Inhibition of systemic TNF-alpha cytotoxicity in cancer patients by D-peptidoglycan

The current study was designed to investigate direct inhibitory effects of N-acetylglucosaminyl-muramyldipeptide (GMDP) over the cytotoxic nature of TNF-α. A lactate dehydrogenase (LDH) assay of the inhibition of TNF-α cytotoxicity was donein vitro on the following cell lines: A549 (human lung carcinoma cells), A431 (human breast cancer cells) and L929 (mouse breast cancer cells). In a double-blind placebo-controlled trial, cancer patients with an elevated activity of all five LDH isoensymes were randomized to receive either a GMDP solution or a placebo; 63 patients were evaluated every third day for the mean daily number of episodes of nausea or vomiting, changes in clinical status, cell blood count and blood chemistry. A 95% inhibition of LDH release was noticed on A549 cells. Other cell lines were less sensitive to GMDP, with an observed 72% dose-dependent reduction in LDH activity.In vivo, LDH activity was decreased by 41% (+/−4%) (mean +/−SD) in all 21 subjects who were given 0.5–1.0 mg of GMDP daily. A lowering of LDH activity by 73.4% (+/−4%) was observed in 23 patients who received GMDP at a dosage of 1.5 mg/kg daily. Correspondingly, a 10% (+/−2%) increase in LDH activity was noticed in 19 patients who were given a placebo (P<0.01). During the follow-up period, the overall clinical condition of all patients treated with GMDP was improved. No side effects were observed. In nine patients who experienced nausea from tumor toxicity before treatment, the symptom subsided. In parallel, an extremely beneficial effect on lipids metabolism was noticed in all patients with elevated cholesterol and trigliceride levels. A dietary supplementation of GMDP has been shown to reduce systemic TNF-α cytotoxicity during tumor shock.     

利多卡因对老年胃癌根治术患者术后认知功能障碍的影响

目的:观察利多卡因对老年胃癌患者术后认知功能障碍的预防作用。方法:选择择期胃癌手术患者80例,ASA分级Ⅱ或Ⅲ级,性别不限,年龄大于等于60岁,BMI20-25 kg/m~2,随机分为2组(利多组和对照组):利多组40例,麻醉诱导前静脉给予利多卡因1.0 mg/kg,然后以1.5 mg/kg/h速率静脉输注至术毕前30 min;对照组40例,给予同等剂量和同等用法的生理盐水。术中维持BIS值在40-60。术后两组均行经静脉患者自控镇痛(patient controlled intravenous analgesia,PCIA),PCIA镇痛泵配法:两组均为芬太尼20μg/kg+生理盐水总量300 mL。观察并记录入室时刻(T_0)、气管插管即刻(T_1)、手术开皮即刻(T_2)、开皮后半小时(T_3)以及出手术室时刻(T4)的平均动脉压(MAP)、心率(HR)、脉搏氧饱和度(SpO_2)。记录术前1 d及术后6 h、1 d、2 d、3 d、7 d简易智能量表(mini-mental state examination,MMSE)评分并进行比较,术后评估并记录术后6 h、1 d、2 d、3 d及7 d静息和活动时视觉模拟评分(visual analogue scales,VAS)评分。结果:1与对照组比较,利多组术后6 h、1 d、2 d和3 d静息和活动时VAS疼痛评分均明显降低,差异有统计学意义(P0.05);2利多组4例发生认知功能障碍(10.0%),对照组13例发生认知功能障碍(32.5%),利多组认知功能障碍的发生率和持续时间较对照组明显降低(P0.05),差异均有统计学意义(P0.05)。结论:围术期静脉输注利多卡因可以预防老年胃癌根治术患者术后认知功能障碍,有利于减轻术后疼痛。     

Eradication of Helicobacter pylori Using One-week Triple Therapies Combining Omeprazole with Two Antimicrobials: The MACH I Study

Background. Eradication of Helicobacter pylori provides potential cure in the majority of patients with peptic ulcer disease, and eradication rates of more than 90% have been reported, using omeprazole in combination with two antimicrobials. The choice of antimicrobials, dose regimen and duration of treatment have varied between studies, however, and an optimal treatment still has to be established.
Materials and Methods. We conducted an international, randomized, double-blind, placebo-controlled study involving more than 100 patients in each of six treatment groups in 43 hospital gastrointestinal units in Canada, Germany, Ireland, Sweden, and the United Kingdom. Patients (n=787) with proved duodenal ulcer disease were randomized to treatment twice daily for 1 week with omeprazole, 20 mg (O), plus either placebo (P) or combinations of two of the following anti-microbials: amoxicillin, 1 gm (A), clarithromycin, 250 or 500 mg (C250, C500), or metronidazole, 400 mg (M). Eradication of H. pylori was evaluated by ¹³C-UBT, performed before and 4 weeks after treatment cessation.
Results. The eradication rates for the all-patients-treated analysis were 96%. OAC500; 95%, OMC250; 90%, OMC500; 84%, OAC250; 79%, OAM; and 1%, OP. OAC500 and OMC250 achieved eradication rates with lower 95% confidence interval limits exceeding 90%. All regimens were well-tolerated, 96% of patients complied with their dose regimen, and 2.3% of the patients discontinued treatment owing to adverse events.
Conclusions. Omeprazole triple therapies given twice daily for 1 week produce high eradication rates, are well-tolerated, and are associated with high patient compliance. The two most effective therapies were those combining omeprazole, 20 mg, with either amoxicillin, 1 gm, plus clarithromycin, 500 mg, or metronidazole, 400 mg, plus clarithromycin, 250 mg, all given twice daily.     

The Use of Triethylenethiophosphoramide (Thio-TEPA) in the Treatment of Metastatic Carcinoma of the Breast

Twenty-two patients with metastatic breast cancer were treated by a combination of testosterone and N,N′,N″, triethylenethiophosphoramide (Thio-TEPA). All had undergone mastectomy and received radiation; six had had an oophorectomy and 12 had had oophorectomy and adrenalectomy. For its marrow-stimulating effect testosterone was given intramuscularly, 100 mg. daily for five days; then 100 mg. of depo-testosterone was given intramuscularly once a week. On the sixth day of treatment, 15 mg. of Thio-TEPA was given intramuscularly and repeated daily or every second day until a definite depression of the leukocyte and/or platelet counts occurred. To 15 patients a total dose of 200 mg. or more of triethylenethiophosphoramide was given. Thirteen patients improved subjectively and five of these improved objectively. The duration of improvement varied between one and 12 months. Treatment was most effective in patients with bony metastases.     

Substitution of inhaled beclomethasone dipropionate for ingested prednisone in steroid-dependent asthmatics

The effect of inhaled beclomethasone dipropionate (dose, 400 μg daily) was investigated in 31 prednisone-dependent asthmatics. In a double-blind noncrossover study of 25 patients dependent on a daily prednisone dose of 17.5 mg or less, the dose of ingested prednisone was significantly diminished through the use of beclomethasone as compared with placebo (P < 0.001). In a subsequent single-blind study of the 12 patients who had received placebo, a similar decrease in prednisone dose was possible when these patients received beclomethasone. In all 25 patients the effect of beclomethasone was maintained for 2 years; 9 came to require less beclomethasone and 1 required more. In an additional single-blind study of six patients with severe asthma, dependent on prednisone in a dose of 20 to 25 mg/d, the response to beclomethasone was more variable and less significant (P < 0.01). However, at 2 years there was no significant benefit (P > 0.05) and there were two treatment failures.In patients in whom reduction of dose or discontinuation of prednisone was possible plasma cortisol values before and after corticotropin administration increased significantly (P < 0.001). Prednisone reduction was associated with the appearance of mild musculoskeletal steroid-withdrawal symptoms of short duration in 15 patients, and recurrence of symptoms of rhinitis in 15 patients. Side effects of beclomethasone included episodes of hoarseness in 6 and easily treated oropharyngeal Candida albicans infection in 14.     

Double-blind comparison of tolamolol,propranolol, practolol,and placebo in the treatment of angina pectoris.

Forty-two patients with angina pectoris have completed a randomized, double-blind trial comparing tolamolol 100 mg and 200 mg with propranolol 80 mg, practolol 100 mg, and placebo, all given three times a day. Tolamolol 200 mg thrice daily was found to be equivalent to propranolol 80 mg thrice daily in anti-anginal efficacy. Anginal attack rates and trinitrin consumption were significantly reduced by all active treatments as compared with the placebo but tolamolol and propranolol were the most effective. Tolamolol 200 mg thrice daily was most effective in reducing blood pressure, while propranolol was most effective in reducing the resting heart rate. All treatments except the placebo significantly increased the amount of exercise which could be performed before angina appeared (exercise work), while tolamolol 200 mg thrice daily significantly reduced Robinson''s index when compared with all other active agents. The degree of S-T segment depression induced by exercise was significantly lessened by both tolamolol and propranolol but not by practolol or placebo. There was no difference in patient preference between tolamolol and propranolol but tolamolol at both dose levels was preferred to practolol. Both tolamolol and propranolol are potent adrenergic beta-receptor antagonists and equal in anti-anginal efficacy but tolamolol has the advantage of being cardioselective. It is superior to practolol.     

Comparison of high-dose intravenous methylprednisolone with low-dose oral prednisolone in acute renal allograft rejection in children.

Two corticosteroid regimens were compared in a randomised, prospective study of 48 consecutive acute rejection episodes occurring at least one month after transplantation in 22 children who had received renal allografts. The higher dose schedule (intravenous methylprednisolone 600 mg/m2 daily for three days) was no more effective than the lower (oral prednisolone 3 mg/kg daily for three days) in reversing rejection, being successful in 70% as opposed to 72% of episodes. Few major side effects were seen with either treatment, but unpleasant sensations were reported much more frequently in the group given intravenous methylprednisolone; this regimen was much more disruptive of the patient''s life. Oral prednisolone in the dosage described is as effective as about 10 times that dose of intravenous methylprednisolone; it is much cheaper and is viewed as less unpleasant by patients.     

Effect of a Dietary Herbal Supplement Containing Caffeine and Ephedra on Weight,Metabolic Rate,and Body Composition*

Objective: To evaluate the effect of a dietary supplement containing herbal caffeine (70 mg/dose) and ephedra (24 mg/dose; C&E) on metabolic rate, weight loss, body composition, and safety parameters. Research Methods and Procedures: In phase I, 12 healthy subjects with a BMI of 25 to 35 kg/m² had resting metabolic rate (RMR) measured for 2 hours after ingesting C&E or a placebo on two occasions 1 week apart, followed by a 1‐week washout before phase II. In phase II, these 12 and 28 additional subjects were randomized to a 12‐week, double‐blind trial comparing C&E (3 times/day) to placebo. In phase III, the C&E group was given open‐label C&E for 3 months, and the placebo group was given C&E for 6 months. Results: In phase I, C&E gave an average 8 ± 0.1% (SE) rise in RMR over 2 hours compared with placebo (p < 0.01). In phase II, weight loss at 12 weeks was 3.5 ± 0.6 kg with C&E compared with 0.8 ± 0.5 kg with placebo (p < 0.02). The percentage fat lost, shown by DXA, was 7.9 ± 2.9% with C&E and 1.9 ± 1.1% with placebo (p < 0.05). Pulse decreased more in the placebo group that in the C&E group (p < 0.03). There were no differences in lipid levels or blood pressure. In phase III, there was a 6‐month loss of 7.3% and 7.8% of initial body weight for the groups on placebo and C&E during phase II, respectively. There were no serious adverse events. Discussion: C&E increased RMR significantly by 8% compared with placebo, promoted more weight and fat loss than placebo, and was well tolerated.     

"Third drug" trial: comparative study of antihypertensive agents added to treatment when blood pressure remains uncontrolled by a beta blocker plus thiazide diuretic.

Hydralazine, labetalol, methyldopa, minoxidil, prazosin, and placebo were compared when added by random allocation to atenolol 100 mg and bendrofluazide 5 mg daily in a series of 238 hypertensive patients inadequately controlled by the beta blocker-diuretic combination. Atenolol was withdrawn in those allocated to labetalol, and minoxidil was given only to men. The order of acceptability was: placebo, hydralazine, prazosin, methyldopa, minoxidil, labetalol. Minoxidil was more effective than the other active drugs, which had similar potency to one another. All the active agents were more effective than placebo. Hydralazine was the most generally suitable third drug, with prazosin a close second. Minoxidil was especially effective in patients with less severe hypertension but the same regimen caused fluid retention in those with more severe disease. Labetalol should probably be introduced at a low dose (150 mg daily) even when replacing full doses of a previously administered beta blocker.     

Double-blind Evaluation of Verapamil,Propranolol, and Isosorbide Dinitrate against a Placebo in the Treatment of Angina Pectoris

In the treatment of angina pectoris a double-blind evaluation of verapamil (Cordilox) at two dose levels—namely, 80 mg thrice daily and 120 mg thrice daily—propranolol (Inderal) 100 mg thrice daily, and isosorbide dinitrate (Vascardin) 20 mg thrice daily has been made against a placebo. The assessment was based on relief from daily attacks of angina on effort and the response to a whole-body exercise test. We can find no statistically significant difference between the effects of verapamil (120 mg three times a day) and propranolol (100 mg three times a day) in the treatment of angina of effort. Both of these preparations are more effective than a placebo both in the reduction of daily attacks (P < 0·01) and in the prolongation of exercise test (P < 0·05). Isosorbide dinitrate (20 mg three times a day) appears to be no more effective than a placebo in the treatment of angina on effort, but 14 out of 32 patients experienced headache of such severity that even when the dose was reduced to 10 mg thrice daily this drug therapy had to be withdrawn. Both propranolol (100 mg three times a day) and verapamil (120 mg three times a day) had a significant lowering effect on the diastolic blood pressure as measured with the patient standing (P < 0·01).     

New non-steroidal aromatase inhibitors: focus on R76713

R76713 is a novel triazole derivative which selectively blocks the cytochrome P450-dependent aromatase. In human placental microsomes, in FSH-stimulated rat and human granulosa cells and in human adipose stromal cells, 50% inhibition of estradiol biosynthesis was obtained at drug concentrations of 2-10 nM. In PMSG-injected female rats, R76713 lowered plasma estradiol levels by 50 and 90% 2 h after single oral doses of 0.005 and 0.05 mg/kg respectively. After 1 mg/kg, estradiol levels were suppressed by 90% for 16 h. In male cynomolgus monkeys, R76713 dose-dependently (0.03-10 micrograms/kg) inhibited peripheral aromatization with an ED50 of 0.13 microgram/kg without altering metabolic clearance rates and conversion ratios. In vitro R76713 had no effect on other P450-dependent steroidogenic enzymes up to 1000 nM at least. In rats, LHRH-, ACTH- and sodium-deprived diet stimulated plasma testosterone, corticosterone and aldosterone levels were not modified 2 h after single oral administrations of R76713 (up to 20 mg/kg). Furthermore, R76713 did not show any in vitro or in vivo estrogenic or antiestrogenic property. R76713 also induced regression of DMBA-induced mammary tumors after daily oral administration of 1 mg/kg b.i.d. In male volunteers (n = 4), a single oral dose of 5 and 10 mg lowered median plasma estradiol levels from 70 pM to the detection limit of the assay (40 pM) 4, 8 and 24 h after intake whereas no changes were detected after placebo administration. In premenopausal women (n = 15), receiving a single oral dose of 20 mg, median plasma estradiol levels decreased from 389 pM (before) to 168, 133 and 147 pM, 4, 8 and 24 h after intake whereas they remained above 420 pM after placebo (n = 7).     

Metformin Decreases Food Consumption and Induces Weight Loss in Subjects with Obesity with Type II Non-Insulin-Dependent Diabetes

Metformin often promotes weight loss in patients with obesity with non-insulin-dependent diabetes mellitus (NIDDM). The mechanism may be attributed to decreased food intake. This study has tested the effect of metformin on satiety and its efficacy in inducing weight loss. Twelve diet-treated NIDDM women with obesity were randomly given two dose levels (850 mg or 1700 mg) of metformin or placebo at 0800 for three consecutive days followed by a meal test on the third day on three occasions using a 3times3 Latin square design. The number of sandwich canapes eaten in three consecutive 10-minute periods beginning at 1400 hours was used to quantitate food intake, and the level of subjective hunger was rated just before the sandwich meal with a linear analogue hunger rating scale at 1400 after a 6-hour fast. The prior administration of metformin produced a reduction in calorie intake after each of the two doses of metformin treatment. The 1700-mg metformin dose had the most marked appetite suppressant action. Similarly, hunger ratings were significantly lowered after metformin, and the effect was most pronounced after the administration of 1700 mg of metformin. To assess the efficacy of metformin in reducing bodyweight, 48 diet-treated NIDDM women with obesity who had failed to lose weight by diet therapy were first placed on a 1200-kcal ADA (American Diabetes Association) diet before being randomized to receive either metformin (850 mg) or placebo twice daily in a double-blind fashion for 24 weeks. A 4-week single-blind placebo lead-in period preceded and a 6-week single-blind placebo period followed the 24-week double-blind treatment period. Subjects treated with metformin continued to lose weight throughout 24 weeks of treatment; their mean maximum weight loss was 8 kg greater than that of the placebo group, with corresponding lower HbA1C and fasting blood glucose levels at the end of the active treatment period. These results indicate that metformin decreases calorie intake in a dose-dependent manner and leads to a reduction in bodyweight in NIDDM patients with obesity.     

Kinetics and effect of percutaneous administration of dihydrotestosterone in children

BACKGROUND: Percutaneous administration of dihydrotestosterone (DHT) has been successful in promoting phallic growth in infants and children with 5 alpha-reductase deficiency raised as males. We investigated whether percutaneous administration of DHT is similarly effective in patients with micropenis due to alternative diagnoses. METHODS: Six patients (age range 1.9-8.3 years) with micropenis of variable etiology were studied prospectively. 2.5% DHT gel was applied to the phallus once daily at a dose of 0.15-0.33 mg/kg body weight. Serum DHT concentrations were measured at 0, 2, 4, 8, 12 and 24 h following application of DHT gel. RESULTS: Peak DHT concentrations were attained within 2-8 h after application of the gel and subsequently remained within the normal adult range in all but 1 patient, who had received the lowest dose of 0.15 mg/kg. An increase in phallic growth, ranging from 0.5-2.0 cm, was achieved after 3-4 months of treatment in all patients whose DHT concentrations were maintained within adult range. CONCLUSION: Percutaneous administration of DHT in a dose of 0.2-0.3 mg/kg once daily for a period of 3-4 months may be useful in the management of patients with testosterone biosynthetic defects, who have sufficient masculinization to warrant male sex assignment, or in patients with micropenis prior to reconstructive surgery.     

Carbamazepine produces nonspecific effects on cocaine self-administration in rats.

Anecdotal evidence in humans suggest that carbamazepine suppresses cocaine-induced rush and craving. Such claims are unsupported in controlled trials using a placebo control. In the present study, rats were trained to self-administer i.v. cocaine in daily 2-hr sessions in which every tenth lever press delivered 1 mg/kg cocaine. After responding was stable, they were injected before each session with the vehicle for 2 days followed by carbamazepine for 2 days. At a 7 mg/kg dose, carbamazepine was without effect, whereas 15 mg/kg suppressed responding for cocaine only on the second (day 4) day of carbamazepine treatment. With 4 consecutive days of treatment, carbamazepine (15 mg/kg) reduced cocaine-maintained responding slightly, but significantly. In another group of animals trained to lever-press for food reinforcement, carbamazepine (15 mg/kg) also significantly decreased the rate of responding, suggesting that the suppression of responding was not specific to cocaine-reinforced behavior.     

Modulation of hematologic and immunologic effects of high dose chemotherapy by interleukin-2 in a murine tumor model.

To determine if intensive chemotherapy consisting of cyclophosphamide (C), etoposide (E), and cisplatin (P) (CEP) may be usefully combined with recombinant human interleukin-2 (rhIL-2), we examined a murine tumor model designed to approximate a common clinical situation: macroscopic, drug-resistant cancer. Using C57BL/6 mice with extensive tumor burden 10 days after intravenous B16 melanoma cell injection, we observed (1) C, E, and P synergize to enhance survival but do not cure mice at the highest tolerable dose (C = 200 mg/kg, E = 60 mg/kg, and P = 3 mg/kg); (2) rhIL-2 at 3 x 10(5) U (subcutaneously) daily for 4 days administered 10-18 days after B16 injection significantly improves survival; (3) CEP plus rhIL-2 is more effective than CEP alone only when rhIL-2 is administered before CEP; (4) CEP suppresses IL-2-induced lymphokine-activated killer cell activity in the spleen; and (5) rhIL-2 protects mice incompletely from the immunologic and hematologic suppression of CEP. Our results suggest that intensive chemotherapy combined with rhIL-2 may be beneficial. The success of any such combination may be schedule dependent.     

Intradermal administration of lipopolysaccharide in treatment of human cancer

 Lipopolysaccharide (LPS) has been recognized as a potent antitumor agent in animal tumor models; however, its use in human cancer therapy has been limited to only one trial, in which LPS from Salmonella was given intravenously. It was not very successful because of poor tumor response and was also toxic. We originally developed LPS prepared from Pantoea agglomerans (LPSp), and this was a well-purified, small-molecular-mass (5 kDa) agent. We chose intradermal rather than intravenous administration in the hope that the former would release LPS slowly into the bloodstream, and thus be less toxic while preserving antitumor activity. In our animal tumor models, intradermal administration was indeed less toxic and more beneficial for tumor regression than intravenous administration. We made a pilot study with intradermal administration of LPSp on the treatment of ten advanced cancer patients. Five of them had evaluable tumor, which had failed earlier to respond to conventional chemotherapy. Cyclophosphamide was also administered in this trial, in anticipation of its synergistic effect with LPSp. In this study LPSp was injected intradermally into each patient twice a week, starting with an initial dose of 0.4 ng/kg, and raising it to 600 or 1800 ng/kg. A 400-mg/m² dose of cyclophosphamide was given intravenously every 2 weeks. After completion of the dose escalation, the treatment was continued for at least 4 months, and it was found that 1800 ng/kg LPSp was well tolerated. A significant level of cytokines was observed in the sera for at least 8 h. These results indicate higher tolerable doses and remarkably more continuous induction of the cytokines than were reported in a previous study by others using intravenous administration. Three of the five evaluable tumors showed a significant response to our combined therapy. Intradermally administered, LPS was less toxic and elicited a tumor response in combination with cyclophosphamide; it can thus can be applied to cancer treatment even in humans. Received: 3 August 1995 / Accepted: 2 April 1996     

Comparison of intravenous infusions of iloprost and oral nifedipine in treatment of Raynaud's phenomenon in patients with systemic sclerosis: a double blind randomised study.

OBJECTIVE--To compare the long term effects of short term intravenous infusions of iloprost with those of oral nifedipine in patients with Raynaud''s phenomenon associated with systemic sclerosis. DESIGN--Double blind, placebo controlled, randomised group comparison. SETTING--Dermatology outpatient clinic. PATIENTS--Twenty three patients with Raynaud''s phenomenon associated with well documented systemic sclerosis (American Rheumatism Association criteria) and with typical abnormalities in fingernail folds on capillaroscopy. INTERVENTIONS--Twelve patients were randomised to receive intravenous infusions of iloprost starting at 0.5 ng/kg/min and increased by 0.5 ng/kg/min every 15 minutes to a maximum of 2.0 ng/kg/min for eight hours on three consecutive days with a further single infusion at week 8. Placebo capsules were given concurrently. Eleven patients were randomised to receive nifedipine, starting at 30 mg daily and increased to 60 mg daily after four weeks for another 12 weeks. Infusions of placebo were given in the same manner as the infusions of iloprost. One patient from each group withdrew because of social reasons and three patients receiving nifedipine withdrew because of side effects. END POINT--Reduction in number, duration, and severity of attacks of Raynaud''s phenomenon, reduction in number of digital lesions, increase in digital blood flow. MEASUREMENTS AND MAIN RESULTS--Measurements were taken at 0, 4, 8, 12, and 16 weeks. Both regimens produced a reduction in the number, duration, and severity of attacks of Raynaud''s phenomenon. The mean (SE) number of digital lesions was reduced with iloprost (from 3.5 (1.6) to 0.6 (0.3] and with nifedipine (from 4.3 (0.8) to 1.4 (0.5] after 16 weeks. Hand temperature and digital and microcirculatory blood flow were increased with iloprost but not with nifedipine. CONCLUSION--Both iloprost and nifedipine are beneficial in the treatment of Raynaud''s phenomenon. With nifedipine, however, side effects are common. Short term infusions of iloprost provide longlasting relief of symptoms, and side effects occur only during the infusions and are dose dependent.     

Chronic cytoprotection: pentadecapeptide BPC 157, ranitidine and propranolol prevent, attenuate and reverse the gastric lesions appearance in chronic alcohol drinking rats.

Unlike severe gastric damage acutely induced by ethanol administration in rat, the ulcerogenic effect of chronic alcohol administration (3.03 g/kg b.w. or 7.28 g/kg b.w.) given in drinking water, producing liver lesions and portal hypertension, is far less investigated. Therefore, focus was on the antiulcer effect of the gastric pentadecapeptide BPC 157, GEPPPGKPADDAGLV, M.W. 1419, known to have a beneficial effect in variety of gastrointestinal lesions models (10 microg or 10 ng/kg b.w. i.p. or i.g.), ranitidine (10 mg/kg b.w. i.g.) and propranol (10 mg/kg b.w. i.g.) or saline (5 ml/kg b.w. i.p./i.g.; control). They were given once daily (1) throughout 10 days preceding alcohol consumption, (2) since beginning of alcohol drinking till the end of the study, (3) throughout the last month of alcohol consumption, 2 months after alcohol drinking had been initiated. Gastric lesions were assessed, at the end of 3 months drinking [(1), (2)] or with respect to therapeutic effect of medication before medication or at the end of therapy. Pentadecapeptide BPC 157, ranitidine and propranolol may prevent gastric lesion development if given prophylactically, before alcohol drinking. Likewise, they attenuate the lesion appearance given once daily throughout the drinking period. Importantly, when given therapeutically, they may antagonize otherwise pertinent lesion presence in stomach mucosa of the drinking rats. Thus, these results demonstrate that pentadecapeptide BPC 157, ranitidine and propranol may prevent, attenuate or reverse the gastric lesions appearance in chronically alcohol drinking rats, and may be used for further therapy, while the other studies showed that their effect (except to ranitidine) is parallel with their beneficial effect on liver lesion and portal hypertension.     

Cochleates: New Lipid-Based Drug Delivery System

Abstract

Cochleates are a lipid-based tailored drug delivery system formed by the precipitation of a negatively charged lipid and a cation, for example phosphatidylserine and calcium. Hydrophobic, amphiphilic, negatively or positively charged moieties are suitable candidates to be delivered via cochleates. Various procedures have been developed allowing the control of cochleate particle size, including the trapping and hydrogel methods, which use either a direct addition or a slow diffusion of calcium into the negatively charged liposome/drug suspension. The efficacy of cochleates to encapsulate and deliver drugs was evaluated using amphotericin B as a model. Amphotericin B cochleates (CAMB) were compared to Fungizone® and AmBisome®, two commercially available AmB products. Parenterally, CAMB was given IP to ICR mice infected with Candida albicans. 100% survival was observed with low doses of CAMB (0.5 mg/kg/day, 10 days) compared to 60% for Fungizone, at the same dose. Tissue burden studies were conducted in parallel. Mice were treated daily from day 1 to day 7 post challenge and tissue burden assessed at day 8. In the kidneys, all three formulations were comparable in reducing colony counts. In the spleen, CAMB at 10 mg/kg/day was comparable to AmBisome given IV at the same dose. At 1 mg/kg/day, CAMB was more potent than Fungizone and AmBisome. Oral administration of CAMB in C57BL/6 mice, at 10 mg/kg results in high levels of AmB in target tissues. Multiple daily doses (10) showed accumulation of AmB in key tissues (liver, lungs, spleen, and kidneys) and AmB tissue concentrations are raised to therapeutic levels. Orally administered CAMB are highly effective against fungal infections in mice at very low doses. Balb/C mice were infected with Candida albicans and were given oral CAMB as a daily dose for 15 days. Comparison was done to AmBisome given orally at 10 mg/kg and Fungizone IP. 100% survival was obtained with CAMB at doses as low as 0.5 mg/kg/day (15 days). CAMB eradicate Candida from lungs when given at 2.5 mg/kg/day and was comparable to Fungizone given IP at almost the same dose (2 mg/kg/day). The comparison between CAMB and AmBisome shows that oral CAMB is 10 times more effective than oral AmBisome in reducing colony counts in both kidneys and lungs. Orally administered CAMB were non-toxic even at the highest dose of 50 mg/kg/day (14 days). This was demontrated by 100% survival of the animals and normal histopathology analysis. No lesions in the kidneys, GI tract, lungs, liver and spleen was observed despite the substantial amount of AmB in these organs. AmB cochleate promise to be a safe, broad spectrum, effective and orally available, antifungal formulation.     

The use of 2-substituted 5-nitroimidazoles in the treatment of chronic murine Trypanosoma brucei infections with central nervous system involvement

Chronic infections of Trypanosoma brucei GVR 35/2 in mice, normally relapse after conventional chemotherapy because infective trypanosomes in the brain escape the action of the drug and are able to multiply and eventually re-establish a parasitaemia. However, if treatment consists of a single dose of 1 x 20 mg/kg suramin followed 3 or 4 days later by a 2-substituted 5-nitroimidazole, given intraperitoneally, either as a single dose or as a course of daily injections, relapses rarely occur and the majority of the mice are permanently cured. The minimum effective levels for the three 5-nitroimidazole compounds (Merck Sharp and Dohme, Rahway, NJ, USA) were two doses of 10 mg/kg of L611,744; four doses of 10 mg/kg of MK 436; and three doses of 10 mg/kg of L634,549. Generally it was more effective to divide a given total dose into two or more daily doses, rather than to give the 4-nitroimidazole as a single treatment. The effective dose levels are low enough to be of practical significance and, if the 5-nitroimidazoles were ever licensed for humans, might well prove to be an alternative to melarsoprol treatment for the elimination of trypanosomes from the central nervous system.