The pharmacokinetics of boron was studied in rats by administering a 1 ml oral dose of sodium tetraborate solution to several groups of rats (n=20) at eleven different dose levels ranging from 0 to 0.4 mg/100 g body weight as boron. Twenty-four-hour urine samples were collected after boron administration. After 24 h the average urinary recovery rate for this element was 99.6+/-7.9. The relationship between boron dose and excretion was linear (r=0.999) with a regression coefficient of 0.954. This result suggests that the oral bioavailability (F) of boron was complete. Another group of rats (n=10) was given a single oral injection of 2 ml of sodium tetraborate solution containing 0.4 mg of boron/100 g body wt. The serum decay of boron was followed and found to be monophasic. The data were interpreted according to a one-compartment open model. The appropriate pharmacokinetic parameters were estimated as follows: absorption half-life, t1/2a=0.608+/-0.432 h; elimination half-life, t1/2=4.64+/-1.19 h; volume of distribution, Vd = 142.0+/-30.2 ml/100 g body wt.; total clearance, Ctot=0.359+/-0.0285 ml/min per 100 g body wt. The maximum boron concentration in serum after administration (Cmax) was 2.13+/-0.270 mg/l, and the time needed to reach this maximum concentration (Tmax) was 1.76+/-0.887 h. Our results suggest that orally administered boric acid is rapidly and completely absorbed from the gastrointestinal tract into the blood stream. Boric acid in the intravascular space does not have a strong affinity to serum proteins, and rapidly diffuses to the extravascular space in proportion to blood flow without massive accumulation or binding in tissues. The main route of boron excretion from the body is via glomerular filtration. It may be inferred that there is partial tubular resorption at low plasma levels. The animal model is proposed as a useful tool to approach the problem of environmental or industrial exposure to boron or in cases of accidental acute boron intoxication.

Animals↗

PubMedDate not supplied

Effects of diltiazem on renin-aldosterone and ACTH-adrenocortical function during upper abdominal surgery.

STUDY OBJECTIVE: To observe the effects of continuous intravenous infusion of diltiazem on the renin-aldosterone system and ACTH-adrenocortical axis responses during surgical stimulation. DESIGN: Randomized study of intravenous diltiazem. SETTING: Operating room at the Hyogo Medical College Hospital. PATIENTS: Twenty-three patients undergoing upper abdominal surgery were divided into two groups: the control group (n = 10) and the diltiazem group (n = 13). All the patients were without any complications and classified as ASA physical status I. INTERVENTIONS: Patients in the diltiazem group received an infusion of 10 micrograms/kg/min for 90 to 120 minutes following skin incision. MEASUREMENTS AND MAIN RESULTS: Plasma adrenocorticotropic hormone, plasma aldosterone and cortisol concentrations, and plasma renin activity were determined with radioimmunoassay before the induction of anesthesia at 10, 30, 60, and 90 minutes after skin incision and at the end of anesthesia. Renin activity did not change significantly. Maximal increases in plasma adrenocorticotropic hormone, aldosterone, and cortisol observed 90 minutes after skin incision were 355 +/- 95 pg/ml, 118 +/- 30 pg/ml, and 14.2 +/- 2.3 micrograms/dl in the control group versus 246 +/- 41 pg/ml, 119 +/- 25 pg/ml, and 15.0 +/- 1.8 micrograms/dl in the diltiazem group, respectively, and there were no significant differences between these groups. Adrenocorticotropic hormone was significantly lower in the diltiazem group compared with that in the control group 60 minutes after the start of surgery (p less than 0.05). There was marked natriuresis (40 +/- 25 microEq/min vs 470 +/- 147 microEq/min at the 90-minute mark) and diuresis (0.16 +/- 0.13 ml/min vs 2.53 +/- 0.88 ml/min) in the diltiazem group. CONCLUSIONS: Diltiazem at this dose increased urine output and sodium excretion without affecting most of these hormonal responses to surgical stimulation. These findings suggest that diltiazem has beneficial renal effects independent of hormonal concentrations.

Abdomen↗

PubMedDate not supplied

Inhibition of lymphocyte proliferative responses by renal cell carcinoma extract.

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Carcinoma, Renal Cell↗

PubMedDate not supplied

Suppression of lectin, alloantigen, and xenoantigen-induced T-cell proliferation by Genistein.

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Antigens, CD↗

PubMedDate not supplied

Immune inhibitory effects of renal cell carcinoma extract on lectin and alloantigen-induced peripheral blood and tumor infiltrating lymphocyte blastogenesis.

The presence of tumor infiltrating lymphocytes (TIL) has been attributed to the host cell mediated immune response against the evolving malignancy. However, due to specific evasive and escape mechanisms, the immune competent cells are rendered ineffective. One such mechanism may be the production of immune suppressor substance(s), inhibiting lymphocyte proliferation, and subsequently, their transformation into effector cells. To evaluate a possible impact of RCC extract on lectin and alloantigen-induced proliferation of TIL and peripheral blood lymphocytes (PBL) from renal cell carcinoma (RCC) patients and from healthy control human subjects. Tumor extract and TIL were derived from 13 patients with RCC undergoing radical nephrectomy. Tumor infiltrating lymphocytes and PBL from these patients were activated with Concanavalin A (Con-A), Phytohemoglutinine (PHA) or Pokeweed (PW) and the rate of blastogenesis was measured by (3)H Thymidine incorporation. The same procedure was used in assay with PBL from control healthy blood donors. There was a significant reduction (88.6%) in the proliferative response to ConA of TIL compared to PBL from the same patients (P = 0.007). A similar decrease was seen following stimulation by PHA (85.8%, P = 0.01) and PW mitogen (78.5%, P = 0.001). A 79.5% decrease in response level of TIL to alloantigens compared to PBL from RCC patients (P = 0.021), was observed. Lectin induced proliferative response of RCC patients was significantly lower in the presence of RCC extract (82.9%) compared to normal kidney extract (P = 0.008). Alloantigenic stimulation of healthy individual PBL was also decreased significantly in the presence of RCC extract (92.9%, P = 0.0001) compared to normal kidney extract. Similarly, lectin induced stimulation of healthy control PBL in the presence of RCC extract was significantly lower (83.2%, P = 0.003). Our data suggest that RCC extract contains an immune suppressive substance(s), capable of inhibiting lymphocyte proliferative response of tumor infiltrating lymphocytes as well as of PBL from patients and healthy individuals alike. This may be one of the mechanisms by which the tumor evades the transformation of lymphocytes into effector killer cells, and thus affects the biological inter-relationship between tumor and host. Identification of this substance and its gene may provide an effective anti-tumoral treatment modality.

Adenocarcinoma, Clear Cell↗

PubMedDate not supplied

Synthesis of polyamidoamine dendrimers having poly(ethylene glycol) grafts and their ability to encapsulate anticancer drugs.

Polyamidoamine dendrimers having poly(ethylene glycol) grafts were designed as a novel drug carrier which possesses an interior for the encapsulation of drugs and a biocompatible surface. Poly(ethylene glycol) monomethyl ether with the average molecular weight of 550 or 2000 was combined to essentially every chain end of the dendrimer of the third or fourth generation via urethane bond. The poly(ethylene glycol)-attached dendrimers encapsulating anticancer drugs, adriamycin and methotrexate, were prepared by extraction with chloroform from mixtures of the poly(ethylene glycol)-attached dendrimers and varying amounts of the drugs. Their ability to encapsulate these drugs increased with increasing dendrimer generation and chain length of poly(ethylene glycol) grafts. Among the poly(ethylene glycol)-attached dendrimers prepared, the highest ability was achieved by the dendrimer of the fourth generation having the poly(ethylene glycol) grafts with the average molecular weight of 2000, which could retain 6.5 adriamycin molecules or 26 methotrexate molecules/dendrimer molecule. The methotrexate-loaded poly(ethylene glycol)-attached dendrimers released the drug slowly in an aqueous solution of low ionic strength. However, in isotonic solutions, methotrexate and adriamycin were readily released from the poly(ethylene glycol)-attached dendrimers.

Antineoplastic Agents↗

PubMedDate not supplied

Temperature-dependent associating property of liposomes modified with a thermosensitive polymer.

Novel temperature-sensitive liposomes having surface properties that can be controlled by temperature were designed as liposomes coated with poly(N-isopropylacrylamide), which exhibits a hydrated coil to dehydrated globule transition at ca. 32 degrees C. To obtain the polymer with anchoring groups to the liposome, a copolymer of N-isopropylacrylamide and octadecyl acrylate (99:1, mol/mol) was synthesized by radical copolymerization. The copolymer revealed the transition near 30 degrees C. Liposomes made from various phospholipids were prepared by sonication and coated with the copolymer. When dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine were used as liposome lipids, remarkable aggregation and fusion of the copolymer-modified liposomes took place between the transition temperature of the copolymer and the gel-liquid-crystalline transition temperature (Tc) of the lipid membranes. However, above the Tc, association between the liposomes was much less significant, although the copolymer is still hydrophobic. In the case of the copolymer-modified dilauroylphosphatidylcholine liposome, the membrane of which takes on a liquid-crystalline state under the experimental conditions, association between the liposomes also hardly occurred even when the copolymer became hydrophobic. On the other hand, below the transition temperature of the copolymer, the copolymer-modified liposomes were very stable and aggregation of the liposomes was not observed, irrespective of membrane lipid. Results obtained in this study demonstrate that the copolymer chains fixed on the surface of the liposome with a solid membrane promote aggregation and fusion of the liposomes by hydrophobic interactions between the copolymer chains and/or between the copolymer chains and the liposome membranes above the transition temperature of the copolymer.

Acrylamides↗

PubMedDate not supplied

Temperature sensitization of liposomes using copolymers of N-isopropylacrylamide.

To obtain liposomes which release the contents in response to ambient temperature, liposomes modified with copolymers of N-isopropylacrylamide with varying lower critical solution temperatures have been designed. Poly(N-isopropylacrylamide-co-acrylamide)s with various compositions were synthesized by free-radical copolymerization. The lower critical solution temperature of the polymer increased with increasing acrylamide content in the polymer. Poly(N-isopropylacrylamide-co-acrylamide-co-N, N-didodecylacrylamide)s were also prepared via the same method as the thermosensitive polymers having anchor groups to the liposome membrane. Calcein-loaded dioleoylphosphatidylethanolamine/egg yolk phosphatidylcholine (6:4, w/w) liposomes were coated with these polymers by incubating the liposomes with aqueous solutions of the polymers. The liposomes hardly released the contents below the lower critical solution temperature of the polymer, but the release was greatly enhanced above that temperature. The liposomes were also made from a mixture of the same lipids and the polymer. The liposome revealed a more drastic release property than the liposomes prepared by the incubation with the polymer solution, because the polymer chains were bound on both surfaces of the membrane. The close relationship between lower critical solution temperatures of the polymers and temperature regions where enhancement of the release from the polymer-fixed liposomes demonstrates that the release was triggered by alteration of the polymers from a hydrophilic state to a hydrophobic state occurring at their lower critical solution temperatures.

Acrylamides↗

PubMedDate not supplied

Design of dendritic macromolecules containing folate or methotrexate residues.

Polyether dendritic compounds bearing folate residues on their surface were prepared as model drug carriers with potential tumor cell specificity. Starting from ester-terminated polyether dendrimers, hydrazide groups were easily introduced to the surface of the dendrimers by reaction with hydrazine. Folate residues were then conjugated to the hydrazide chain ends of the dendrimers by direct condensation with folic acid in the presence of a condensing agent or by reaction with an active ester derivative of folic acid. Essentially complete functionalization of the terminal hydrazide groups was achieved for both the first and the second generation dendrimers with four and eight hydrazide groups. For the G-2 dendrimer with 16 hydrazide groups, an average number of only 12.6 folate residues were attached to each dendrimer. The conjugates are soluble in aqueous medium above pH 7.4. In addition, a similar conjugation of the antitumor drug methotrexate to the dendrimer was also investigated. Once optimized, these molecules may form the basis for a novel family of multivalent drug carriers.

Antineoplastic Agents↗