Interagency coordination in drug research and regulation : hearings before the Subcommittee on Reorganization and International Organizations of the Committee on Government Operations, United States Senate, Eighty-seventh Congress, second session. Agency coordination study (pursuant to S. Res. 276, 87th Cong.). Review of cooperation on drug policies among Food and Drug Administration, National Institutes of Health, Veterans' Administration, and other agencies. ...

Pt. 4-5 titles vary: "Eighty-eighth Congress, first session. Agency Coordination Study (pursuant to S. Res. 27, 88th Cong., as amended). Review of cooperation on drug policies among (the) Food and Drug Administration, National Institutes of Health, Veterans' Administration, and other agencies.

Optimization Problem in a Class of Linear System. Application to Multiple Drug Administration

2000 Mathematics Subject Classification: 62H15, 62P10.

Growth hormone resistance and somatomedins in children with end-stage liver disease awaiting transplantation

Background: The success of orthotopic liver transplantation as treatment for end-stage liver disease has prompted investigation of strategies to maintain or improve nutrition and growth in children awaiting transplantation, because malnutrition is an adverse prognostic factor. The purpose of this study was to evaluate the effect of recombinant human growth hormone therapy on body composition and indices of liver function in patients awaiting transplant. Methods: The study was designed as a placebo- controlled, double-blind, crossover trial. Patients received 0.2 U/kg growth hormone, subcutaneously, or placebo daily for 28 days during two treatment periods, separated by a 2-week washout period. Ten patients (mean age, 3.06 ± 1.15 years; range, 0.51-11.65 years, five men), with extrahepatic biliary atresia (n = 8) or two with Alagille's syndrome (n = 2), with end-stage liver disease, completed the trial while awaiting orthotopic liver transplantation. Height, weight, total body potassium, total body fat, resting energy expenditure, respiratory quotient, hematologic and multiple biochemical profile, number of albumin infusions, insulin-like growth factor-1 and 1, growth hormone binding protein (GHBP), and insulin-like growth factor binding protein-1 (IGFBP-1) and insulin-like growth factor binding protein (IGFBP-3) were measured at the beginning and end of each treatment period. Results: Growth hormone treatment was associated with a significant decline in serum bilirubin (-34.6 ± 16.5 μmol/l vs. 18.2 ± 11.59 μmol/l; p < 0.02) but there was no significant effect on any anthropometric or body composition measurements, or on any biochemical or hematologic parameters. Conclusions: These children with end-stage liver disease displayed growth hormone resistance, particularly in relation to the somatomedin axis. Exogenous growth hormone administration may be of limited value in these patients

Endogenous corticosteroids and insulin in acute inflammation

Carrageenin-induced inflammatory responses in the hindpaws of rats were quantitated by measuring: (1) alterations in volumes of the paws; and (2) alterations in concentration of dye, previously injected intravenously, which was recovered in perfusates from the paws. The inflammatory response in one paw was attenuated by previously inducing an inflammatory response in the contralateral paw. The effect was abolished by pretreatment with insulin. Indexes of adrenal activity were increased after the induction of the inflammatory response and they were not attenuated by pretreatment with insulin. Adrenal hyperactivity was characterized by increased serum corticosterone concentration, decreased adrenal ascorbic acid content, and reduced number of circulating eosinophils. It is concluded that inflammatory stimuli which lead to alterations in microvessels depend on a facilitatory effect of insulin. This effect is antagonized by glucocorticoids released in enhanced concentrations after the application of noxious stimuli. Therefore, endogenous insulin and glucocorticoids act as modulators of inflammatory responses.

Heparin, heparin plus ASA and dipyridamole, and arteriovenous fistula as adjuvant methods to prevent rethrombosis after venous thrombectomy. Experimental study in rabbits

Venous rethrombosis following thrombectomy is a common event. The aim of the present study was to verify the action of heparin, heparin plus acetyl salicylic acid (ASA) and dipyridamole, and of an arteriovenous fistula (AVF) in the prevention of this complication. Thrombosis was induced in 48 male rabbits by the injection of thrombin in a segment of the left jugular vein, in which the blood flow was arrested for 10 minutes. After 48 hours, the animals were randomly allocated into one of 4 groups of treatment: (1) control, (2) subcutaneous heparin (600 S.I. Units/kg - 8/8 hours), (3) heparin, in the same dose, plus ASA (10 mg/kg/once a day), and dipyridamole (0.5 mg/kg thrice a day), (4) an AVF was surgically constructed between the left carotid after and the left maxillar vein. After 30 minutes, thrombectomy was performed. The venous blood flow, the hematocrit, activated partial thromboplastin time and thrombin time tests were performed before, right after the thrombectomy and 48 hours after thrombectomy. Venography was performed after thrombectomy and at the end of the experiment. The animals were killed 48 hours after thrombectomy and the veins were examined macroscopically. Venous rethrombosis was significantly prevented only in the AVF group (9/12), when compared to control group (0/12), heparin group (1/12) and heparin plus antiaggregating agents group (2/12). These results validate further clinical and experimental investigations with the use of AVF to prevent rethrombosis after venous thrombectomy, when a reduction of venous flow is present.

ESTUDO CLINICO DO TETANO. REVISAO - 1994

The author did a review entitled clinical aspects of tetanus emphasizing the etiology, epidemiology, pathogenesis, diagnostic, clinical aspects, differential diagnosis, laboratorial tests, treatment, complications and prophylaxis.

Immunisation of dogs, hamsters and guinea pigs against Rhipicephalus sanguineus using crude unfed adult tick extracts

Naive experimental groups of dogs, hamsters and guinea pigs were inoculated three times subcutaneously with unfed adult extract of the tick Rhipicephalus sanguineus and challenged with adult R. sanguineus to evaluate resistance. The acquisition of resistance was based on alterations of some reproductive and feeding performance parameters of female ticks such as female and egg mass weights, engorgement, pre-oviposition and incubation periods, larval hatchability rate and efficiency rates of female ticks in converting their food reservoir to eggs and larvae. Dogs did not develop resistance under these experimental conditions; guinea pigs and hamsters, to a lesser extent, acquired an effective immunity to ticks as demonstrated by the impairment of the reproductive and feeding performance. However, the resistance induced by inoculation of the extract in the rodents seemed not to be as efficient as that induced by successive infestations.

Reinforcing properties of fencamfamine: Involvement of dopamine and opioid receptors

Fencamfamine (FCF) is a psychostimulant classified as an indirect dopamine agonist. The conditioning place preference (CPP) paradigm was used to investigate the reinforcing properties of FCF. After initial preferences had been determined, animals were conditioned with FCF (1.75, 3.5, or 7.0 mg/kg; IP). Only at the dose of 3.5 mg/kg FCF produced a significant place preference. Pretreatment with SCH23390 (0.05 mg/kg, SC) or naloxone (1.0 mg/kg SC) 10 min before FCF (3.5 mg/kg; IP) blocked both FCF-induced hyperactivity and CPP. Pretreatment with metoclopramide (10.0 mg/kg; IP) or pimozide (1.0 mg/kg, IP), respectively, 30 min or 4 h before FCF (3.5 mg/kg; IP), which blocked the FCF-induced locomotor activity, failed to influence place conditioning produced by FCF. In conclusion, the present study suggests that dopamine D 1 and opioid receptors are related to FCF reinforcing effect, while dopamine D 2 subtype receptor was ineffective in modifying FCF-induced CPP.

Influence of simvastatin on bone regeneration of tibial defects and blood cholesterol level in rats

The purpose of this study was to evaluate the effects of simvastatin, by oral or subcutaneous administration, on tibial defects regeneration and blood cholesterol level in rats. A surgical defect was made on the right tibia of 40 male animals assigned to 4 groups (n=10), based on two routes of administration and on the use or not of simvastatin: subcutaneous injection of simvastatin (7 mg/kg) (group AT) or only the vehicle of drug suspension (group AC), above the defect area, for 5 days; and 20 mg/kg of simvastatin macerated on water (group BT) or only water (group BC), orally, daily, during the whole observation period. The animals were sacrificed after 15 or 30 days, when blood samples were analyzed to check plasma cholesterol levels. Tibiae were removed and, after decalcification and routine laboratorial processing, histological and histomorphometrical analyses were carried out. ANOVA was used for statistical analysis at 5% signficance level. The histological and histomorphometrical analyses showed significant differences only between the experimental periods (p<0.05). Animals sacrificed after 30 days showed better bone repair (p<0.05). There was no statistically significant difference (p>0.05) for blood cholesterol levels between the groups. In conclusion, simvastatin administration either orally or subcutaneously did not improve bone repair of experimental tibial defects and did not alter blood cholesterol levels in rats.

Synergist interaction between angiotensin II and DOCA on sodium and water balance in rats

Blockade of central angiotensin receptors with the specific antagonist [Leu8]-ANG II abolished water ingestion and water and sodium excretion induced by infusion of angiotensin II (ANGII) into the lateral ventricle (LV) of rats. The antagonist reduced but did not suppress the salt appetite induced by ANGII infusion. Subcutaneous injection of deoxycorticosterone acetate (DOCA) caused increases in water and 3% NaCl ingestion and decreases in sodium excretion. When central ANGII infusion was combined with peripheral DOCA, the water intake was similar to that induced by ANGII alone and the ingestion of 3% NaCl was increased, whereas sodium excretion was inhibited. When ANGII was infused alone, a detailed temporal analysis of fluid and sodium balance showed a negative balance similar those saline controls that persisted throughout the experiment. Combined administration of ANGII and DOCA induce significant changes in water and sodium balance. Sodium and water maintained a positive balance through out the 8-h experiment. The data support an interaction of central ANGII and DOCA on sodium intake and water and sodium balance. © 1994.

Alterations in the water intake caused by central inhibition of angiotensin-converting enzyme in the rat

In the present study we investigated the effects of central (i.c.v.) and subcutaneous (s.c.) injections of a 2 μg dose of lisinopryl, an inhibitor of angiotensin I(ANGI)-converting enzyme (CE), on water intake. I.c.v. but not s.c. injection of lisinopryl abolished drinking in response to s.c. isoprenaline (100 μg/kg) and significantly reduced drinking in response to 24 h water deprivation or s.c. polyethylene glycol (30% w/v, 10 ml/kg). Lisinopryl had no effect on water intake induced by cellular dehydration (s.c. injection of hypertonic saline (2 M NaCl)). These results are consistent with the hypothesis that lisinopryl acts as a CE blocking agent in the brain. The thirst challenge induced by hypotension using isoprenaline acts primarily by generating ANGII systemically and centrally. The other thirst challenges such as cellular dehydration are independent of the ANGII in the brain. This conclusion was made possible by utilizing a new CE blocking agent at a smaller dose than normally used for other ANG I-CE inhibitors. © 1992.

An adaptive drug delivery design using neural networks for effective treatment of infectious diseases: A simulation study

An adaptive drug delivery design is presented in this paper using neural networks for effective treatment of infectious diseases. The generic mathematical model used describes the coupled evolution of concentration of pathogens, plasma cells, antibodies and a numerical value that indicates the relative characteristic of a damaged organ due to the disease under the influence of external drugs. From a system theoretic point of view, the external drugs can be interpreted as control inputs, which can be designed based on control theoretic concepts. In this study, assuming a set of nominal parameters in the mathematical model, first a nonlinear controller (drug administration) is designed based on the principle of dynamic inversion. This nominal drug administration plan was found to be effective in curing "nominal model patients" (patients whose immunological dynamics conform to the mathematical model used for the control design exactly. However, it was found to be ineffective in curing "realistic model patients" (patients whose immunological dynamics may have off-nominal parameter values and possibly unwanted inputs) in general. Hence, to make the drug delivery dosage design more effective for realistic model patients, a model-following adaptive control design is carried out next by taking the help of neural networks, that are trained online. Simulation studies indicate that the adaptive controller proposed in this paper holds promise in killing the invading pathogens and healing the damaged organ even in the presence of parameter uncertainties and continued pathogen attack. Note that the computational requirements for computing the control are very minimal and all associated computations (including the training of neural networks) can be carried out online. However it assumes that the required diagnosis process can be carried out at a sufficient faster rate so that all the states are available for control computation.