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PubMed2002

Sensitization to the neuroendocrine, central monoamine and behavioural effects of murine tumor necrosis factor-alpha: peripheral and central mechanisms.

Systemic administration of murine tumour necrosis factor-alpha (mTNF-alpha; 0.1-2.0 microg, i.p.) dose-dependently increased plasma corticosterone and augmented monoamine utilization within the paraventricular nucleus of the hypothalamus (PVN), locus coeruleus, medial prefrontal cortex (PFC), central and medial amygdala. A time-dependent sensitization was induced in mice, wherein reexposure to mTNF-alpha 28 days (but not 1 day) following the initial cytokine treatment provoked marked signs of illness (diminished activity, ptosis, piloerection) and increased plasma corticosterone levels. Serotonin (5-HT) activity was augmented upon mTNF-alpha reexposure at the 1- or 28-day intervals in the PFC and medial amygdala, respectively. Intracerebroventricular (i.c.v.; 1-500 ng) mTNF-alpha did not promote illness, but modestly increased plasma corticosterone levels. Neither the illness nor the corticosterone changes were subject to a sensitization upon i.c.v. cytokine reexposure. Acute i.c.v. mTNF-alpha increased norepinephrine (NE), 5-HT and dopamine (DA) activity within the PVN and median eminence/arcuate nucleus complex (ME/ARC), and NE utilization within the central amygdala. Subsequent i.c.v. mTNF-alpha further enhanced the hypothalamic monoamine variations. Finally, systemic (i.p.) mTNF-alpha pretreatment did not proactively influence sickness or corticosterone responses upon later i.c.v. cytokine challenge, but augmented locus coeruleus NE activity and 5-HT and DA utilization within the ME/ARC. It is suggested that the sensitization with respect to sickness and corticosterone activity in response to mTNF-alpha reflect the involvement of peripheral mechanisms. Moreover, it appears that mTNF-alpha promotes central neurochemical plasticity through independent central and peripheral mechanisms.

Animals↗
PubMed2002

Pilomotor seizures: symptomatic vs. idiopathic report of two cases and literature review.

We report pilomotor seizures in two patients who presented with piloerection or gooseflesh spreading in a pattern similar to the 'Jacksonian march'. Gooseflesh was confined to the ipsilateral side in most of the episodes. Occasionally it spread to the contralateral side. It was also associated with other autonomic symptoms and complex partial features of temporal lobe origin. Simple partial status that progressed to complex partial status occurred in the second patient. Very rarely secondary generalization occurred. The cause was left sphenoid meningioma and temporal tip contusion in the first case. It was idiopathic in the second case, although a positive family history of complex partial seizures was obtained in this patient. Interictal electroencephalogram (EEG) showed left temporal focus in the first and bitemporal foci with right fronto-temporal dominance in the second. Parenteral phenytoin controlled the partial complex status in the second and carbamazepine controlled the episodes in both cases. To our knowledge all reported cases were symptomatic and our case of idiopathic aetiology is the first to be recorded. We endorse that pilomotor seizures are autonomic in nature and constitute a subtype of simple partial seizures. These autonomic simple partial seizures may progress to, or be a component of, complex partial seizures of temporal lobe origin. Based on their dominance in such a symptom complex and careful interpretation of the ictal history, it can be logically concluded that pilomotor seizures may be underestimated by both patients and physicians.

Adult↗
PubMed1998

Treatment of suspected heat illness.

1. Despite advances in the art and science of fluid balance, exertional heat illness -- even life-threatening heat stroke -- remains a threat for some athletes today. 2. Risk factors for heat illness include: being unacclimatized, unfit, or hypohydrated; certain illnesses or drugs; not drinking in long events; and a fast finishing pace. 3. Heat cramps typically occur in conditioned athletes who compete for hours in the sun. They can be prevented by increasing dietary salt and staying hydrated. 4. Early diagnosis of heat exhaustion can be vital. Early warning signs include: flushed face, hyperventilation, headache, dizziness, nausea, tingling arms, piloerection, chilliness, incoordination, and confusion. 5. Pitfalls in the diagnosis of heat illness include: confusion preventing self-diagnosis; the lack of trained spotters; rectal temperature not taken promptly; the problem of "seek not, find not;" and the mimicry of heat illness. 6. Heat stroke is a medical emergency. Mainstays of therapy include: emergency on-site cooling; intravenous fluids; treating hypoglycemia as needed; intravenous diazepam for seizures or severe cramping or shivering; and hospitalizing if response is slow or atypical. 7. The best treatment is prevention. Tips to avoiding heat illness include: rely not on thirst; drink on schedule; favor sports drinks; monitor weight; watch urine; shun caffeine and alcohol; key on meals for fluids and salt; stay cool when you can; and know the early warning signs of heat illness.

Acclimatization↗
PubMed1986

Preterm labor in the quadriplegic parturient.

The occurrence of preterm labor is not uncommon in the pregnant quadriplegic. Early diagnosis is hampered by the inability of most quadriplegics to sense uterine contractions in the usual way. A patient we recently treated for preterm labor learned to recognize contractions by the associated symptoms of autonomic hyper-reflexia: flushing, headache, and piloerection. Tocolytic therapy was successful and a favorable neonatal outcome occurred. Increased awareness by the physician and the pregnant quadriplegic patient is encouraged so that symptoms of autonomic hyper-reflexia may be recognized as potentially indicative of uterine contractions.

Adult↗
PubMedDate not supplied

Short-term repeated-dose toxicity profile of archaeosomes administered to mice via intravenous and oral routes.

Archaeosomes, liposomes made from polar ether lipids of archaea, show promise for vaccine and drug delivery applications. The potential toxicity of intravenously (14, 70, or 140 mg/kg/day for 5 consecutive days) and orally (gavaged at 55, 275, or 550 mg/kg/day for 10 consecutive days) administered unilamellar archaeosomes, prepared from the total polar lipids (TPLs) extracted from several species of archaea, was assessed in female BALB/c mice. Liposomes prepared from an ester phospholipid composition were included for comparative purposes. Control groups of mice were administered 0.1 ml phosphate-buffered saline (PBS) by either route. Animals were monitored at least once daily for temperature, body weight, and clinical signs of adverse reactions. One day after the last dose, the mice were sacrificed. Blood was collected for selected biochemical/enzyme analyses, and the major organs (heart, lungs, liver, spleen, kidneys) were weighed and examined macroscopically. In addition, the spleens were examined histologically. At the two lower dosages of intravenously administered vesicles, there were no significant indications of toxicity, as compared with the PBS-administered control group. At the highest intravenous dose of 140 mg/kg/day, archaeosomes prepared from the TPL of the extreme halophiles, Halobacterium salinarum and Natronobacterium magadii, indicated potential toxicity, as evidenced by clinical signs (hyperactivity and/or piloerection), drop in body temperature, and loss in body weight. Spleens from mice administered some archaeosomes types, primarily at the highest intravenous dose tested, were enlarged, had increased organ weight, and microscopic examination revealed mild to moderate expansion of the red pulp with increased numbers of hematopoietic cells, but no changes in the white pulp. There were similar clinical signs at one or more of the higher oral doses of the ester liposomes and some of the archaeosome types; however, no other apparent toxicity was observed. Based on this limited mouse study, archaeosomes were generally well tolerated after intravenous or oral delivery at the dosages so indicated in this study.

Administration, Oral↗
PubMed2004

Final report of the amended safety assessment of Dioscorea Villosa (Wild Yam) root extract.

Dioscorea Villosa (Wild Yam) Root Extract is an extract of the rhizomes of the wild yam, D. villosa. A manufacturing process was described in which cut up and ground rhizomes are combined with an eluant (e.g., oleyl alcohol), the plant material precipitated with addition of a miscible solvent, washed, and redissolved in the original eluant. The extract contains glycoside and steroidal saponins (< or =0.4%), diosgenin (< or =3.5%), alkaloids, tannins, phytosterols, and starch. Levels of heavy metals, 1,4-dioxane, chloroform, methylene chloride, trichloroethylene, and benzene are reported to be below limits of detection. Although only one use was reported to the U.S. Food and Drug Administration (in a body and hand preparation), industry reported uses in body and hand creams, lotions, powders, and sprays at a concentration of 0.00001% (equivalent to 0.000002% plant solids), and in moisturizing creams, lotions, powders, and sprays at concentrations up to 15% (equivalent to 0.5% plant solids). Preparations fromD. villosaare used in herbal medicine for treatment of a variety of ailments and by the pharmaceutical industry in the preparation of steroids. Using Dioscorea Villosa (Wild Yam) Root Extract prepared via a specified process, it is possible to produce a stable extract with a narrow range of diosgenin content. The extract produced using this methodology was tested in acute and short-term toxicity tests, dermal irritation tests, a sensitization test, an ocular irritation test, a rat uterotropic assay, and genotoxicity tests. An acute oral toxicity test produced hypoactivity, piloerection, and dyspnea and a death in 1 of 10 rats at 2 g/kg using the specified extract, but no toxicity in rats given 0.5 g/kg. A dermal toxicity test using the specified extract demonstrated no acute toxicity in rats. Both a 7-day local tolerance test and a 28-day dermal toxicity test in rats produced no significant adverse effects at the maximum tested concentration of 10%. A single application of undiluted extract to the intact and abraded skin of rabbits produced sufficient irritation for the test material to be rated"irritant,"but a 10% dilution was not irritating. Undiluted extract was only mildly irritating to the conjuctiva of the rabbit eye; irritation in the iris and cornea was mild and transient. Undiluted extract was not irritating during the induction phase of a guinea pig sensitization study, nor did challenge with a 25% dilution elicit any sensitization. The specified extract at concentrations up to 500 mg/kg/day did not have any estrogenic activity in the juvenile rat uterotrophic assay. Genotoxicity assays in bacterial and mammalian systems were negative, except that Ames test strain TA 1537 was positive at one dose level using the plate incorporation method, but not using a preincubation method. Although the concentration at which the actual plant extract is used in cosmetic products is low, one of the primary safety concerns with this plant extract is the possible metabolic/endocrine activity, e.g., estrogen-like or progesterone-like activity as a result of the presence of small amounts of plant phytosterols such as diosgenin. Extracts prepared as described in this safety assessment, with an upper limit of 3.5% diosgenin, did not have any estrogenic activity, demonstrating that it is possible to produce material that does not present this specific safety concern. Although extracts from pesticide-free plants were not considered genotoxic and it was the view of the Cosmetic Ingredient Review (CIR) Expert Panel that there do not appear to be any components that could be carcinogenic, pesticide residues could raise this issue. It was urged that manufacturers limit pesticide residues to the limit previously used for lanolin of not more than 40 ppm (with not more than 10 ppm for any one residue). Based on these data, it was concluded that Dioscorea Villosa (Wild Yam) Root Extract is safe as used in cosmetic formulations. This conclusion regarding safety, however, is valid only for extracts prepared in a manner that produces a similar chemical profile as that described in this report, particularly as regards diosgenin. Extracts not prepared in a manner that produces a similar chemical profile would be considered safe if they have a similar safety test profile.

Animals↗
PubMedDate not supplied

Safety evaluation of ABELCET, an amphotericin B lipid complex (ABLC): toxicity studies in rats.

ABELCET (ABLC) is a widely used amphotericin B lipid complex formulation that is approved for use in the treatment of invasive fungal infections in patients who are refractory or intolerant of conventional amphotericin B (AmB). The safety profile of ABLC has been characterized in two acute and two repeat-dose toxicity studies in rats. The acute toxicity studies indicated that single intravenous doses of ABLC are at least 20 times less toxic than conventional amphotericin B doses without the lipid formulation, Fungizone. Intravenous doses of 0, 1, 3, or 10 mg/kg/day to groups of rats (10 to 15 rats/sex/group) for 31 days elicited no mortality or overt clinical signs of toxicity, whereas alternate intravenous/intraperitoneal doses (three each per week) for 6 months, produced one death in the control group, one in the intermediate-dose group, and two in the high-dose group. Clinical signs (predominantly piloerection and hunched posture at 10 mg/kg/day) were attributed to granulomatous inflammatory lesions in the abdominal wall, mesentery, and omentum, which were produced by the intraperitoneal injections of ABLC. Feed consumption and body weight gains decreased in high-dose male rats in the one-month study and were significantly lower in male rats at 3 and 10 mg/kg/day in the 6-month study. In contrast, water consumption increased in male and female rats in both studies. Trends of minimal to moderate, dose-related increases in relative kidney, liver and spleen weights, and histological evidence of hypertrophy and hyperplasia of reticuloendothelial cells in the liver and spleen and mild, dose-related impairment of renal function occurred in both the 1- and 6-month studies. Examination of high-dose rats following a recovery period of 28 days after completion of 31 days of dosing suggested that treatment-related changes were reversible. The observed changes for ABLC are similar to those for other amphotericin B lipid formulations, such as AmBisome (LAmB), except for the hepatoxicity, which was observed for LAmB, but not for ABLC.

Amphotericin B↗
PubMedDate not supplied

Comparative toxicity of 1,2,3,4-, 1,2,4,5-, and 1,2,3,5-tetrachlorobenzene in the rat: results of acute and subacute studies.

Groups of 10 male and 10 female rats were dosed orally with 1,2,3,4-, 1,2,4,5-, or 1,2,3,5-tetrachlorobenzene (TCB) at levels that ranged from 200 to 4000 mg/kg, and were observed clinically for 14 d. LD50 values for 1,2,3,4-, 1,2,4,5-, and 1,2,3,5-TCB were found to be 1470, 3105, and 2297 mg/kg, respectively, in male rats. In females, the LD50 values were found to be 1167 and 1727 mg/kg for 1,2,3,4- and 1,2,3,5-TCB, respectively. Clinical signs of toxicity included depression, flaccid muscle tone, prostration, piloerection, loose stool, hypothermia, dacryorrhea, coma, and death. In a subacute study, groups of 10 males and 10 females were fed diets containing 0, 0.5, 5.0, 50, or 500 ppm 1,2,3,4-, 1,2,4,5-, or 1,2,3,5-TCB for 28 d. No deaths or clinical signs of toxicity were observed, and neither growth rate nor food consumption was affected. At 500 ppm, 1,2,4,5- but not 1,2,3,4- or 1,2,3,5-TCB caused a significant increase in the liver weight and serum cholesterol of male and female rats. Hepatic microsomal aniline hydroxylase and ethoxyresorufin deethylase were induced by 500 ppm 1,2,4,5-TCB. Hepatic microsomal aminopyrine demethylase activity was increased by the administration of this compound at 50 ppm and higher in males and at 500 ppm in the females. Rats fed 1,2,3,4- and 1,2,3,5-TCB at 500 ppm also showed a significant increase in aminopyrine demethylase activity. Moderate to severe histological changes were found in the liver, thyroid, kidney, and lungs of rats fed 500 ppm 1,2,4,5-TCB. Histological changes in the tissues produced by the administration of the 1,2,3,4- and 1,2,3,5-isomer were mild even at the highest dose levels. Tissue residue data showed that 1,2,4,5-TCB accumulated at much higher levels than the other two isomers. The results suggest that the position of chlorine substitution can affect the tissue accumulation and toxicity of chlorinated benzenes in rats.

Animals↗
PubMed2000

The reproductive and developmental toxicity of the antifungal drug Nyotran (liposomal nystatin) in rats and rabbits.

Nyotran is a liposomally encapsulated i.v. formulation of the antifungal polyene nystatin. This drug was evaluated in a series of reproductive toxicity studies, according to the guidelines outlined by the International Conference on Harmonization (ICH). A fertility and early embryonic development study (SEG I) and a prenatal and postnatal development (SEG III) study were conducted in rats, and embryo-fetal development (SEG II) studies were conducted in rats and rabbits. Nyotran was administered iv in all studies. In SEG I and SEG III, rats were administered daily doses of 0.5, 1.5, or 3.0 mg/kg Nyotran. In both studies, parental mortality and toxicity in the 3.0 mg/kg dose group necessitated the lowering of the high dose to 2.0 mg/kg/day. Parental toxicity, in the form of decreased body weights, decreased food consumption, and piloerection were also observed at the 1.5 mg/kg/day dose level in the SEG I and SEG III studies. Despite the parentally toxic doses in the SEG I study, there was no effect of Nyotran on F0 male or female fertility or early embryonic development of F1 offspring. In the SEG III study, lactational body weights of the F1 generation were decreased at all Nyotran dose levels. There was no effect on pre-wean developmental landmarks, but post-wean development was affected by Nyotran administration at all dosage levels. Preputional separation was delayed in the 1.5 and 3.0/2.0 mg/kg/day F1 offspring, auditory startle function was decreased in F1 females at all dose levels, and motor activity was decreased in male F1 offspring at all dose levels. However, there were no treatment-related effects on the subsequent mating of the F1 generation and resulting F2 offspring. In SEG II studies, rats and rabbits were also administered 0.5, 1.5, or 3.0 mg/kg/day of Nyotran during gestation. The high dose in these SEG II studies was not lowered, as the maternal animals were able to tolerate the shorter duration of dosing. Maternal effects in rabbits were observed only in the high-dose group and were limited to decreased food consumption and decreased absolute and relative liver weight. Decreased food consumption in high-dose dams and clinical weight loss in some animals at the mid- and high-dose levels evidenced maternal toxicity in rats. Nyotran did not have any effect on Caesarian section parameters in either rats or rabbits and no effect on the incidence of fetal malformations in rabbits. A statistically significant increase in mild hydrocephaly, observed in 4 rat fetuses, was seen at the highest dose level of 3.0 mg/kg/day. The biological significance and relationship to Nyotran treatment of this finding is not clear. This finding may represent a change in the background incidence or a change in the pattern of responsiveness of this strain of rat fetus to the test chemical. Toxicokinetic data were also collected in the SEG II rabbit and rat studies for comparison to human exposures. In both species, systemic exposure to the nystatin at effective antifungal concentrations was demonstrated. The systemic exposures in rats and rabbits were, however, considerably less than have been reported in humans administered clinical doses of 2 or 4 mg/kg/day Nyotran. Thus, humans tolerate higher dosages and systemic exposures of Nyotran relative to rats and rabbits and there is no margin of safety in either dosage level or systemic exposure to drug. Given this lack of a margin of safety and the effects on postnatal development in F1 rats, caution should be exercised when using this drug in females of childbearing potential.

Abnormalities, Drug-Induced↗
PubMed2001

Evaluation of the developmental toxicity of isoeugenol in Sprague-Dawley (CD) rats.

Isoeugenol, used as a perfumery and flavoring agent, was evaluated for developmental toxicity. Timed-pregnant CD((R)) outbred albino Sprague-Dawley rats received isoeugenol (250, 500, or 1000 mg/kg/day) or vehicle (5 ml/kg corn oil) by gavage on gestational days (gd) 6 through 19. Maternal food and water consumption, body weight, and clinical signs were monitored at regular intervals throughout gestation. At termination (gd 20), confirmed-pregnant females (23-25 per group) were evaluated for gestational outcome. All live fetuses were weighed and examined for external malformations, and approximately 50% were evaluated for visceral or skeletal malformations. There were no treatment-related maternal deaths. Clinical signs associated with isoeugenol exposure included dose-related evidence of sedation and aversion to treatment (rooting behavior) in all isoeugenol groups, as well as an increased incidence of piloerection at >/= 500 mg/kg/day. Maternal body weight, weight gain, and gestational weight gain (corrected for gravid uterine weight) were reduced at all doses in a dose-related manner. Gravid uterine weight was significantly decreased at the mid and high doses, whereas maternal relative liver weight was increased at all three dose levels. During treatment (gd 6 to 20), maternal relative food consumption was significantly decreased at the high dose, and maternal relative water consumption was elevated in the mid- and high-dose groups. Prenatal mortality (resorption or late fetal death) was unaffected. At 1000 mg/kg/day, average fetal body weight/litter was decreased by 7% (male) or 9% (female). Incidences of fetal morphological anomalies were statistically equivalent among groups, except for an increase in the incidence of unossified sternebra(e), a skeletal variation, at the high dose. In summary, the maternal toxicity lowest observed adverse effect level (LOAEL) was 250 mg/kg/day based primarily on reduced body weight and gestational weight gain (corrected for gravid uterine weight), and the maternal toxicity no observed adverse effect level (NOAEL) was not determined in this study. The developmental toxicity LOAEL was 1000 mg/kg/day based on intrauterine growth retardation and mildly delayed skeletal ossification. The developmental toxicity NOAEL was 500 mg/kg/day.

Abnormalities, Drug-Induced↗
PubMed1995

Inhalation toxicity study of a haloalkene degradant of sevoflurane, Compound A (PIFE), in Sprague-Dawley rats.

BACKGROUND: Under certain circumstances in the clinical setting, contact of the anesthetic sevoflurane with a CO2 absorbent (e.g., soda lime, Baralyme) leads to the formation of a degradant designated as pentafluoroisopropenyl fluoromethyl ether (PIFE; Compound A). Previous studies have shown that the kidney is the primary target organ for toxicity in the rat. This study was designed to determine the impact of PIFE on rat renal histology correlated with functional changes. The findings are discussed in terms of probable mechanism of action and relevance to humans. METHODS: Male and female Sprague-Dawley rats were exposed to 0, 30, 61, 114, or 202 ppm PIFE for a single 3-h period via nose-only inhalation. Rats were observed daily for behavioral changes or external physical signs of toxicity (i.e., lacrimation, dyspnea, piloerection, etc.) and body weights were recorded at 6, 4, and 1 day preexposure and 1, 3, 7, and 13 days postexposure. Animals were evaluated for hematologic, clinical chemistry and/or urinalysis changes immediately postexposure and/or at 1, 4, and 14 days postexposure. Rats were killed, subjected to a macroscopic postmortem examination, and evaluated for histopathologic changes in all major tissues and organs at 1, 4, and 14 days postexposure. RESULTS: Labored breathing was observed in 3 of the 20 and 2 of the 20 rats in the 114 ppm and 202 ppm groups, respectively, during the 3-h exposure period. No significant reductions in body weight gain were noted during the 2-week study period. Clinical chemistry evaluations revealed increases in blood urea nitrogen and creatinine 1 day postexposure in males and females exposed to 202 ppm PIFE. Changes in urinary glucose, protein and N-acetyl-beta-glucoaminidase/creatinine were evident one day postexposure in males and females exposed to 202 ppm and in males exposed to 114 ppm PIFE. Most values were within normal ranges by 4 or 14 days postexposure. No drug-related alterations in hematologic parameters were noted. Evidence of olfactory epithelial degeneration and desquamation in the nasal turbinates was noted at 4 days postexposure in male and female rats exposed to 202 ppm PIFE. Concentration-dependent renal tubular necrosis and tubular cell hyperplasia, in the corticomedullary border, were observed in males and females exposed to 114 and 202 ppm PIFE. The severity of tubular necrosis in both males and females was considered minimal to slight at the 114 ppm exposure concentration and slight to moderate at the 202 ppm exposure. Both the numbers of affected animals and severity were reduced over time. The most marked changes in serum and urine chemistry were associated with the animals described as having moderate renal necrosis. Male rats appeared more susceptible to nephropathy than female rats. There were no other PIFE-related histopathologic findings. CONCLUSIONS: The renal histopathologic findings in this study are consistent with those reported in previous acute studies in rats after PIFE administration. Functional changes in the kidney, as evidenced by serum chemistry and urinalyses, were observed at exposure concentrations that induced morphologic alterations.

Anesthetics, Inhalation↗
PubMed1997

Apoptosis in lymphoid and parenchymal cells during sepsis: findings in normal and T- and B-cell-deficient mice.

OBJECTIVES: To determine if apoptosis (programmed cell death) occurs systemically in lymphoid and parenchymal cells during sepsis. To examine the potential role of T and B cells in the apoptotic process using knockout mice deficient in mature T and B lymphocytes. DESIGN: Prospective, randomized, controlled trial. SETTING: Animal laboratory in a university medical setting. INTERVENTIONS: Cecal ligation and puncture (CLP) (n = 34) or sham surgery (n = 13) was performed in female ND4 mice and, 15 to 22 hrs postoperatively, thymus, lung, heart, spleen, ileum, colon, liver, kidney, brain, and muscle were obtained and examined for apoptosis. A second group of mice (Rag-1) which are totally deficient in mature T and B cells also underwent CLP (n = 14) or sham surgery (n = 14) and had examination of tissues for apoptosis. MEASUREMENTS AND MAIN RESULTS: Four methods with varying sensitivities and specificities were used to detect apoptosis, including: a) DNA agarose gel electrophoresis; b) terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL); c) electron microscopy; and d) light microscopy. In CLP mice, multiple methods demonstrated apoptosis in lymphocytes in thymus, spleen, ileum, colon, lung, and skeletal muscle. In addition to lymphocytes, parenchymal cells in ileum, colon, lung, and to a lesser extent, in skeletal muscle and kidney were apoptotic in CLP mice. There was no evidence of apoptosis by any method of detection in liver, brain, or heart. Results in Rag-1 mice which are deficient in T and B cells demonstrated extensive apoptosis in thymus, spleen, and ileum with less degrees of apoptosis in colon and lung. Both lymphoid cells and parenchymal cells were apoptotic. Rag-1 mice which underwent CLP did not die prematurely and there were no apparent observable differences in the physical response (tachypnea, piloerection, lethargy, etc), or intra-abdominal bowel inflammation/adhesions compared with CLP mice with normal T and B cells. CONCLUSIONS: Apoptosis is an important mechanism of cell death in lymphocytes and parenchymal cells in sepsis and occurs systemically in many organs. Apoptosis may be an important cause of immunologic suppression in sepsis by inducing widespread lymphocyte depletion. Alternately, apoptosis may be beneficial to host survival by down-regulating the inflammatory response which accompanies sepsis. The degree to which parenchymal cell apoptosis is contributing to multiple organ failure cannot be determined from the present study. Findings in Rag-1 mice demonstrate that mature T and B cells and their secretory products are not necessary for apoptosis to occur during sepsis and that apoptotic cell death is not restricted to T or B cells. Apoptosis may be a key regulator of the balance between the pro- and anti-inflammatory process.

Animals↗
PubMed1981

Neural influences on experimental flap survival.

We have constructed a consistent, reproducible experimental model for the study of skin flap survival consisting of paired flaps that are identical except for the presence or absence of innervation. While the denervated flap survived to only 70 percent of its original length, the innervated flap survived completely in all cases. We then studied the effect of adrenergic innervation on flap survival by performing a chemical sympathectomy using 6-hydroxydopamine. We observed that loss of sympathetic innervation, as measured by absence of piloerection and catecholamine fluorescent staining, resulted in flap necrosis even in the presence of intact somatic and sensory function. We have concluded that the observed differences in survival between the innervated and denervated flaps appear to be dependent at least in part of the presence or absence of noradrenergic regulation of the microcirculation within the flaps.

Animals↗
PubMed1998

Effect of aminoguanidine on plasma nitric oxide by-products and blood flow during chronic peritoneal sepsis.

We hypothesized that plasma nitric oxide (NO), generated via inducible NO synthase (iNOS) or endothelial constitutive NO synthase and measured via its by-products NO2- and NO3- (NO2- + NO3- = NOx) would increase and remain elevated during chronic peritoneal sepsis. We further hypothesized that treatment with aminoguanidine (AG; 50 mg/kg), a selective iNOS inhibitor, would decrease NO production and alter blood flow. Sprague Dawley rats were randomized to septic and nonseptic groups. Septic rats received an intraperitoneal cecal slurry (200 mg of cecal material/5 mL 5% dextrose-H2O/kg); control rats received sterile 5% dextrose-H2O (5 mL/kg) only. Plasma NOx and hemodynamics were measured 0, 4, 12, 24, and 48 h after sepsis or sham induction. We also examined the effect of AG, an iNOS inhibitor, on plasma NOx levels and tissue blood flow at 24 h. Septic rats uniformly displayed signs of sepsis, including lethargy, piloerection, and diarrhea. NOx levels were significantly elevated compared with controls at 4, 12, 24, and 48 h (p < or = .05). Septic rats also demonstrated hypotension (t = 12, 24, and 48 h) and tachycardia (t = 4, 12, 24, and 48 h). The infusion of AG (50 mg/kg intravenously for 30 min) at 24 h significantly decreased plasma NOx in septic animals. Plasma NOx concentrations returned to basal levels by 90 min after infusion of AG. In addition, blood flow studies demonstrated that AG treatment in nonseptic rats resulted in a significant decrease in blood flow to the stomach, skin, and adipose tissue, whereas AG infusion did not significantly alter the regional perfusion profile in septic animals. Furthermore, treatment with AG did not significantly alter mean arterial pressure in either group; however, nonseptic animals exhibited a decrease in stroke volume, and septic animals demonstrated an increase in heart rate. In contrast to the rise and fall of NOx levels in endotoxemia, this study demonstrates that the initial rise is sustained during 48 h of peritoneal sepsis. This sustained increase in NOx levels in this model correlated with the observable signs of systemic infection and may relate to enhanced iNOS activity. AG infusion demonstrated variable effects on regional tissue blood flow profiles in septic and nonseptic animals and attenuated the increase in plasma NOx levels in septic animals, an index of iNOS activity.

Animals↗
PubMed1991

Inter-mouse strain differences in the in vivo anti-CD3 induced cytokine release.

Triggering of the CD3 molecule by in vivo injection of the hamster anti-murine CD3 monoclonal antibody 145-2C11 in adult BALB/c mice leads to massive although transient T cell activation. High levels of tumour necrosis factor (TNF), interferon-gamma (IFN-gamma), IL-2, IL-3 and IL-6 are released into the circulation 1 to 8 h after a single 10 micrograms 145-2C11 i.v. injection. This release induces an impressive self-limited physical reaction associating hypothermia, hypomotility (as assessed by actimetry), diarrhoea, piloerection and even death when high doses (a single dose of greater than 100 micrograms/mouse injection) are administered. In vivo injection of 145-2C11 to other selected mouse strains, namely NZW, CBA/J and C3H/HeJ, induced both different cytokine release patterns and sickness. 145-2C11 induced significant release of TNF and IL-2 in all four strains. At variance, IFN-gamma was only detected in BALB/c mice sera which, in terms of physical reaction (hypothermia and hypomotility) were the most affected. Higher and long-lasting circulating IL-3/GM-CSF levels were present in CBA/J sera, correlating with a later recovery. These results underline heterogeneity in the in vivo cell activation pattern among different mouse strains, when triggering T lymphocytes via the CD3/Ti molecule as compared to exclusive targeting of monocyte/macrophages by means of lipopolysaccharide.

Animals↗
PubMed2007

Control of shivering during regional anaesthesia: prophylactic ketamine and granisetron.

BACKGROUND: The aim of the present study was to compare placebo, ketamine, granisetron and a combination of ketamine and granisetron in the prevention of shivering caused by regional anaesthesia. METHODS: In this prospective, randomized, double-blind study, 160 ASA I and II patients undergoing urological surgery were included. Subarachnoid anaesthesia was performed in all patients with bupivacaine 15 mg. The patients were randomly allocated to receive saline (group P, n= 40), ketamine 0.5 mg (group K, n= 40), granisetron 3 mg (group G, n= 40) or ketamine 0.25 mg + granisetron 1.5 mg (group KG, n= 40). Shivering was graded as 0 = no shivering, 1 = piloerection or peripheral vasoconstriction but no visible shivering, 2 = muscular activity in only one muscle group, 3 = muscular activity in more than one muscle group but not generalized, and 4 = shivering involving the whole body. If 15 min after spinal anaesthesia and concomitant administration of a prophylactic dose of one of the study drugs, the patients shivered according to at least grade 3, the prophylaxis was regarded as ineffective and intravenous (i.v.) pethidine 25 mg was administered. RESULTS: After 15 min, the number of patients with observed shivering was 22 in group P, 6 in group G, 7 in group GK and 0 in group K. The difference between group K and all the other groups was statistically significant (P < 0.0001). The number of patients with a shivering score of 3 was statistically significantly higher in group P compared with the other groups. CONCLUSION: The prophylactic use of 0.5 mg/kg i.v. ketamine was effective in preventing shivering developed during regional anaesthesia.

Adult↗
PubMed2004

A randomized crossover study to evaluate Ro 115-1240, a selective alpha1A/1L-adrenoceptor partial agonist in women with stress urinary incontinence.

OBJECTIVES: To investigate the potential therapeutic benefits of the selective alpha1A/1l-adrenoceptor partial agonist Ro 115-1240 in women with mild-to-moderate stress urinary incontinence (SUI). PATIENTS AND METHODS: Thirty-seven women with mild-to-moderate SUI were enrolled in a randomized, placebo-controlled crossover study. Patients received 1.5 mg Ro 115-1240 twice daily or matching placebo for 2 or 4 weeks. Voiding diaries were used to record the number of SUI episodes, urge incontinence episodes and pads used. Sitting blood pressures and heart rate were recorded at each visit. RESULTS: Ro 115-1240 was associated with a significantly lower mean weekly number of SUI episodes than placebo (8.4 vs 6.0; P= 0.0079), a 28% relative improvement over placebo. There was also a significantly lower mean number of pads used and wet pads changed/week with Ro 115-1240 than with placebo (P = 0.0055 and 0.0066, respectively). The most frequently reported treatment-emergent adverse events were scalp tingling, headache, chills, piloerection, and pruritus. Generally these events were transient and mild to moderate. There was a slightly lower mean sitting heart rate with Ro 115-1240 than with placebo, but no difference in mean systolic or diastolic blood pressure between treatments. CONCLUSIONS: This study suggests that selective alpha1A/1l-adrenoceptor partial agonists have the potential to improve the symptoms of SUI with little or no cardiovascular effect. These results are encouraging and a randomized controlled trial of Ro 115-1240 in a larger population with SUI is warranted to substantiate these findings.

Adolescent↗
PubMed2005

Effect of medetomidine and its antagonism with atipamezole on stress-related hormones, metabolites, physiologic responses, sedation, and mechanical threshold in goats.

OBJECTIVE: To evaluate the effects of medetomidine and its antagonism with atipamezole in goats. STUDY DESIGN: Prospective randomized crossover study with 1 week between treatments. ANIMALS: Six healthy 3-year-old neutered goats (three male and three female) weighing 39.1-90.9 kg (60.0 +/- 18 kg, mean +/- SD). METHODS: Goats were given medetomidine (20 microg kg(-1), IV) followed, 25 minutes later, by either atipamezole (100 microg kg(-1), IV) or saline. Heart and respiratory rate, rectal temperature, indirect blood pressure, and mechanical threshold were measured, and sedation and posture were scored and blood samples obtained to measure epinephrine, norepinephrine, free fatty acids, glucose, and cortisol concentrations at baseline (immediately before medetomidine), 5 and 25 minutes after medetomidine administration, and at 5, 30, 60, and 120 minutes after the administration of antagonist or saline. Parametric and nonparametric tests were used to evaluate data; p < 0.05 was considered significant. RESULTS: Medetomidine decreased body temperature, heart rate, and respiratory rate and increased mean arterial blood pressure, cortisol, and glucose. Recumbency occurred 89 +/- 50 seconds after medetomidine administration. All goats were standing 86 +/- 24 seconds after atipamezole administration whereas all goats administered saline were sedate and recumbent at 2 hours. Tolerance to compression of the withers and metacarpus increased with medetomidine. From 5 to 120 minutes after saline or atipamezole administration, there were differences in body temperature, glucose, and cortisol but none in heart rate or blood pressure. Three of the six goats receiving saline developed bloat; five of six urinated. After atipamezole, four of six goats developed piloerection and all goats were agitated and vocalized. CONCLUSION: At the doses used, atipamezole antagonized the effects of medetomidine on recumbency, sedation, mechanical threshold, and the increase in glucose. Atipamezole increased the rate of return of cortisol toward baseline, and prevented further decline in rectal body temperature. CLINICAL RELEVANCE: Atipamezole may be used to antagonize some, but not all effects of medetomidine.

Adrenergic alpha-Agonists↗