Detomidine Binding to Guinea Pig Liver Imidazoline Receptors (I-Receptors) Shows Marked Positive Cooperativity

The binding of [³H]-idazoxan to guinea pig liver membranes was measured in the presence of 3 μM rauwolscine, which prevented the binding [³H]-idazoxan to α₂-adrenergic receptors. Under these conditions the radioligand bound to saturable imidazoline receptors (I-receptors) with a K_d of 18 nM and a B_max of 665 fmol mg^-1 protein. Six drugs which were used to compete for [³H]-idazoxan in the liver caused competition curves of widely varying steepness. Fitting the competition curves to the standard four parameter logistic function showed that the Hill coefficients (n_H) varied from 2.02 (detomidine) to 0.43 (UK-14,304), The n_H's obtained in liver for the six compounds correlated strongly (r = 0.99; P< 0.001) with the corresponding n_H's obtained in a previous study on the guinea pig kidney where the drugs were also tested in competition with [³H]-idazoxan (Wikberg et al. 1992). Good correlation was also found for the Log(K_i) values of drugs determined in the two tissues (r = 0.96; P< 0.005). Whereas the standard logistic function accurately described the competition curves of the 5 drugs tested in the liver for which the competition curve Hill coefficients varied between 0.43 to 1.41 (UK-14,304, rilmenidine, histamine and d- and 1-medetomidine), it did not accurately fit the detomidine competition curves. Instead the detomidine competition curves could be more accurately described by a model composed of the sum of two independent logistic functions. Using this model detomidine appeared to compete with [³H]-idazoxan with two apparent affinity components, one with a K_i of 0.26 μM and an n_H of 3.24 and the other with a K_i of 4.9 μM and an n_H of 1.09. The proportion of the affinity components were 72% of the higher and 28% of the lower affinity. The data are discussed with the notion that guinea pig liver and kidney I-receptors are similarly regulated by both positive and negative allosteric cooperative interactions.     

Autoradiographic discrimination of melanocortin receptors indicates that the MC3 subtype dominates in the medial rat brain

In the present study, we developed an autoradiographic method to visualize the distribution of melanocortin (MC) receptors 3 and 4 in sagittal sections of the rat brain. The method takes advantage of the MC3 and MC4 receptor selective compounds, γ1-MSH and HS014. First, we characterized the binding of γ1-MSH, HS014 and the radioligand [ ]NDP–MSH to the rat MC3 and MC4 receptors expressed in COS cells. [ ]NDP–MSH was found to be non-selective, whereas γ1-MSH showed a 40-fold preference for the rat MC3 receptor, and HS014 an over 300-fold preference to the rat MC4 receptor. Second, to discriminate between the MC3 and MC4 receptors in rat brain sections, the sections were incubated with [ ]NDP–MSH in the presence of graded concentrations of the MC3 selective ligand, γ1-MSH, or the MC4 selective ligand, HS014. From the autoradiograms thus made, competition curves of γ1-MSH and HS014 could be constructed for different regions of the rat brain. Our results indicate that in the nucleus accumbens shell, the medial preoptic area, and the ventromedial nucleus of the hypothalamus, there is a clear dominance of the MC3 receptor, whereas in the lateral septum and the olfactory tubercle, there seem to be present both MC3 and MC4 receptors, although the MC3 receptor may still be the dominating subtype. In the optic layer of the superior colliculus, our data indicate a more abundant expression of the MC4 receptor. In the ventral tegmental area, there might be an additional MSH-peptide binding site of unknown origin.     

Update on adverse drug events associated with parenteral iron.

BACKGROUND: We previously compared the safety profile of three formulations of intravenous iron used during 1998-2000 and found higher rates of adverse drug events (ADEs) associated with the use of higher molecular weight iron dextran and sodium ferric gluconate complex compared with lower molecular weight iron dextran. Since that time, iron sucrose has become widely available and clinicians have gained additional experience with sodium ferric gluconate complex. METHODS: We obtained data from the United States Food and Drug Administration (FDA) on ADEs attributed to the provision of four formulations of intravenous iron during 2001-2003, including higher and lower molecular weight iron dextran, sodium ferric gluconate complex and iron sucrose. We estimated the odds of intravenous iron-related ADEs using 2 x 2 tables and the chi(2) test. RESULTS: The total number of reported parenteral iron-related ADEs was 1141 among approximately 30,063,800 doses administered, yielding a rate of 3.8 x 10(-5), or roughly 38 per million. Eleven individuals died in association with the ADE. Relative to lower molecular weight iron dextran, total and life-threatening ADEs were significantly more frequent among recipients of higher molecular weight iron dextran and significantly less frequent among recipients of sodium ferric gluconate complex and iron sucrose. The absolute rates of life-threatening ADEs were 0.6, 0.9, 3.3 and 11.3 per million for iron sucrose, sodium ferric gluconate complex, lower molecular weight iron dextran and higher molecular weight iron dextran, respectively. Based on differences in the average wholesale price of iron sucrose and lower molecular weight iron dextran in the US, the cost to prevent one life-threatening ADE related to the use of lower molecular weight iron dextran was estimated to be 5.0-7.8 million dollars. The cost to prevent one lower molecular weight iron dextran-related death was estimated to be 33 million dollars. CONCLUSIONS: The frequency of intravenous iron-related ADEs reported to the FDA has decreased, and overall, the rates are extremely low. This is the fourth report suggesting increased risks associated with the provision of higher molecular weight iron dextran. Life-threatening and other ADEs appear to be lower with the use of non-dextran iron formulations, although the cost per ADE prevented is extremely high.     

Detection of immunoglobulin heavy chain gene rearrangements by polymerase chain reaction analysis on lymph node imprints and fine-needle aspirate smears: a comparison of five different imprint preparations.

Five different preparations of lymph node imprints from 39 patients were studied to determine which preparations are suitable for obtaining interpretable results with polymerase chain reaction (PCR)-based detection of immunoglobulin heavy chain gene rearrangements and whether there are significant discrepancies in the patterns obtained. The sensitivity and specificity of this test for the diagnosis of B-cell lymphoma were assessed. The five imprints were stained with May-Grünwald-Giemsa (MGG) and coverslipped, stained with MGG but not coverslipped, fixed in acetone only, air-dried only, or immunostained, respectively. The efficiency of the PCR was 0% for immunocytochemically stained slides, 87% for air-dried only and air-dried/MGG-stained/coverslipped slides, 95% for air-dried/MGG-stained/not coverslipped slides, and 100% for imprints that were air-dried/acetone-fixed. There was total agreement in results in 87% cases studied. Discrepancies never resulted in false-positive test results. The overall sensitivity was 50%, and specificity was 100%. Based on these results, we have devised guidelines for tissue treatment when only stained slides are available. In a prospective study with 19 fine-needle aspirate specimens, the efficiency of the PCR increased to 100%, and sensitivity improved to 81%.     

Nuclear DNA Distribution in Neuroendocrine Gastroenteropancreatic Tumors Before and During Treatment

The nuclear DNA contents of tumor cells in 73 patients with endocrine gastrointestinal tumors, 19 patients with endocrine pancreatic tumors (EPT) and 54 patients with malignant carcinoid tumors were determined before and after treatment. The DNA profiles were divided into diploid and aneuploid. In untreated patients, 9 out of 10 (90%) primary EPT and all 9 primary malignant carcinoid tumors (100%) were diploid. Tumor cell imprints from liver metastases of patients with untreated EPT showed aneuploidy in 5 of 11 cases, but only in 7 out of 46 DNA records from patients with untreated carcinoid liver metastases. DNA alteration from diploid to aneuploid profiles occurred in 2 patients with endocrine pancreatic tumors who had received chemotherapy. A change from diploid to aneuploid records was also seen in 7/23 (30%) carcinoid tumors after treatment. The DNA patterns before and after treatment did not show any correlation with survival or treatment response.     

Screen filtration pressure and quantity of microaggregates: a nonexisting relationship

In 22 units of stored canine blood, the relationships between screen filtration pressure and number and volumes of microaggregates were studied. No correlations were found. As high screen filtration pressure in transfused blood has been associated with organ dysfunction, its measurement may have some clinical merit.     

Three-Day Treatment of Acute Lower Urinary Tract Infections in Women

The aim of this study was to determine if a three-day treatment of lower urinary tract infection (UTI) is effective. 215 women with symptoms of lower UTI, seen in general practice, were randomly allocated to a double-blind study and given either amoxycillin 1000 mg twice a day for three days or trimethoprim 90 mg/sulphadiazine 410 mg (co-trimazine) 2 tablets initially, then one tablet twice daily for three days. 157 women (73%) had significant bacteriuria. Therapeutic efficacy was evaluated in 146 patients. One week after treatment had started, 88 % of the women in the amoxycillin group and 100% in the co-trimazine group were cured (p<0.01). After a follow-up period of four weeks, the cumulative relapse frequencies were 19% and 9% respectively. Adverse reactions were mild in most cases. Two patients, both on co-trimazine, had to discontinue treatment because of nausea and vomiting. Vulvovaginal irritation was more often reported by women treated with amoxycillin (n=8) than by those treated with co-trimazine (n = 1) (p<0.05). It is concluded that a three-day course of amoxycillin or co-trimazine in lower UTI is safe, causes few adverse reactions, is simple to administer and comfortable for the patient. Co-trimazine seems to be more effective than amoxycillin.     

Effect of cGMP Derivatives on Contraction Relaxation Cycle,Release of Norepinephrine and Protein Kinase Activity in Guinea Pig Vas Deferens

Abstract: Contractions of the guinea pigs vas deferens were induced by field stimulation and the effects of derivatives of cGMP were tested on the contraction-relaxation cycle. Relaxation was induced by 8-Br-cGMP and O^2′-mb-cCMP. On the contrary, db-cGMP and N²-mb-cGMP potentiated the contraction. The relaxant effect of 8-Br-cGMPwas not mimiced by 8-Br-5′GMP, instead the latter caused the opposite effect. Since neither 8-Br-cGMP nor db-cGMP affected the release of norepinephrine on field stimulation the cGMP derivatives induced their effects at a postsynaptic site. 8-Br-cGMP was found to be 100-fold more potent than cGMP to stimulate protein kinase activity in crude extracts from guinea pig was deferens. N²-mb-cGMP and O^2′-mbcGMP were approximately equipotent to cGMP while db-cGMP was less active. 8-Br-5′-GMP did not stimulate the protein kinase. It is suggested that the results support the hypothesis that cGMP acts as a relaxant in the smooth muscle of the vas deferens. The potentiation caused by db-cGMP and N²-mb-cGMP on contractions could be dependent on the substitution in the guanine moiety of the molecules with the butyryl group. Their effect was thus probably unrelated to a specific cGMP effect.     

Venous endoscopy in thrombectomy of the iliac veins using the choledochoscope

In the present communication venoscopy using a flexible choledochoscope is advocated after thrombectomy of the iliac veins. In 10 patients operated upon for occlusive thrombi in the pelvic veins, venoscopy was used to assess the status of the vein. The procedure was conveniently performed using a regular flexible choledochoscope. Venoscopy gave detailed information of the veins and lead to altered therapy in seven of the 10 patients. Venoscopy is recommended for intra-operative control during surgical thrombectomy and the use of a choledochoscope can simplify this procedure.