Pharmacokinetics of deguelin, a cancer chemopreventive agent in rats.

PURPOSE: To study the pharmacokinetics of deguelin, a naturally occurring potential cancer chemopreventive agent, in rats. METHODS: [3H]Deguelin was administered intravenously (i.v.) under anesthesia, and blood samples were collected over 24 h. [3H]Deguelin and metabolites were extracted from plasma with ethyl acetate, and quantified by HPLC. Data were analyzed with the WinNolin pharmacokinetic software package to determine pharmacokinetic parameters. A three-compartment first-order elimination model was used to fit the plasma concentration-time curve. In addition, deguelin concentrations in tissues after i.v. and intragastric (i.g.) administration were determined by HPLC, and excretion (feces and urine) was evaluated over a 5-day period after i.g. administration. RESULTS: Deguelin exhibited a mean residence time (MRT) of 6.98 h and terminal half-life (t1/2(gamma)) of 9.26 h. The area under the curve (AUC) and total clearance (Cl) were 57.3 ng.h/ml and 4.37 l/h per kg, respectively, with an apparent volume of distribution (V) and volume of distribution at steady-state (Vss) of 3.421 l/kg and 30.46 l/kg, respectively. Following i.v. administration, the relative levels of tissue distribution were as follows: heart > fat > mammary gland > colon > liver > kidney > brain > lung. Following i.g. administration, the relative levels of tissue distribution were as follows: perirenal fat > heart > mammary gland > colon > kidney > liver > lung > brain > skin. Within 5 days of i.g. administration, about 58.1% of the [3H]deguelin was eliminated via the feces and 14.4% via the urine. Approximately 1.7% of unchanged deguelin was found in the feces, and 0.4% in the urine. CONCLUSIONS: An initial pharmacokinetic investigation of deguelin showed that this rotenoid has a relatively long MRT and half-life in plasma in the rat. The compound distributed in the tissues and excreted as metabolites, mainly via the feces.

Pharmacokinetics and tissue distribution of betulinic acid in CD-1 mice.

Betulinic acid is a naturally occurring pentacyclic triterpenoid. Betulinic acid has recently been selected by the National Cancer Institute for addition into the RAID (Rapid Access to Intervention in Development) programme. The agent exhibits potential anti-tumour activity and functions in this regard via apoptosis. The objective of the present study was to determine the pharmacokinetics of betulinic acid in CD-1 mice. Serum samples were obtained at designed times after a single 250 or 500 mg/kg intraperitoneal (IP) dose of betulinic acid. Tissue samples (skin, heart, liver, spleen, kidney, lung, brain, colon, caecum, ovary, uterus, thymus, lymph node, bladder, perirenal fat, mammary gland and small intestine) were collected after betulinic acid administration (500 mg/kg). Betulinic acid was extracted with methylene chloride and quantitatively analysed by HPLC/MS. Oleanolic acid and madecassic acid were used as internal standards. Pharmacokinetic parameters were calculated using the WinNonlin pharmacokinetic software package. A two-compartment, first-order model was selected for pharmacokinetic modelling. The results showed that after IP 250 and 500 mg/kg betulinic acid, the serum concentrations reached peaks at 0.15 and 0.23 h, respectively. The 250 and 500 mg/kg above betulinic acid IP doses were found to have elimination half-lives of 11.5 and 11.8 h and total clearances of 13.6 and 13.5 L/kg/h, respectively. The pharmacokinetic parameters observed for IP betulinic acid 500 mg/kg in the skin of mice were as follows: k(a) (h(-1)) 0.257, k(10) (h(-1)) 0.234, t(1/2(alpha)) (h) 2.63, t(1/2(beta)) (h) 20.2, V (L/kg) 0.61, AUC (microg/h/mL) 3504, T(max) (h) 3.90 and C(max) (microg/mL) 300.9. The distribution of betulinic acid in tissues at 24 h post-IP administration in a descending order was as follows: perirenal fat, ovary, spleen, mammary gland, uterus, bladder, lymph node, liver, small intestine, caecum, lung, thymus, colon, kidney, skin, heart and brain.

Cancer chemopreventive activity mediated by deguelin, a naturally occurring rotenoid.

Deguelin, a natural product isolated from Mundulea sericea (Leguminosae), was shown previously to mediate strong inhibition of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC) activity in cell culture and to reduce the formation of preneoplastic lesions when mouse mammary glands were exposed to 7,12-dimethylbenz(a)anthracene. As reported currently, deguelin was synthesized and evaluated for chemopreventive activity in the two-stage 7,12-dimethylbenz(a)anthracene/TPA skin carcinogenesis model with CD-1 mice and in the N-methylnitrosourea mammary carcinogenesis model with Sprague Dawley rats. In the mouse skin study, deguelin reduced tumor incidence from 60% in the control group to 10% in the group treated with a dose of 33 microg, and multiplicity was reduced from 4.2 in the control group to 0.1 in the treatment group. When the dose was increased 10-fold to 330 microg, no tumors were observed in the treatment group. These results correlated with the potential of deguelin to inhibit TPA-induced mouse epidermal ODC activity. When applied topically as a single dose in a time range of 2 h before to 2 h after TPA treatment, deguelin (384 microg) reduced ODC induction by TPA (6.17 microg) by more than 85%. Time course studies indicated that deguelin (33 microg) inhibited TPA (1.17 microg)-induced ODC activity by 70% without affecting the kinetics of induction over a period of 10 h. Complete inhibition of ODC induction was observed at a dose of 330 microg of deguelin. In the rat mammary tumorigenesis study, intragastric administration of 2 or 4 mg of deguelin/kg of body weight daily, 5 days/week, reduced tumor multiplicity from 6.8 tumors/rat in the control group to 5.1 or 3.2 tumors/animal, respectively. At the 4 mg of deguelin/kg of body weight dose level, the tumor latency period was significantly increased. Tumor incidence, however, was unaffected. These data indicate that deguelin exhibits cancer chemopreventive effects in skin and mammary tumorigenesis models and that additional studies are warranted to characterize the cancer chemopreventive or chemotherapeutic potential of this substance more fully.

Cancer chemopreventive activity of resveratrol, a natural product derived from grapes.

Resveratrol, a phytoalexin found in grapes and other food products, was purified and shown to have cancer chemopreventive activity in assays representing three major stages of carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen and to induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation (antiprogression activity). In addition, it inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.

Cisplatin nephrotoxicity in a patient with a single kidney.

OBJECTIVE: To describe a patient with a single kidney who experienced cisplatin-associated nephrotoxicity. CASE SUMMARY: A 78-year-old African-American woman with squamous cell carcinoma of the base of her tongue (T4N2M1) was admitted electively to our institution for the first cycle of chemotherapy. Her past medical history was significant for a left nephrectomy secondary to well-differentiated papillary transitional cell carcinoma of the left renal pelvis, hypothyroidism, asthma, and coronary artery disease. Her blood urea nitrogen (BUN) was 27 mg/dL of urea, and serum creatinine was 1.2 mg/dL. On admission she was hydrated adequately, and was treated with an evening dose of cisplatin 100 mg/m2 (180 mg) in 250 mL of NaCl 0.9% solution in a 3-hour infusion, and a 5-day course of fluorouracil 1000 mg/m2 (1800 mg) in a 24-hour infusion. Serum creatinine and BUN concentrations following cisplatin administration were 1.1 mg/dL and 8 mg/dL, respectively. Four days after cisplatin therapy, a decline in renal function was observed, with an increase in serum creatinine and BUN concentrations to 4.0 mg/dL and 31 mg/dL, respectively. These tests remained elevated throughout her hospitalization. With hemodialysis treatments a resolution in altered mental status was observed; however, her chronic renal failure persisted. She was subsequently discharged and followed in the outpatient renal, geriatric, and oncology clinics. DISCUSSION: Cisplatin is a principal chemotherapeutic agent used in the treatment of a variety of solid tumors. Nephrotoxicity is a major complication associated with this compound. Although many clinicians believe that cisplatin nephrotoxicity is unlikely to occur in patients with a single kidney, recent reports have suggested otherwise. The physiologic changes of the aging kidney are such that they should foster cisplatin clearance rather than expose the kidney to the drug's nephrotoxic potential. In addition, evening administration of cisplatin is thought to minimize nephrotoxicity. We describe a 78-year-old woman with a single kidney who developed nephrotoxicity following a single evening dose of cisplatin. Details of the patient's history and cisplatin-associated complication and therapy are discussed. CONCLUSIONS: Cisplatin circadian rhythmic pharmacotherapy to minimize cisplatin toxicity in patients with a single kidney appears to be controversial and needs further evaluation.

Compatibility of oral morphine sulfate solution with enteral feeding products.

OBJECTIVE: Patients with terminal cancer often receive continuous enteral nutrition and oral medications concomitantly through nasogastric or gastrostomy feeding tubes. This study evaluated in vitro the compatibility of morphine sulfate (MS) solution 2 mg/mL (Roxane Laboratories) with three enteral nutrition products (Jevity [J], Osmolite-HN [O], and Pulmocare [P]) at 22 and 37 degrees C for 48 hours and J alone at 50 degrees C for 48 hours. METHODS: Mixtures containing 1 mg/mL MS were prepared with each enteral product: J, O, and P (Ross Laboratories). Serial samples (1 mL) were collected from each mixture and analyzed for morphine by reverse-phase HPLC. An analog pH meter was used to measure the pH of each mixture at scheduled intervals. RESULTS: The addition of MS 2 mg/mL (MS2) to J caused an immediate decrease in pH from 6.24 +/- 0.01 to 4.96 +/- 0.05 and a noticeable precipitate/phase separation. No phase separation was observed with a 1 mg/mL mixture of MS and J, O, and P when they were prepared with a more concentrated MS solution (20 mg/mL, MS20) (Roxanol Intensol). The pH declined linearly for all three enteral feeding products as the MS20 concentration was increased from 0 to 1 mg/mL. The precipitate observed in the mixture of MS2 with J was probably caused by the decrease in pH, which was caused by the greater volume fraction of MS solution. The concentration of morphine in the supernatant of a MS2/J solution was 0.83 mg/mL, and the concentration of MS in a homogeneous MS20/J solution was 0.86 mg/mL. At 48 hours, there was negligible (< 2 percent) morphine decomposition in all MS admixtures at all temperatures. No microbial growth was observed in any admixture at 24 hours. Electrophoretic analysis demonstrated equal protein migration and molecular weight distribution for J and MS/J solutions. CONCLUSIONS: MS is stable in enteral feeding solutions at temperatures from 22 to 50 degrees C. MS2 is associated with a pH-dependent protein precipitation (but not destruction of the proteins), resulting in disproportionate concentrations of morphine in the supernatant and precipitate. This incompatibility may adversely affect enteral feeding analgesic delivery. We, therefore, recommend MS 20 mg/mL for this method of oral MS delivery, because of its superior compatibility and stability with enteral feeding products.

Treatment of massive pulmonary embolism with centrally administered tissue-type plasminogen activator.

We report the use of centrally administered tissue-type plasminogen activator for three patients who presented with massive pulmonary embolism to the emergency department. In all patients, rapid improvement of pulmonary arterial pressures ensued by the end of the drug infusion, while the presenting symptoms of chest pain and shortness of breath subsided.

Intravenous esmolol in acute aortic dissection.

Acute aortic dissection is a devastating condition requiring prompt intensive pharmacologic management geared toward control of blood pressure and reduction in myocardial contractility (change in velocity/change in time). The treatment of choice currently is sodium nitroprusside and intravenous propranolol hydrochloride. During acute aortic dissection, hemorrhage may spread into the interatrial septum, extending to the atrioventricular junctional tissues, thus causing conduction abnormalities. Adverse effects of long-acting beta-blockers, including bradycardia, heart failure, and bronchospasm, may limit their usefulness because these effects persist for a long time after discontinuation. This may be detrimental, especially in patients with compromised cardiac function, bronchospastic disease, or both. We report a case of a 64-year-old woman with compromised cardiac function and aortic dissection who was successfully treated with esmolol hydrochloride (an ultrashort-acting beta-blocker) and sodium nitroprusside.