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Biomedical subjects

R T Dorr

Publications and source records attributed to R T Dorr.

At least 55 records · Page 3Linked to original sources
PubMed1996

2-[2'-(Dimethylamino)ethyl]-1,2-dihydro- 3H-dibenz[de,h]isoquinoline-1,3-diones with substituents at positions 4, 8, 9, 10, and 11. Synthesis, antitumor activity, and quantitative structure-activity relationships.

New 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3- diones with substituents at the 4, 8, 9, 10, and 11 positions were synthesized. Diazonium salts prepared from aminoazonafides were key intermediates for many of the analogues. Six of the new compounds were more potent than azonafide in a panel of tumor cells including human melanoma and ovarian carcinoma and murine L1210 leukemias. Three of these compounds, the 10-OCH3, 10-OC2H5, and 10-F analogues, had better ratios of cardiotoxicity to tumor-cell toxicity than azonafide. Eight compounds were not cross-resistant with MDR L1210 leukemia, and the 10-CN analogue was more potent against solid tumor cells than leukemia cells. The 9-OH, 10-CN, and 10-F analogues had high potency against both sensitive and resistant cell lines of MFX 7 breast carcinoma and WiDr colon carcinoma and sensitivity A599 lung carcinoma. Advantages of the 10-Cl, 10-NH2, and 10-CN analogues over azonafide were apparent in P388 leukemia in mice, and the 10-CN analogue was more effective than doxorubicin in this assay. Quantitative structure-activity relationship studies revealed statistically significant correlations between DNA binding strength of 8- and 10-substituted azonafides, as measured by deltaTm, and toxicity to tumor cells. There also were correlations between substituent size, as measured by MR, and cytotoxicity for 9- and 10-substituted azonafides and between MR and deltaTm for 4- and 11-substituted azonafides. Lipophilicity of substituents (pi) correlated with cytotoxicity for 9-, 10-, and 11-substituted azonafides. These results lend support to a model in which DNA binding strength influences cytotoxic potency, and lipophilicity increases DNA binding whereas large substituents decrease it.

Animals↗
PubMed1996

Skin ulceration potential of paclitaxel in a mouse skin model in vivo.

BACKGROUND: THe antimitotic agent paclitaxel is highly active in the therapy of several tumor types, including ovarian and breast cancer. The commercial formulation (Taxol) is supplied in a vehicle containing alcohol and the surfactant Cremophor EL (polyethoxylated castor oil). Whereas Phase I studies did not describe extravasation necrosis, more recent case reports have suggested that paclitaxel can cause soft tissue necrosis if inadvertently extravasated. The efficacy of various antidotal maneuvers, if any, was not known. METHODS: Dehaired, BALB/c mice were given intradermal (ID) injections of paclitaxel 0.3 mg, 0.6 mg, or 1.2 mg, or Cremophor EL, 0.1 mL, into the dorsal skin. The sites were observed thrice weekly for evidence of ulceration. Perpendicular widths of skin ulcers were measured by caliper and multiplied to yield a lesion area in cm2. The lesion area multiplied by time in days was integrated by computer to yield cumulative ulceration areas in (cm2 x days). Potential pharmacologic adjuvants were injected ID after paclitaxel. These included saline (0.05 mL), albumin (0.05 mL), hyaluronidase (15 Units), and hydrocortisone (2.5 mg). Topical adjuvants included dimethylsulfoxide solution, (0.1 mL), cooling to 8-10 degrees C or heating to 43-44 degrees C for 30 minutes after ID paclitaxel. RESULTS: Dose-dependent skin ulcers that lasted 12-17 days were created with the 3 ID paclitaxel doses. The two higher paclitaxel dose levels, 0.6 mg and 1.2 mg, were selected for antidote studies. Hyaluronidase and saline were effective ID antidotes for lesions induced by the 0.6-mg paclitaxel dose, but not for the higher paclitaxel dose of 1.2 mg (P<0.05 by analysis of variance). None of the topical adjuvants or other ID adjuvants significantly reduced paclitaxel-induced skin ulcers in the mice. CONCLUSIONS: Paclitaxel has experimental vesicant potential in the ID mouse skin model. Clinical extravasations of paclitaxel may be treated by subcutaneous injections of hyaluronidase diluted in saline.

Animals↗
PubMed1996

6- and 7-substituted 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h] isoquinoline-1,3-diones: synthesis, nucleophilic displacements, antitumor activity, and quantitative structure-activity relationships.

New 2-[2'-(dimethylamino)ethyl]-3H-dibenz[de,h]isoquinoline-1,3-diones with substituents at the 6- and 7-positions were prepared. Nucleophilic aromatic displacement was a key reaction in the syntheses. Ten of the new compounds were more potent than the unsubstituted compound, azonafide, in a panel of tumor cells including human melanoma and ovarian cancer and murine sensitive and MDR L1210 leukemia. They also were less cardiotoxic in cell culture. Four of these compounds were not cross-resistant with the MDR leukemia, and one of them, 6-ethoxyazonafide, was nearly as potent against solid tumor cells as leukemia cells. These compounds also had good potency against human breast, colon, and lung cancer cells, including doxorubicin and mitoxantrone resistant cell lines. Advantages of the new analogues over azonafide were less in vivo, but 6-ethoxyazonafide was more effective against L1210 leukemia and subcutaneous B16 melanoma in mice. Although correlations of antitumor potency in cells and physicochemical properties of substituents were not found, there were statistically significant correlations of DNA melt transition temperature (delta Tm) with potency in solid tumor cells and sensitive and MDR resistant L1210 leukemia cells for 6-substituted azonafides and with solid tumors for 7-substituted azonafides.

Animals↗
PubMed1996

Antitumor activity of combretastatin-A4 phosphate, a natural product tubulin inhibitor.

The tubulin-binding natural product combretastatin A-4 (CA-4) was tested for antitumor activity against fresh human tumors in vitro and 2 mouse tumors, both in vitro and in vivo. In colony forming assays using 10% fetal bovine serum, CA-4 was inhibitory in 27/40 human ovary cancers with a mean IC50 of 3.18 micrograms/mL for a 1-hour exposure (n = 35 specimens) and 0.27 microgramf1p4for a continuous exposure to CA-4 for 11-14 days (n = 5 specimens). Murine B-16 melanoma and P-388 leukemia were also highly sensitive to CA-4 in vitro with an identical IC50 value of 0.0007 micrograms/mL for continuous drug exposure for 8 days. Comparable in vitro cell culture studies performed in serum concentrations higher than 10%, revealed a significant loss of cytotoxic potency. Using the same reversed-phase HPLC technique as developed for paclitaxel, CA-4 was shown to bind to serum proteins (> or = 30,000 mw) > 99% and to albumin approximately 70%. CA-4 was only marginally active (25% increased lifespan) in DBA/2 mice bearing P-388 leukemia who were given doses of 100 mg/kg IP on either days, 1, 5 and 9 (p = 0.075 by Wilcoxon analysis) or on consecutive days 1-9 (p = 0.19 compared to control). A higher IP dose of 150 mg/kg on days 1, 5 and 9 did not delay subcutaneous B-16 melanoma tumor growth in C57/B1 mice. These findings demonstrate a substantial loss of antitumor efficacy for CA-4 in physiologic serum concentrations in vitro. No consistent antitumor activity was observed in two murine tumor models in vivo.

Animals↗
PubMed1996

Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study.

A pilot phase I study was conducted with a cyclic heptapeptide analog of alpha-melanocyte stimulating hormone (alpha-MSH). The lactam-bridged molecule, called Melanotan-II (MT-II), has the structure Ac-Nle4-Asp5-His6-D-Phe7-Arg8-Trp9-Lys10 alpha-MSH4-10-NH2 (MT-II) and has superpotent melanotropic activity in vitro. A single-blind, alternating day (saline or MT-II), placebo-controlled trial was conducted in 3 normal male volunteers at the starting dose of 0.01 mg/kg of MT-II. Subcutaneous injections of MT-II or saline were given daily (Monday-Friday) for 2 consecutive weeks. Two subjects were escalated by 0.005 mg/kg increments to 0.03 mg/kg and one to 0.025 mg/kg. The 0.03 mg/kg dose produced Grade II somnolence and fatigue in one of two subjects (WHO standards). Mild nausea, not requiring antiemetic treatment, was reported at most MT-II dose levels. A stretching and yawning complex appeared to correlate with the onset of spontaneous, penile erections which were intermittently experienced for 1-5 hours after MT-II dosing, depending on the MT-II dose. Two subjects had increased pigmentation in the face, upper body and buttock, as measured by quantitative reflectance and by visual perception 1 week after MT-II dosing ended. These results demonstrate that MT-II has tanning activity in humans given only 5 low doses every other day by subcutaneous injection. The recommended single MT-II dose for future Phase I studies is 0.025 mg/kg/day.

Adult↗
PubMed1996

Cardioprotection of rat heart myocytes with amifostine (Ethyol) and its free thiol, WR-1065, in vitro.

Cultured neonatal rat heart myocytes form a synchronously-contracting cell syncytium from one to two days after isolation, plating on plastic and incubation at 37 degrees C. On day 3 after plating, myocytes were exposed to the anthracycline doxorubicin, 0.1-10 micrograms/ml, for 1 h with or without a 15-min pretreatment with the thiophosphate compound amifostine (WR-2721, Ethyol) or its dephosphorylated metabolite, WR-1065. The concentration of each WR-compound was limited to 2 micrograms/ml or 10% of the maximal achievable plasma concentration of amifostine after an intravenous dose of 740 mg/m2. Both amifostine and the free thiol significantly reduced doxorubicin-induced heart-cell toxicity, measured by adenosine triphosphate content normalised to total cellular protein. A concurrent 1-h exposure to these compounds and doxorubicin was also cardioprotective, but neither compound was effective when administered after doxorubicin. Although both amifostine and WR-1065 were approximately equipotent in preventing doxorubicin-induced cardiotoxicity, only amifostine significantly increased glutathione levels in the myocytes. These results complement prior in vitro and in vivo studies in rodents showing cardioprotectant activity for amifostine and its free thiol, WR-1065, when administered prior to doxurubicin.

Amifostine↗
PubMed1996

Disposition and metabolism of topically administered alpha-tocopherol acetate: a common ingredient of commercially available sunscreens and cosmetics.

Skin cancers are a serious health problem in the United States. One common method of skin cancer primary prevention is use of sunscreens. Research has been conducted to ascertain the role of active ingredients of sunscreen products in photoprotection and possible carcinogenesis. In contrast, little is known about the "other ingredients", listed or unlisted, on sunscreen product labels. One such ingredient is vitamin E. usually in the form of alpha-tocopherol acetate. Results of recent studies of skin carcinogenesis in an ultraviolet (UV) B mouse carcinogenesis model suggest that topically applied alpha-tocopherol acetate does not prevent and, under some conditions, enhances skin cancer development and growth, whereas the free unesterified from of alpha-tocopherol significantly reduces experimental UVB carcinogenesis. We have performed a Phase II cancer prevention study to evaluate whether topically applied alpha-tocopherol acetate is absorbed in human skin and metabolizes to the free or other forms. In this double-blind study, 19 men and women > 30 years of age who had at least three actinic keratoses on their forearms were randomly assigned to apply alpha-tocopherol acetate (125 mg/g) or difluoromethylornithine cream to their arms twice daily for three months. Blood samples and photographs and punch biopsies of actinic keratoses were obtained before and at the end of the study (Month 4). Plasma and skin concentrations of free alpha-tocopherol, alpha-tocopherol acetate, and gamma-tocopherol were analyzed by high-performance liquid chromatography at Month 4. The results of this report focus only on data obtained from the 11 participants randomized to the alpha-tocopherol acetate arm of the study. Topically applied alpha-tocopherol acetate was substantially absorbed in skin, with no evidence of conversion within skin to its unesterified form (i.e., free alpha-tocopherol). There was no evidence of systemic availability or biotransformation of topically applied alpha-tocopherol acetate. In summary, we have determined that alpha-tocopherol acetate is not metabolized to the free form of alpha-tocopherol in plasma or skin.

Administration, Topical↗
PubMed1996

Liposomal amikacin: improved treatment of Mycobacterium avium complex infection in the beige mouse model.

Disseminated Mycobacterium avium complex (MAC) infection has reached epidemic proportions and is a major cause of morbidity and mortality in AIDS patients. We have developed a liposomal preparation of amikacin, VS107, which incorporates the drug in 54-65 nm diameter unilameller phospholipid vesicles and is stable at 4 degrees C for more than 4 months. VS107 exhibits superior microbiological and pharmacological activity over the free amikacin and improves the survival of mice in the established model for MAC infection. The serum half-life of VS107 in mice was 9.1 h and a peak serum level of 730 mg/L was obtained after administering three doses of 160 mg/kg. For the therapeutic study, beige mice infected with 10(7) cfu M. avium complex strain 101 were randomised to be treated with placebo liposomes, buffer, free amikacin or VS107 The drugs were administered via the caudal vein thrice weekly for 1, 3, 5 or 7 weeks beginning 5 days after infection. After 51 days of treatment with VS107, the number of viable M. avium in the liver and spleen was a 100 fold lower than was achieved with conventional amikacin (P < 0.01), and more than six decimal logarithms lower than was found untreated controls (P < 0.001). VS107 was well tolerated and might be a suitable candidate for treating human MAC infections.

Amikacin↗
PubMed1996

Cytoprotective agents for anthracyclines.

Anthracycline-induced cardiotoxicity is believed to be related to the generation of reactive oxygen species by at least two mechanisms: enzymatic reduction of the quinone with subsequent redox cycling and/or formation of an iron-anthracycline complex capable of intramolecular reduction and redox cycling. Both pathways may lead to the production of superoxide anions and highly reactive metabolites, such as hydroxyl radicals and hydrogen peroxide. As a result, membrane lipid peroxidation may ensue, producing damage in tissues like the heart, which have low antioxidant defenses (superoxide dismutase glutathione and especially, glutathione-peroxidase). Pharmacologic methods of interrupting this cycle have involved numerous antioxidants, such as the sulfhydryls N-acetylcysteine and cysteamine, and the lipophilic vitamin alpha tocopherol. Unfortunately, none of these compounds has been proven to be cardioprotective in patients receiving doxorubicin. In contrast, the water-soluble d-isomer of the iron chelator razoxane, dexrazoxane or ICRF-187, has been shown to reduce doxorubicin-induced cardiomyopathy. This has afforded greater cumulative doses of doxorubicin to be safely administered. The cytoprotective effect is apparently limited to the heart since there is no effect on antitumor efficacy and, unfortunately, no reduction in gastrointestinal toxicity, and with a slight increase in myelosuppression. More recent preclinical studies have also demonstrated cardioprotective activity for the aminothiol amifostine (WR-2721). In vitro, this agent has been shown to scavenge superoxide anions and hydroxyl radicals, the latter effect mediated by the active (dephosphorylated) metabolite, WR-1065. In tumor-bearing mice, amifostine reduces the lethality of high doses of doxorubicin without affecting antitumor activity. Finally, in vitro studies in neonatal rat heart cells have shown direct evidence of anthracycline cardioprotection for both amifostine and WR-1065. Cytoprotective drug levels of either agent were limited to 2.0 microg/mL, which is one tenth of the achievable peak plasma levels in humans. At this concentration, a 15-minute sulfhydryl pretreatment significantly prevented doxorubicin-induced depressions of myocyte adenosine triphosphate levels. Overall, these studies suggest that amifostine may have cytoprotective activity against doxorubicin-induced cardiac damage. Animal studies in a chronically dosed doxorubicin model are indicated; if positive, clinical trials testing this hypothesis will be warranted.

Amifostine↗
PubMed1996

Safety of autotransplants with high-dose melphalan in renal failure: a pharmacokinetic and toxicity study.

Melphalan (MEL) is probably the most effective chemotherapeutic agent in multiple myeloma (MM) with a clear dose-response effect. It can be escalated without excessive toxicity to 200 mg/m2, a myeloablative dose requiring hematopoietic stem cell support. Patients with marked renal insufficiency, not an infrequent finding in MM, have either received reduced doses or have been excluded from therapy with high-dose MEL. A prospective study was performed to evaluate the relationship between MEL pharmacokinetics and renal function in 20 patients with MM. Six patients had severe renal insufficiency (creatinine clearance, <40 ml/min), including five on chronic hemodialysis. Three patients with severe renal impairment first received a low test dose of MEL (16 mg/m2) for pharmacokinetic studies. All patients received 200 mg/m2 MEL divided into two equal doses of 100 mg/m2 i.v. on 2 consecutive days, followed by the administration of peripheral blood stem cells. MEL pharmacokinetics, performed after the first dose of 100 mg/m2, was not adversely affected by impaired renal function. The median half-life (t1/2), area under the concentration curve, and clearance of MEL were 1.1 h, 5.5 mg h/liter, and 27.5 liter/h, respectively, in patients with a creatinine clearance of <40 ml/min compared to 1.9, 7.9, and 23.6 for the others. Renal insufficiency also had no apparent negative impact on the quality of peripheral blood stem cell collections and did not adversely affect posttransplant engraftment, transfusion requirements, incidence of severe mucositis, or overall survival. However, it was associated with longer durations of fever (P = 0. 0005) and hospitalization (P = 0.004). No transplant-related deaths were observed. Plasma t1/2 and area under the concentration curve differed by a factor of 10 and MEL clearance by a factor of 5 between patients with the lowest and highest values. These large variations in MEL elimination could not be explained by patient or disease characteristics. We conclude that renal failure does not require dose reduction of MEL in autologous transplant. Due to marked interindividual variation in MEL elimination, pharmacokinetically guided dosing as well as cellular pharmacology studies may be helpful in achieving a more uniform antitumor effect.

Adult↗
PubMed1995

Amino-substituted 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H- dibenz[de,h]isoquinoline-1,3-diones. Synthesis, antitumor activity, and quantitative structure--activity relationship.

Sets of 2-[2-(dimethylamino)ethyl]-1,2-dihydro-3H- dibenz[de,h]isoquinoline-1,3-diones with amino and actylamino groups at each of the eight positions on the anthracene nucleus were synthesized from appropriately substituted anthracenes. Their evaluation in in vitro antitumor and cardiotoxicity assays revealed a very strong dependence of potency on the position of substitution. Certain compounds, including the 4-, 5-, 7-, and 9-amino derivatives, showed significantly higher potency than the unsubstituted parent compound, azonafide. Among them, 7-aminoazonafide had low cardiotoxicity relative to cytotoxicity. In general, the acetylamino analogues were less potent than the amino derivatives against tumor cells and neonatal rat heart myocytes; however, 5-(acetylamino)azonafide was highly cardiotoxic. 9-Aminoazonafide was more efficacious than azonafide or amonafide against P388 leukemia in mice. Statistically significant correlations were made between the ability of amino analogues to increase the transition melt temperature (delta Tm) of DNA and their potency against solid tumors, leukemia cells, or cardiac myocytes.

Adenine↗
PubMed1995

Antidote studies of vinorelbine-induced skin ulceration in the mouse.

The new cantharanthine-modified vinca alkaloid vinorelbine (Navelbine) was administered intradermally (ID) to dehaired BALB/c mice. Dose-dependent skin lesions were produced over the range 0.01-0.5 mg/mouse, with complete healing after 9-35 days. Local (ID) injections of hydrocortisone and saline were ineffective at blocking vinorelbine-induced skin ulceration. Topical skin heating to 43 degrees C or cooling to 10 degrees C were also ineffective. In contrast, hyaluronidase, 15 Units ID, following vinorelbine significantly reduced skin lesions. These results show that vinorelbine is a vesicant and that inadvertent extravasations may be managed with subcutaneous injection of the spreading factor enzyme, hyaluronidase.

Analysis of Variance↗
PubMed1995

Preclinical pharmacokinetics and antitumor activity of imexon.

Imexon is an aziridine compound originally studied for immune-enhancing effects on lymphocytes. The drug was well-tolerated in humans and was shown to be active in a variety of animal tumor models. Recently, imexon has demonstrated antitumor activity in human multiple myeloma cell lines in vitro. The pharmacokinetics of the compound using normal phase HPLC assay were studied in normal mice and in dogs with mast cell tumors. Doses of 100 mg/kg given intraperitoneally produced peak plasma levels over 100 micrograms/ml in mice and the drug was rapidly eliminated with half lives of 8 minutes (alpha phase) and 29 minutes (beta phase). Only 20% of an oral imexon dose was absorbed in the mouse. In dogs, the alpha and beta phase half lives ranged from 18-26 minutes and 91-110 minutes, respectively. Peak levels over 100 micrograms/ml were obtained following intravenous doses of 12.5 mg/kg and 25 mg/kg. Imexon was active in mice bearing either P-388 or L-1210 leukemia, but not in mice with B-16 melanoma. These results suggest that cytotoxic drug concentrations can be obtained in vivo and that imexon is active in lymphoproliferative tumors.

Administration, Oral↗
PubMed1995

Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function.

The narrow therapeutic index of anticancer drugs presents a clinical dilemma when these agents are administered to patients with impaired or unstable renal function. The purpose of this review is to (i) describe the nephrotoxicity of certain anticancer drugs, (ii) evaluate the fraction of renal clearance for pertinent anticancer drugs, and (iii) make general recommendations for the dosing of these drugs in the presence of impaired renal function. Pharmacokinetic, pharmacodynamic, and clinical toxicity information was obtained from current scientific and clinical literature. Recommendations for dosage adjustment of drugs is based on their nephrotoxicity, or renal clearance equal to or exceeding 30% of the administered dose. The specific formula used to calculate dosage adjustment of renally cleared anticancer drugs is based on fundamental pharmacokinetic principles. In addition, prospectively validated formulae for the dosage adjustment of specific agents, such as carboplatin are also reviewed. Forty-eight anticancer drugs are reviewed in this report. Nephrotoxicity is associated with 12 of these agents (Table 1). Renal clearance equal to or exceeding 30% of the administered dose is a characteristic of 17 of the drugs studied (Table 2), and a general recommendation for dose adjustment of these anticancer drugs is presented in Table 3. Renal clearance that is less than 30% of the administered dose is a feature of 31 anticancer drugs (Table 4) included in this review. This report provides general guidelines to adjust doses of renally excreted or nephrotoxic anticancer drugs in patients who present with altered renal function.

Antineoplastic Agents↗
PubMed1994

Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: a randomized trial.

BACKGROUND: Retinoids enhance differentiation of most epithelial tissues. Epidemiologic studies have shown an inverse relationship between dietary intake or serum levels of vitamin A and the development of cervical dysplasia and/or cervical cancer. Pilot and phase I investigations demonstrated the feasibility of the local delivery of all-trans-retinoic acid (RA) to the cervix using a collagen sponge insert and cervical cap. A phase II trial produced a clinical complete response rate of 50%. PURPOSE: This randomized phase III trial was designed to determine whether topically applied RA reversed moderate cervical intraepithelial neoplasia (CIN) II or severe CIN. METHODS: Analyses were based on 301 women with CIN (moderate dysplasia, 151 women; severe dysplasia, 150 women), evaluated by serial colposcopy, Papanicolaou cytology, and cervical biopsy. Cervical caps with sponges containing either 1.0 mL of 0.372% beta-trans-RA or a placebo were inserted daily for 4 days when women entered the trial, and for 2 days at months 3 and 6. Patients receiving treatment and those receiving placebo were similar with respect to age, ethnicity, birth-control methods, histologic features of the endocervical biopsy specimen and koilocytotic atypia, and percentage of involvement of the cervix at study. Treatment effects were compared using Fisher's exact test and logistic regression methods. Side effects were recorded, and differences were compared using Fisher's exact test. RESULTS: RA increased the complete histologic regression rate of CIN II from 27% in the placebo group to 43% in the retinoic acid treatment group (P = .041). No treatment difference between the two arms was evident in the severe dysplasia group. More vaginal and vulvar side effects were seen in the patients receiving RA, but these effects were mild and reversible. CONCLUSIONS: A short course of locally applied RA can reverse CIN II, but not more advanced dysplasia, with acceptable local side effects. IMPLICATIONS: A derivative of vitamin A can reverse or suppress an epithelial preneoplasia, lending further support to the notion that chemoprevention of human cancer is feasible.

Administration, Intravaginal↗
PubMed1994

A comparison of HPLC and bioassay methods for plasma melanotan-II (MT-II) determination: application to a pharmacokinetic study in rats.

The pharmacokinetic profile of the melanotropic peptide, melanotan-II (MT-II), was determined in rats following a 0.3 mg kg-1 intravenous dose. Regression analysis of the plasma MT-II concentrations determined using HPLC and bioassay methods indicated the existence of a significant linear correlation (r = 0.90, p < 0.001). The plasma concentration versus time plots determined using the two assay methods yielded biphasic disposition profiles that were essentially superimposable. The following pharmacokinetic parameters were assessed from plasma concentration versus time data using both methods: Cmax, AUC, CLs, t1/2 beta, MRT, Vd beta, and Vss. Statistical comparison showed that the parameters measured by each method were not significantly different (at the 0.05 level) except for t1/2 beta, MRT and Vss. The presence of even one aberrant data point in the beta-phase can significantly influence t1/2 beta when only a few data points are available in the beta-phase. Since MRT and Vss were calculated from t1/2 beta it is not surprising that these two parameters also differed between methods.

Amino Acid Sequence↗
PubMed1994

Effect of sulfhydryl compounds and glutathione depletion on rat heart myocyte toxicity induced by 4-hydroperoxycyclophosphamide and acrolein in vitro.

Neonatal rat heart myocytes were used to study the acute cardiotoxic effects of cyclophosphamide (CTX) metabolites. The myocytes were equi-sensitive to 4-hydroperoxycyclophosphamide (4HPC) and acrolein in vitro with 50% inhibitory concentrations (IC50) of 123 microM and 152 microM, respectively. The parent compound, CTX, was inactive and the myocytes were much less sensitive to the bis-chloroethylamine alkylator, mechlorethamine (IC50 = 1161 microM). Cellular glutathione (GSH) levels were initially reduced and then transiently elevated following exposure to 4HPC. With acrolein, GSH levels were reduced to unmeasurable levels at all time points. With the addition of 0.5 mM L-buthionine sulfoximine (BSO), myocyte GSH levels were reduced from control values of 120 nmol/mg protein to < 10 nmol/mg protein without causing direct cytotoxicity. However, pretreatment with BSO significantly enhanced the cardiotoxic effects of 4HPC. Finally, two exogenous sulfhydryl-containing compounds were shown to block the myotoxic effects of both 4HPC and acrolein. Mesna and N-acetylcysteine increased at concentrations of 0.01 microgram/ml and 0.1 microgram/ml roughly increased the IC50 of 4HPC by 2-3-fold. These results suggest that acrolein and 4HPC are equipotent cytotoxins and that a transient depletion in GSH accompanies this toxic effect in cardiac myocytes.

Acrolein↗