Effects Of Prolonged Administration Research Articles

Reversible infertility in male dog following prolonged treatment of Malassezia dermatitis with ketoconazole

BackgroundKetoconazole, an antifungal agent, adversely affects spermatogenesis in rodents, but knowledge on adverse effects of prolonged administration of ketoconazole on the fertility of male dogs is lacking. A case of reversible infertility with azoospermia in a male American Staffordshire terrier treated with ketoconazole is reported here.Case presentationA seven-year old male American Staffordshire terrier treated for 3 months with ketoconazole for a persistent Malassezia dermatitis displayed reduced libido and mating of 3 bitches had been unsuccessful. The dog was presented at the clinic 40 days after the treatment had been stopped. At first presentation, low libido and complete absence of sperm in the ejaculate (azoospermia) associated with low testosterone level were found. Repeated examinations revealed that sperm quality and testosterone level had restored 100 days after ketoconazole had been withdrawn. Thereafter, the dog successfully mated 2 bitches.ConclusionThe treatment with ketoconazole for 3 months may have led to reversible infertility characterized by azoospermia. Therefore, owners of stud dogs should be informed of this risk prior to initiating such treatment and in case of infertility, previous treatment with ketoconazole should be considered as a possible cause.

Вплив тривалого введення глутамату натрію на ураження слизової оболонки шлунка, викликані методом іммобілізованого водоімерсійного стресу у щурів

Вплив тривалого введення глутамату натрію на ураження слизової оболонки шлунка, викликані методом іммобілізованого водоімерсійного стресу у щурів

Gluten and casein supplementation does not increase symptoms in children with autism spectrum disorder.

A gluten- and casein-free diet is often given to children with autism spectrum disorder (ASD). We aimed to determine the effect of gluten and casein supplementation on maladaptive behaviour, gastrointestinal symptom severity and intestinal fatty acids binding protein (I-FABP) excretion in children with ASD. A randomised, controlled, double-blind trial was performed on 74 children with ASD with severe maladaptive behaviour and increased urinary I-FABP. Subjects were randomised to receive gluten-casein or a placebo for seven days. We evaluated maladaptive behaviour before and after supplementation, using I-FABP excretion, the approach withdrawal problem composite subtest of the Pervasive Developmental Disorder Behavior Inventory and the Gastrointestinal Symptom Severity Index. The mean approach withdrawal problem composite score was significantly higher before supplementation than after, both in the placebo and in the gluten-casein group. However, the mean difference was not significant and may have been caused by additional therapy. There was no significant difference in gastrointestinal symptoms and urinary I-FABP excretion. Administrating gluten-casein to children with ASD for one week did not increase maladaptive behaviour, gastrointestinal symptom severity or urinary I-FABP excretion. The effect of prolonged administration or other mechanisms of enterocyte damage in ASD should be explored.

Integrative Gynecology and Women's Healthcare.

Complementary treatment approaches have been increasingly demanded by women during the last several decades to relieve their gynecological disorders, reduce side effects of conventional hormonal or cancer treatment, and enhance health-related quality of life. As many women do not disclose their complementary therapies to their gynecologists or oncologists, treatment plans are often not coordinated. Thus, the risk of adverse events and interactions of complementary with conventional therapies may be increased. Sharing of information between providers of conventional and complementary treatments is important to optimize health outcomes and safety. Integrative gynecology that combines conventional treatment with evidence-based complementary therapies and mind/body medicine has become a growing field of healthcare that strives to serve this demand. In integrative gynecology, conventional and complementary approaches are joined in a way that aims to optimize outcomes and prevent adverse events. The papers selected for this special issue represent a good panel for addressing this challenge. Additionally, the selected topics and papers represent the rich and many-facet knowledge, which we have the pleasure of sharing with the readers. Because of limited space, we can allow only a part of gynecological studies with high quality to be published in this special issue. More research and publication space are definitely needed for integrative gynecology in the future. The special issue contains ten papers. Two of them are related to bone loss. One paper introduces a screening system to identify Chinese herbs or formulae which will increase either HER2 or ERα protein expression of MCF-7 human breast cancer cell. Three papers are related to breast cancer risk of commonly used Chinese herbs; one of them considers the breast cancer risk of Chinese herbal remedies among hormone users, while another covers the subsequent endometrial cancer problems when tamoxifen users consume Ginseng. One paper focuses on the ovarian cancer risk of the herb-drug interaction between fermented wheat germ extract and cisplatin or docetaxel. One paper provides precious observational result of the effects of passive hydrotherapy among women in their ≥34th week of gestation. One paper tries to disclose the possible mechanism of Chinese herb for treating endometriosis. Finally, one paper introduces a practical method for studying the effectiveness and safety of traditional Chinese remedies for women with dysmenorrhea. In a paper titled “Bian Zheng Lun Zhi as a Complementary and Alternative Treatment for Menstrual Cramps in Women with Dysmenorrhea: A Prospective Clinical Observation,” P.-Y. Lin et al. explore questions related to the strengths, weaknesses, challenges, and accomplishments of TCM treatments based on Bian Zheng Lun Zhi theory, along with the results of active surveillance proactively in women with primary dysmenorrhea or endometriosis. The following three articles focus on the observational evaluation of integrative and/or complementary therapies in human populations. In a paper titled “Concurrent Use in Taiwan of Chinese Herbal Medicine Therapies among Hormone Users Aged 55 Years to 79 Years and Its Association with Breast Cancer Risk: A Population-Based Study,” Y.-T. Tsai et al. evaluate the breast cancer risk of consuming Chinese herbs, especially the extent to which the hormone users used Chinese herbs concurrently. In another paper titled “The Prescription Pattern of Chinese Herbal Products Containing Ginseng among Tamoxifen-Treated Female Breast Cancer Survivors in Taiwan: A Population-Based Study,” W.-L. Hsu et al. investigate the inhibitory relationship between Ginseng consumption and subsequent endometrial cancer among tamoxifen users. In a third article titled “Effects of Passive Hydrotherapy WATSU (WaterShiatsu) in the Third Trimester of Pregnancy: Results of a Controlled Pilot Study,” A. M. Schitter et al. carry out a controlled pilot study to assess the potential therapeutic effects of passive hydrotherapy on self-reported stress, pregnancy-related pain, mood and quality of life, amount of amniotic fluid, blood flow characteristics, spontaneous course of breech presentations, and prospects of external cephalic versions in women in their ≥34th week of gestation. In a paper titled “Preventive Effects of Collagen Peptide from Deer Sinew on Bone Loss in Ovariectomized Rats,” H. Zhang et al. test the preventive effect of deer sinew on ovariectomy-induced bone loss. In a paper titled “Prolonged Diuretic Activity and Calcium-Sparing Effect of Tropaeolum majus: Evidence in the Prevention of Osteoporosis,” L. N. Barboza et al. are considering the diuretic effects of prolonged administration of Tropaeolum majus in ovariectomized rats and the interrelationship between calcium excretion and bone turnover. In a paper titled “Propolis is an Efficient Fungicide and Inhibitor of Biofilm Production by Vaginal Candida albicans,” I. R. G. Capoci et al. test the minimum inhibitory concentration and the minimum fungicidal concentration and assess the cell viability, protein, and carbohydrate characteristics of the biofilm of clinical isolates from vulvovaginal candidiasis to Propolis.

Prolonged Diuretic Activity and Calcium-Sparing Effect of Tropaeolum majus: Evidence in the Prevention of Osteoporosis.

Although several studies indicate high effectiveness in the use of the hydroethanolic extract from Tropaeolum majus (HETM) as a diuretic, the impact of its prolonged use in the presence of low estrogen levels remains unclear. Thus, the aim of this study was to investigate the diuretic effects of prolonged administration of HETM in ovariectomized rats and their interrelationship between calcium excretion and bone turnover. Forty-two female Wistar rats were ovariectomized (OVX) and treated orally with different doses of HETM (3, 30, and 300 mg/kg) for 4 weeks. On the first day of treatment and at weekly intervals for four weeks the diuretic activity was evaluated. Electrolyte concentrations and creatinine levels were estimated from urine sample of each rat. The serum lipids, urea, creatinine, and osteocalcin were also measured at the end of the experiment. The data revealed that the HETM was able to sustain its diuretic effect after prolonged treatment. Moreover, its use has not affected the urinary calcium or potassium excretion, reduces lipid levels, and maintains osteocalcin levels similarly to untreated rats. These findings support the potential of HETM as a candidate to be used in clinical conditions in which the renal loss of calcium is not desired.

Effect Of Acute And Prolonged Administration Of Ethyl Acetate Fraction Of Psidium Guajava Aqueous Leaf Extract On Tissue Histology And Some Haematological Values In Chickens.

The effect of oral administration of ethyl acetate fraction of Psidium guajava aqueous leaf extract on tissue histology and red blood cell values was investigated in chickens. The study involved use of male chicks of ISA brown cockerel breed that were orally exposed to the extract acutely to determine the median lethal dose and daily sub-lethal dose were administered for 28 days and effects on body weight, red blood cell parameters and tissue histology was evaluated. In acute toxicity study, single oral arithmetic doses of the extract were given to test groups with the control group given normal saline. The oral LD50 was calculated to be 1800 mg/kg bd. wt. For the effect of prolonged administration of the fraction, daily administration of graded doses of the extract were given to test groups for 28 days and a control group was given normal saline. There was significant (P<0.05) increase in weight gain compared to control. No significant (P<0.05) changes in red blood cell values between extract treated groups and that of the control. Generalised mononuclear cellular infiltrations observed in all organs were indicative of cellular degenerative changes and could be attributed to possible stimulation of the immune system by the extract. The high LD50 of the extract was therefore, an indication of low toxicity however, lesions observed suggested that the fraction should be used with caution.

FTIR Assessment of the Effect of Ginkgo biloba Leave Extract (EGb 761) on Mammalian Retina

Ginkgo biloba extract has been therapeutically used for several decades to increase peripheral and cerebral blood flow as well as for the treatment of dementia. The extract contains multiple compounds such as flavonoids and terpenoids that are thought to contribute to its neuroprotective and vasotropic effects. In this study, we investigated the effect of prolonged administration of EGb 761, up to 10weeks, on mammalian retina using Fourier transform infrared spectroscopy (FTIR). Two main groups were involved in this study: the normal group (n=10); and EGb-administrated group (n=50) that received-orally-a dose of 40mg/kg/day EGb 761. The results demonstrated that EGb administration was associated with different beneficial effects on the retinal constituents especially the underlying amide I protein secondary structure components as well as the NH-OH region. It concluded that the optimum daily administration period of EGb (40mg/kg) for ophthalmic applications that targeting the retina ranges from 5 to 8weeks.

Pharmacological modulation with prolonged administration of moderate doses of steroid in a murine model of septic acute lung injury after burn insult

Many patients who experience surgical stress including burn injury become susceptible to severe sepsis and septic organ dysfunction including acute lung injury (ALI), which remains the primary contributor to morbidity and mortality in burn patients. Proinflammatory cytokines including several chemokines are implicated in this process. The pharmacological modulation with steroid inhibiting the process of cytokine synthesis may serve as effective therapy for the prevention of tissue injury and the resultant organ dysfunction including respiratory failure. We developed a murine model of septic ALI after burn insult and examined the effects of prolonged administration of moderate doses of steroid.

Metabolic Effects of Prolonged Melatonin Administration and Short-Term Fasting in Laboratory Rats

The aim of this work was to evaluate the effect of prolonged administration of the pineal hormone melatonin and short-term fasting on metabolic variables in male and female Wistar:Han rats. Melatonin (MEL, 4 μg/ml of tap water) was administered daily since the 5th week of age. The control group drank tap water. Rats were fed a standard type of diet ad libitum and were kept in the light regimen L:D - 12:12 h. The experiment was terminated after 11 (variant B) or 12 (variant A) weeks of MEL administration. The animals were sacrificed by quick decapitation following overnight fasting (variant A) or 48-h fasting (variant B). Selected organs and tissues were removed and weighed and selected metabolic variables in the serum and tissues were determined. MEL decreased body mass independent of food and water intake in both sexes. In males (variant A) MEL increased the weight of the heart muscle, spleen and adrenals; it decreased the absolute weight of epididymal fat and increased serum corticosterone and phospholipids concentration in comparison with controls. In females, serum glucose decrease and liver triacylglycerols increase were found. After 48-h fasting (variant B) liver, spleen and adrenal weight increase in MELdrinking females was found. In males MEL increased the thymus weight and decreased the epididymal fat weight. In both sexes MEL increased serum corticosterone and liver glycogen concentration; MEL increased serum glucose in males and serum cholesterol concentration in females. Changes in the evaluated variables were also related to fasting duration prior to decapitation. A 48-h fasting at the end of the prolonged MEL intake (variant B vs. A) decreased the absolute liver weight in both sexes and the epididymal/periovarial fat weight, and increased thymus weight in males. In females it decreased the absolute heart muscle weight and increased the spleen weight. In males, 48-h fasting increased serum corticosterone and phospholipids concentration; it decreased the liver triacylglycerols content in females and the liver cholesterol content in males and females. In both sexes 48-h fasting increased glucose concentration in the serum and glycogen concentration in the liver and heart muscle as well as triacylglycerols and cholesterol concentration in the serum, phospholipids concentration in the liver and bone marrow and decreased malondialdehyde concentration in the liver. Forty-eight hour fasting after prolonged MEL administration resulted in a wider range of carbohydrate and lipid metabolism alterations of young rats of both sexes.

A randomized placebo-controlled trial of prolonged prednisolone administration to patients with HELLP syndrome remote from term: Maternal and neonatal complications

ADMINISTRATION TO PATIENTS WITH HELLP SYNDROME REMOTE FROM TERM: MATERNAL AND NEONATAL COMPLICATIONS P.J. VAN RUNNARD HEIMEL, A. J. M. HUISJES, A. FRANX, C. KOOPMAN, M. L. BOTS, H. W. BRUINSE, University Medical Center Utrecht, Obstetrics and Gynaecology, Utrecht, The Netherlands, Netherlands, Gelre Ziekenhuizen Apeldoorn, Obstetrics and Gynaecology, Apeldoorn, The Netherlands, Netherlands, Erasmus University Medical Centre Rotterdam, Obstetrics and Gynaecology, Rotterdam, The Netherlands, Netherlands, University Medical Center Utrecht, Neonatology, Utrecht, The Netherlands, Netherlands, University Medical Center Utrecht, Julius Center for Health Science and Primary Care, Utrecht, The Netherlands, Netherlands OBJECTIVE: Several reports have shown a beneficial effect of corticosteroids on HELLP syndrome. However, there is a lack of RCTs of corticosteroids in HELLP syndrome in the antepartum period for more than 48 hours. Prednisolone is a glucocorticoid with limited transplacental passage. This randomized, double-blind, placebo-controlled study was undertaken to evaluate the effect of prolonged administration of high-dose prednisolone on maternal, perinatal and neonatal outcome in patients suffering early onset HELLP syndrome. STUDY DESIGN: 31 pregnant women were included suffering HELLP syndrome with an onset prior to 30 weeks gestation. Prior to inclusion all women received 2 intramuscular doses of betamethasone 11.4 mg 24 hours apart to promote fetal lung maturation. Patients received either prednisolone (n = 15) or placebo (n = 16) 50 mg intravenously twice a day. Maternal outcome measures were presence of liver hematoma and rupture, pulmonary oedema, renal failure and placental abruption. Perinatal outcome measures were gestational age at delivery, occurrence of perinatal death, birth weight and Apgar score. Neonatal outcome measures were occurrence of neonatal complications during admission at the neonatal intensive care unit (NICU) and the duration of admission at the NICU. Long-term neonatal follow-up was also performed at 6, 15 and 24 months. RESULTS: In the placebo group two liver hematomas and one liver rupture occurred, the latter resulting in maternal death. In both treatment groups a placental abruption occurred. Four perinatal deaths occurred in the placebo SMFM Abstracts S41

A comparison of Doppler waveform parameters versus flow-mediated vascular dilation of the brachial artery in preeclamptic and normotensive women

VASCULAR DILATION OF THE BRACHIAL ARTERY IN PREECLAMPTIC AND NORMOTENSIVE WOMEN INNA LANDRES, MARIA SMALL, ADESH SIRJUSINGH, SAMUEL RAMSAWAK, KEITH WILLIAMS, Yale University, Obstetrics & Gynecology, New Haven, Connecticut, Yale University, OB/GYN, New Haven, Connecticut, University of the West Indies, Mount Hope, Port of Spain, Trinidad and Tobago OBJECTIVE: Flow mediated dilation of the Brachial artery is impaired with endothelial dysfunction. We previously identified that brachial artery waveforms were changed in preeclamptic women. We therefore sought to compare Doppler waveform analysis with Flow Mediated Vascular Dilation (FMVD) measurements in Preeclamptic and Normotenstive women. STUDY DESIGN: We conducted a nestled case-control of 12 preeclamptic vs 20 normotensive women, matched for gestational age, maternal age and ethnicity. Research was conducted at three hospitals and two geographic settings; (1) YaleNew Haven Hospital in New Haven CT, (2) Mount Hope Maternity and (3) Port of Spain General Hospital in, Trinidad. Brachial artery doppler waveform measurements were done at baseline and 90s post cuff-release. From the doppler waveforms we assessed % change in Peak Systolic Velocity, systolic acceleration and acceleration time and compared them with % change in (FMVD). Statistical analysis using student t tests, chi squared analysis and correlation coefficient was done as necessary. RESULTS: The % change PSV at 90s in normotensives vs preeclamptics was (13.5% G 22.7 vs 20.5% G 27.8) (P = .432). The % change in mean FMVD in the normotensives vs the preeclamptics was (4.3% G 4.7 vs -0.52% G 2.2) (P = .031). Correlation between the % change in the doppler waveform parameters and % change in mean FMVD identified only % change in peak systolic velocity (P = .040) as significant. CONCLUSION: FMVD remains the gold standard for assessment of endothelial dysfunction .A correlation was observed between the doppler measured % change in Peak Systolic Velocity and flow mediated vascular dilation. Although % change in the other doppler waveforms parameters did not correlate with flow mediated dilation they were done at 90 s and may need to be more appropriately measured earlier, corresponding to the peak of flow mediated vascular dilation. 111 A RANDOMIZED PLACEBO-CONTROLLED TRIAL OF PROLONGED PREDNISOLONE ADMINISTRATION TO PATIENTS WITH HELLP SYNDROME REMOTE FROM TERM: MATERNAL AND NEONATAL COMPLICATIONS P.J. VAN RUNNARD HEIMEL, A. J. M. HUISJES, A. FRANX, C. KOOPMAN, M. L. BOTS, H. W. BRUINSE, University Medical Center Utrecht, Obstetrics and Gynaecology, Utrecht, The Netherlands, Netherlands, Gelre Ziekenhuizen Apeldoorn, Obstetrics and Gynaecology, Apeldoorn, The Netherlands, Netherlands, Erasmus University Medical Centre Rotterdam, Obstetrics and Gynaecology, Rotterdam, The Netherlands, Netherlands, University Medical Center Utrecht, Neonatology, Utrecht, The Netherlands, Netherlands, University Medical Center Utrecht, Julius Center for Health Science and Primary Care, Utrecht, The Netherlands, Netherlands OBJECTIVE: Several reports have shown a beneficial effect of corticosteroids on HELLP syndrome. However, there is a lack of RCTs of corticosteroids in HELLP syndrome in the antepartum period for more than 48 hours. Prednisolone is a glucocorticoid with limited transplacental passage. This randomized, double-blind, placebo-controlled study was undertaken to evaluate the effect of prolonged administration of high-dose prednisolone on maternal, perinatal and neonatal outcome in patients suffering early onset HELLP syndrome. STUDY DESIGN: 31 pregnant women were included suffering HELLP syndrome with an onset prior to 30 weeks gestation. Prior to inclusion all women received 2 intramuscular doses of betamethasone 11.4 mg 24 hours apart to promote fetal lung maturation. Patients received either prednisolone (n = 15) or placebo (n = 16) 50 mg intravenously twice a day. Maternal outcome measures were presence of liver hematoma and rupture, pulmonary oedema, renal failure and placental abruption. Perinatal outcome measures were gestational age at delivery, occurrence of perinatal death, birth weight and Apgar score. Neonatal outcome measures were occurrence of neonatal complications during admission at the neonatal intensive care unit (NICU) and the duration of admission at the NICU. Long-term neonatal follow-up was also performed at 6, 15 and 24 months. RESULTS: In the placebo group two liver hematomas and one liver rupture occurred, the latter resulting in maternal death. In both treatment groups a placental abruption occurred. Four perinatal deaths occurred in the placebo group versus three neonatal deaths in the prednisolone group. No further differences were found in perinatal and neonatal outcome measures. At longterm neonatal follow-up no differences could be demonstrated. CONCLUSION: Although administration of prednisolone to patients suffering early onset HELLP syndrome did not significantly improve maternal, perinatal and neonatal outcome measures, a trend towards a beneficial effect on the occurrence of maternal complications could be shown.

Inhibition by rat C-erbB-2/neu antisense oligonucleotide of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

The effect of prolonged administration of a rat C-erbB-2/neu (C-erbB-2) antisense oligonucleotide on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and on the labeling and apoptotic indices of gastric cancer was examined in Wistar rats After oral treatment with MNNG for 25 weeks, the rats received intraperitoneal injections of a C-erbB-2 antisense-liposome complex or a sense-liposome complex at a dose of 50 microgram oligonucleotide/kg body weight every other day until the end of the experiment in week 52. In week 52, the incidence of gastric cancers was significantly lover in rats treated with the C-erbB-2 antisense oligonucleotide than in rats treated with the sense oligonucleotide. Administration of the C-erbB-2 antisense oligonucleotide also significantly decreased the bromodeoxyuridine-labeling index and significantly increased the apoptotic index of gastric cancers. The mean cellular fluorescence of gastric antral cells in MNNG-treated rats was positively correlated with the dose of FITC-labeled C-erbB-2 antisense oligonucleotide. Our findings indicate that the antisense oligonucleotide inhibits gastric carcinogenesis through decreased cell proliferation and increased apoptosis induction and suggest that antisense strategies may provide new treatment for gastric cancer.

Effect of prolonged administration of the serotonin4 (5-HT4) receptor agonist cisapride on aldosterone secretion in healthy volunteers

In man, serotonin (5-HT) has been shown to stimulate aldosterone secretion through activation of 5-HT4 receptors, In particular, we have observed that oral administration of a single dose of the 5-HT4 receptor agonist cisapride (10 mg) induces a 5-fold increase in plasma aldosterone levels in healthy volunteers. Surprisingly, the usual disorders associated with hyperaldosteronism, i.e. hypertension and hypokalemia, have never been reported during chronic treatment with cisapride. In the present study, we have investigated the effect of prolonged oral administration of cisapride (10 mg, 3 times/day during 7 days) on aldosterone secretion in 12 healthy volunteers, in a simple blind fashion versus placebo. On day I of the treatment, cisapride induced a significant increase in plasma aldosterone levels (PAL) which returned to the values observed after placebo treatment within 10 hrs. On days 2 and 3, PAL were similar in cisapride- and placebo-treated subjects. Urinary aldosterone, kalemia and reninemia were not influenced by cisapride during the 7 days of the treatment. The present study shows that cisapride only exerts a transient stimulatory effect on aldosterone secretion in healthy volunteers. These data explain why long-term administration of 5-HT4 agonists does not affect blood pressure in man. They also indicate that prolonged stimulation of adrenal 5-HT4 receptors in vivo yields to a rapid desensitization phenomenon, as previously observed in vitro.

Enhancement by aminoguanidine of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats

The effects of prolonged administration of aminoguanidine on gastric carcinogenesis induced by N-methyl-N-nitro-N-nitrosoguanidine (MNNG), the ornithine decarboxylase activity of the gastric wall, and the labeling index of the gastric mucosa were investigated in inbred Wistar rats. The rats received 12.5 or 25.0 mg/kg body weight of aminoguanidine s.c. every other day after oral MNNG treatment for 25 weeks. Prolonged administration of aminoguanidine at 25.0 mg/kg body weight, but not at 12.5 mg/kg body weight, significantly increased the incidence of gastric cancers in experimental week 52. However, it did not influence the histologic types of gastric cancers. Aminoguanidine at 25.0 mg/kg body weight also significantly increased the ornithine decarboxylase activity of the antral portion of the gastric wall and the labeling index of the antral epithelial cells. These findings indicate that aminoguanidine enhances gastric carcinogenesis and suggest that its effect may be related to increased proliferation of antral epithelial cells.

Somatic and renal effects of growth hormone in rats with chronic renal failure.

Recombinant human growth hormone (rhGH) has been widely used to improve growth in children with chronic renal failure (CRF). However, there has been great concern that GH may aggravate renal disease and hasten the progression to end-stage renal failure. We therefore investigated the effect of prolonged administration of rhGH at various doses on somatic growth and renal function and structure in rats with CRF, divided into four groups based on rhGH dose (vehicle, 0.4, 2.0, and 10.0 IU/day). rhGH was administered subcutaneously daily for 8 weeks. The mean growth was significantly greater in rats treated with high-dose rhGH (10.0 IU) than those treated with low-dose rhGH (P = 0.0089) or vehicle (P = 0.0011). Body weight gain increased in parallel with body length (Creatinine clearance at the end of the experiment was significantly lower in rats on high or medium-dose rhGH than those on low-dose rhGH and controls (P < 0.05). The glomerular sclerosing index was greater in rats treated with higher doses of rhGH. There were significant differences between rats treated with high-dose rhGH and controls (P = 0.0144) and also between rats on medium-dose rhGH and controls (P = 0.0065). Although there was no significant difference, rats treated with higher doses of rhGH tended to excrete more protein. Renal insulin-like growth factor-I (IGF-I) content and circulating IGF-I and IGF-II levels did not significantly differ among groups. We conclude that: (1) GH improves somatic growth failure in rats with CRF, but prolonged administration of GH dose-dependently induces deterioration in renal function and structure and (2) this effect was induced neither via circulating IGF-I and IGF-II nor by local production of IGF-I, but seems to be direct.

Effects of prolonged administration of Musa paradisiaca L. (banana), an antiulcerogenic substance, in rats

In Brazil, unripe banana as well as the latex obtained from the top of the inflorescence are popularly used in the treatment of gastroduodenal ulcers, especially in the poorest regions. However, adverse effects in fasted subjects treated with unripe banana have been described. Thus, the antiulcerogenic effects of Brazilian banana samples and possible toxic effects of prolonged administration of unripe banana in rats were studied. The analysed samples of Musa paradisiaca showed antiulcer effects in all models employed. Moreover, following 5 weeks of oral treatment with unripe powdered banana, small alterations in some haematologic and biochemical parameters were observed. No significant differences were observed on evaluated physiological parameters. These results provide evidence that treatment with unripe banana is acceptable and could be recommended by official health authorities. © 1997 John Wiley & Sons, Ltd.

Fetal model of single ventricle physiology: Hemodynamic effects of oxygen, nitric oxide, carbon dioxide, and hypoxia in the early postnatal period

Background: In patients with single ventricle physiology, the distribution of flow to the systemic and pulmonary circulations, which are in parallel, largely depends on the relative resistances in the respective vascular beds. Although neonatal palliation in patients with single ventricle physiology has become more common, medical management during the perinatal and perioperative periods is often based primarily on personal and institutional experience and is complicated by the transition to postnatal life and the effects of cardiopulmonary bypass. The lack of an animal model that suitably mimics single ventricle physiology has impeded progress in this area. Objective: The purpose of the current study was to investigate the effects of respiratory manipulations on pulmonary hemodynamics in the early neonatal period in a reproducible model of single ventricle physiology created in utero. Methods: A 10 mm Damus-Kaye-Stansel aortopulmonary anastomosis was created in fetal sheep ( n = 14) at 140 ± 1.2 days' gestation, with pulmonary blood flow provided through a 5 mm aortopulmonary shunt after ligation of the main pulmonary artery distally. Two to 3 days after delivery at term, lambs ( n = 11) underwent an open sternotomy and 30 minutes of deep hypothermic circulatory arrest. Both before and after bypass, respiratory manipulations, including administration of nitric oxide (80 ppm), 100% oxygen, 10% oxygen, and 5% carbon dioxide, were performed and hemodynamic variables were measured. Results: Nitric oxide and oxygen caused a decrease in pulmonary vascular resistance and an increase in the pulmonary/systemic blood flow ratio, both before and after bypass. Hypoxia and carbon dioxide produced a significant rise in pulmonary vascular resistance and a significant drop in the ratio of pulmonary to systemic blood flow. Conclusions: Oxygen, nitric oxide, and carbon dioxide all appear to be useful means of manipulating pulmonary vascular resistance and pulmonary/systemic blood flow ratio in neonatal lambs with single ventricle physiology, but further investigation is necessary to understand their dose responsive effects and the effects of prolonged administration. (J T horac C ardiovasc S urg 1996;112:437-49)

Effects of a 7-day treatment with a novel, orally active, growth hormone (GH) secretagogue, MK-677, on 24-hour GH profiles, insulin-like growth factor I, and adrenocortical function in normal young men.

To assess the effects of prolonged administration of a novel analog of GH-releasing peptide (MK-677), nine healthy young men participated in a randomized, double blind, three-period cross-over comparison of orally administered placebo and 5- and 25-mg doses of MK-677. Each period involved bedtime administration of the drug for 7 consecutive days. At the end of each period, plasma levels of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) were measured at 0745 h, and 24-h profiles of plasma GH and cortisol were obtained at 15-min intervals together with the 24-h urinary excretion of free cortisol. Profiles of plasma free cortisol were calculated at hourly intervals. The amounts of GH secreted were similar in all three conditions, but GH pulse frequency was increased with both dosages of the drug, primarily because of an increase in the number of low amplitude pulses. Plasma IGF-I levels were increased in a dose-dependent manner, whereas IGFBP-3 levels were increased only with the highest dosage. There was a positive relationship between GH pulse frequency and IGF-I increase. Except for an advance in the nocturnal nadir and in the morning elevation, MK-677 had no effect on cortisol profiles. In particular, 24-h mean levels of plasma total and free cortisol and urinary excretion of free cortisol were similar under all conditions. The present data suggest that the use of MK-677 for the treatment of relative somatotropic deficiency, particularly in older adults compromised by such deficiency, deserves further investigation.

Inhibition by amiloride of experimental carcinogenesis induced by azaserine in rat pancreas.

The effects of prolonged administration of the diuretic amiloride on pancreatic carcinogenesis induced by azaserine and on the labeling index of carcinogen-induced pancreatic lesions were investigated in Wistar rats. Rats were given 25 weekly injections of 10 mg/kg body weight azaserine and also 5 mg/kg body weight amiloride every other day until the end of the experiment at week 62. Carcinogen-induced pancreatic lesions were examined by histochemical techniques and were classified as ATPase-positive or ATPase-negative. In week 62, quantitative histologic analysis showed that prolonged administration of amiloride significantly reduced the number and size (as percent of parenchyma) of ATPase-positive pancreatic lesions, which are closely correlated with the subsequent development of pancreatic cancer. Amiloride also significantly decreased the labeling index of carcinogen-induced pancreatic lesions, but not of the surrounding acinar cells. In contrast, amiloride has no significant influence on the number and size of ATPase-negative pancreatic lesions. These findings indicate that amiloride inhibits pancreatic carcinogenesis, and that this effect may be related to the reduction of ATPase-positive lesions and to amiloride's inhibition of cell proliferation in neoplastic lesions of the pancreas.

Tetradecylthioacetic acid reduces the amount of lipid droplets, induces megamitochondria formation and increases the fatty acid oxidation in rat heart

The effects of prolonged administration (3 months) of a 3-thia fatty acid analogue and omega-3-fatty acids on cardiac fatty acid oxidation and the volume fraction of lipid droplets and mitochondria in cardiomyocytes were investigated. Doses were 1 g/day/kg body weight, except 150 mg/day/kg body weight for tetradecylthioacetic acid (a 3-thia fatty acid). One group served as control and did not receive any treatment. The volume fraction of lipid droplets in cardiomyocytes was significantly lower in the tetradecylthioacetic acid group compared to the other groups. Mitochondrial β-oxidation was 60% greater and fatty acyl-CoA oxidase activity was increased by 430% in the tetradecylthioacetic acid group compared to control. This was accompanied by a greater volume fraction of mitochondria in cardiomyocytes (0.514±0.032% in tetradecylthioacetic acid v 0.318±0.007% in control) which was due to an increased size of mitochondria. The volume fraction of mitochondria was also greater in eicosapentaenoic acid (EPA) treated rats compared to control, but the enzymic activities were unaffected. Docosahexaenoic acid (DHA) treatment resulted in a greater volume fraction of lipid droplets in the cardiomyocytes, but the volume fraction of mitochondria and enzymic activities were unaltered. These results indicate that EPA and DHA have different effects on the modulation of mitochondrial biogenesis. Tetradecylthioacetic acid treatment results in megamitochondria formation and increased peroxisomal and mitochondrial β-oxidation with a concomitant reduction of lipid droplets in the cardiomyocytes.