What is your diagnosis? Circumscribed metallic foreign body in the pelvic canal.
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Animals↗
Biomedical subjects
R J Barrett
Publications and source records attributed to R J Barrett.
N-0861 selectively antagonizes adenosine A1 receptors in vivo.
Experiments were performed to determine the antagonistic actions of (+/-)N6-endonorbornan-2-yl-9-methyladenine (N-0861) at A1 and A2 adenosine receptors in vivo, and to evaluate the pharmacodynamics of the observed responses. The selectivity of antagonism of A1 vs. A2 receptors by N-0861 was evaluated by generating dose-response curves to adenosine-induced bradycardia (A1 effect), and vasodilation in the in situ constant-flow perfused rat hindquarter vasculature (A2 effect). N-0861, at doses greater than or equal to 1 mumol/kg + 0.04 mumol/kg per min, i.v. produced dose-related rightward shifts of the A1 dose-response curve, but had no effect on the A2 dose-response curve at doses as high as 100 mumol/kg, i.v. In contrast, the non-selective A1/A2 adenosine receptor antagonist 8-phenyltheophylline antagonized both A1 and A2 receptor-mediated responses to adenosine. The minimum effective i.v. dose and the duration of action of N-0861 were determined by evoking bradycardic responses to i.v. adenosine (A1 effect) in anesthetized, vagotomized, beta-blocked rats before and after single bolus doses of vehicle or N-0861 (0.3, 0.6, 1.0, 3.0 or 10.0 mumol/kg). The lowest i.v. dose of N-0861 to antagonize A1 receptor-mediated bradycardia was 0.3 mumol/kg i.v.; the duration of effect ranged from 1 min (following 0.3-1 mumol/kg) to approximately 2.5 h (following 10 mumol/kg). N-0861 is a selective (by greater than or equal to 333-fold) antagonist of adenosine A1 receptors.
Adenine↗
Tolerance, withdrawal, and supersensitivity to dopamine mediated cues in a drug-drug discrimination.
Rats were trained to discriminate between 0.25 mg/kg amphetamine (AMPH) and 0.03 mg/kg haloperidol (HAL) in a two-lever drug discrimination task. In order to test for a drug-induced withdrawal state, animals were assigned to one of three chronic treatment groups and given injections of AMPH, HAL, or distilled water (DW) for 10 consecutive days. Subjects from each treatment condition were then tested at 24, 48, or 72 h after the final injection. At the 24 h retest interval, subjects injected with AMPH responded as though administered an acute dose of HAL (0.028 mg/kg) and subjects injected with chronic HAL responded as though administered an acute dose of AMPH (0.15 mg/kg). By 72 h choice behavior had returned to pretreatment values. To determine whether the rebound observed after 10 days of drug treatment was present after a single injection, independent groups of subjects were injected with single doses of either 10 mg/kg AMPH or 1.0 mg/kg HAL and then retested from 4 h to 48 h later. Single doses of both AMPH and HAL produced significant rebounds that peaked between 20 h (AMPH) and 24 h (HAL) following administration. In a third experiment, animals were tested with or without acute doses of drug following pretreatment with either HAL or AMPH. Receptor supersensitivity accounts for the tolerance observed to HAL 24 h after treatment with 1.0 mg/kg HAL, whereas receptor subsensitivity accounts for the tolerance observed 20 h after treatment with 10 mg/kg AMPH.
Animals↗
Phase II trial of ifosfamide and mesna in leiomyosarcoma of the uterus: a Gynecologic Oncology Group study.
OBJECTIVE: The purpose of this study was to evaluate the activity of ifosfamide (isophosphamide) in patients with advanced or recurrent leiomyosarcoma not previously exposed to chemotherapy. STUDY DESIGN: This is a phase II groupwide study of the Gynecologic Oncology Group. Thirty-five patients were treated with ifosfamide 1.5 gm/m2 daily intravenously for 5 days with mesna (mercaptoethane sodium sulfonate). Fifty-six patients had received prior abdominal hysterectomy and 15 prior radiotherapy. The dose was reduced to 1.2 gm/m2 daily in patients who had received prior radiotherapy. RESULTS: Gynecologic Oncology Group grade III or IV granulocytopenia occurred in 4 (11%) patients, and none had grade IV thrombocytopenia. One (2.8%) patient had grade IV neurotoxicity. Partial responses were observed in 6 of 35 (17.2%) patients. The 95% confidence interval for response was 6.6% to 33.7%. CONCLUSION: These results indicate that ifosfamide has modest activity in patients with advanced or recurrent leiomyosarcomas of the uterus.
Adult↗
Selective pelvic and periaortic lymphadenectomy does not increase morbidity in surgical staging of endometrial carcinoma.
OBJECTIVE: The objective of this study was to retrospectively assess whether there was increased morbidity associated with the addition of selective pelvic and periaortic lymphadenectomy to hysterectomy in patients with endometrial carcinoma. STUDY DESIGN: From 1977 through 1988, 196 patients undergoing selective pelvic and periaortic lymphadenectomy plus hysterectomy were compared with 104 patients who underwent hysterectomy alone for endometrial adenocarcinoma. RESULTS: Only after adjusting for covariates was selective pelvic and periaortic lymphadenectomy associated with a higher estimated blood loss, which increased linearly with weight and was higher for black than for white women. The transfusion rate was similar for the two groups (selective pelvic and periaortic lymphadenectomy 6%, hysterectomy 10%). The mean blood loss was significantly different among the four gynecologic oncology surgeons (range 343 to 652 ml). The operating time primarily depended on patient weight and race, surgeon, and estimated blood loss. Postoperative hospital stay increased significantly with age, surgeon, wound infections, thrombotic events, and serious complications. Selective pelvic and periaortic lymphadenectomy had no effect on wound infections, which were directly related to operating time. Seventy-five (38%) of the selective pelvic and periaortic lymphadenectomy group and 19 (18%) of the hysterectomy group (p < 0.01) received whole-pelvic radiation with no difference in bowel complications (selective pelvic and periaortic lymphadenectomy 2/75, hysterectomy 1/19). The risk of serious complications was associated only with increasing age. CONCLUSION: Selective pelvic and periaortic lymphadenectomy in patients with endometrial carcinoma does not significantly add to morbidity from hysterectomy, which is related primarily to other factors such as patient weight, age, and race; operating time; and surgeon.
Adenocarcinoma↗
Reproductive, menstrual, and medical risk factors for endometrial cancer: results from a case-control study.
OBJECTIVE: Our objective was to evaluate the risk for endometrial cancer in relation to reproductive, menstrual, and medical factors. STUDY DESIGN: A case-control study of 405 endometrial cancer cases and 297 population controls in five areas of the United States enabled risk to be evaluated. RESULTS: A major risk factor was the absence of a prior pregnancy (relative risk 2.8, 95% confidence interval 1.7 to 4.6). The protective effect of pregnancy appeared to reflect the influence of term births, because spontaneous and induced abortions were unrelated to risk. Among nulliparous women infertility was a significant risk factor, with women having sought medical advice having nearly eight times the risk of those without difficulty conceiving. After adjustment for other reproductive characteristics, age at first birth and duration of breast-feeding were not related to risk. CONCLUSIONS: Elevated risks were found for subjects reporting early ages at menarche (relative risk 2.4 for ages < 12 vs > or = 15) and longer days of flow (relative risk 1.9 for > or = 7 vs < 4 days), but there was no relationship with late ages at natural menopause. Height was not associated with risk, but there was a significant relation to weight, with the risk for 200 versus < 125 pounds being 7.2 (95% confidence interval 3.9 to 13.3). After adjustment for weight and other factors, histories of hypertension and gallbladder disease were not significantly related to risk, but an effect of diabetes persisted (relative risk 2.0, 95% confidence interval 1.1 to 3.6). Hirsutism developing at older ages was also significantly related (relative risk 2.0, 95% confidence interval 1.2 to 3.4).
Adult↗
A phase II trial of leuprolide acetate in patients with advanced epithelial ovarian carcinoma. A Gynecologic Oncology Group study.
Twenty-five evaluable patients with advanced or recurrent epithelial ovarian carcinoma that was no longer controllable with surgery, radiation therapy, and/or chemotherapy were treated with leuprolide acetate, a gonadotropin-releasing hormone agonist, 1 mg subcutaneously daily. One partial response (4%) was observed among the 25 patients. The upper 95% confidence bound of the response rate is 17.6%. Fifteen patients (60%) exhibited stable disease for at least 8 weeks, and 9 patients (36%) developed progressive cancer while receiving treatment. The regimen was well tolerated with no patient experiencing life-threatening toxicity. Mild toxicities included leukopenia in 2 patients (8%), thrombocytopenia in 2 patients (8%), gastrointestinal toxicity in 5 patients (20%), anemia in 4 patients (16%), hot flashes in 1 patient (4%), and facial swelling in 1 patient (4%). Thus, leuprolide acetate was well tolerated but has insignificant activity in treating patients with chemotherapy-refractory ovarian adenocarcinoma.
Adenocarcinoma↗
Combined interferon alfa and doxorubicin in the treatment of advanced cervical cancer.
Interferon alfa and doxorubicin have been shown to have synergistic effects when tested in vitro with cells derived from cervical cancers. A clinical trial was designed, testing interferon alfa plus doxorubicin in patients with advanced or recurrent cervical cancers. Twenty-one patients were given interferon alfa, 10 million units per square meter intramuscularly and 10 million units per square meter intravenously over a 30-minute infusion period. One hour later 20 mg/m2 doxorubicin was given intravenously slowly over a 2-hour period. Treatments were repeated once weekly for 3 weeks. Initial response evaluation was done at week 5, and treatment was continued on an every-other-week schedule for patients showing favorable responses or stable disease. Bone marrow, hepatic, and renal toxicities were minimal. Fever and malaise were the major sources of toxicity. Of the 17 evaluable patients, six had clinical partial responses. Two of the responders have enjoyed more than 5 years' survival. This regimen is well tolerated and does have efficacy in some patients with advanced cervical cancers.
Adenocarcinoma↗
Rebound cue state following a single dose of haloperidol.
It has been reported that chronic administration of haloperidol produces an amphetamine-like rebound cue state. The experiments reported here were designed to assess whether a similar rebound phenomenon would result from a single dose of haloperidol. Rats were trained to discriminate .5 mg/kg amphetamine from distilled water. Five groups were formed to allow testing of haloperidol's effect at 12, 18, 24, 30, and 36 hr postinjection. Each animal was given 0, .5, 1.0, and 1.5 mg/kg haloperidol at its appropriate injection time in a counterbalanced fashion with one week between each test. A shift in the dose-response function of amphetamine that occurred during these weeks, however, precluded appropriate analysis of haloperidol's effects. Given this result, a second experiment was conducted using a between-subjects design. Half of the animals were injected with 1 mg/kg haloperidol 23 hr prior to testing, whereas the others were injected with distilled water. When tested, the haloperidol group responded 33% of the time on the amphetamine-correct lever, whereas the control group responded at 20%. The observation of posthaloperidol rebound in the between-subjects study and the failure to find significant temporal patterns of rebound phenomena using a within-subjects design have both theoretical and methodological importance.
Amphetamine↗
Carbonic anhydrase inhibitors are antiarthritic in the rat.
Adjuvant-induced arthritis in rats was attenuated by the therapeutic administration of carbonic anhydrase inhibitors. Female Lewis rats with established disease were treated daily (day 18 through day 50) with various carbonic anhydrase inhibitors; oedema and joint integrity (X-ray) were determined post-treatment. Acetazolamide, ethoxzolamide, methazolamide, and dichlorphenamide reduced paw oedema and attenuated the deterioration of the joints of rats with adjuvant arthritis. However, no carbonic anhydrase inhibitor tested possessed significant, acute, anti-inflammatory activity in the carrageenan-paw oedema test. The activity of carbonic anhydrase inhibitors in the chronic model of inflammation may be due to their reported inhibition of bone resorption.
Acetazolamide↗
Synthesis, calcium-channel-blocking activity, and antihypertensive activity of 4-(diarylmethyl)-1-[3-(aryloxy)propyl]piperidines and structurally related compounds.
A series of 4-(diarylmethyl)-1-[3-(aryloxy)propyl]piperidines and structurally related compounds were synthesized as calcium-channel blockers and antihypertensive agents. Compounds were evaluated for calcium-channel-blocking activity by determining their ability to antagonize calcium-induced contractions of isolated rabbit aortic strips. The most potent compounds were those with fluoro substituents in the 3- and/or 4-positions of both rings of the diphenylmethyl group. Bis(4-fluorophenyl)acetonitrile analogue 79 was similar in potency to bis(4-fluorophenyl)methyl compound 1. The methylene analogue of 1 (78) and derivatives of 1 that contained a hydroxyl (76), carbamoyl (80), amino (81), or acetamido (82) substituent on the methyl group were less potent. In most cases, substituents on the phenoxy ring, changes in the distance between the aryloxy group and the piperidine nitrogen, and the substitution of S, N(CH3), or CH2 for the oxygen atom of the aryloxy group had only a small to moderate effect on the potency. The best compounds in this series were more potent than verapamil, diltiazem, flunarizine, and lidoflazine, but were less potent than nifedipine. Compounds were evaluated for antihypertensive activity in spontaneously hypertensive rats (SHR) at an oral dose of 30 mg/kg. Of the 55 compounds tested, only nine produced a statistically significant (p less than 0.05) reduction in blood pressure greater than 20%; all of these compounds had fluoro substituents in both rings of the diphenylmethyl group. One of the most active compounds in the SHR at 30 mg/kg was 1-[4-[3-[4-[bis(3,4-difluorophenyl)methyl]-1- piperidinyl]propoxy]-3-methoxyphenyl]ethanone (63), which produced a 35% reduction in blood pressure and was similar in activity to nifedipine. At lower doses, however, 4-[bis(4-fluorophenyl)methyl]-1-[3-(4-chlorophenoxy)propyl]piperidine (93) was one of the most effective antihypertensive agents, producing reductions in blood pressure of 17 and 11% at oral doses of 10 and 3 mg/kg, respectively; 63 was inactive at 10 mg/kg.
Animals↗
AHR-16303B, a novel antagonist of 5-HT2 receptors and voltage-sensitive calcium channels.
In vivo and in vitro methods were used to characterize AHR-16303B, a novel compound with antagonistic action at 5-HT2 receptors and voltage-sensitive calcium channels. The 5-HT2 receptor-antagonistic properties of AHR-16303B were demonstrated by inhibition of (a) [3H]ketanserin binding to rat cerebral cortical membranes (IC50 = 165 nM); (b) 5-hydroxytryptamine (5-HT)-induced foot edema in rats (minimum effective dose, (MED) = 0.32 mg/kg orally, p.o.); (c) 5-HT-induced vasopressor responses in spontaneously hypertensive rats (SHR) (ID50 = 0.18 mg/kg intravenously (i.v.), 1.8 mg/kg p.o.), (d) 5-HT-induced antidiuresis in rats (MED = 1 mg/kg p.o.), and (e) platelet aggregation induced by 5-HT + ADP (IC50 = 1.5 mM). The calcium antagonist properties of AHR-16303B were demonstrated by inhibition of (a) [3H]nimodipine binding to voltage-sensitive calcium channels on rabbit skeletal muscle membranes (IC50 = 15 nM), (b) KCl-stimulated calcium flux into cultured PC12 cells (IC50 = 81 nM), and (c) CaCl2-induced contractions of rabbit thoracic aortic strips (pA2 = 8.84). AHR-16303B had little or no effect on binding of radioligands to dopamine2 (DA2) alpha 1, alpha 2, H1, 5-HT1 alpha, beta 2, muscarinic M1, or sigma opioid receptors; had no effect on 5-HT3 receptor-mediated vagal bradycardia; and had only minor negative inotropic, chronotropic, and dromotropic effects on isolated guinea pig atria. In conscious SHR, 30 mg/kg p.o. AHR-16303B completely prevented the vasopressor responses to i.v. 5-HT, and decreased blood pressure (BP) by 24% 3 h after dosing.
Animals↗
Cardiovascular and renal actions of AHR-16303B, an antagonist of 5-HT2 receptors and calcium channels, in hypertensive and normotensive rats.
The cardiovascular and renal responses to AHR-16303B, a novel antagonist of 5-hydroxytryptamine (5-HT2) receptors and calcium channels, were examined in spontaneously hypertensive (SHR) and normotensive rats (NTR) and compared with verapamil and ritanserin. In SHR, AHR-16303B (10-300 mg/kg orally, p.o.) produced dose-related reductions in mean arterial blood pressure (MABP), accompanied by modest isokaliuretic diuresis and unchanged heart rate (HR). In NTR, 10-30 mg/kg p.o. AHR-16303B had no effect on MABP or renal excretory function; 100 and 300 mg/kg reduced MABP but had only transient effects on HR; 100 mg/kg produced antidiuresis in NTR. Both strains of rats tolerated doses of AHR-16303B as high as 300 mg/kg. In both SHR and NTR, verapamil (10-100 mg/kg p.o.) produced dose-related reductions in MABP, antinatriuresis at 60 and 100 mg/kg, and variable effects on HR. Oral ritanserin had no effect on MABP of SHR or NTR at 3 or 10 mg/kg. AHR-16303B is unique in that it simultaneously antagonizes 5-HT2 receptors and produces safe and effective reduction of elevated BP without altering HR or triggering renal compensatory antidiuresis. At effective 5-HT2/calcium antagonistic doses, AHR-16303B has no effect on cardiorenal homeostasis in normotensive animals.
Administration, Oral↗
Tuboovarian pregnancy associated with elevated maternal serum alpha-fetoprotein. A case report.
Tuboovarian implantation is a rare form of pregnancy that is difficult to diagnose in early gestation. A patient with a tuboovarian pregnancy presented with abnormally elevated initial screening maternal serum alpha-fetoprotein (MSAFP). The elevated MSAFP and a pelvic mass of uncertain etiology on ultrasonography delayed the diagnosis until laparotomy was performed. Elevated MSAFP accompanied by oligohydramnios and a pelvic mass is a particularly suspect finding for a tuboovarian or other type of extrauterine implantation.
Adult↗
Adaptation of brain 5HT2 receptors after mianserin treatment: receptor sensitivity, not receptor binding, more accurately correlates with behavior.
This study investigates the possibility that mianserin, a serotonin-2 (5HT2) receptor antagonist, produces a prolonged antagonism of quipazine discrimination, consistent with its prolonged biochemical effects. Rats were trained on a saline-quipazine (1.5 mg/kg) discrimination; following acquisition, the animals were assigned to groups and given injections of 2.0 mg/kg mianserin. Individual groups were tested at 45 min and successive 12-hr intervals for their ability to discriminate 0.75 mg/kg of quipazine, a dose that elicited 75% responding on the quipazine lever. Blockade of the quipazine cue persisted for 48 hr following mianserin administration. The above procedure was replicated using lower doses of mianserin (0.25, 0.10 and 0.05 mg/kg) and two other 5HT2 antagonists, pizotifen and metergoline (2.0 mg/kg), both of which showed similar profiles of extended antagonism. Changes in both receptor density and receptor sensitivity were investigated as possible mechanisms of mianserin's prolonged activity. Analysis of [3H]ketanserin binding revealed that a single 2.0-mg/kg dose of mianserin produced a significant decrease in the number of receptor sites (44%) 24 hr after treatment; however, this loss of sites recovered by 36 hr post-injection and could therefore not account for mianserin's continued antagonism at this and later times. 5HT-mediated phosphoinositide hydrolysis in cerebral cortex slices was used as a measure of 5HT2 receptor sensitivity. Treatment of rats with 2 mg/kg of mianserin caused a marked reduction in the maximum phosphoinositide response to 5HT that persisted for up to 36 hr. Hence, the time course for recovery of 5HT2 receptor sensitivity corresponded more closely to behavioral recovery than did 5HT2 receptor binding.
Animals↗
Drug discrimination training during chronic drug treatment affects the development of tolerance.
The purpose of this experiment was to evaluate the extent to which continued drug discrimination training during chronic drug treatment affects the development of tolerance. Rats were trained to discriminate distilled water from 0.75 mg/kg amphetamine in a two-lever drug discrimination task. Two groups were then given a chronic drug regimen of 13 daily injections of either distilled water or 10 mg/kg amphetamine. Drug discrimination training was continued for half of each chronic drug group. Tolerance was apparent only in the group that was not trained during the chronic amphetamine treatment. The data support the conclusion that continued training throughout the chronic drug treatment provides the opportunity for reinforced correct responding as both nondrug- and drug-cue states are gradually shifted by the chronic drug regimen.
Animals↗
Protective effect of p-chlorophenylalanine in glycerol-induced acute renal failure in rats.
1. Studies were conducted to test the hypothesis that glycerol-induced acute renal failure in rats may be mediated by 5-hydroxytryptamine. 2. The tryptophan hydroxylase inhibitor, p-chlorophenylalanine, or saline was administered for 4 days before performance of 24 h clearance studies after glycerol administration. 3. p-Chlorophenylalanine significantly reduced the nephrotoxic effect of glycerol, as evidenced by improved glomerular filtration rate, urine volume excretion and absolute sodium excretion, and reduced plasma creatinine concentration. 4. These results suggest that glycerol-induced acute renal failure may be mediated by the renovascular and/or tubular actions of 5-hydroxytryptamine.
Acute Kidney Injury↗
CA-125 values predictive of clinical response during second-line chemotherapy for epithelial ovarian cancer.
Between November 1984 and January 1987, 19 patients with epithelial ovarian cancer were monitored with CA-125 values during second-line therapy. There was a statistically significant association between clinical response to therapy and CA-125 trend when trend was defined as a greater than or equal to 26% change in CA-125 from baseline value to last value prior to demonstration of clinical response (p = 0.0002). In 8 of 11 patients (73%), increasing CA-125 values were predictive of clinical progression during second-line therapy. In six of seven patients (86%), decreasing values predicted clinical regression. Three patients began second-line therapy with baseline values less than 35 U/ml. Two of these progressed during second-line therapy while the third progressed in follow-up. Two of four complete clinical responders completed second-line therapy with values less than 35 U/ml. Both progressed in follow-up with increasing CA-125 values. In this analysis, a 26% change in CA-125 values was a useful predictor of clinical response in patients receiving second-line therapy for epithelial ovarian cancer. Patients undergoing second-line chemotherapy with values less than 35 U/ml may still benefit from CA-125 monitoring.
Adenocarcinoma↗