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Biomedical subjects

R Bass

Publications and source records attributed to R Bass.

At least 19 recordsLinked to original sources
PubMed1996

A novel nonpsychotropic cannabinoid, HU-211, in the treatment of experimental pneumococcal meningitis.

Typical features of pneumococcal meningitis have been demonstrated in rats inoculated with Streptococcus pneumoniae. HU-211, a novel noncompetitive N-methyl-D-aspartate antagonist recently demonstrated to inhibit tumor necrosis factor-alpha production under various conditions, improves recovery in some experimental models of brain injury. The present study tested the efficacy of HU-211 in combination with antimicrobial therapy in reducing brain damage in experimental pneumococcal meningitis. S. pneumoniae-infected rats were treated with saline alone, ceftriaxone alone, or with combination of ceftriaxone and HU-211 18 h after inoculation of the bacteria. Brain edema and blood-brain barrier impairment 48 h after infection were significantly (P<.05) reduced suggest that HU-211 when given concomitantly with antibiotics attenuates brain damage in the rat model of pneumococcal meningitis.

Animals↗
PubMed1996

Inhibition of tumor necrosis factor alpha (TNFalpha) activity in rat brain is associated with cerebroprotection after closed head injury.

We recently demonstrated that closed head injury (CHI) in the rat triggers the production of tumor necrosis factor alpha (TNFalpha) in the contused hemisphere. Other investigations have shown that this cytokine plays a role in the inflammatory response following trauma. The present study was designed to determine whether inhibition of TNFalpha production or activity affects the development of cerebral edema as well as neurological dysfunction and hippocampal cell loss after CHI. To this end, we used two pharmacological agents, each acting via a different mechanism: pentoxifylline (PTX), which attenuates the production of TNFalpha, and tumor necrosis factor binding protein (TBP), a physiological inhibitor of TNFalpha activity. Both agents significantly lessened peak edema formation at 24 h and facilitated the recovery of motor function for < or = 4 days postinjury. In addition, TBP attenuated disruption of the blood-brain barrier and protected hippocampal cells. PTX significantly lowered the brain TNFalpha level (by approximately 80%), and TBP completely abolished the activity of recombinant human TNF when they were added at the same time in the in vitro bioassay. We suggest, therefore, that a decrease in TNFalpha level or the inhibition of its activity is accompanied by reduced brain damage.

Animals↗
PubMed1996

Polyamines induce blood-brain barrier disruption and edema formation in the rat.

Polyamines (PA) are derived from ornithine by the enzyme ornithine decarboxylase (ODC), which is activated very rapidly as acute and delayed responses to brain ischemia and trauma. Polyamines play a role in the disruption of the blood-brain barrier (BBB) in different pathological states. This study examined the effect of exogenous polyamines, administered intracerebrally (i.c.v.) or intracarotidly on BBB function. Putrescine, spermidine and spermine, given individually, were found to disrupt BBB integrity within 15 min of i.c.v. administration (p = 0.03; p = 0.0013; p = 0.042 vs saline treated rats, respectively). The effect was still evident after 1 h; however, since the saline treated rats also showed increased permeability of Evans blue at this time, there was no statistical difference between polyamines or saline treated rats 1 h post injection. When injected into the carotid artery, rapid increase in BBB permeability was found 1 min after putrescine and spermidine (p < 0.01 vs saline), with a slight decline at 15 min. A slower effect was noticed after spermine administration which reached significance only at 15 min. These results suggest a role for PA as mediators of vasogenic edema formation in the brain soon after brain injuries which induce increased production of these compounds.

Analysis of Variance↗
PubMed1995

Long-term effect of HU-211, a novel non-competitive NMDA antagonist, on motor and memory functions after closed head injury in the rat.

HU-211 is a synthetic, non-psychotropic cannabinoid which acts as a non-competitive NMDA antagonist and antioxidant. We studied the drug's therapeutic window as well as its long-term effect on cognitive and motor functions in a model of closed head injury (CHI) in the rat. A weight-drop device was used to induce CHI in either anesthetized male rats. HU-211 (5 mg/kg) was administered i.v. to the experimental groups. For the therapeutic window study, drug was injected at 4 or 6 h after CHI. Edema (water content) and clinical status (neurological severity score, NSS) were evaluated at 24 h. Reduction of edema was slight, whereas improvement of NSS was significant when the drug was administered at 4 or 6 h (P = 0.0023 and 0.059, respectively). To determine the drug's long-term effect, it was administered 1 h after CHI and additional doses were later given. NSS was evaluated for a period of 30 d. A single dose of HU-211 given 1 h post-CHI improved the clinical outcome during the 30 d period (P < 0.01). Repetitive doses of HU-211 injected during the post traumatic period had similar effects. Cognitive functions were evaluated in the Morris water maze, with rats trained either before or after CHI. CHI resulted in a highly significant impairment of these abilities, whereas HU-211 treatment 1 h after CHI improved performance. Our results indicate that HU-211 is a potent cerebroprotective agent, with a therapeutic window of about 4 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

The effect of the adrenocortical axis upon recovery from closed head injury.

Fragments and analogs of the hormone ACTH were previously shown to have beneficial effect on the outcome of head injury, while elevated levels of corticosterone (CS) exacerbate it. In the present study we investigated the role of the hypothalamo-pituitary-adrenal (HPA) axis in the pathophysiology of closed head injury (CHI). CHI was produced in ether-anesthetized rats by a calibrated weight-drop device. After evaluating the functional status according to a set of criteria, at 1 and 24 h, the rats were sacrificed and cortical tissue was removed to determine its water content. CHI was also produced in rats that underwent surgical procedures to remove their adrenal gland (ADEX) or the pituitary (HypoX), thus altering the levels of their circulating HPA hormones. Given after CHI, to rats with intact HPA axis, ACTH reduced edema and improved recovery. ADEX rats (6 days postsurgery) had 10-fold higher levels of plasma ACTH. ADEX rats subjected to CHI showed improved functional outcome (p = 0.008) and reduced edema (p = 0.02). We then produced CHI in three groups of rats: HypoX (15 days postsurgery), HypoX treated with ACTH, and controls. In HypoX rats, CHI resulted in increased mortality (35% vs 0) and edema in the surviving rats, and a slower recovery, as compared with the control. Mortality was prevented, edema slightly reduced, and recovery significantly improved after administration of 1-24-ACTH to HypoX rats with CHI. Our results suggest that ACTH has a cerebroprotective effect on the outcome of CHI.

Adrenal Glands↗
PubMed1994

Closed head injury triggers early production of TNF alpha and IL-6 by brain tissue.

In a model of closed head injury (CHI) in the rat we have shown the activation of phospholipase A2 and the production of eicosanoids after injury: at 15 min, mainly 5-hydroxyeicosatetraenoic acid (5-HETE), and at 24 h, mainly prostaglandin E2. The present study was designed to test whether CHI can also trigger the production of cytokines in the brain. CHI was induced in ether-anesthesized rats by a weight-drop device falling over the exposed skull covering the left hemisphere, 1-2 mm lateral to the midline in the midcoronal plane. In the posttraumatic period (1-24 h), the rats were decapitated, cortical tissue from the injured zone of the contused and contralateral hemispheres was removed and sonicated, and cytokine activity was assessed. Whereas no tumor necrosis factor alpha (TNF alpha) activity was found in normal brain tissue, it was detectable in the contused hemisphere (approximately of 72 +/- 50 pg/mg protein) as early as 1 h post-CHI. TNF alpha levels increased at 2 h, peaked at 4 h, (approximately of 609 +/- 540 pg/mg protein), and declined thereafter. At parallel intervals, only low levels of TNF alpha were detected in the contralateral hemisphere. In normal brain, interleukin-6 (IL-6) was nondetectable. Following CHI, high levels of IL-6 were present, although their accumulation lagged behind that of TNF alpha by 2-4 h, peaking at 8 h (62 +/- 31 ng/mg protein). We suggest that the rapid production of TNF alpha and IL-6 following CHI is a local inflammatory response of brain tissue to primary insult.

Animals↗
PubMed1992

The uninsured and the debate over the repeal of the Massachusetts universal health care law.

OBJECTIVES: The debate in Massachusetts over the repeal of the first state-based "pay or play" universal health plan is discussed using data from a survey of 1066 Massachusetts households. The survey attempted to measure the problems of the uninsured, to estimate the likelihood that they would buy insurance if offered, and to calculate the proportion of the uninsured who would be covered under an employer mandate. DESIGN: A survey conducted in person and by telephone in 1066 households, with an oversample of uninsured households, using stratification, clustering, disproportionate sampling, and poststatistical weighting. PARTICIPANTS: Adults aged 18 years and older who were knowledgeable about the insurance status of persons in their household. MAIN OUTCOME MEASURES: Insurance status, employment status, access to and use of health services, and willingness to purchase health insurance. RESULTS: First, the present system of hospital-based uncompensated care in Massachusetts is inadequate by itself to meet the needs of uninsured residents. Uninsured persons are less likely than insured ones to seek medical care for chronic health problems and serious symptoms requiring evaluation. Second, 83% of uninsured families and 24% of uninsured individual respondents would purchase one of several insurance options with 30% of the cost subsidized. Last, the employer mandate provisions of the legislation would cover 43% of the uninsured in Massachusetts. CONCLUSION: In the current economic climate, the political viability of the universal health care plan and similar national initiatives is uncertain given the intractable conflict between perceptions of the financial stability of small businesses that do not offer insurance and the health care needs of uninsured individuals.

Cluster Analysis↗
PubMed1992

A proposed approach to regulating contaminated soil: identify safe concentrations for seven of the most frequently encountered exposure scenarios.

Since 1980, more than 10,000 sites in the United States have been shown to contain soil which has elevated concentrations of various xenobiotics. Since that time, guidelines for deciding whether the level of contamination is worthy of concern have been proposed or promulgated by dozens of local, state, and federal regulatory agencies. Unfortunately, there has been little consistency in the guidelines suggested for each soil contaminant. For example, (a) the basis or rationale for some of the cleanup levels is unclear, (b) approaches to setting cleanup levels vary between states and agencies, (c) cleanup objectives often vary among agencies within the same state, and (d) the cleanup levels are usually set in a scientifically haphazard manner. This paper proposes that the most cost-effective and efficient way to quickly regulate contaminated soil is to establish "safe" concentrations for each chemical for the seven most common exposure scenarios. These exposure scenarios include (1) residential, (2) industrial, (3) agricultural, (4) recreational, (5) groundwater, (6) wildlife and aquatic species, and (7) runoff/erosion of particulates to waterways. The scientific approach and rationale for calculating the cleanup criteria are illustrated by evaluating dioxin and benzene, toluene, and xylene (BTX). The methods suggested here indicate that levels of dioxin of 25 and 50 ppb in residential and industrial soils, respectively, should be acceptable. The predominant concern for the agricultural and recreational scenarios is the runoff of particulates to waterways. For BTX, benzene will dictate the degree of cleanup and the primary hazard at most residential sites will be the inhalation of vapors. Benzene concentrations of 2.5, 14, and 250 ppm should be acceptable for residential, industrial, and recreational soils, respectively. Depending on the depth to groundwater and aquifer use, protection of groundwater may be the driving concern for establishing BTX cleanup levels and must be determined using site-specific factors.

Adult↗
PubMed1992

Are newer scientific concepts in regulatory toxicology used timely and appropriately?

Laws regulating toxicology (e.g. toxic thresholds allowed, poison classes or definition of necessary preclinical testing) might improve health and save lives. Scientific facts will always serve as a mandatory base for political decision-making, but there will also be additional influences (perception and acceptance of risks, possible benefits, economic considerations etc.). These latter factors may vary considerably from one society to another. The Delaney clause prohibited the marketing of any product which was found to be carcinogenic in animals. Due to their benefits, exceptions were made for drugs. In other countries, too, other chemicals could be an exception due to a different perception of the risk or different scientific evaluation. Clear cases of major events always trigger changes in legislation. When in 1937 a newly-marketed sulfanilamide elixir led to severe kidney damage and 70 deaths, the FDA quickly endorsed the propositions of the investigation team set up by the American Medical Association: animal testing in two species with histopathologic examination before a marketing authorization could be granted became mandatory. A similarly rapid reaction followed in Europe when it was detected that Thalidomide was responsible for malformations in the offspring of mothers who had taken the drug in early pregnancy. When the effects are more difficult to link to a chemical, there may be time delays in regulatory actions. However, a sophisticated evaluation system was introduced for better monitoring of drug and chemical hazards. Some examples will be given in order to discuss the difficulties of timely and appropriate use of scientific findings.

Animals↗
PubMed1992

Current guidelines for the preclinical safety assessment of therapeutic proteins.

Guidelines concerning the preclinical safety assessment of therapeutic proteins are available, e.g. in the European Community (EC Notes for Guidance). Unlike rather rigidly prescribing test systems such as those known for chemical substances, it is agreed that for biotechnologically-produced products, testing may be quite different. Those guidelines which allow for a true case-by-case development have been considered the best; however, regulatory authorities are expected to disagree ex post with the approach chosen earlier. To allow for a scientific rationale, which includes the freedom to deviate from the expected norm, guidance must include an offer for discussion of requirements. This combination of recommendations (not requirements) with optional discussions has been the European approach. Although the American approach is known to be somewhat more case-by-case oriented, and the Japanese approach is known to be somewhat more strict, the outcome of drug development, i.e. the application of guidance, in the three regions has been strikingly similar. This underlines the importance of a pharmaceutical manufacturer and his ability to interpret the rules in the light of the product to be developed.

Animals↗
PubMed1991

Considerations regarding the development of individual nonclinical test strategies in the European Community.

The wish of pharmaceutical companies to be given the most binding possible preclinical test programmes for a new product, and the tendency of authorities to regulate to a great extent the preclinical testing of new drugs (especially at a multinational level), has led to differing requirements and practices in preclinical testing in different areas of the world. These differing requirements and practices have of necessity brought in their wake varying scientific criteria, with particular regard to animal protection, ethical standards, as well as imposing apparently unjustified extra financial costs. In order to improve this situation, the development of drug-specific preclinical test strategies is proposed in a drafted E. C. Note for Guidance, which incorporates already existing drug-testing guidelines and method recommendations. This draft Note for Guidance points to general methods of analysing problems and reaching decisions and thus appears to be worthy of recommendation as practical and desirable. It requires the co-operation of drug producers and supervisory authorities at a high scientific and ethical level. With regard to the state-of-the art and the socio-political background, the fulfillment of these requirements would appear not only to be appropriate but also imperative. To put them into practice would contribute enormously to the improvement of drug development and to de-emotionalization of the public debate. Therefore, comments on these draft guidelines from societies and associations are urgently sought and awaited with keen interest.

Animals↗
PubMed1990

Basic requirements for the toxicity testing of antimicrobial agents.

The regulations in different countries on the toxicological testing of antimicrobial agents are similar and harmonized on an international basis. Existing requirements cover both the standard investigations performed with any other new class of therapeutic drug and investigations necessary due to the specific features of anti-infective agents. Such features are the therapeutic target (the microorganisms), the need to provide adequate treatment of patients even during clinical trials, and the potential of the drug to induce certain adverse reactions. The combination of toxicity tests used will be determined by the drug, its class and current knowledge.

Animals↗
PubMed1989

Stereological study of the developing distal femoral growth plate.

The distal femoral growth plate has a uniquely convoluted structure comprised of four mammillate processes. Factors contributing to the development of these processes and overall plate geometry were explored using three-dimensional image analysis of the canine distal femoral epiphysis. The growth plate at birth remains relatively flat until ossification of the epiphysis begins at 1 week of age. Epiphyseal ossification proceeds eccentrically, projecting in the medial-lateral and anterior-posterior directions. Growth plate activity indexed by [3H]thymidine labeling and plate thickness revealed regional differences in cell proliferation. This was measured as a decreased labeling index and thinning of the growth plate in areas capped by the ossifying epiphysis. The eccentric ossification pattern and associated variations in growth plate activity result in definition of an "intraphyseal" groove and medial-lateral oriented sulcus. The groove and sulcus bisect the plate into four quadrants, giving rise to a convoluted structure composed of four areas of plate elevations termed mammillary processes (MP). By 5 weeks, the pattern of ossification results in greater development of the MP in the anterior-medial quadrant and in decreasing order, in the posterior-medial, anterior, and posterior-lateral quadrants. By 10 weeks, a uniform rate of cell proliferation was observed coincident with completion of ossification of the epiphysis. The data suggest that localized variations in growth plate proliferation are associated with ossification of the epiphysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1987

Experience with mutagenicity testing of new drugs: viewpoint of a regulatory agency.

Quality and quantity of mutagenicity testing were analyzed for drugs with new active compounds which were submitted for registration in the Federal Republic of Germany from mid 1982 to mid 1986. A large variety of deficiencies was found, applying to selection and number of mutagenicity tests as well as to test performances. Only 65 out of the 144 drugs submitted for registration were tested sufficiently in the initial phase of registration. From 1982 to 1986 this situation has not been changed markedly. Inadequate test performance still remains the main reason for insufficient testing, leading in some cases to artificially positive results. For in vivo tests the selection of test species was mainly motivated by technical reasons and not by characteristics of the test compound. Most of the insufficiencies were eliminated during the second phase of registration. In some cases insufficient mutagenicity testing led to consequences concerning risk-benefit assessment of the drug and its regulation.

Animals↗