The effect of intravenous tissue-type plasminogen activator in a rat model of embolic cerebral ischemia

Thrombolytic agents may be useful in the treatment of cerebral ischemia caused by arterial thrombosis or embolic occlusion. A trial of intravenous human tissue-type plasminogen activator (rt-PA) was carried out in seven male Sprague-Dawley rats subjected to embolic cerebral ischemia, with eight control animals. One-hour-old autogenous blood clot was injected into the internal carotid artery. A 30-minute infusion of 10 micrograms/kg/minute of rt-PA or saline followed. Areas of ischemia at two hours post-embolization were assessed by digital image processing of serial iodo-14C-antipyrine autoradiographic images. The volumes of "no-flow" (NF) and "low-flow" (LF) regions were calculated. One animal in each group suffered no detectable ischemia; the remainder had well-defined regions of middle and posterior cerebral artery ischemia. No animal sustained a hemorrhagic lesion. Treatment produced no noticeable effect on the patency of cervical vessels. Total NF and LF volumes were less for the treated group but did not reach statistical significance by t-test. In middle cerebral distribution sections, however, LF volume was significantly less (p less than 0.05) for treated animals (150 vs. 191 mm3), primarily due to a more significant decrease in LF volume in the anterior-middle cerebral overlap zone (47 vs. 90 mm3; p less than 0.025). Fibrinogen levels were not altered by drug treatment (p greater than 0.30).     

Evaluation of zuclopenthixol acetate to decrease handling stress in wapiti

Handling stress and capture myopathy are important consequences of intensively managing wildlife species. Over the last 15 yr, the use of long-acting neuroleptic (LAN) drugs in wildlife has increased, and these drugs have become a valuable tool for decreasing capture and handling stress in many species. At this time, reports on the use of these drugs in North American species are limited. The major objective of this study was to evaluate the use of the LAN, zuclopenthixol acetate (Clopixol-Acuphase), to decrease both quantifiable and subjective measurements of stress and activity in wild wapiti (Cervus elaphus, North American elk). This blinded, randomized study took place in February 1999 in Manitoba (Canada) and involved 11 animals receiving the drug and 12 animals acting as controls. At 24 hr after drug administration, there were measurable and significant decreases in the stress and activity of treated animals versus controls during handling. Treated animals had significantly lower mean body temperatures (39.0 versus 40.6 C), less hemoconcentration (mean packed cell volume 0.42 versus 0.49, mean hemoglobin 159.09 versus 181.75 g/L, mean total protein 65.0 versus 70.25 g/L), lower mean serum cortisol (97.91 versus 139.50 mmol/L), lower mean blood lactate (3.39 versus 5.98 mmol/L), and were less metabolically acidotic (mean pHv 7.45 versus 7.34, mean bicarbonate 29.36 versus 24.25 mmol/L, mean base excess 5.64 versus -0.83 mmol/L). Only control animals had evidence of muscle damage based on serum biochemistry (creatine phosphate values of two animals of 42,080 and 25,887 U/L). No animals developed clinical capture myopathy, and no animals died. Measurable effects of this drug were still apparent at 72 hr post-administration. The results of this study support the use of Clopixol-Acuphase in wapiti as a means to decrease handling stress and activity.     

The mechanism of reducing thiopentone dose in elderly patients undergoing surgery

The dose of thiopentone required to induce anesthesia in adults decreasing with age is not due to pharmacodynamic change. The change of pharmacokinetic properties of thiopentone with age in undergoing surgery patient's arterial blood was investigated in seven elderly (67-82 yr) and six young (21-33 yr) patients of both sexes. Thiopentone (3 mg kg-1) was administered intravenously and arterial blood samples were obtained immediately after the injection to measure plasma and red blood cell thiopentone concentrations by an HPLC method. Plasma protein binding was studied using ultracentrifuge method. The disappearance of thiopentone from the arterial blood was described by a two-compartment open model. The distribution rate constant (alpha) was significantly larger in the young patients (p less than 0.001). The distribution half-life was longer in the elderly (p less than 0.05). Both the input microscopic rate constant, K21, and the exit microscopic rate constant, K12, with the central compartment were significantly larger in the young patients. (p less than 0.02 and p less than 0.001, respectively). The difference between the exit and input microscopic rate constant, K12-K21, was much larger in the young patients (p less than 0.001). The plasma protein binding was significantly reduced in the elderly (p less than 0.05). The apparent overall volume of distribution, Vd was not significantly different between young and elder patients. However, the volume of distribution of the central compartment was smaller in the young patients (p less than 0.05). This was probably due to the difficulty of estimation of initial thiopentone plasma concentration post-equilibrium in the central compartment after administration of thiopentone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Observations on acute gastric dilatation in nonhuman primates.

In the years 1967-1977 we diagnosed 23 cases of acute gastric dilatation in monkeys. Fourteen of these animals were Macaca mulatta, five Macaca fascicularis, and one each of Macaca nemestrina, Aotus trivirgatus, Saimiri sciureus, and Colobus guereza. Fourteen of the animals were males, nine were females, and all were adults or subadults. Mortality was 78% (18 of 23 animals). Thirteen of the animals had received on anesthetic, immobilizing, or tranquilizing drug 1-2 days before developing acute gastric dilatation; seven monkeys were overfed, and two had been transferred from one area to another the day prior to developing the disease. Two animals were found dead in their cages with no apparent cause for the gastric dilatation. Five Macaca mulatta and three Macaca fascicularis recovered following treatment, but two Macaca mulatta subsequently succumbed to another episode of acute gastric dilatation. Treatment consisted of evacuation of the stomach, correction of blood volume deficits and acid-base disturbances by administration of appropriate fluids, and supportive therapy for shock.     

The effect of hypovolemia on the renal and cardiovascular responses to atrial natriuretic factor (ANF) infusion.

The renal and cardiovascular effects of ANF infusion have been examined in separate series of experiments; in conscious instrumented sheep following either hemorrhage (10 mL/kg body weight) or removal of 500 mL of plasma by ultrafiltration. Renal arterial infusion of hANF (99-126) at 50 micrograms/h increased sodium excretion from 99 +/- 30 to 334 +/- 102 (p less than 0.05) in normal animals, and from 77 +/- 31 to 354 +/- 118 mumol/min in hemorrhaged animals. Similarly in sheep following ultrafiltration, cardiac output and stroke volume were reduced by intravenous infusion of ANF (100 micrograms/h), although these effects were less marked than those observed in normal animals. The rapid modulation of natriuretic responses to ANF observed in volume expanded animals is not seen in this model of acute volume depletion suggesting that the mechanism through which the renal response to ANF is modulated in low sodium or volume states is not simply the reverse of that which produces rapid enhancement of response following blood volume expansion.     

Effects of evaporative cooling on the regulation of body water and milk production in crossbred Holstein cattle in a tropical environment

The aim of this study was to determine how evaporative cooling modifies body function with respect to water metabolism and other variables relevant to milk synthesis in crossbred cattle. The study was conducted on two groups of 0.875HF:0.125RS crossbred Holstein cattle (87.5%) housed in an open-sided barn with a tiled roof (non-cooled animals) and in a close-sided barn under an evaporative cooling system (cooled animals). The maximum ambient temperature and relative humidity for the non-cooled group were 33 degrees C and 61%, with the corresponding values for the evaporatively cooled barn being 28 degrees C and 84%, respectively. The temperature humidity index (THI) of under non-cooled conditions was higher (P < 0.05) than that in the cooled barn. Rectal temperatures and respiration rates of non-cooled animals were higher (P < 0.05) than those of cooled animals. Daily dry matter intake (DMI) of cooled animals was higher while water intakes were lower (P < 0.05) than those of non-cooled animals. The mean absolute values of plasma volume, blood volume, and extracellular fluid (ECF) of cooled animals were significantly higher (P < 0.05) than those of non-cooled animals throughout all stages of lactation. Milk yields of cooled animals were higher by 42%, 36% and 79% on average than those of non-cooled animals during early-, mid- and late-lactation, respectively. The decline in milk yields as lactation advances was markedly apparent in late-lactating non-cooled animals, while no significant changes in milk composition at different stages of lactation were observed in either group. Mean arterial plasma concentrations, arteriovenous concentration differences (A-V differences) and the extraction ratio across the mammary gland for acetate, glucose and triglyceride of cooled animals were not significantly different compared with values for non-cooled animals. No differences were seen in plasma hormonal levels for triiodotyronine (T(3)) and insulin-like growth factor-1 (IGF-1), but plasma cortisol and thyroxine (T(4)) levels tended to be lower in non-cooled animals. This study suggests that low cooling temperature accompanied by high humidity influences a galactopoietic effect, in part through increases in ECF, blood volume and plasma volume in association with an increase in DMI, which partitions the distribution of nutrients to the mammary gland for milk synthesis. Cooled animals were unable to maintain high milk yield as lactation advances even though a high level of body fluids was maintained during long-term cooled exposure. The decline in milk yield, coinciding with a decrease in net energy for lactation as lactation advances, could be attributed to a local change within the mammary gland.     

Reduced pulsatile luteinizing hormone and testosterone secretion with aging in the male rat

To identify possible age-dependent changes in the feedback relationship between the brain-pituitary and testes, we examined the minute-to-minute patterns of plasma luteinizing hormone (LH) and testosterone (T) in intact, young male rats and compared these profiles to those of old animals. Young (3 mo; n = 11) and old (22 mo; n = 12) Sprague-Dawley rats were fitted with indwelling venous catheters and between 24 and 48 h later, were bled without anesthesia, by remote sampling, at 10-min intervals for 8 h. Blood samples of 400 microliter were withdrawn, and an equivalent volume of a blood replacement mixture was infused after each sample. Plasma LH and T levels in each sample were measured by radioimmunoassay (RIA). Plasma T levels in old animals failed to show the transient oscillations observed in young animals. Mean plasma T levels were 50% lower in old compared to young animals (P less than 0.001). Plasma patterns of LH in old animals, like their younger counterparts, showed statistically significant episodic increases, whose apparent pulse frequency was inappropriately low for their circulating T level (although not statistically different from the young group). Pulse amplitude in the old animals was 66% lower in the old compared to the young group (P less than 0.015). We conclude that age-associated alterations in brain mechanisms governing LH secretion underline these endocrine changes.     

Ion-sparing diuresis by 2,3-dibenzylbutane-1,4-diol, a synthetic mammalian-lignan derivative.

Diuretic properties of a synthetic lignan, 2,3-dibenzylbutane-1,4-diol (hattalin), and a naturally occurring arctigenin were examined in BALB/c male mice and Wistar male rats. Intra peritoneal administration of hattalin (50 mg/kg) in mice increased urine volume by 1.7-3.1 fold that of placebo-treated animals 40-260 min after administration (p less than 0.05 vs control). In contrast, 100 mg/kg of arctigenin had no effect on urine volume in mice. Hattalin (100 mg/kg), arctigenin (100 mg/kg), or furosemide (50 mg/kg) as a positive control was administered orally to rats, and accumulated urine volume was measured for up to 6-12 h. The urine volume of animals administered with hattalin showed 1.4-1.5 fold that of placebo-treated animals after 2-6 h of administration (P less than 0.05, n = 10). On the other hand, arctigenin showed no significant effect on urine volume for up to 12 h after administration (n = 8). The urine volume in animals administered with furosemide (n = 10) was 2.0-3.0 fold that of placebo-treated animals (P less than 0.01). Furosemide increased total Na+, K+, or Cl- excretion by 1.9, 1.8 or 2.2 fold, respectively, when compared with placebo-treated controls (P less than 0.01), whereas hattalin decreased Na+ excretion by 3.6 times (P less than 0.01), K+ excretion by 1.4 times (not significant), and Cl- excretion by 3.1 times (P less than 0.01). Serum Na+ and K+ levels did not change in both furosemide- and hattalin-administered rats, however, serum Cl- levels in these animals significantly decreased (P less than 0.01) when compared with controls. The results suggest that the diuretic property of hattalin is due to a novel mechanism which is different from that of furosemide or other diuretics modifying the ion-exchange at the uriniferous tubules.     

Population pharmacokinetics of methotrexate in the guinea pig.

The population pharmacokinetics of an antitumoral and antiinflammatory agent, methotrexate (MTX), a folic acid antagonist, was studied in guinea pigs. Animals received an acute intraperitoneal injection of 0.25, 1 or 5 mg/kg MTX. Blood sampling was carried out for 12 hrs. after MTX administration and plasma drug concentrations were measured by fluorescence polarization immunoassay. The pharmacokinetic (PK) parameters were computed using the bayesian population model. MTX reached the level of detection at 3 hrs. for the animals injected with the lowest dose (0.25 mg/kg), at 3.5 hrs. for those animals which had the intermediate dose (1 mg/kg) and more than 6 hrs. for animals having received the highest dose (5 mg/kg). Each kinetic parameter (half life, total clearance - CLt, volume of distribution at steady state - VDSS, mean residence time - MRT - and area under curve - AUC) didn't show any significant difference between doses. MTX kinetic was linear for the first two doses (0.25 and 1 mg/kg MTX) and non-linear thereafter. MTX presented a one compartment distribution.     

Early effects of tobacco smoke exposure on vascular dynamics in the microcirculation.

The purpose of these studies is to examine the early effects of chronic tobacco smoke exposure on vascular dynamics in the mesenteric microcirculation. Female rats were exposed daily to tobacco smoke from five reference cigarettes for a period of 2 mo. At the end of this period the smoke-treated rats had gained 12 g less than sham-treated controls, and arterial blood pressure in the smoke-treated animals was slightly less than pressure in the sham-treated animals. These are characteristic effects of tobacco smoke exposure on rats. Following the treatment period, red blood cell (RBC) velocity in single mesenteric capillaries and microvascular pressures in arterioles and venules were measured in accordance to established methods. There was no significant difference in pressure distribution on the arterial side of the mesenteric vascular network, but pressure in the venules of the smoke-treated animals was significantly higher than that of the sham-treated group. In association with the higher venular pressure in the smoke-treated animals, capillary RBC velocity (an index of capillary flow) was significantly lower. The reduction in velocity was in proportion to the decrease in pressure drop (arteriole-venule) across the capillary network.     

Effects of alloxan-induced diabetes on hemorheology in rabbits.

Plasma viscosity (PV), apparent whole blood viscosity (WBV), relative blood viscosity (RV) and erythrocyte deformability (filterability) (EDF) were determined in 13 New Zealand White (NZW) rabbits with alloxan induced-diabetes (AID) and 8 normal NZW rabbits, matched for age, sex and weight. AID rabbits were divided into two groups depending on the duration of hyperglycemia (long-term, greater than 6.0 months (n = 7), and short-term, less than or equal to 3.0 months of hyperglycemia, n = 6). Comparing long-term AID rabbits to normal animals, we found significant increases in WBV (P less than 0.001, 0.005 for high and low rates of shear, respectively), and a marked reduction in EDF (P less than 0.001). There was no significant difference in PV between long-term AID and normal rabbits. Conversely, PV was significantly increased in rabbits with short-term diabetes (P less than 0.01) while there was a concurrent significant increase in WBV measured at high and low rates of shear (P less than 0.001, 0.001, respectively). No difference was detected in EDF between normal and short-term AID rabbits. Furthermore, in long-term AID rabbits there was a strongly positive correlation between RV and reduced erythrocyte deformability (r = 0.94, P = 0.006) while WBV strongly correlated with PV (r = 0.92, P = 0.004) in the short-term AID subgroup. We conclude from these data: (1) elevated blood viscosity in long term AID rabbits is associated with reduced erythrocyte filterability; and (2) elevated WBV in short-term AID rabbits is associated with increased PV.     

Alveolar diffusion-perfusion interactions during high-altitude residence in guinea pigs.

We previously reported in weanling guinea pigs raised at high altitude (HA; 3,800 m) an elevated lung diffusing capacity estimated by morphometry from alveolar-capillary surface area, harmonic mean blood-gas barrier thickness, and pulmonary capillary blood volume (Vc) compared with litter-matched control animals raised at an intermediate altitude (IA; 1,200 m) (Hsia CCW, Polo Carbayo JJ, Yan X, Bellotto DJ. Respir Physiol Neurobiol 147: 105-115, 2005). To determine if HA-induced alveolar ultrastructural changes are associated with improved alveolar function, we measured lung diffusing capacity for carbon monoxide (DLCO), membrane diffusing capacity for carbon monoxide (DMCO), Vc, pulmonary blood flow, and lung volume by a rebreathing technique in litter-matched male weanling Hartley guinea pigs raised at HA or IA for 4 or 12 mo. Separate control animals were also raised and studied at sea level (SL). Resting measurements were obtained in the conscious nonsedated state. In HA animals compared with corresponding IA or SL controls, lung volume and hematocrit were significantly higher while pulmonary blood flow was lower. At a given pulmonary blood flow, DLCO and DMCO were higher in HA-raised animals than in control animals without a significant change in Vc. We conclude that 1) HA residence enhanced physiological diffusing capacity corresponding to that previously estimated on the basis of structural adaptation, 2) adaptation in diffusing capacity and its components should be interpreted with respect to pulmonary blood flow, and 3) this noninvasive rebreathing technique could be used to follow adaptive responses in small animals.     

Apparent unmasking of [3H]GDP binding in rat brown-fat mitochondria is due to mitochondrial swelling

The presence of and biochemical background for the so-called 'unmasking' phenomenon in rat brown-fat mitochondria was investigated (i.e. the apparent increase in [3H]GDP binding to the 'uncoupling' protein thermogenin, without a concomitant increase in the amount of the protein). It was found that an unmasking could be observed both 1 h after norepinephrine injection and after 1 h cold stress, provided that the rats were preacclimated to 28 degrees C. The unmasking could be observed both when a filtration method and when a centrifugation method for determination of [3H]GDP-binding capacity were used; however, the absolute values were higher with the filtration method. Based on observations of slower cytochrome-c oxidase sedimentation during centrifugation, the possibility that the matrix volume of brown-fat mitochondria isolated from warm-acclimated animals was smaller than that of cold-stressed animals was investigated with 3H2O. The cold stress increased the matrix volume from being nearly non-existent to about 1 microliter/mg. A preswelling procedure in an ionic medium could similarly increase the matrix volume in mitochondria from warm-acclimated animals but was without significant effect in the already swollen mitochondria from cold-stressed animals or from animals adapted to a lower temperature. In mitochondria from warm-acclimated animals, the ionic preswelling procedure was fully able to increase the apparent amount of GDP binding to that observed in mitochondria from cold-stressed animals, but it was practically without effect on GDP binding in mitochondria from cold-stressed animals or from animals acclimated to a lower temperature. It is concluded that the apparent 'unmasking' phenomenon, observed when the tissue is less activated than in normal control situations, is not (as hitherto anticipated) due to a specific change in thermogenin as such, but is a reflection of a general mitochondrial phenomenon.     

Inheritance of low erythrocyte catechol-o-methyltransferase activity in man.

Catechol-O-methyltransferase activity was measured in blood obtained from 373 randomly selected subjects aged 16-18, 262 consecutive adult blood donors, and 201 first-degree relatives of subjects with RBC COMT activity of less than 8 U. The distribution of RBC COMT activity in a randoly selected populations was apparently bimodal with a nadir at approximately 8 U. Of a randomly selected population, 23% had low RBC COMT activity (less than 8 U), Because of previous reports of a significant sibling-sibling correlation of RBC COMT activity and because of the presence of a subgroup of subjects with low enzyme activity, RBC COMT activity was measured in blood from first-degree relatives of probands with low erythrocyte enzyme activity in 48 families. The results of segregation analyses of the data were compatible with autosomal recessive inheritence of an allele for low RBC COMT activity. RBC COMT in blood samples from siblings of probands inthese families also showed an apparent biomodal distribution.     

Responses of neurons in the rostral ventrolateral medulla to whole body rotations: comparisons in decerebrate and conscious cats

The responses to vestibular stimulation of brain stem neurons that regulate sympathetic outflow and blood flow have been studied extensively in decerebrate preparations, but not in conscious animals. In the present study, we compared the responses of neurons in the rostral ventrolateral medulla (RVLM), a principal region of the brain stem involved in the regulation of blood pressure, to whole body rotations of conscious and decerebrate cats. In both preparations, RVLM neurons exhibited similar levels of spontaneous activity (median of ～17 spikes/s). The firing of about half of the RVLM neurons recorded in decerebrate cats was modulated by rotations; these cells were activated by vertical tilts in a variety of directions, with response characteristics suggesting that their labyrinthine inputs originated in otolith organs. The activity of over one-third of RVLM neurons in decerebrate animals was altered by stimulation of baroreceptors; RVLM units with and without baroreceptor signals had similar responses to rotations. In contrast, only 6% of RVLM neurons studied in conscious cats exhibited cardiac-related activity, and the firing of just 1% of the cells was modulated by rotations. These data suggest that the brain stem circuitry mediating vestibulosympathetic reflexes is highly sensitive to changes in body position in space but that the responses to vestibular stimuli of neurons in the pathway are suppressed by higher brain centers in conscious animals. The findings also raise the possibility that autonomic responses to a variety of inputs, including those from the inner ear, could be gated according to behavioral context and attenuated when they are not necessary.     

Role of pulmonary blood flow in postpneumonectomy lung growth.

To study the influence of blood flow on postpneumonectomy lung growth, we banded the left caudal lobe pulmonary artery of eight ferrets in such a way that blood flow to the caudal lobe did not increase when the right lung was excised 1 wk later. The fraction of the cardiac output received by the right lung before pneumonectomy was therefore directed entirely to the left cranial lobe. Three weeks after pneumonectomy the weight, volume, and protein and DNA contents of the two lobes of the left lung were measured and compared with those of five unoperated animals and eight animals after right pneumonectomy alone. Although its perfusion did not increase after pneumonectomy, the left caudal lobe of banded animals participated in compensatory growth, increasing in weight and protein and DNA contents. Although the cranial lobe of banded animals received 25% more of the cardiac output than the same lobe in pneumonectomized animals, cranial lobe volume and protein and DNA contents in the two groups were similar. Caudal lobes were smaller in banded than in simple pneumonectomized animals and tended to contain less protein, whereas the cranial lobes tended to be heavier. We conclude that increased pulmonary perfusion is not necessary for compensatory lung growth in adult ferrets, but it may modify this response.     

Differential sympathetic outflow and vasoconstriction responses at kidney and skeletal muscles during fictive locomotion

We compared sympathetic and circulatory responses between kidney and skeletal muscles during fictive locomotion evoked by electrical stimulation of the mesencephalic locomotor region (MLR) in decerebrate and paralyzed rats (n = 8). Stimulation of the MLR for 30 s at 40-microA current intensity significantly increased arterial pressure (+38 +/- 6 mmHg), triceps surae muscle blood flow (+17 +/- 3%), and both renal and lumbar sympathetic nerve activities (RSNA +113 +/- 16%, LSNA +31 +/- 7%). The stimulation also significantly decreased renal cortical blood flow (-18 +/- 6%) and both renal cortical and triceps surae muscle vascular conductances (RCVC -38 +/- 5%, TSMVC -17 +/- 3%). The sympathetic and vascular conductance changes were significantly dependent on current intensity for stimulation at 20, 30, and 40 microA. The changes in LSNA and TSMVC were significantly less than those in RSNA and RCVC, respectively, at all current intensities. At the early stage of stimulation (0-10 s), decreases in RCVC and TSMVC were significantly correlated with increases in RSNA and LSNA, respectively. These data demonstrate that fictive locomotion induces less vasoconstriction in skeletal muscles than in kidney because of less sympathetic activation. This suggests that a neural mechanism mediated by central command contributes to blood flow distribution by evoking differential sympathetic outflow during exercise.     

Beagle puppy model of intraventricular hemorrhage: ethamsylate studies

Intraventricular hemorrhage (IVH) remains a major problem of preterm neonates, and ethamsylate, an inhibitor of specific prostaglandin-synthetic enzymes has been demonstrated to prevent IVH in these patients. We have examined the effects of ethamsylate on newborn beagle pups who were, by randomized computerized design, assigned to four cells consisting of (a) either ethamsylate or saline pretreatment and (b) either insulted or not insulted with hemorrhagic hypovolemia/volume re-expansion. Prostaglandin levels were obtained prior to and thirty minutes following administration of the solutions and 14C iodoantipyrine autoradiography was performed for cerebral blood flow (CBF) determinations. Ethamsylate produced a significant decrease in the incidence of IVH in this model (p less than 0.05). Following drug administration, ethamsylate-pretreated pups had significant declines in thromboxane B2 and 6-keto PGF1 alpha levels, the major breakdown products of thromboxane A2 and prostacyclin. Although ethamsylate significantly lowered baseline CBF in all brain regions examined in insulted and non-insulted pups (p less than 0.05), in the drug-treated group it did not prevent the changes seen in CBF to the germinal matrix region which were detected in the saline-pretreated pups. Nor did it significantly blunt the blood pressure changes in response to the hemorrhagic hypovolemia/volume re-expansion insult found in the latter group of animals. In addition, only ethamsylate pretreated pups had marked hypotensive responses to the reperfusion phase of the insult. Although the diminution of baseline CBF may contribute to the prevention of neonatal IVH which this drug has been demonstrated to exhibit, ethamsylate may also act as a capillary stabilizing agent.     

Hamycin: separation of toxicity and antifungal activity in mice.

Hamycin, either alone or in suspension as hamycin-cholesterol complex, was intravenously administered to mice in a single dose. Plasma antifungal activity at different time intervals and LD₅₀ at varying drug: cholesterol proportions were studied. Hamycin alone was eight-fold more toxic than the hamycin-cholesterol complex. While the antifungal activity of hamycin in plasma rapidly declined by first order kinetics, the activity of hamycin-cholesterol complex in plasma was maintained at the initial high level for a prolonged period and with a 12-fold increase in the apparent volume of distribution of the drug. The therapeutic implications of these findings are discussed.     

Drug residue formation from ronidazole,a 5-nitroimidazole. IV. The role of the microflora

When radioactive 1-methyl-5-nitroimidazole-2-methanol carbamate, ronidazole, labeled at the 4,5-ring positions was administered orally to germ-free and conventional rats, a much larger fraction of the radioactivity was excreted in the feces of the conventional animals. Determination of the total radioactive residues present in the carcass, blood, plasma, liver, fat and kidney 5 days after dosing indicated that the carcass of the germ-free animals contained a greater quantity of residue than that of conventional rats. On the other hand, the blood of the conventional animals contained a much higher level of radioactivity than that of the germ-free animals. These results show that while the microflora influence the distribution of the drug their presence is not obligating for the formation of persistent tissue residues in rats dosed with ronidazole.