Rapid Iv Injection Research Articles

Assessment of Intravenous Drugs Admixtures Incompatibilities at Nekemte Referral Hospital, West Ethiopia

Intravenous admixtures are the preparations consisting of sterile drug products added to an IV fluid (s) for medication purposes. Especial concerns are required for such drugs since the reversal of toxicity and/or unwanted effects following incompatibilities are cumbersome to deal with. Concern drugs that may cause irritation or toxicity when given as a rapid direct IV injection are also prepared as IV admixtures. The ultimate goal of this assessment was to figure out the actual practices on the ground in IV medications administered in NRH with IV fluids emphasizing on incidence and prevalence of incompatibility between drugs themselves or with IV fluids. This study was a cross-sectional prospective observational study which investigated the potential incompatibilities associated with IV admixture, & the incidence of IV drug administration errors using available evidence-based medicine sources at Nekemte Referral Hospital in West Ethiopia. The data was collected from patient medication Charts and prescription papers for patients treated within a period of 2 months. The study period was from February 2017 to April 2017 at the medical and pediatrics wards of NRH. About patients using IV admixtures were followed within this study period. The prevalence of identified incompatibility among IV admixtures ingredients was 28.94%. The identified compatibility was only 25.43%, while 38.59%were undocumented combinations, and 7.01% were variable. The most commonly encountered incompatible drug-solute combinations were Ringer lactate (61.8%), Insulin + DNS (29.4) and Ceftriaxone + Phenytoin + 0.9% NaCl (8.8%). Also, the incompatible drug-drug combinations detected in this study were Ceftriaxone+ heparin and clopidgrel+cimetidine combinations. Based on the findings of this study, the following can be concluded; there is a high prevalence of incompatibilities among IV admixtures. The types of incompatibilities were both drug-solute and drug-drug incompatibilities. Prescribers and administrators of IV admixtures were recommended to check plausibility before administration to prevent such incompatibilities which can compromise the treatment outcome of patients.

Acute myocardial ischemia enhances the vanilloid TRPV1 and serotonin 5-HT3 receptor-mediated Bezold-Jarisch reflex in rats

AbstractThe Bezold-Jarisch reflex is characterized by a sudden bradycardia associated with hypotension induced by the activation of the vanilloid TRPV1 and serotonin 5-HT3 receptors. This reflex is associated with several health conditions, including myocardial infarction. The aim of the present study was to elucidate the influence of acute experimental myocardial ischemia on the reflex bradycardia induced by anandamide and phenylbiguanide, agonists of the TRPV1 and 5-HT3 receptors, respectively.In urethane-anesthetized rats, the rapid iv injection of anandamide (0.6µmol/kg) or phenylbiguanide (0.03µmol/kg) decreased heart rate (HR) by about 7–10% of the basal values. Myocardial ischemia (MI) was induced by ligation of the left anterior coronary artery. The agonists were injected 5min before MI (S1) and 10, 20 and 30min thereafter (S2–S4).MI potentiated the anandamide-induced reflex bradycardia by approximately 105% at S2 and 70% at S3 but had no effect at S4. This amplificatory effect of MI was virtually abolished by the TRPV1 receptor antagonist capsazepine (1µmol/kg) and was not modified by the cannabinoid CB1 receptor antagonist rimonabant (0.1µmol/kg). MI also amplified the reflex bradycardia elicited by phenylbiguanide by approximately 110, 60 and 90% (S2, S3 and S4, respectively), and this effect was sensitive to the 5-HT3 receptor antagonist ondansetron (3µmol/kg).In conclusion, our results suggest that acute myocardial ischemia augments the Bezold-Jarisch reflex induced via activation of TRPV1 and 5-HT3 receptors located on sensory vagal nerves in the heart.

55: Treating postpartum anemia with intravenous ferric carboxymaltose in a randomized controlled study

A RANDOMIZED CONTROLLED STUDY MELVIN H. SEID, RALPH ROGERS, QUINN DINH, Lyndhurst Gynecologic Associates, Winston Salem, North Carolina, Women’s Clinical Research, Newburgh, Indiana, American Regent/Luitpold Pharmaceuticals, Norristown, Pennsylvania OBJECTIVE: To evaluate the superiority, safety and tolerability of ferric carboxymaltose (FCM) to oral iron in postpartum women with iron deficiency anemia (IDA). FCM is a novel non-dextran iron agent given in large doses by rapid IV injection. STUDY DESIGN: In a randomized, controlled, superiority designed pivotal trial, 289 women 10 days post-delivery with hemoglobin 10g/dL were randomized and received: (a) FCM up to 1,000mg IV over 15 minutes, repeated weekly to correct anemia up to maximum total calculated dose of 2,500mg, or (b) Oral ferrous sulfate 325mg (65mg elemental iron) thrice daily for 6 weeks. RESULTS: Patients (n 142) received 293 IV doses of FCM (mean total dose 1504mg) in 1, 2, or 3 injection(s) [5%, 84%, or 11% respectively]; 147 received oral iron. FCM group compared with oral iron group was: (1) more likely to achieve hemoglobin (Hb) 12g/dL (91% vs. 67%, p .0001) in a shorter time period (14 days vs. 27 days, p .0002) with sustained success (85% vs. 58%) at Day 42, (p .0001), (2) more likely to achieve Hb rise 3.0g/dL at any time (91% vs. 65%, p .0001) in a shorter time period (15 days vs. 28 days, p .0001), and (3) more likely to attain higher transferrin saturation (TSAT) (36% vs. 28%) and ferritin (647 ng/mL vs. 12 ng/mL), p .0001. Drug-related adverse events (AEs) were lower with FCM (11%) than oral iron (22%). Urticaria (2%) was the only drug-related AE occurring in 2% of the FCM group. Constipation (11%;0%), elevated ALT (4%; 0.7%), elevated AST (2%;0.7%), and nausea (2%;1.4%) were more common with oral iron than FCM, respectively. No hypotensive or drug-related serious AEs such as hypersensitivity or anaphylactic reactions were reported in either treatment group. CONCLUSION: Ferric carboxymaltose (FCM) was safe and well-tolerated. FCM was superior to oral iron in increasing Hb 12g/dL earlier with greater sustained success. FCM was more effective in raising TSAT and ferritin. This non-dextran IV iron agent may fulfill an unmet medical need for safe, rapid administration of iron in single doses up to 1,000mg in postpartum women with IDA.

Relationship Between Carotids Sinus Massage, Test With Adenosine and Head-Up Tilt Test in Patients With Syncope

The aim of study was comparison of results of carotids sinus massage (CSM) and adenosine test (AT) in patients with syncope diagnosed by head-up tilt test (HUTT). We observed 169 pts (81 men, 88 women) aged 18-58 yrs (x38,2 yrs) with syncope referred to HUTT. All pts underwent standard HUTT (HUTT-s) acc. To Westminster protocol. Additional tilt with isoproterenol infusion (HUTT-I) was preformed in pts with negative HUTT-s. HUTT was assessed as positive if reproduced symptoms referred by patients. Carotid sinus massage and rapid IV injection of 12 mg of adenosine were done in all pts. RR pauses > 6s induced by adenosine injection or RR pause > 3 s and/or blood pressure fall induced by CSM were assumed as positive tests results. 16 pts (9,5%) had positive AT and 18 pts (10,6%) had positive CSM. Positive AT was observed in 10% pts with negative HUTT-s; in no pts with positive HUTT-s, in 23,1 % of pts with negative HUTT-I and in 8% of positive HUTT-I Positive CSM was observed in 20% pts with negative HUTT-s; in 13,3% pts with positive HUTT-s, in no pts with negative HUTT-I and in 8% of positive HUTT-I Carotid sinus hypersensitivity was no more frequently observed in patients with positive HUTT-I than in positive HUTT-s. Positive AT results were more frequent in pts with negative results of HUTT (both HUTT-s and HUTT-I) Carotid sinus hypersensitivity as a kind of neurocardiogenic syncope seems to have different mechanism than vaso-vagal syncope. HUTT-I rather do not induce syncope by carotid hypersensitivity mechanism. Adenosine may by useful in the diagnosis of syncope in patients with negative results of head-up tilt test.

Evaluation of glucose tolerance and insulin sensitivity in llama crias

To investigate glucose tolerance and insulin sensitivity in llama crias. 7 llamas (age range, 14 to 30 days). On each of 2 sequential days, crias were administered glucose (0.5 g/kg) via rapid i.v. injection. On 1 day (randomly determined for each cria), regular insulin (0.2 U/kg) or 0.9% NaCl solution (0.002 mL/kg) was administered i.v. 15 minutes after glucose administration. Blood samples were collected before (baseline) and at 5, 15, 30, 45, 60, 90, 120, 180, and 240 minutes after glucose administration for determination of plasma glucose and insulin concentrations; fractional turnover rates and plasma half-life of glucose were calculated. The data were compared over time and between days (ie, between glucose treatments with and without insulin administration). A peak plasma glucose concentration of 342 +/- 47 mg/dL was detected at 5 minutes after glucose administration and llamas cleared glucose from plasma within 60 minutes; at 15 minutes, plasma insulin concentration attained a peak value of 33 +/- 13 microU/mL (ie, triple the baseline value). During the 15- to 45-minute interval, fractional turnover rate of glucose was 1.10 +/- 0.24%/min and plasma half-life was 65.7 +/- 13.4 minutes. Insulin significantly increased glucose turnover and resulted in hypoglycemia within 75 minutes of administration. Healthy immature llamas have glucose tolerance and insulin sensitivity superior to that of adults. However, whether sick crias retain the pancreatic sufficiency and tissue responsiveness that are likely responsible for the rapid glucose clearance in healthy individuals is not known.

Imaging of benign hepatic masses.

Using helical CT and rapid i.v. injection of contrast material, benign hepatic masses are discovered in at least 20% of subjects. To minimize expensive and invasive evaluation, an orderly approach to the interpretation of these lesions is necessary. Many benign lesions have a near pathognomonic appearance on a properly performed and interpreted CT scan. Others can have the diagnosis confirmed by a specific and well-chosen follow-up study, such as contrast-enhanced MR. In this article we present the most common types of benign hepatic masses and our approach to their diagnosis.

The effect of guaiphenesin on romifidine/ketamine anaesthesia in ponies

The purpose of this study was to investigate the effect of a single dose (50 mg/kg) of guaiphenesin on recumbency time, surgical conditions and the ‘quality’ of anaesthesia in ponies anaesthetised for castration. Sixteen ponies were sedated with romifidine 100 μg/kg and anaesthetised with ketamine (2.2 mg/kg). Ponies allocated to Group A received no treatment and those in Group B were given 50 mg/kg of a 15% guaiphenesin solution. Guaiphenesin was given as a rapid iv injection immediately after induction of anaesthesia. All ponies were subsequently castrated. The mean (± se) time of recumbency in Group A was 20.9 ± 1.37 min and in Group B 27.2 ± 2.1 min to (P<0.05). Subjective assessment scores for the quality of surgical conditions and anaesthesia itself were significantly greater (indicating better conditions) in ponies receiving guaiphenesin, although there was no difference between groups in the quality of recovery.

Arterio-Venous Ethanol Levels in Blood and Plasma After Intravenous Injection in Rabbits

Arterio-venous ethanol concentrations in both whole blood and plasma were determined as a function of time in the rabbit. Following IV injection of 1.0 g/kg, both arterial and venous ethanol concentrations showed an abrupt decline occurring immediately after the end of the administration, followed by a pseudolinear phase that persisted for the length of the experiment. This work substantiates the arterio-venous ethanol concentration differences reported in the literature. It illustrates that equal arterial and venous ethanol concentrations may not be achieved readily after rapid IV injection. Moreover, it demonstrates a faster decay of ethanol concentrations in arterial than in venous plasma.

A Kinetic Analysis of the Effects of β-Phenylethylamine on the Concentrations of Dopamine and Its Metabolites in the Rat Striatum

The purpose of this investigation was to determine whether the increase in the dopamine (DA) concentration in the rat striatum after a rapid iv injection of β-phenylethylamine (PEA) can be quantitatively explained by the alteration of the striatum PEA concentration using a constructed DA metabolism model and to examine whether the time courses of the striatum DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentration can be described by this DA metabolism model. The time courses of PEA concentration in plasma and the striatum were determined by gas chromatography–mass spectrometry. The plasma PEA concentration was described by a two-compartment model with nonlinear elimination kinetics. The striatum PEA concentration was about 10 times higher than the plasma PEA concentration. The time course of the striatum PEA concentration was described by a diffusion-limited model including a Michaelis–Menten type transport system from plasma to the striatum and nonlinear elimination from the striatum. The DA concentration in the striatum increased immediately after PEA injection. In contrast, the DOPAC concentration in the striatum decreased immediately. HVA concentration in the striatum increased gradually. Assuming that the enhancement of DA concentration in the striatum after PEA injection is caused by the competitive inhibition of PEA on the reuptake of DA into DA neuronal terminals (and the metabolism from DA to DOPAC is then competitively inhibited by PEA in the DA neuronal terminals), the relationship between the enhancement of DA concentration and PEA concentration in the striatum was analyzed using a constructed DA metabolism model. The enhancement of the DA concentration in the striatum was described quantitatively by this model. Thus, it was clarified that a quantitative relationship between PEA concentration and the enhancement of DA concentration in the striatum is present after PEA injection. However, the time courses of the striatum DOPAC (lower dose) and HVA (time delay) concentrations could not be described by this model. These results indicated that other factors might be necessary to explain the time courses of the DOPAC and HVA concentrations in the striatum after PEA injection, such as the separate evaluation of the effect of PEA on the reuptake of DA into DA neuronal terminals and on the monoamine oxidase-B (MAO-B) activity in the DA neuronal terminals, and the metabolic pathway from DOPAC to HVA.

Pharmacokinetics of phenolsulfonphthalein in sheep

Summary Pharmacokinetic variables of phenolsulfonphthalein (psp) were determined in sheep after rapid iv injection and iv infusion to steady state. In Suffolk wethers, an average of &lt; 75% of an iv administered dose was eliminated in urine, indicating that measures of systemic clearance overestimate renal clearance in this species. Furthermore, psp elimination from plasma was more rapid in Suffolk than Rambouillet wethers and, in Suffolk ewes, systemic clearance decreased from mean ± sd 7.8 ± 0.3 ml/min/kg of body weight to 4.7 ± 1.1 ml/min/kg at steady-state plasma concentration of 2.4 ± 0.3 and 151.3 ± 31.8 μg/ml, respectively. These observations indicate that, similar to that in other species, systemic clearance of psp in sheep is concentration-dependent and that significant differences may exist between breeds.

Pulmonary Mechanical Responses to Intravenously Administered Capsaicin in Guinea-pigs: Effect of Peptidase Inhibitors

Summary: In order to examine the role of peptidases in modulating bronchoconstrictor responses to iv administered capsaicin, a potent C-fiber stimulant, we measured changes in pulmonary conductance ( G L ) and dynamic compliance ( C dyn) in anesthetized mechanically ventilated guinea-pigs. Control guinea-pigs, and guinea-pigs treated with the neutral endopeptidase (NEP) inhibitors thiorphan (1.7 mg/kg) or SCH32615 (1 mg/kg), the angiotensin converting enzyme (ACE) inhibitor captopril (5.7 mg/kg), or combinations of NEP and ACE inhibitors, were given increasing doses of capsaicin by rapid iv injection. The doses of capsaicin required to cause a 50% decrease in G L and C dyn (ED 50 G L and ED 50 C dyn respectively) were computed for each animal. None of the peptidase inhibitors, when given alone, had any effect on the changes in pulmonary mechanics induced by capsaicin. However, combined administration of thiorphan and captopril, or SCH32615 and captopril, caused a decrease in ED 50 C dyn for capsaicin, and prolonged the time during which the peak changes in G L induced by capsaicin persisted. These data support the hypothesis that substances whose degradation is inhibited by combined NEP and ACE inhibitors contribute to the bronchoconstriction induced by iv administered capsaicin. This profile of enzymatic degradation is consistent with the tachykinin, substance P.

Evaluation of a single injection of 99mTc-labeled diethylenetriaminepentaacetic acid for measuring glomerular filtration rate in horses

Summary Glomerular filtration rate (gfr) was measured in 12 clinically normal horses, using the standard inulin clearance method, and values were compared with values for 2 methods, using a single rapid iv injection of 99mTc-la-beled diethylenetriaminepentaacetic acid (99mTc-dtpa). The first 99mTc-dtpa method used a 2-compartment model to calculate gfr blood clearance of the tracer. The second method used sequential digital gamma camera images of the kidneys to determine fractional accumulation of the total dose of the tracer in the kidneys (percentage of injected dose, gamma camera) from 0 to 10 minutes after radionuclide administration. Linear correlation among the 3 methods was determined. Mean (± SD) gfr, using the inulin clearance method, was 154.67 ± 42.28 ml/min/100 kg of body weight. Mean gfr, using the 2-compartment blood clearance curve, was 146.92 ± 27.49 ml/min/100 kg. Mean gfr, using percentage of injected dose (gamma camera method) was 154.7 ± 22.00 ml/min/100 kg. The percentage of injected dose (gamma camera method) did not correlate significantly to the inulin clearance results. However, a significant (r = 0.666, P &lt; 0.018) correlation was observed between the inulin method and the 99mTc-dtpa blood clearance method. Significant (P &lt; 0.0001) difference also was observed in the split function of the equine kidneys, with gfr of the right kidney contributing 60.1 ± 9.12% of the total function, as determined by 99mTc-dtpa gamma camera imaging. Because the 99mTc-dtpa blood clearance method does not require urine collection, it may be a more practical procedure to measure gfr in the horse.

Indocyanine green disposition in healthy dogs and dogs with mild, moderate, or severe dimethylnitrosamine-induced hepatic disease

Summary Disposition kinetics of indocyanine green (icg) were used to evaluate hepatic function in healthy Beagles (group 1; n = 6) and Beagles with progressive hepatic disease induced by oral administration of dimethylnitrosamine, a hepatospecific toxin. Three classes of hepatic disease were defined by histologic features: mild (group 2; n = 5), moderate (group 3; n = 6), and severe (group 4; n = 5). Disposition of icg was studied 3 weeks following the last dose of toxin. A rapid iv injection of 0.5 mg of icg/kg was administered and serum samples were obtained at certain intervals during 60-minute periods. Serum icg was analyzed by use of visible spectrophotometry. Disposition kinetics were determined from serum icg concentrations vs 15- and 60-minute time curves and compared between one another and among groups. Data based on 60-minute time curves were not significantly different from those based on 15-minute curves. Area under the curve for icg was greatest in group 3. Clearance of icg was decreased and mean resident time was increased in groups 3 and 4, compared with those in groups 1 and 2. When disposition data (60 minutes) were normalized for differences in hepatic weight among dogs, group-3 mean resident time was significantly greater than that of group 4. This study supports the diagnostic benefits of using icg disposition kinetics as a method of evaluating hepatic function in dogs with progressive liver disease.

A dose-response study of nalbuphine for post-thoracotomy epidural analgesia

The analgesic efficacy and side-effects of epidural nalbuphine (0.075-0.3 mg.kg-1) were compared with epidural morphine 0.1 mg.kg-1 in a randomised double-blind study in post-thoracotomy patients. The drugs were administered via a lumbar epidural catheter one hour before the end of surgery. Efficacy was assessed using visual analogue pain scores and supplementary iv fentanyl requirements; respiratory function was studied with an inductive plethysmograph and arterial blood gas analysis; and plasma nalbuphine levels were measured. Pain scores and fentanyl supplementation were lowest in the morphine group (P less than 0.01). No dose-response effect was apparent in the nalbuphine dose-range studied. Respiratory depression was more common in patients receiving morphine (higher mean PaCO2P less than 0.01, more frequent apnoeas greater than 15 sec P less than 0.05, and incidence of PaCO2 greater than 50 mmHg requiring naloxone P less than 0.01). There were no differences in haemodynamic variables, sedation, or other side-effects among the groups. The pharmacokinetic profile of epidural nalbuphine was similar to that seen with rapid iv injection. The results indicate that, relative to morphine, lumbar epidural nalbuphine is an ineffective analgesic after thoracotomy. Despite the lower incidence of respiratory depression its administration by this route cannot be recommended.

Stimulation of testosterone production in the cynomolgus monkey in vivo by deglycosylated and desialylated human choriogonadotropin.

Modifications of carbohydrate structures of hCG, such as deglycosylation or desialylation, have been shown to reduce the biological activity of the hormone derivatives in vivo. We posed the question of whether deglycosylated hCG (dg-hCG) and desialylated hCG (ds-hCG) would behave as agonists at the LH/CG receptor in the primate in vivo, as this would bear on their potential clinical utility as LH/CG agonists or antagonists. Thus, we administered large doses (approximately 3 nmol) of highly purified dg-hCG, ds-hCG, hCG, or normal saline as a rapid iv injection to adult male cynomolgus monkeys (n = 3/group). Mean areas under the curves of plasma T over the first 6 h achieved with dg-hCG and ds-hCG were about 5-fold, significantly (P less than 0.05) greater than that in the saline controls and not significantly (P greater than 0.05) different from that in hCG-injected animals. Despite comparable plasma T responses in the first 6 h, mean plasma concentrations of ds-hCG, dg-hCG, and hCG differed dramatically among the groups. Plasma ds-hCG and dg-hCG levels were undetectable by 15 and 180 min, respectively, while the mean plasma hCG level was more than 2.10 nmol/L at 360 min. These data indicate that 1) dg-hCG is a full agonist at the LH/CG receptor in the primate in vivo, despite having minimal intrinsic activity in the rat Leydig cell adenyl cyclase assay and being able to near-completely antagonize hCG action therein; and 2) ds-hCG is a full agonist in the monkey in vivo, capable of stimulating a full testicular response over 6 h, despite being cleared from the circulation in 15 min. We conclude that the signal transduction system at the monkey LH/CG receptor is capable of achieving full steroidogenesis despite dramatically shortened exposure to stimulus or exposure to a stimulus with markedly reduced adenyl cyclase-stimulating activity in vitro.

Prolactin and calcium metabolism: influence of hyperprolactinemia on immunoreactive parathyroid hormone levels in man and in the rat.

Serum prolactin, parathyroid hormone, P and Ca serum levels were measured in 15 patients (12 women and 3 men) with hyperprolactinemia, and in 6 normal male volunteers who underwent a TRH test (100 micrograms by rapid iv injection) in order to obtain a short-term pharmacologically-induced hyperprolactinemia. A pituitary gland graft under the kidney capsule was carried out on 26 Sprague-Dawley male rats, which became hyperprolactinemic since the transplanted pituitary was stripped of the inhibitory hypothalamic control. Another group of 10 rats was injected with L-sulpiride (0.1 mg/kg). The serum PTH levels in patients and in subjects with induced hyperprolactinemia were within the normal range and there was no correlation between serum PRL and PTH levels. The same occurred both in transplanted and L-sulpiride injected rats. Our results suggest that prolactin does not modify PTH secretion in vivo and therefore, in contrast with previous data, it should not be considered a physiologically relevant secretagogue for parathyroid hormone.

A phase-II clinical trial of 4'-epi-doxorubicin in advanced solid tumors.

Sixty-six patients with advanced solid tumors were treated with 4'-epi-doxorubicin at a dose of 90 mg/m2 by rapid IV injection every 21 days until the disease had progressed or to a maximum cumulative dose of 540 mg/m2. Myelosuppression, nausea and vomiting, and alopecia were the almost frequent side effects, but their incidence seemed lower than that after a comparable dosage of doxorubicin. After a cumulative dose of 540 mg/m2 a significant decrease of QRS complex deflection on the electrocardiogram was detected, but no case of congestive heart failure was observed. Partial remission and minor remission were achieved, respectively, in nine (15%) and five (9%) out of 59 evaluable patients for a median duration of 6 months. Partial remission occurred in anthracycline-sensitive tumors like breast cancer (4 of 13), lung cancer (1 of 17), head and neck cancer (1 of 8), gastric cancer (2 of 4), and ovarian cancer (1 of 1).

Preclinical toxicology studies with acyclovir: Acute and subchronic tests

Acyclovir (ACV), a new antiherpes drug, was evaluated for toxicity in a series of acute and subchronic toxicity tests. Oral LD 50 values were greater than 10 000 mg/kg in male ICR mice and greater than 20 000 mg/kg in male Long Evans rats. When ACV was given iv, the LD 50 was 405 mg/kg for male mice and greater than 600 mg/kg for male rats. Additionally, LD 50 values for male rats treated sc were 1070, 790, 678, and 650 mg/kg in rats that were respectively, 3, 10, 28 and 71 days old indicating that very young rats were not more sensitive to acute toxic effects of ACV. There were no signs of toxicosis in CD-1 mice given ACV by gavage at dose levels of 50, 150 and 450 mg/kg/day for 1 month. Obstructive nephropathy occurred in rats given 20, 40 and 80 mg/kg/day once each day by rapid iv injection for 3 weeks. Both 5 and 10 mg/kg/day were no effect dose levels. Renal damage caused by precipitation of drug crystals in renal tubules and collecting ducts in rats given ACV by rapid iv injection was readily reversible within 2 weeks. Beagle dogs were given doses of 10, 20, 25, 50 and 100 mg/kg b.i.d. by rapid iv injection for 1 month. All 8 dogs given 100 mg/kg b.i.d. died by the 8th day of treatment; 5 of 8 dogs given 50 mg/kg b.i.d. died after 21 to 31 days of treatment. At 50 and 100 mg/kg b.i.d. the clinical signs of toxicosis were numerous and mainly resulted from the underlying morphological and functional changes associated with hypoplasia of the esophageal and gastrointestinal mucosa, lymphoid tissue, and bone marrow. At the 20 and 25 mg/kg b.i.d. dose levels the kidney was the target organ; the principal indications of altered renal function were increased water intake and hyposthenuria. The dose level of 10 mg/kg b.i.d. was a no effect level for Beagle dogs treated iv. Thus, in subchronic experiments, the rapid iv injection of acyclovir caused precipitation of crystals in the renal tubules, resulting in obstructive nephropathy in rats and dogs. Primary toxicity occurred only in the dog where high doses of acyclovir caused hypoplasia of certain tissues with rapid cell turnover.

The effect of lithium on glucose- and tolbutamide-induced insulin release and glucose tolerance in the intact rat.

The effects of lithium on stimulus-induced insulin release and glucose tolerance were examined in intact, unanesthetized, and unrestrained rats with indwelling intravascular catheters. In the first study, a 150-mg iv glucose pulse was administered at 30 min after rapid iv injection of lithium carbonate (1 meq/kg) or vehicle. After the glucose pulse, mean serum glucose levels throughout the observation period were significantly greater in the lithium-treated rats than in the vehicle-treated (control) rats. Similarly, a mean glucose disappearance rate of 2.8 +/- 0.2%/min in the lithium-treated rats was significantly less (P < 0.02) than the mean glucose disappearance rate of 3.4 +/- 0.2%/min observed in the control rats. In response to glucose pulse, acute insulin release was significantly inhibited in the lithium-treated rats compared with that observed in the control rats. In the second study, a 10-mg tolbutamide pulse was administered 30 min after a rapid iv injection of lithium carbonate or vehicle. Acute insulin release in response to tolbutamide pulse was markedly inhibited in the lithium-treated rats compared with that observed in the control rats. In lithium-treated rats, the decline in serum glucose between 10-45 min after the tolbutamide pulse was significantly less than that observed in the control rats. Therefore, in the intact rat, lithium inhibits glucose- and tolbutamide-induced insulin release, which, in turn, causes glucose intolerance and prevents tolbutamide-induced hypoglycemia.

Hormone ontogeny in the ovine fetus. VIII. The effect of thyrotropin-releasing factor on prolactin and growth hormone release in the fetus and neonate.

As part of studies on the ontogeny of PRL secretion and regulation, the effect of TRF on PRL release was studied in the chronically catheterized ovine fetus and neonate. After a 2-h control period, 250 μg TRF were given by rapid iv injection to seven fetuses between 88—133 days gestation (term, 147 days) and five lambs between 4—17 days old. All animals exhibited a prompt increase in the concentration of plasma PRL. In three fetuses with basal PRL concentrations less than 10 ng/ml (88, 89, and 111 days old), PRL rose from a mean value of 3.1 ± 2.0 to 11.5 ± 5.6 (SE) ng/ml 15 min after TRF and was 10.7 ± 5.0 ng/ml at 90 min. In four fetuses with basal PRL concentrations greater than 10 ng/ml (112, 121, 124, and 133 days old), significantly (P ≪ 0.05) more PRL was secreted; the mean concentration of PRL increased from 36.9 ± 12.1 to 88.2 ± 21.7 ng/ml at 15 min and was 77.8 ± 22.8 ng/ml at 90 min. In five neonates (5, 6, 10, 10, and 17 days old), PRL rose from 13.1 ± 2.3 to 81.6 ± 20.1 ng/ml at 15 min and fe...