Testing commercially available folic acid capsules.
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Capsules↗
Biomedical subjects
A al-Achi
Publications and source records attributed to A al-Achi.
Need for quality-control testing of extemporaneously prepared oral solids.
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Aspirin↗
A possible nonspecific site of action of amiodarone on newborn rat heart cell in culture.
Amiodarone and its major metabolite desethylamiodarone are potent antiarrhythmic drugs that have multiple pharmacological effects on the heart. We examined the effect of both drugs on the neonatal rat heart monolayer cell culture. The cells were stimulated with L-arterenol (10(-7) M) and choleratoxin (1.5 micrograms/ml). Both the spontaneous pulsation rate and intracellular cAMP level were followed. Amiodarone (10(-7) M) or desethylamiodarone (10(-7) M), incorporated into phosphatidylcholine vesicles, decreased the stimulated cell pulsation rate 3 min after addition of drugs, and the level of intracellular cAMP 30 min after addition as well. Propranolol (10(-7) M) had no further effect on the pulsation rate after 3 min. In the presence of amiodarone and propranolol the stimulation of L-arterenol was completely abolished and both the pulsation rate and cAMP level proved to be lower than the control values. The stimulation of choleratoxin on pulsation rate was also decreased by addition of amiodarone and the cAMP level was lowered after 30 min as well. Desethylamiodarone exhibited similar behavior to amiodarone although it proved to be less effective. It is unlikely that amiodarone and desethylamiodarone act on beta-adrenergic receptors in a competitive manner. Our data suggests that amiodarone and its metabolite could act in a nonspecific manner perturbing the hydrophobic interaction in the cell membrane and thereby decoupling the receptor or the nucleotide regulator protein and adenylate cyclase.
Amiodarone↗
Buccal administration of human insulin in streptozocin-diabetic rats.
This study investigates the use of the buccal route of administration in the delivery of human insulin in rats. Streptozocin-induced diabetic female Wistar rats were used in this study. Insulin (100 U) either free (i.e., insulin solution) or associated with a carrier, namely erythrocyte-ghosts (EG) and liposomes-vesicles (LEV), was administered buccally. Blood samples were collected from the tail over a period of 5 hr. These results indicate that insulin absorption occurred, as evidenced from a decrease in blood glucose concentration, and in the case of free insulin and erythrocyte-ghosts-insulin (EG-INS). The magnitude of the blood glucose level decline was at its maximum of 39.53 mg/dl (at 2 hr) and 26.23 mg/dl (at 4 hr) for free insulin and EG-INS, respectively. No significant difference in the blood glucose level profile was observed after either LEV or liposomes-vesicles-insulin (LEV-INS). This study demonstrates the ability of human insulin to be absorbed from the mouth cavity when it is instilled in the form of a simple solution or EG-INS suspension. This absorption resulted in a definite pharmacological effect but not a significant therapeutic effect.
Absorption↗
Classification of antineoplastic treatments by their differential toxicity toward putative oxygenated and hypoxic tumor subpopulations in vivo in the FSaIIC murine fibrosarcoma.
In order to investigate the effect of environmentally determined conditions on the cytotoxicity of anticancer treatments, Hoechst 33342 dye selected tumor subpopulations were separated after in vivo treatment and plated for single cell colony survival. The 10% brightest cells were assayed as putative normally oxygenated cells and the 20% dimmest as putative hypoxic cells. At single therapeutic doses, cyclophosphamide treatment resulted in the largest differential killing between bright and dim cells (6.3-fold bright greater than dim); 1,3-bis(2-chloroethyl)-1-nitrosourea was 3.2-fold more cytotoxic toward bright cells and carboplatin was 2.4-fold more toxic toward bright cells. Both radiation (10 Gy) and melphalan were 2.2-fold more toxic to bright cells, while cis-diamminedichloroplatinum(II) was 1.8-fold, thiotepa was 1.2-fold and procarbazine was 1.3-fold more toxic to bright cells. Actinomycin D was 3.4-fold more toxic to bright cells. Adriamycin was 2.2-fold, vincristine was 2.1-fold, and etoposide was 1.6-fold more toxic to bright cells. Bleomycin and 5-fluorouracil were also tested and were 1.5- and 2.3-fold more toxic to bright cells, respectively. Only four treatments were more toxic to dim cells: mitomycin C (3.5-fold), misonidazole (1.5-fold), etanidazole (3.5-fold), and 43 degrees C, 30 min local hyperthermia (2.6-fold). In an attempt to shift the pattern of dim cell sparing, Fluosol-DA plus carbogen (95% O2/5% CO2) breathing was added to treatment with radiation (10 Gy), melphalan, cis-diamminedichloroplatinum(II), and etoposide. Although each of these treatments became significantly more toxic with the addition of Fluosol-DA/carbogen, only with melphalan did the combination overcome the sparing of dim cells. These results indicate that cells located distally from the tumor vasculature are significantly less affected by most anticancer drugs and suggest that successful therapeutic strategies against solid tumors will involve greater use of the few treatments which are more toxic toward this tumor subpopulation.
Animals↗
The interaction of cisplatin plus etoposide with radiation +/- hyperthermia.
The addition of concurrent etoposide and cisplatin to radiation +/- hyperthermia was evaluated in the murine FSaIIC fibrosarcoma tumor system. Tumor growth delay (TGD) demonstrated that when the drugs were tested with radiation (3 Gy daily X 5) plus (43 degrees X 30 min) local hyperthermia, cisplatin/hyperthermia/radiation (TGD approximately 25 days) was significantly more effective than etoposide/hyperthermia/radiation (TGD approximately 14 days). The addition of etoposide to cisplatin/hyperthermia/radiation, however, yielded a significantly longer growth delay (approximately 34 days). Tumor cell survival studies demonstrated that hyperthermia (43 degrees C, 30 minutes) was dose modifying for etoposide cytotoxicity (dose modifying factor approximately 2.0 as determined by comparisons of the slopes of the curves). The addition of etoposide to cisplatin modified cisplatin killing only slightly at 37 degrees C or 43 degrees C. Considerable additional cell kill was observed over a range of radiation doses with cisplatin, hyperthermia, and etoposide added singly or in combination, especially at the lowest radiation dose tested (5 Gy), but essentially no dose modification was observed. Evaluation of Hoechst 33342 dye-selected tumor subpopulations demonstrated that cisplatin, etoposide, radiation (10 Gy), etoposide plus radiation, and cisplatin plus radiation killed significantly fewer dim (presumably hypoxic) cells than bright (presumably normally oxygenated) cells. Hyperthermia killed more dim than bright cells. The combination of hyperthermia with cisplatin and radiation, however, resulted in approximately 5-fold lesser kill in dim cells, and the addition of etoposide increased this differential to 6.4-fold. These results indicate that etoposide adds small but measurable antitumor effects when used with cisplatin alone or with cisplatin in combination with radiation +/- hyperthermia (especially at lower radiation fraction sizes).
Animals↗
Cross-resistance and glutathione-S-transferase-pi levels among four human melanoma cell lines selected for alkylating agent resistance.
A panel of four cell sublines, each selected for resistance to a different antineoplastic agent, has been developed from a human malignant melanoma cell line G3361. Following repeated exposure to escalating doses of the drug of interest, cloned sublines were developed that are 9-fold resistant to cisplatin (G3361/CP), 11-fold resistant to 4-hydroxyperoxy-cyclophosphamide (4-HC) (G3361/HC), 4-fold resistant to carmustine (BCNU) (G3361/BCNU), and 4-fold resistant to melphalan (G3361/PAM). The cross-resistance of each resistant cell line was determined for cisplatin, BCNU, 4-HC, melphalan, carboplatin, nitrogen mustard, and Adriamycin. In general, the alkylating agent-resistant cell lines were specifically resistant to the drug used for selection with the exception of the G3361/CP line, which was greater than 10-fold resistant to the cisplatin analogue carboplatin, 4-fold resistant to 4-HC, and slightly (1.5-fold) resistant to melphalan, and the G3361/BCNU line, which was slightly (1.8-fold) resistant to melphalan. Collateral sensitivity of the G3361/CP, G3361/PAM, and G3361/4HC lines to killing by BCNU was also observed. Glutathione-S-transferase activity was elevated in each of the alkylating agent-resistant cell lines by 3- to 5-fold with chlorodinitrobenzene substrate. On Western blotting, the glutathione-S-transferase-pi (GST-pi) isoenzyme protein was elevated in the resistant cells by 3- to 5-fold. A complementary DNA (pTS4-10) coding for GST-pi has been cloned from a lambda gt11 library, sequenced, and used as a probe to determine the relative levels of GST-pi mRNA in the alkylating agent-resistant cell lines. GST-pi mRNA levels were elevated (8- to 15-fold) in the resistant cell lines, indicating that the GST-pi increases were mediated through an increase in mRNA levels. GST-pi elevations are a frequent event in cells selected for alkylating agent resistance, and in some cases, of multiple drug resistance. However, the lack of cross-resistance among cell lines selected for resistance to different alkylating agents, all of which have elevated GST-pi levels, indicates that increased levels of GST-pi cannot be the predominate mechanism for resistance to the tested drugs in these cell lines.
Alkylating Agents↗