent antitumor agents.

Animals↗

PubMed1988

Increased cytotoxicity and reversal of resistance to cis-diamminedichloro-platinum(II) with entrapment of cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum (II) in multilamellar lipid vesicles.

The role of liposome entrapment in modulating the cytotoxicity of a lipophilic cisplatin derivative was assessed. cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum++ +(II) (NDDP) was tested in suspension (free NDDP) or entrapped in multilamellar vesicles composed of dimyristoylphosphatidyl choline and dimyristoylphosphatidyl glycerol (L-NDDP). Against LoVo colon carcinoma cells sensitive to cisplatin, L-NDDP was two times more cytotoxic in vitro than free NDDP and cisplatin (Do 7 microM for L-NDDP, 15 microM for free NDDP, and 16 microM for cisplatin). Against LoVo cells resistant to a concentration of 3 micrograms/ml of cisplatin, L-NDDP was three times more cytotoxic than free NDDP and cisplatin (Do 14 microM for L-NDDP, 45 microM for free NDDP, and 48 microM for cisplatin). In in vivo studies, free NDDP was less potent and less active than L-NDDP against i.p. L-1210 leukemia (free NDDP, optimum %T/C 148 at a dose of 75 mg/kg; L-NDDP, optimum %T/C 185 at a dose of 25 mg/kg) and i.p. L1210/PDD leukemia (free NDDP, optimum %T/C 128 at a dose of 50 mg/kg on Days 1, 5, and 9; L-NDDP, optimum %T/C 200 at a dose of 12.5 mg/kg on Days 1, 5, and 9). Free NDDP administered i.v. was inactive against liver metastases of M5076 reticulosarcoma (%T/C 102) while L-NDDP showed significant activity (%T/C 140). The single dose i.v. LD50 in mice of free NDDP and L-NDDP were similar (79.4 mg/kg for free NDDP and 64.5 mg/kg for L-NDDP). These studies show that NDDP is a liposome-dependent drug since it can only be satisfactorily formulated in the liposomal form and since the liposomal carrier plays a crucial role in determining its antitumor activity.

Animals↗

PubMed1988

Cellular pharmacology of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum (II) in mouse resident peritoneal macrophages, Kupffer cells, and hepatocytes.

The in vitro and in vivo interaction of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum++ + (II) (L-NDDP) with mouse resident peritoneal macrophages (RPM), Kupffer cells (KC), and hepatocytes was studied. The peak in vitro uptake of L-NDDP by RPM was 12.5 ng elemental platinum/100 micrograms cell protein and constituted 0.2% of the platinum available for phagocytosis. The subsequent release of platinum by RPM was rapid initially, with a 20-fold increase over the first 4 h, followed by a plateau; ultrafilterable (free) platinum constituted 50% of the total platinum released at 24 h. The retained intracellular platinum in RPM at 24 h was close to 50% of that initially present. The peak in vitro uptake of L-NDDP by KC was 11.3 ng platinum/100 micrograms cell protein and amounted to 0.2% of the platinum available for phagocytosis. The release of platinum by KC was detectable only after 4 h of incubation and increased 3-fold over the next 14 h. The ultrafilterable platinum released by KC at 18 h was 40% of the total platinum released. The retained intracellular platinum in KC at 18 h was 33% of that initially present. The peak in vitro uptake of L-NDDP by hepatocytes was almost 50 ng platinum/100 micrograms cell protein and constituted 0.8% of the platinum available for intake. Following the i.v. injection of L-NDDP, hepatocytes contained up to 6-fold higher platinum concentrations than KC. This observation was supported by transmission electron microscopy showing a higher concentration of multilamellar vesicles within hepatocytes than in KC, 5 min after i.v. injection of L-NDDP. These findings suggest that L-NDDP becomes available to the liver following i.v. injection, that both macrophages and hepatocytes play a role in the metabolism of L-NDDP, and that Kupffer cells could mediate a sustained release of platinum in the liver following the interaction with L-NDDP, indicating the potential of L-NDDP for the treatment of tumors in the liver.

Animals↗

PubMed1988

Organ distribution and tumor uptake of liposome entrapped cis-bis-neodecanoato trans-R, R-1,2 diaminocyclohexane platinum (II) administered intravenously and into the proper hepatic artery.

Blood and tissue levels of elemental platinum (Pt) were measured after the administration of a liposomally entrapped cisplatin analogue, cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (L-NDDP). In mice bearing subcutaneous B16 melanoma tumors, Pt tumor levels were not significantly different in animals treated i.v. with an equimolar dose of L-NDDP or cisplatin. In rabbits bearing liver tumors of VX2 carcinoma, i.v. administration of L-NDDP resulted in 2- to 20-fold higher Pt levels in all tissues (including VX2 tumors) except the brain and peripheral nerve than in animals treated with an equimolar dose of cisplatin. Compared with i.v. administration, inoculation of either drug into the proper hepatic artery resulted in a severalfold increase of Pt levels in the VX2 tumors. Blood and other tissue levels were not substantially changed by intraarterial (i.a.) administration. These studies show that (1) multilamellar lipid vesicles can adequately deliver a lipophilic cisplatin analogue (NDDP) to nonphagocytic tumors when administered i.v. and (2) the inoculation of L-NDDP into the proper hepatic artery results in higher Pt tumor levels than with i.v. administration but does not decrease the systemic distribution of the drug.

Animals↗

PubMed1988

Toxicity and anti-tumor activity of hydrophobic diammine and diaminocyclohexane platinum complexes entrapped in multilamellar vesicles.

The toxicity and anti-tumor activity of a lipophilic diaminocyclohexane (DACH) platinum complex entrapped in liposomes (liposomal-cis-bis-neodecanoato-trans-R, R-1, 2-DACH platinum II-L-NDDP) were compared with those of the liposomal preparation of the same compound without the DACH group (liposomal-cis-bis-neodecanoato-(diammine) platinum II-L-CNDP). Both liposomal preparations had the same liposome size distribution, drug entrapment efficiency (greater than 95%), and liposome stability (greater than 95%). Although no differences were observed in the mouse LD50 (60.2 mg/kg for L-NDDP vs 67.8 mg/kg for L-CNDP), the liposome entrapped non-DACH compound (L-CNDP) was more nephrotoxic than the liposome entrapped DACH compound (L-NDDP), but much less than cisplatin (CDDP) (mean BUN elevation 4 days after the administration of the LD50 dose 67 mg% for L-CNDP vs 30 mg% for L-NDDP vs 255 mg% for CDDP). L-NDDP was not cross-resistant with CDDP against L1210/CDDP leukemia while L-CNDP was cross-resistant (%T/C 200 for L-NDDP, 112 for CDDP, and 100 for L-CNDP). In addition, L-NDDP was slightly more active than L-CNDP against i.p. L1210/0 leukemia and i.v. M5076 reticulosarcoma. These studies suggest that the attachment of a cyclohexane group to the amino functions of lipophilic platinum complexes results in a decrease of the nephrotoxicity and a lack of cross-resistance with CDDP. The lack of cross-resistance is preserved when the compounds are entrapped and delivered in a liposomal carrier but not when they are delivered in a micellar suspension.

Animals↗

PubMed1987

Treatment and prophylaxis of experimental liver metastases of M5076 reticulosarcoma with cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum (II) encapsulated in multilamellar vesicles.

cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum++ +-(II) (NDDP) was encapsulated in multilamellar vesicles composed of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol at a 7:3 molar ratio. Compared with cisplatin, i.v. administration of an equimolar dose of liposome-encapsulated NDDP (L-NDDP) resulted in 15-fold higher peak platinum levels in the spleen (204.7 versus 13.3 micrograms/g dry tissue), 5-fold higher in the lungs (116.4 versus 21.0 micrograms/g dry tissue), 3-fold higher in the liver (71.6 versus 23.9 micrograms/g dry tissue), and 4-fold higher in the blood (14.8 versus 3.9 micrograms/ml). At the optimal dose and schedule, L-NDDP administered i.p. in mice bearing peritoneal L1210 leukemia resulted in the percentage of median survival time of treated mice divided by median survival time of control mice (%T/C) of 312 versus 225 for cisplatin and free NDDP. When administered i.v., L-NDDP was also more active than cisplatin against L1210 leukemia inoculated i.v. (%T/C 186 versus 142). L-NDDP was markedly active against L1210 leukemia resistant to cisplatin (%T/C, 200 versus 112 for cisplatin). In mice bearing liver metastases of M5076 reticulosarcoma, L-NDDP was significatnly more effective than cisplatin at equimolar doses (mean survival time, 57 +/- 9 (SD) days for L-NDDP versus 42 +/- 3 days for cisplatin, P less than 0.05). L-NDDP was also effective in preventing liver metastases of M5076 when administered up to 24 h prior to tumor inoculation (mean survival, 28 +/- 2 days for L-NDDP versus 22 +/- 2 days for cisplatin, P less than 0.05). L-NDDP is significantly non-cross-resistant with cisplatin and more effective against phagocytic and nonphagocytic murine tumors.

Animals↗

PubMed1987

Ultrastructural and freeze fracture localization of multilamellar liposomes containing a lipophilic cisplatin analogue in normal tissues and liver metastases of M5076 reticulosarcoma.

The tissue localization of multilamellar vesicles (MLV) (size 0.5-5.0 microns) composed of dimyristoylphosphatidyl choline (DMPC) and dimyristoylphosphatidyl glycerol (DMPG) (molar ratio 7:3) containing a lipophilic cisplatin analogue (NDDP) was studied in mice by freeze fracture (FF) and transmission electron microscopy (TEM). Liposomes were observed within cytoplasmic vacuoles of hepatocytes and Kupffer cells in normal mice as early as 5 minutes after intravenous (iv) administration of MLV-NDDP. Liposomes within hepatocytes were more numerous but smaller in diameter (0.5-2.0 microns) than those within Kupffer cells (2.0-4.0 microns). In normal lung examined by FF or TEM at 5 minutes after MLV-NDDP administration, liposomes were only observed in the intravascular space. Liposomes could not be identified within Type I or II pneumocytes nor within the alveolar space. Two hours after iv administration, the distribution within the liver showed an increased number of liposomes in the hepatocytes with some evidence of liposome decomposition. The distribution in the lung was virtually identical to that observed at 5 minutes. The pattern of tissue localization within lung and liver of empty MLV 5 minutes and 2 hours after iv administration was identical to that of MLV-NDDP. In mice bearing gross liver metastases of M5076 reticulosarcoma, liposomes were present in the cytoplasm of tumor cells as well as normal cells 5 minutes and 2 hours after the iv administration of MLV-NDDP. These studies suggest that MLV composed of DMPC and DMPG containing NDDP are able to cross the liver sinusoidal capillaries and gain access to both hepatocytes from normal liver and malignant cells of M5076 reticulosarcoma from liver metastases.

Animals↗

PubMed1986

Central nervous system prophylaxis with combined intravenous and intrathecal methotrexate in diffuse lymphoma of aggressive histologic type.

With the use of a multivariate regression model, 21 patients with diffuse lymphoma were identified as having greater than 15% risk of experiencing relapse in the central nervous system (CNS). The efficacy of a combination of sequential intravenous methotrexate (MTX) (1 g/m2) and intrathecal MTX in preventing relapse in the CNS and improving survival times was assessed. A comparable historical control group of patients with similar risk of CNS relapse and who did not receive any CNS prophylaxis was used. The CNS relapse-free survival rate (RFS) was improved in patients who received CNS prophylaxis (95% versus 59% at 2 years; P = 0.01). Pretreatment serum lactic dehydrogenase (LDH) levels correlated with the incidence of relapse in the CNS in the control group (P = 0.01). In patients with high pretreatment serum LDH levels (greater than 225 U/L), CNS RFS was improved in those who received CNS prophylaxis (RFS at 2 years: 91% versus 46%; P = 0.02). Both CNS RFS (100% versus 38% at 2 years; P = 0.03) and survival rates (100% versus 38% at 2 years; P = 0.02) were improved in six patients with histologic type other than large cell. In 15 patients with large cell lymphoma, no significant differences in CNS RFS (93% versus 75% at 2 years; P = 0.29) and survival rates (43% versus 44% at 2 years; P = 0.56) were observed. Cerebrospinal fluid MTX levels were above the therapeutic level of 1 X 10(-6) M for at least 20 hours in 90% of courses of combined MTX. The MTX combination used is an effective and non-neurotoxic CNS prophylaxis method. Because the comparison between different methods of CNS prophylaxis is difficult to make without a precise idea of the expected CNS relapse rate, use of the multivariate regression technique is recommended.

Adult↗

PubMed1986

Decreased adenosine deaminase (ADA) and 5'nucleotidase (5NT) activity in peripheral blood T cells in Hodgkin disease.

The purine metabolic enzymes adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), and 5'nucleotidase (5NT) play an important role in normal lymphocyte differentiation. Abnormal levels of one or all of these enzymes have been associated with immunodeficiency diseases and lymphoproliferative disorders. ADA, PNP, and 5NT activity was measured in peripheral blood T cells from 24 patients with Hodgkin disease (HD) (12 in complete remission and 12 with active disease) to determine whether an association existed between enzyme abnormalities and the decreased cellular immune function previously described in this disorder. HD patients had a significantly decreased absolute lymphocyte count (1,618 +/- 1107/mm3; mean +/- SD) compared to controls (2,320 +/- 980; p less than .001). ADA, PNP, and NT activity was assessed in lymphocyte extracts by measuring the conversion of radiolabeled substrates to products over time. ADA activity expressed as mean +/- SEM nanomoles/10(6) lymphocytes/hr was significantly decreased in T cells from HD patients (84.6 +/- 7.5) compared to controls (128 +/- 12.3; p less than 0.025). Likewise, 5NT was significantly decreased in HD patients (12.7 +/- 1.3) compared to controls (24.0 +/- 3.6; p less than .005). There was not a significant difference in PNP activity between both groups. Low 5NT activity was present irrespective of whether patients had active disease (12.1 +/- 1.5) or were in unmaintained complete remission (14.5 +/- 2.4). These findings suggest that biochemical abnormalities may be responsible for or related to the persistent abnormalities in T-cell function noted throughout the clinical course of HD.

5'-Nucleotidase↗

PubMed1986

Pharmacokinetics and tissue distribution of liposome-encapsulated cis-bis-N-decyl-iminodiacetato-1,2-diaminocyclohexane-platinum (II).

The pharmacokinetics and tissue distribution of a lipophilic analogue of cisplatin, cis-bis-N-decyl-iminodiacetato-1,2-diaminocyclohexane platinum (II) (N-decyl-IDP), were studied after the i.v. administration of the free drug in suspension in phosphate-buffered saline (F-N-decyl-IDP) and encapsulated in multilamellar liposomes comprising dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol at a molar ratio of 7:3 (L-N-decyl-IDP). The encapsulation efficiency and stability at 14 days of L-N-decyl-IDP were greater than 95%. The blood clearance of both forms of the drug fit a two-compartment model. The peak blood level of elemental platinum for L-N-decyl-IDP was fourfold higher than for the free drug (24.2 versus 6.1 micrograms/ml). In consequence, a fourfold difference in the volumes of distribution was observed (176 ml/kg for L-N-decyl-IDP versus 608 ml/kg for F-N-decyl-IDP). Liposome encapsulation reduced the drug clearance by threefold; therefore, the CXT of L-N-decyl-IDP was threefold higher than that of F-N-decyl-IDP (1308 micrograms platinum/ml per min versus 395 micrograms platinum/ml per min). Tissue platinum levels were significantly increased by liposome encapsulation in the lung (33 versus 3.6 micrograms/g), spleen (38.3 micrograms/g versus none detected), and liver (16.2 versus 11.7 micrograms/g), and unchanged in the kidneys. Although only F-N-decyl-IDP resulted in detectable levels of platinum in the small bowel (70.5 micrograms/g), the stool excretion was similar for both forms of the drug. The organ distribution changes secondary to liposome encapsulation may result in an increased antitumor activity of N-decyl-IDP in tumors involving the lung, spleen, and liver, and avoidance of gastrointestinal toxicity.

Animals↗

PubMed1986

Effects on the monocyte-macrophage system and antitumor activity against L1210 leukemia of cis-bis-cyclopentenecarboxylato-trans-R,R-1,2-diaminocyclohexane -platinum (II) encapsulated in multilamellar vesicles.

Multilamellar vesicles (MLVs) composed of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol at a molar ratio of 7:3 were used as carriers of cis-bis-cyclopentenecarboxylato-trans-R,R-1,2-diaminocyclohexane-p latinum (II) (CPDP). The encapsulation efficiency of liposomal CPDP (L-CPDP) was 87.6%, and its stability in normal saline at 14 days was 94.4%. The in vitro and in vivo effects on the function of the monocyte-macrophage system and the antitumor activity against L1210 leukemia were investigated in CD-1 and (C57BL/6J X DBA/2J)F1 mice. L-CPDP and cisplatin (CDDP) caused a comparable inhibition of murine-resident peritoneal macrophage (PM) protein and RNA synthesis and superoxide anion release. PM-mediated tumor cell cytotoxicity was completely inhibited at a concentration of 10 micrograms CDDP and L-CPDP/ml but not at concentrations of 1 and 5 micrograms/ml. The differences in plasma clearance of 99mTc-labeled MLV and phagocytic capacity of the liver among animals pretreated with the maximum tolerated doses of L-CPDP (25 mg/kg), empty liposomes, or CDDP (10 mg/kg) were not statistically significant (plasma clearance % of control: 105, 110, and 100, respectively: P greater than .05; liver uptake % of control: 87, 96, and 104, respectively: P greater than .05). At the maximum tolerated doses, the antitumor activity of L-CPDP against L1210 leukemia was similar to that of CDDP when a single dose was administered [median survival of treated mice/median survival of control mice X 100 (%T/C): 181 vs. 175] and slightly higher with the use of a triple-dose schedule (%T/C: 275 vs. 225). L-CPDP is easy to prepare, has a high-encapsulation efficiency and stability, is not more toxic than CDDP to the monocyte-macrophage system, and is at least as effective as CDDP against L1210 leukemia.

Animals↗

PubMed1986

Toxicity and antitumor activity of cis-bis-cyclopentenecarboxylato-1,2-diaminocyclohexane platinum(II) encapsulated in multilamellar vesicles.

The potential of multilamellar vesicles (MLVs) as carriers of cis-bis-cyclopentenecarboxylato-1,2-diaminocyclohexane platinum(II) (CPDP), a lipophilic cisplatin derivative, was assessed. MLVs composed of dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphatidylglycerol (DMPG), and cholesterol at different molar ratios were tested. The MLV-CPDP preparation with the highest antitumor activity against L1210 leukemia in vivo was DMPC:DMPG 7:3-CPDP. The encapsulation efficiency of this preparation was 66 +/- 4% (SD); the stability in 0.9% NaCl solution at 4 degrees C was 89% at 14 days and 93% 18 h after incubation in human AB serum at 37 degrees C. The toxicities of DMPC:DMPG 7:3-CPDP and free CPDP (suspended in hydroxypropyl cellulose) administered i.p. were similar (50% lethal dose = 75 versus 91 mg/kg; blood urea nitrogen values 96 h after the administration of the 50% lethal dose = 32.0 versus 34.4 mg/dl). The mean %T/C [(median survival time of treated mice divided by median survival time of control mice) X 100] obtained after a single i.p. injection of the optimal dose of each preparation tested was 215 (range 200 to 232) for DMPC:DMPG 7:3-CPDP, 175 (range 158 to 209) for DMPG-CPDP, 162 (range 136 to 179) for free CPDP, and 178 (range 169 to 189) for cisplatin. Using a multiple i.p. injection schedule (injections on Days 1, 5, and 9), DMPC:DMPG 7:3-CPDP was more active than free CPDP and cisplatin (%T/C: 403, 284, and 253% respectively). DMPC:DMPG 7:3-CPDP is less toxic and more active against L1210 leukemia in vivo than is cisplatin. The encapsulation of CPDP in MLVs composed of DMPC:DMPG 7:3 provides an adequate vehicle for the administration of this lipophilic compound and enhances its antitumor activity against L1210 leukemia.

Animals↗

PubMed1985

Liver involvement in multiple myeloma.

One hundred twenty-eight records of patients with multiple myeloma were reviewed to assess the incidence and manifestations of liver involvement. Histologic study of the liver was available in 21 patients. Diffuse infiltration of the liver by plasma cells was observed in 10 patients, myeloid metaplasia in four, amyloidosis in two, toxic hepatitis in two, and extrahepatic cholestasis secondary to infiltration of the peripancreatic tissue by plasma cells in one. The clinical signs of plasma cell infiltration of the liver consisted of hepatomegaly in seven patients, mild elevation of liver enzymes in five, and portal hypertension in two. Jaundice was only observed in patients with hepatitis or extrahepatic cholestasis. Liver infiltration by plasma cells did not appear to have a major prognostic significance.

Biopsy↗

PubMed1985

Distribution of radiolabeled multilamellar liposomes injected intralymphatically and subcutaneously.

The distribution of negatively charged multilamellar vesicles (MLV) composed of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol administered subcutaneously (s.c.) and intralymphatically (i.l.) was studied in rats and dogs. In rats, the drainage of 99mTc-MLV from the s.c. space was slow, with 35% of the activity still remaining at the site of injection after 48 h and minimal systemic distribution (less than 5% at any time point). In the dog, 99mTc-MLV and 111In-MLV injected s.c. on the dorsal surface of a hindpaw were drained both by the lymphatic system and the systemic circulation; at 24 and 72 h, significant activity still remained at the site of injection. Lymphatic uptake was almost limited to the popliteal nodes and was enhanced by dividing the dose in several s.c. injections. Liver and kidney uptake was also observed, most likely as a result of direct liposome absorption into the systemic circulation. The i.l. administration (via left hindpaw) of 99mTc-MLV to a dog resulted in an immediate uptake in the abdominal and mediastinal lymph nodes, and in the liver and spleen. Compared with small unilamellar vesicles, MLV injected s.c. can provide a slower and more prolonged delivery of drugs to the regional lymph nodes.

Animals↗

PubMed1985

Superoxide anion (O-2) production by peripheral blood monocytes in Hodgkin's disease and malignant lymphoma.

Superoxide anion (O-2) is the first metabolite of the monocyte oxygen burst pathway, which plays an important role in the monocyte microbicidal function. The capacity of peripheral blood monocytes to produce O-2 was studied in 63 patients with Hodgkin's disease (31 with active disease and 32 in complete remission), 15 patients with active malignant lymphoma, and 57 normal control subjects. O-2 release was quantified by evaluating superoxide dismutase-inhibitable reduction of cytochrome c after stimulation of monocytes with phorbol myristate acetate. Results were expressed in nanomols O-2 per mg protein per hour. O-2 production was lower than normal in patients with active Hodgkin's disease (163.3 v 214.5, P less than .05). It was normal in patients with Hodgkin's disease in complete remission (216.2 v 214.5, P greater than .05) and high in patients with malignant lymphomas (317.9 v 214.5, P less than .01). Within the group with active Hodgkin's disease, patients in relapse after therapy had a lower O-2 production than those previously untreated (99.8 v 181.8, P less than .01). Stage of disease was unrelated to the defect. The presence of B symptoms and a decreased delayed type hypersensitivity to recall skin test antigens were associated with normal O-2 production. The results obtained suggest that monocyte dysfunction is part of the immune dysregulation associated with active Hodgkin's disease. The O-2 determination is a relatively easy test to perform and may be useful in identifying the patients with Hodgkin's disease who have an increased risk of opportunistic infections.

Adult↗

PubMed1985

Distribution of technetium-99m-labeled multilamellar liposomes in patients with Hodgkin's disease.

The distribution of 99mTc-labeled multilamellar liposomes composed of dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidylglycerol (DMPG) at a molar ratio of 7:3, administered intravenously, was studied in ten patients with Hodgkin's disease (HD). The dose of lipid was 150 mg/m2 and the mean dose of radioactivity injected per patient was 8.1 mCi (range 6.7-9.8). Whole-body imaging techniques were used, and for each organ an uptake index was calculated as the percent photographic density (PD) relative to the PD of the liver. Results were compared to those in a group of six patients with other malignancies. Increased liposome uptake in several skeletal areas was observed in one patient with HD with diffuse bone involvement and in the bone marrow of two patients with HD with bone marrow involvement. No definite liposome uptake was observed in lymph nodes involved by HD or in tumor areas of patients with other malignancies. Patients with HD had a significantly higher uptake by bone marrow (23.8% compared with 10.2% at 4 hr p = 0.02), and lungs (59.6% compared with 25.0% at 4 hr, p = 0.01) than patients with other malignancies. Among patients with HD, the uptake by bone marrow and lungs were higher in those with constitutional symptoms (bone marrow at 4 hr 31.4% compared with 16.2%, p = 0.02; lungs at 4 hr 68.8% compared with 50.4%, p = 0.19) and with liver involvement (bone marrow at 4 hr 30.8% compared with 16.8%, p = 0.03; lungs at 4 hr 73.6% compared with 45.6%, p = 0.03). These results suggest that patients with HD have a different pattern of distribution of multilamellar liposomes which may be related to a combination of nonspecific stimulation of the reticuloendothelial system and tumor uptake. It does not appear that liposomal 99mTc is capable of adequately imaging HD for clinical diagnosis.

Adult↗