Effect of dose schedule of vitamin E and hydroxethylruticide on intestinal toxicity induced by adriamycin

CDF1 mice receiving Adriamycin, 12 mg/kg IP develop a toxic GI mucositis. The mean survival in CDF1 mice after Adriamycin injection was found to be 6.5 +/- 2.0 weeks and could be increased by alcohol or acetate Vitamin E pretreatment (with 2 g/kg qDx7d) to 22.06 +/- 12.3 weeks or by treatment with Venoruton after Adriamycin (qDx7 with 1.5 g/kg) to 23.7 +/- 12.7 weeks. Other schedules were ineffective or harmful. The ability of Venoruton to enhance survival when given after Adriamycin encouraged us to proceed to tumor bearing mice. The maximum survival with CDF1 mice bearing 5 X 10(6) L1210 cells was 1 +/- 0.2 week which could be increased to 2.17 +/- 0.8 weeks with optimal dose Adriamycin (10 mg/kg). Optimum survival with Venoruton and a single dose of Adriamycin was 2.45 +/- 0.91 weeks with Venoruton, 1.5 g, qd X 14, and 12 mg/kg Adriamycin. Treatment of L1210 bearing mice with Adriamycin, 10 mg/kg on days 1 and 8, yielded a survival of 2.23 +/- 0.7 weeks. An equitoxic regimen of Adriamycin, 11 mg/kg on days 1 and 9, plus Venoruton, 1.5 g, qd X 14, increased survival 30% to 3.08 +/- 2.9 weeks. Venoruton is a promising agent to increase the therapeutic index of Adriamycin.     

Fractionated total body irradiation and high dose cyclophosphamide: a preparative regimen for bone marrow transplantation for patients with hematologic malignancies in first complete remission

We treated 73 patients with hematologic malignancies in first complete remission (acute lymphoblastic leukemia = 23 patients; acute non-lymphoblastic leukemia = 25 patients; chronic myelogenous leukemia in first chronic phase = 20 patients, and high grade lymphoma = five patients) with a uniform preparative regimen consisting of fractionated total body irradiation (1,320 cGy) and high dose cyclophosphamide (100 mg/kg), followed by allogeneic bone marrow transplantation. By radiation dosimetry we demonstrated that the calculated doses were delivered accurately and reproducibly. Actuarial survival rates (+/- SEM) in complete remission were as follows: Acute lymphoblastic leukemia = 74 +/- 9%; acute nonlymphoblastic leukemia = 50 +/- 11%; and chronic myelogenous leukemia = 55 +/- 11%. Actuarial relapse rates for these three diagnoses were 19 +/- 9%, 17 +/- 11%, and 0% respectively. Three of the five lymphoma patients are alive in complete remission at 22+, 28+, and 54+ months. Overall probability of survival for the 73 patients was 59 +/- 7%. Interstitial pneumonia, usually associated with cytomegalovirus infection and graft-versus-host disease, and relapse of the underlying malignancy were the major causes of death.     

Potentiation of the efficacy of murine L1210 leukemia vaccine by a novel immunostimulator 7-thia-8-oxoguanosine: Increased survival after immunization with vaccine plus 7-thia-8-oxoguanosine

Summary We have investigated the ability of a novel immunopotentiator, 7-thia-8-oxoguanosine (7T8OG) to increase the efficacy of a weakly immunogenic murine L1210 leukemia vaccine. The vaccine was prepared by irradiating L1210 leukemia cells in a cesium source with a total of 6000-R dose. DBA/2 mice were treated with 150 mg/kg 7T8OG and/or with vaccine consisting of 10⁷ irradiated cells. In combination therapy, mice first received the vaccine and then were injected with 75 mg/kg 7T8OG 2 h and 4 h after vaccination. One week after the last treatment all mice were inoculated with 10⁴ live leukemia cells intraperitoneally. Control, untreated mice (n = 66) injected with 10⁴ live leukemia cells had a mean survival time ± standard error of 10.5±0.2 days. Treating mice (n = 66) with one, two or three doses of 7T8OG administered i.p. 1 week apart did not increase survival (mean survival time = 10.7 days). Mice immunized with one, two or three doses of vaccine had 14.5±1.1, 45.4±6.2 and 68.3±10.6 days mean survival, respectively. 7T8OG-stimulated vaccination increased the survival dramatically. The best survival was noted when the mice were treated with 2× (vaccine + 7T8OG). Immunization of mice (n = 30) with this treatment regimen increased the mean survival to 156±10.0 days. Over 90% of mice that were treated this way had a cumulative survival time greater than 160 days. In contrast, only 12% of the mice immunized twice with the leukemia vaccine alone survived over 160 days. These results suggest a rationale for the use of this immuno-potentiator with various vaccines for a more effective immunization.     

Postirradiation glucan administration enhances the radioprotective effects of WR-2721

Based on murine survival studies, endogenous hemopoietic spleen colony formation (E-CFU), and recovery of bone marrow and splenic granulocyte-macrophage colony-forming cells (GM-CFC), it was demonstrated that the postirradiation administration of glucan, an immunomodulator and hemopoietic stimulant, enhances the radioprotective effects of WR-2721. LD50/30 dose reduction factors for mice treated with WR-2721 (200 mg/kg approximately 30 min before irradiation), glucan (250 mg/kg approximately 1 h after irradiation), or both agents were 1.37, 1.08, and 1.52, respectively. Enhanced survival in mice treated with both agents appeared to be due in part to glucan's ability to accelerate hemopoietic regeneration from stem cells initially protected from radiation-induced lethality by WR-2721. Following a 10-Gy radiation exposure, E-CFU numbers in mice treated with saline, WR-2721, glucan, or both WR-2721 and glucan were 0.05 +/- 0.03, 6.70 +/- 1.05, 0.95 +/- 0.24, and 33.90 +/- 2.96, respectively. Similarly, bone marrow and splenic GM-CFC numbers were greater in mice treated with both WR-2721 and glucan than in mice treated with either agent alone. These results demonstrated at least additive radioprotective effects when mice were given WR-2721 prior to irradiation and glucan following irradiation. These effects appeared to depend on the sequential cell protection mediated by WR-2721 and hemopoietic repopulation mediated by glucan.     

Effects of combined therapy with thalidomide and glucantime on leishmaniasis induced by Leishmania major in BALB/c mice

For treating Leishmania major infection in BALB/c mice, we used thalidomide in conjunction with glucantime. Groups of mice were challenged with 510(3) metacyclic promastigotes of L. major subcutaneously. A week after the challenge, drug treatment was started and continued for 12 days. Thalidomide was orally administrated 30 mg/kg/day and glucantime was administrated intraperitoneally (200 mg/kg/day). It was shown that the combined therapy is more effective than single therapies with each one of the drugs since the foot pad swelling in the group of mice received thalidomide and glucantime was significantly decreased (0.9 +/- 0.2 mm) compared to mice treated with either glucantime, thalidomide, or carrier alone (1.2 +/- 0.25, 1.4 +/- 0.3, and 1.7 +/- 0.27 mm, respectively). Cytokine study showed that the effect of thalidomide was not dependent on IL-12; however, it up-regulated IFN-gamma and down-regulated IL-10 production. Conclusively, thalidomide seems promising as a conjunctive therapy with antimony in murine model of visceral leishmaniasis.     

Nitrendipine: an antidote to cardiac and lethal toxicity of cocaine

Nitrendipine, a Ca2+ modulator was tested in the rat as an antagonist to the cardiac toxicity of cocaine and as an antidote to the acute lethal effects of this drug. In a first series of experiments, nitrendipine (1.46 X 10(-3) mg/kg/min) when simultaneously administered intraarterially with cocaine (2 mg/kg/min) suppresses the arrhythmias induced by cocaine and increases survival time from 73 +/- 33 min to 309 +/- 118 min and the lethal dose of cocaine from 146 +/- 66 mg/kg to 618 +/- 236 mg/kg (p less than 0.003). Nitrendipine also protects the heart from the acute morphological lesions induced by cocaine administration and antagonizes some of the central effects of cocaine. In a second series, 5 rats administered 60 mg/kg of cocaine intraperitoneally had a survival time of 8'06 +/- 5'20. Death was attributed to convulsions and respiratory arrest. Animals treated with nitrendipine (129 +/- 23 mg/kg) 4'30" after cocaine administration survived. Nitrendipine appears to have general protective effects against cocaine cardiac toxicity and the acute lethal effects of this alkaloid.     

Anti-diabetic effect of ginsenoside Re in ob/ob mice

We evaluated the anti-diabetic effects of ginsenoside Re in adult male C57BL/6J ob/ob mice. Diabetic ob/ob mice with fasting blood glucose levels of approximately 230 mg/dl received daily intraperitoneal injections of 7, 20 and 60 mg/kg ginsenoside Re for 12 consecutive days. Dose-related effects of ginsenoside Re on fasting blood glucose levels were observed. After the 20 mg/kg treatment, fasting blood glucose levels were reduced to 188+/-9.2 and 180+/-10.8 mg/dl on Day 5 and Day 12, respectively (both P<0.01 compared to vehicle group, 229+/-9.5 and 235+/-13.4 mg/dl, respectively). The EC(70) of ginsenoside Re was calculated to be 10.3 mg/kg and was used for subsequent studies. Consistent with the reduction in blood glucose, there were significant decreases in both fed and fasting serum insulin levels in mice treated with ginsenoside Re. With 12 days of ginsenoside treatment, glucose tolerance of ob/ob mice increased significantly, and the area under the curve for glucose decreased by 17.8% (P<0.05 compared to vehicle treatment). The hypoglycemic effect of the ginsenoside persisted even at 3 days of treatment cessation (blood glucose levels: 198+/-13.1 with ginsenoside treatment vs. 253+/-20.3 mg/dl with vehicle, P<0.01). There were no significant changes in body weight or body temperature. Preliminary microarray analysis revealed differential expression of skeletal muscle genes associated with lipid metabolism and muscle function. The results suggest that ginsenoside Re may prove to be useful in treating type 2 diabetes.     

Ginseng berry reduces blood glucose and body weight in db/db mice.

In this study, we observed anti-diabetic and anti-obesity effects of Panax ginseng berry in adult C57BL/Ks db/db mice and their lean littermates. Animals received daily intraperitoneal injections of Panax ginseng berry extract at 150 mg/kg body wt. for 12 consecutive days. On Day 5, the extract-treated db/db mice had significantly lower fasting blood glucose levels as compared to vehicle-treated mice (180.5+/-10.2 mg/dl vs. 226.0+/-15.3 mg/dl, P < 0.01). On day 12, the extract-treated db/db mice were normoglycemic (134.3+/-7.3 mg/dl) as compared to vehicle-treated mice (254.8+/-24.1 mg/dl; P < 0.01). Fasting blood glucose levels of lean mice did not decrease significantly after treatment with extract. After 12 days of treatment with the extract, glucose tolerance increased significantly, and overall blood glucose exposure calculated as area under the curve (AUC) decreased 53.4% (P < 0.01) in db/db mice. Furthermore, db/db mice treated with extract (150 mg/kg body wt.) showed weight loss from 51.0+/-1.9 g on Day 0, to 46.6+/-1.7 g on Day 5, and to 45.2+/-1.4 g on Day 12 (P < 0.05 and P < 0.01 compared to Day 0, respectively). The body weight of lean littermates also decreased at the same dose of extract. These data suggest that Panax ginseng berry extract may have therapeutic value in treating diabetic and obese patients.     

Field immobilization of raccoons (Procyon lotor) with Telazol and xylazine

The effectiveness of tiletamine plus zolazepam (Telazol) and xylazine was evaluated as an immobilizing combination for raccoons (Procyon lotor). Fifteen raccoons were injected intramuscularly with a 3:2 mixture of Telazol (3.2+/-0.6 mg/kg [mean+/-SD]) and xylazine (2.1+/-0.4 mg/kg) at Pictured Rocks National Lakeshore, Michigan, USA, during May-October, 2001-03. Mean induction time was 4.8+/-3.8 min; mean recovery time was 128.5+/-48.4 min. No linear relationships were found between the amount (mg/kg) of Telazol-xylazine injected and induction (r2 = 0.06, P = 0.40) or recovery times (r2 = 0.01, P = 0.78). Mean heart rate, respiratory rate, and body temperature declined through 20 min after induction (P< 0.05). No mortality occurred and no short-term adverse effects were observed in recaptured individuals. I conclude that a 3:2 mixture of Telazol-xylazine is a safe and effective immobilizing agent for raccoons when conducting nonsurgical field procedures. Immobilizing raccoons with Telazol at 3 mg/kg and xylazine at 2 mg/kg should provide up to 60 min of handling time and usually allow full recovery in about 120 min.     

Trypanosoma cruzi: in vitro and in vivo antiproliferative effects of epigallocatechin gallate (EGCg)

The trypanocidal activity of catechins on Trypanosoma cruzi bloodstream trypomastigotes has been previously reported. Herein, we present the effect of epigallocatechin gallate (EGCg) on parasitemia and survival in a murine model of acute Chagas' disease as well as on the epimastigote form of the parasite. Upon intraperitoneal administration of daily doses of 0.8 mg/kg/day of EGCg for 45 days, mice survival rates increased from 11% to 60%, while parasitemia diminished to 50%. No side effects were observed in EGCg-treated animals. Fifty percent inhibition of epimastigotes growth was achieved with 311 microM EGCg 120 h after drug addition. No lysis, total culture growth inhibition or morphological changes were observed upon addition of 1-3mM EGCg at 24 h. This treatment also produced oligosomal fragmentation of epimastigotes DNA, suggesting a programmed cell death (PCD)-like process. All these findings point out EGCg as a potential new lead compound for chemotherapy of Chagas' disease.     

Characteristics of reovirus-mediated chemoimmunotherapy of murine L1210 leukemia

Summary We have previously demonstrated the ability of reovirus to function synergistically with chemotherapy in the treatment of murine EL-4 lymphoma. This study characterizes this treatment regimen in the therapy of L1210 leukemia. Animals with an estimated tumor burden of 10⁷ cells were treated with 9 mg/kg 1,3-bis(2-chloroethyl)-1-nitrosourea. Reovirus type 3, which had been quantitated either by particles or plaque-forming units (pfu), was administered 48 h after chemotherapy. Complete remission of tumor was observed in 80% of the animals which received either 10¹¹ particles or 10⁹ pfu of reovirus. Cured animals were resistant to challenge with homologous tumor, but were susceptible to challenge with heterologous tumor. Reovirus undergoes limited replication at the tumor site, and virus-specific antibody appears only after disappearance of reovirus-infected cells and virus from the ascites fluid. Reovirus appears to function therapeutically by inducing a tumor-specific cytolytic immune response.     

Effect of phenobarbital and thyroxine on hepatocarcinogenesis initiated in mice by nitrosoethylurea and diethylnitrosamine

13-14-day old mice of ICR and CBA strains were given a single intraperitoneal injection of nitrosoethylurea (80 mg/kg) or diethylnitrosamine (50 mg/kg). 2 weeks later, they were given drinking water containing phenobarbital (1 g/L) or thyroxine (2 mg/L). The control mice were given only tap water. 29.4% of male and 42.1% of female ICR mice who had received nitrosoethylurea died of leukemia within 3-6 months after the carcinogen treatment. There was no case of leukemia in mice treated with diethylnitrosamine. Nitrosoethylurea induced 3-more often lung adenomas than diethylnitrosamine. Phenobarbital and thyroxine did not affect development of either leukemias or lung adenomas. By contrast, phenobarbital significantly elevated the number and size of hepatic lesions, whereas thyroxine markedly decreased them in all the experiments. The total and free thyroxine levels were significantly decreased in the blood of mice given phenobarbital and increased in mice given thyroxine. The data obtained indicate that thyroid hormones suppress tumor development in the mouse liver and that the promotion of hepatic tumoro-genesis by phenobarbital is presumably caused by the elimination of this suppressing effect of the thyroid hormones.     

Use of medetomidine-ketamine and atipamezole for reversible immobilization of free-ranging hog deer (Axis porcinus) captured in drive nets

A combination of 0.05 mg/kg medetomidine and 1.5 mg/kg ketamine was used to immobilize nine adult free-ranging hog deer (Axis porcinus) captured in drive nets in the Royal Bardia National Park, Nepal, 22-23 February 2000. The drugs were administered intramuscularly from separate syringes and the mean time (+/-SD) to complete immobilization was 4.6+/-1.0 min. Muscle relaxation was good and no major clinical side effects were seen. Mean values for physiologic parameters, recorded at 10-12 and 18-20 min after drug administration, were 40.6+/-0.5 and 41.1+/-0.6 C, 87+/-5 and 84+/-4%, 107+/-16 and 113+/-16 beats/ min, and 46+/-9 and 40+/-8 breaths/min for rectal temperature, SpO2, pulse rate, and respiratory rate, respectively. All animals received 0.25 mg/ kg atipamezole intramuscularly 20-22 min after administration of medetomidine-ketamine and the mean time to coordinated running was 4.8+/-0.8 min. All animals survived for at least 5 mo post-capture. To reduce stress and to facilitate handling, medetomidine-ketamine and atipamezole are recommended for reversible immobilization of free-ranging hog deer captured in drive nets.     

Synthesis, cytotoxicity and antitumor activity of platinum(II) complexes of cyclopentanecarboxylic acid hydrazide

New platinum(II) complexes of cyclopentanecarboxylic acid hydrazide (cpcah) were prepared, characterized by elemental analysis, IR and 1H NMR spectra, and evaluated for in vitro cytotoxicity in Friend leukemia (FL) and A2780 ovarian tumor cells, induction of apoptosis in FL cells, as well as for in vivo antitumor activity toward murine L1210 leukemia and Lewis lung carcinoma. The spectral analyses indicated a cis-square planar structure of the complexes with hydrazide ligand coordinated via the NH2 group. The compounds exerted significantly lower in vitro and in vivo toxicities as compared with those of cisplatin (cis-diamminedichloroplatinum(II), DDP). On the other hand, the complex [Pt(NH3)(cpcah)Cl2] exhibited antitumor activity against L1210 leukemia in mice comparable to that of cisplatin, resulting at a dose of 42 mg/kg (administered 3 times) in a T/C (mean survival time) of 280%. This compound displayed an in vitro macromolecular synthesis inhibition pattern similar to that of DDP. At concentrations close to the cytostatic ones (10-20 microM) this complex, as well as DDP, was able to induce apoptosis in FL cells as shown by neutral comet assay and morphological analysis. We concluded that there is a correlation between the ability of platinum complexes to induce apoptosis and their antitumor activity.     

Comparison of glycogen store in two strains of rat and guinea-pig under fed and fasted conditions

Glycogen content in the liver, skeletal muscle and heart has been determined in Sprague-Dawley (SD) and Wistar (W) rats and in tricoloured (T) and albino Dunkin Hartley (DH) guinea-pigs. The 12-week-old animals were studied under non-fasted or control conditions (N) and after 48 hr of fast (F48). Hepatic glycogen was higher in DH guinea-pigs (95.6 +/- 3.8 mg g-1) than in W (77.2 +/- 5.3 mg g-1) and SD (80.2 +/- 2.3 mg g-1) rats under N conditions. Mean values for the two strains were slightly higher in guinea-pigs than in rats. After fasting, hepatic glycogen was almost exhausted in the two species but was higher in W (1.5 +/- 0.08 mg g-1) and T (1.5 +/- 0.2 mg g-1) than in SD and DH (0.6 +/- 0.1 mg g-1). The content of glycogen in the anterior muscles of the thigh was comparable in the two strains of rat and guinea-pig, but was twice as high in the guinea-pigs (DH:15.1 +/- 0.6; T: 16.4 +/- 0.7 mg g-1) as in the rats (SD: 8.1 +/- 0.2; W: 7.1 +/- 0.5 mg g-1) under N conditions. In F48 animals, muscular glycogen decreased by 41-46% (rats) and 38-39% (guinea-pigs). Hepatic and extra-liver glycogen stores were calculated and found higher in the guinea-pigs than in the rats. The total utilization during fasting was larger in the guinea-pigs (6140 mg/kg body wt) than in the rats (4500 mg/kg body wt).(ABSTRACT TRUNCATED AT 250 WORDS)     

Anti-hyperglycemic effect of the polysaccharides fraction from American ginseng berry extract in ob/ob mice.

In this study, we evaluated the anti-hyperglycemic effect of a polysaccharides fraction from American ginseng berry extract in diabetic ob/ob mice. All animals received daily intraperitoneal injections of polysaccharides at 150 mg/kg body wt. (n = 5), polysaccharides at 50 mg/kg body wt. (n = 5), or vehicle (n = 5) for 10 consecutive days. On Day 5, as compared to the vehicle-treated mice (230.5 +/- 13.5 mg/dl, mean +/- S.E), mice from both treated groups showed significantly lower fasting blood glucose levels (187.4 +/- 20.5 mg/dl and 187.4 +/- 17.1 mg/dl), respectively (both P < 0.05). On Day 10, compared to the vehicle group (240.1 +/- 12.3 mg/dl), the 50 mg/kg dose group were at 188.4 +/- 12.6 mg/dl (P < 0.05), and the 150 mg/kg dose group were normoglycemic (148.8 +/- 17.6 mg/dl, P < 0.01). Those ob/ob mice treated with vehicle did not, however, show significant changes in fasting blood glucose levels. Data from the intraperitoneal glucose tolerance test (IPGTT) showed that, compared to Day 0, there was a significant improvement in glucose tolerance in animals who received the 50 and 150 mg/kg polysaccharide doses, and the area under the curve (AUC) decreased 15.5% (P < 0.05) and 28.2% (P < 0.01), respectively. Interestingly, after cessation of polysaccharide treatment, the fasting blood glucose levels stayed lower, and returned to control concentration on Day 30. We also observed that the polysaccharides fraction did not affect body weight changes in ob/ob mice. Our data suggest that the polysaccharides fraction from American ginseng berry extract has a potential clinical utility in treating diabetic patients.     

Glutamic acid modification of vincristine toxicity

The principal limiting feature of the antitumor agent, vincristine, in the clinic has been neurotoxicity; there are no known agents which can routinely prevent or decrease this side effect. Glutamic acid in laboratory and clinical investigations in the early 1960s was found to antagonize vinblastine, another clinically useful vinca alkaloid. Glutamic acid 250 mg/kg/d i.p. was given to normal mice treated with repetitive doses of vincristine 1.5 mg/kg every other day. When glutamic acid was given both before and during vincristine administration, it produced a 49-79% increase in survival compared to control mice receiving vincristine only (p less than 0.01). Other schedules of glutamic acid administration were ineffective. Also, there appeared to be a delay in development of neurotoxic manifestations (toe-walking gait) but the results were not as consistent as the improvement in survival. Glutamic acid given to tumor-bearing mice (P-388 and P-1534 murine leukemia) did not inhibit the antitumor effect of vincristine-induced host toxicity in a schedule-dependent fashion without inhibition of the antitumor effect of vincristine.     

Differential depressant effects of general anesthetics on the cardiovascular response to cocaine in mice.

In recent years, murine models have gained increasing importance for studies of cardiovascular physiology and pharmacology, largely due to the development of transgenic strains with specific alterations in phenotype. Differential effects of general anesthetic agents on the cardiovascular responses to cocaine have been reported in larger mammals; therefore, we studied the effects of commonly used anesthetics on heart function and on blood pressure responses to cocaine in Swiss Webster mice. We positioned a polyethylene catheter (PE-10) in the right carotid artery or left ventricle of mice anesthetized with equivalent anesthetic dose of either ketamine-xylazine (KX, 40 mg/kg + 5 mg/kg), pentobarbital (PEN, 40 mg/kg) or alpha-chloralose-urethane (CU, 80 mg/kg + 100 mg/kg). Cocaine (0.3 mg/kg, 1 mg/kg and 3 mg/kg) was administrated via the left jugular vein by bolus injection. In the KX group, the basal mean arterial pressure (MAP) and systolic left ventricular pressure (LVP) were 110 +/- 12 and 120 +/- 13 mmHg, respectively, close to conscious values. However, PEN and CU significantly decreased the basal parameters (P < 0.01 compared to the KX group). The lowest dose of cocaine (0.3 mg/kg) elicited minimal changes. Significant responses were obtained with a 1-mg/kg dose of cocaine (P < 0.01 compared to baseline). However, at 3 mg/kg, a toxic effect of cocaine appeared in all three anesthetic groups. Compared to published conscious animal data, anesthetic agents attenuated the cardiovascular effects of cocaine. Taken together, our results indicate that minimally effective doses of general anesthetics may significantly alter the basal hemodynamic state and the responses to sympathomimetic agents in the murine model, as has been reported in larger mammalian species. We concluded that anesthesia with ketamine-xylazine provides baseline hemodynamic values close to reported values in conscious animals, but also attenuates the hemodynamic response to cocaine.     

Antihyperglycemic activity of Tarralin™, an ethanolic extract of Artemisia dracunculus L.

The studies reported here were undertaken to examine the antihyperglycemic activity of an ethanolic extract of Artemisia dracunculus L., called Tarralin in diabetic and non-diabetic animals. In genetically diabetic KK-A(gamma) mice, Tarralin treatment by gavage (500 mg/kg body wt./day for 7 days) lowered elevated blood glucose levels by 24% from 479+/-25 to 352+/-16 mg/dl relative to control animals. In comparison, treatment with the known antidiabetic drugs, troglitazone (30 mg/kg body wt./day) and metformin (300 mg/kg body wt./day), decreased blood glucose concentrations by 28% and 41%, respectively. Blood insulin concentrations were reduced in the KK-A(gamma) mice by 33% with Tarralin, 48% with troglitazone and 52% with metformin. In (STZ)-induced diabetic mice, Tarralin treatment, (500 mg/kg body wt./day for 7 days), also significantly lowered blood glucose concentrations, by 20%, from 429+/-41 to 376+/-58 mg/dl relative to control. As a possible mechanism, Tarralin was shown to significantly decrease phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression by 28% in STZ-induced diabetic rats. In non-diabetic animals, treatment with Tarralin did not significantly alter PEPCK expression, blood glucose or insulin concentrations. The extract was also shown to increase the binding of glucagon-like peptide (GLP-1) to its receptor in vitro. These results indicate that Tarralin has antihyperglycemic activity and a potential role in the management of diabetic states.     

Steady state pharmacokinetics, metabolism and pharmacodynamics of theophylline in children after unequal twice-daily dosing of a new sustained-release formulation

This was an open-label study in 19 children aged 9-13 years, weighing 27-44 kg, with bronchial asthma. Twenty-four-hour steady-state concentrations of theophylline and its metabolites 1,3-dimethyl uric acid, 3-methyl xanthine and 1-methyl uric acid were assessed after daily dosing of 600 mg (ca 18 mg/kg/day) of the sustained-release theophylline micro-pellet sprinkle system BY158K, for 4 days. The dosing regimen used was an unequal twice-daily dose of 200 mg in the morning after breakfast and 400 mg in the evening after dinner. Twenty-four-hour peak expiratory flow (PEF) profiles were compared before treatment and at steady-state, along with lung function parameters after bronchial provocation. Mean values +/- SD (n = 16) of the steady-state characteristics were Cmin 6.8 +/- 2.1 mg/l, Cmax 14.5 +/- 4.8 mg/l and Cav 10.5 +/- 2.9 mg/l, the plateau time was 11.7 +/- 4.8 hr and peak-trough fluctuation and swing were 72 +/- 21 and 118 +/- 52%, respectively. There was an excellent reproducibility of theophylline pre-dose levels at corresponding time points of the 24-hr sampling period [r = 0.864 (p less than 0.001)]. Mean values +/- SD of the 24 hr average serum metabolite levels were 0.9 +/- 0.2 mg/1 for 1,3-dimethyl uric acid, 0.6 +/- 0.1 mg/1 for 3-methyl xanthine and 0.4 +/- 0.1 mg/1 for l-methyl uric acid. Lung function (n = 17) following bronchial provocation, improved in 10 children after theophylline treatment of 4 days, remained stable in 2 patients and deteriorated in 5 patients. Serum theophylline profiles and PEF profiles ran largely in parallel over the 24-hr period. Six children exhibited typical theophylline induced side-effects, headache (n = 3), nausea (n = 4), dizziness (n = 1), vomiting (n = 4), sleep disturbances (n = 1), pallor (n = 1) and tremor (n = 1), necessitating in 3 children one dose omission/reduction (n = 2) or subsequent dose reduction (n = 1). It has been shown that a twice daily dosing regimen with unequal doses of anhydrous theophylline (BY158K) is well suited to this population of fast metabolisers. The patients were well protected throughout the day, including the critical early morning hours.