Biomedical subjects

C Kaiser

Publications and source records attributed to C Kaiser.

At least 55 records · Page 3Linked to original sources

PubMed1994

Sonographical morphometrical findings of the liver and spleen in Sudanese patients with Schistosoma mansoni induced periportal fibrosis.

Sonographic measurements of the liver, spleen and related blood vessels were performed in 87 healthy controls and in 50 patients with periportal fibrosis (pF) as well as in 52 patients with pF and at least one episode of gastro-oesophageal bleeding due to chronic Schistosoma mansoni infection. There was a progressing shrinkage of the liver paralleled by an increasing rate of patients with a larger left than right liver lobe as involvement of pF due to S. mansoni infection progressed. This was accompanied by an increasing percentage of pathological gallbladder wall enlargement, splenomegaly and an increasing portal vein diameter. It is suggested that organomorphometrical parameters of the liver and spleen can be used for sonographical evaluation of patients with S. mansoni infection as these may be useful for their clinical assessment of the progression of disease.

Adult↗

PubMed1993

A phenylalanine codon deletion at the UGT1 gene complex locus of a Crigler-Najjar type I patient generates a pH-sensitive bilirubin UDP-glucuronosyltransferase.

The characterization (Ritter, J. K., Chen, F., Sheen, Y. Y., Tran, H. M., Kimura, S., Yeatman, M. T., and Owens, I. S. (1992) J. Biol. Chem. 267, 3257-3261) of the single-copy UGT1 gene complex encoding both bilirubin and phenol UDP-glucuronosyltransferases (transferase) has been critical to the determination of genetic defects in Crigler-Najjar Type I patients. The complex (UGT1A-UGT1G) codes for at least two bilirubin, three bilirubin-like, and two phenol transferases. Seven different exons 1, each with an upstream promoter and each encoding the amino terminus of an isoform, are arrayed in series with four common exons (encoding seven identical carboxyl termini) in the 3'-region of the locus. Predictably, a critical mutation in a common exon inactivates the entire locus. A deleterious mutation in an exon 1, as we report here for the UGT1A gene in a Crigler-Najjar Type I patient, predictably affects the amino terminus of that single isoform. The code for the predominant bilirubin isozyme, the HUG-Br1 protein, is missing the phenylalanine codon at position 170 in exon 1 of UGT1A, abolishing a conserved diphenylalanine. We demonstrate that, at the pH (7.6) routinely used for bilirubin glucuronidation studies, both the HUG-Br1 protein and human liver microsomes have approximately one-third the activity seen at the major pH optimum of 6.4 and at low ionic strength. The altered isozyme with nearly normal activity at pH 7.6 is inactive at pH 6.4, a result consistent with the definition of a pH-sensitive mutant. The Km value for bilirubin using the wild-type protein is approximately 2.5 microM at both pH 6.4 and 7.6 and that for the mutant is 5.0 microns at pH 7.6. The structure of the wild-type enzyme compared to that of the mutant indicates that hydrophobic properties at the active center are critical for metabolizing the lipophile-like substrate. The low ion/pH requirements for bilirubin glucuronidation may signal the basis for the distribution of these isozymes to an organelle (endoplasmic reticulum) that can establish compatible conditions/compartments for each catalysis.

Alleles↗

PubMed1993

Examination of the D2/5-HT2 affinity ratios of resolved 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indoles: an enantioselective approach toward the design of potential atypical antipsychotics.

Enantiomers of several N-substituted 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indoles were obtained by the resolution of 2-fluoro-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole and 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole followed by N-alkylation. These, as well as the racemates, were evaluated for their affinity for the 5-HT2 and D2 receptors. Those compounds possessing the 7S,10R stereochemistry were consistently recognized by the 5-HT2 and D2 receptors as the eutomer. 2-Fluoro-11-[4-(4-fluorophenyl)-4-oxobutyl]-5,6,7,8,9,10-hexahydro-7S,10 R- iminocyclohept[b]indole [(7S,10R)-8] had the highest affinity for the 5-HT2 receptor (Ki = 0.80 nM), while its distomer (7R,10S)-8 was the most selective member of this class of bridged gamma-carbolines (D2/5-HT2 = 562). Incorporation of a benzoyl or isosteric benzisoxazole moiety tethered by a four-carbon spacer to a bridged gamma-carboline nucleus, possessing the 7S,10R absolute configuration, produced high affinity ligands for the 5-HT2 and D2 receptors.

Antipsychotic Agents↗

PubMed1993

Bridged gamma-carbolines and derivatives possessing selective and combined affinity for 5-HT2 and D2 receptors.

A series of 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indoles and 6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indoles was prepared. Structural modifications of the lead compound, 11-[4-(4-fluorobenzoyl)propyl]-5,6,7,8,9,10-hexahydro-7,10- iminocyclohept[b]indole (5, Ki = 0.82 nM vs [3H]ketanserin) enabled the identification of the functionality necessary for high affinity at serotonin 5-HT2 and dopamine D2 receptors in ligand binding studies. The indole ring, as well as the benzoyl or isosteric benzisoxazole moiety, were essential for high affinity. Variations of the length of the side chains resulted in ligands having either selective affinity for the 5-HT2 receptor or a combination of 5-HT2 and D2 affinity. In vivo binding studies were performed on selected members in this series. The most potent member, 2-fluoro-11-[4-(4-fluorobenzoyl)butyl]-5,6,7,8,9,10-hexahydro-7,10- iminocyclohept[b]indole (36) had an ED50 of < 1 mg/kg at the 5-HT2 and D2 receptors following oral administration.

Animals↗

PubMed1993

Synthesis and antimuscarinic activity of some 1-cycloalkyl-1-hydroxy-1-phenyl-3-(4-substituted piperazinyl)-2-propanones and related compounds.

A new class of substituted 1-phenyl-3-piperazinyl-2-propanones with antimuscarinic activity is reported. As part of a structure-activity relationship study of this class, various structural modifications, particularly ones involving substitution of position 1 and the terminal piperazine nitrogen, were investigated. The objective of this study was to derive new antimuscarinic agents with potential utility in treating urinary incontinence associated with bladder muscle instability. These compounds were examined for M1, M2, and M3 muscarinic receptor selectivity in isolated tissue assays and for in vivo effects on urinary bladder contraction, mydriasis, and salivation in guinea pigs. Potency and selectivity in these assays were influenced most notably by the nature of the substituent group on the terminal nitrogen of the piperazine moiety. Benzyl substitution was particularly advantageous in producing compounds with functional M3 receptor (smooth muscle) and bladder selectivity; it provided several candidates for clinical study. In vivo, 3-(4-benzyl-piperazinyl)-1-cyclobutyl-1-hydroxy-1-phenyl-2-propanone (24) demonstrated 11- and 37-fold separations in its effect on bladder function versus mydriatic and salivation responses, respectively. The corresponding 2-chlorobenzyl derivative 25 was more than 178-fold selective for M3 versus M1 and M2 muscarinic receptors. 3-(4-Benzylpiperazinyl)-1,1-diphenyl-1-hydroxy-2-propanone (51) was 18-fold selective for M3 versus M1 and 242-fold selective for M3 versus M2 receptors. It was also selective in guinea pigs, where it displayed 20- and 41-fold separations between bladder function and effect on mydriasis and salivation, respectively. In general, the results of this study are consistent with the proposition that the described piperazinylpropanones interact with muscarcinic receptors in a hydrogen-bonded form that presents a conformation similar to that apparently adopted by classical antimuscarinic agents.

Animals↗

PubMed1993

Synthesis and in vitro evaluation of 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indoles: high-affinity ligands for the N,N'-di-o-tolylguanidine-labeled sigma binding site.

A series of 5,6,7,8,9,10-hexahydro-7,10-iminocyclo[b]indoles substituted at the 5 and/or 11 positions was synthesized from tropinone. Affinity for sigma binding sites was determined using [3H]-N,N'-di-o-tolylguanidine ([3H]DTG) and [3H]-(+)-3-(3-hydroxyphenyl)-N-1-propylpiperidine ([3H]-(+)-3-PPP) and for the dopamine D2 receptor labeled with [3H]sulpiride. Nearly all compounds studied in this series possessed a higher affinity for [3H]DTG than [3H]-(+)-PPP-labeled sigma sites, suggesting that [3H]DTG and [3H]-(+)-3-PPP radioligands label pharmacologically distinct sigma binding sites, as reported previously. Substitution at the 11 position with side chains containing a four-carbon tether resulted in compounds having the highest affinity for the [3H]DTG-labeled sigma site. The most potent and selective member of this series was 11-[4-(2-furanyl)butyl]-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept [b] indole (40). Enantioselectivity was investigated by preparing the (+)- and (-)-isomers of 40. These studies revealed that (+)-40 was more potent at the [3H]-DTG-labeled sigma site whereas (-)-40 had a higher affinity at sigma sites labeled with [3H]-(+)-PPP. Racemic 40 was observed to possess a higher affinity than either of its respective enantiomers at both the [3H]DTG- and [3H]-(+)-3-PPP-labeled sites, suggesting an allosteric interaction.

Animals↗

PubMed1993

[Ultrasound diagnosis of the acute abdomen].

In addition to plain X-ray of the abdomen, ultrasonography has proven to be an accurate complementary imaging method in acute abdominal disorders. It may furnish not only additional information but also the final diagnosis in many cases (i.e. acute cholecystitis, pancreatitis, diverticulitis, appendicitis and gynecological diseases). Ultrasound is the method of first choice especially in children, adolescents, young women and when inflammation appears to be the reason for acute abdominal pain. In this paper, the main indications for ultrasound in acute abdominal diseases are pointed out. The most common diseases are shown with their typical ultrasound appearances in short overviews. Particular reference is made to a critical approach, emphasizing relevant further investigations.

Abdomen, Acute↗

PubMed1993

[Sonography of acute appendicitis. A 5-year prospective study of 2074 patients. 2].

High-resolution real-time ultrasound (US) with a 5 MHz transducer has proved to be an important method in the diagnosis of acute appendicitis. In a prospective study we examined 2074 unselected patients with suspected appendicitis to assess the diagnostic and epidemiological value of US. According to the clinical diagnosis females aged 10 to 30 represented the majority of suspected cases. Appendicitis was most often proved in male patients aged 15-30 years. The prevalence of acute appendicitis in childhood is lower (7%) than in elderly patients (33%). US enables the diagnosis of acute appendicitis with a sensitivity of 91%, a specificity of 98% and an overall accuracy of 97%. For differential diagnosis US demonstrates other diseases that mimic acute appendicitis. Thus it is possible to reduce the negative appendectomy rate particularly in children by revealing mesenteric lymphadenitis or terminal ileitis and in young women by directing attention to gynecological diseases.

Acute Disease↗

PubMed1993

NPC 16377, a potent and selective sigma-ligand. I. Receptor binding, neurochemical and neuroendocrine profile.

6-[6-(4-Hydroxypiperidinyl)hexyloxy]-3-methylflavone HCI (NPC 16377), a structurally novel compound, was found to be a highly potent and selective ligand for sigma-sites. Although 5-fold less potent than haloperidol and 2-fold less potent than ifenprodil to inhibit 1,3-di-o-tolylguanidine binding, NPC 16377 (IC50 = 36 nM) was more potent than alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl butanol (BMY 14802), rimcazole and the atypical antipsychotic, clozapine. A similar rank order of potency was observed when [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperdine was used as the radioligand. Like BMY, rimcazole and clozapine, NPC 16377 (IC50 = 2671 nM) had low affinity for dopamine type 2 receptors. Additionally, the compound was only weakly active in 35 additional receptor binding assays including those for serotonin2 and serotonin1C receptors. In vivo, NPC 16377 potently inhibited the binding of [3H]-(+)-N-allylnormetazocine to sigma sites after both intraperitoneal and oral administration. At doses 30-fold in excess of the ID50 to inhibit [3H](+)N-allylnormetazocine, NPC 16377 failed to displace [3H]raclopride from dopamine type 2 binding sites. Unlike haloperidol, BMY 14802, ifenprodil and clozapine, behaviorally effective doses of NPC 16377 did not increase dopamine turnover in the frontal cortex, nucleus accumbens or corpus striatum of rats. In contrast, each of these agents increased circulating levels of both adrenocorticotropin and corticosterone, but only NPC 16377 decreased circulating plasma levels of prolactin. The results of the current study are consistent with the notion that NPC 16377 is a potent, selective and orally active sigma site ligand. At behaviorally relevant doses the compound produces neuroendocrine effects both similar to, and different from, neuroleptics, other sigma-ligands and atypical antipsychotics, while having no effect on dopamine turnover. Given these data, NPC 16377 should prove to be a useful compound to explore further the physiological and functional significance of sigma-sites in brain.

Adrenocorticotropic Hormone↗

PubMed1992

Synthesis and antimuscarinic properties of some N-substituted 5-(aminomethyl)-3,3-diphenyl-2(3H)-furanones.

In a study aimed toward developing new, selective antimuscarinic drugs with potential utility in the treatment of urinary incontinence associated with bladder muscle instability, a series of N-substituted 5-(aminomethyl)-3,3-diphenyl-2(3H)-furanones, conformationally-constrained lactone relatives of benactyzine, was prepared. The compounds were examined in several paradigms that measure muscarinic (M1, M2, and M3) receptor antagonist activity. Selected members of the series that displayed potency and/or selectivity in these tests were studied for their effects on urinary bladder contraction, mydriasis, and salivation in guinea pigs. These studies revealed that incorporation of the amino functionality into an imidazole or pyrazole ring resulted in some novel, potent, and selective antimuscarinic agents. Appropriate alkyl substitution of position 2 of the imidazole strikingly affected muscarinic, particularly M3, receptor activity and may reflect a complementary site of interaction. Some of the compounds selectively reduced bladder pressure in a cystometrogram (CMG) model without producing concomitant mydriatic and salivary effects. The separate and distinct action of several compounds of this series in these in vivo protocols suggests the possibility of subtypes of muscarinic receptors that may correspond to previously characterized molecular cloned subpopulations. In this article, structure-activity relationships for the series of substituted lactones are discussed. These studies led to the identification of (R)-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4,5-dihydro-3,3-diphenyl-2(3H )- furanone (23) as a clinical candidate for treating urinary bladder dysfunction.

Animals↗

PubMed1992

Urine test strips: reliability of semi-quantitative findings under tropical conditions.

Semi-quantitative urinalysis with urine reagent strips (URS) for erythrocyturia (EU), leucocyturia (LU) and proteinuria (PU) was performed in Congolese and Sudanese school children with Schistosoma haematobium and/or S. mansoni infection. Quantitative urinalysis was performed on the same specimen using microscopy and a Neubauer counting chamber for EU and LU and the Coomassie blue dye-binding assay for PU. Microscopically detectable EU of more than 10 cells/microliters was found in 63% of all samples and LU of more than 20 cells/microliters was found in 60% of all samples. With the Coomassie blue method, PU of more than 150 mg/l was detected in 51% of all samples. URS gave positive results of grade 1-3 for EU in 69% of all samples, for LU in 63% of all samples and for PU in 66% of all samples. The sensitivity and specificity of URS compared with standard reference methods were as follow: EU 95% and 75%, LU 81% and 81% and PU 90% and 56%. When the results of all three test were combined, URS differentiated abnormal from normal urine specimens with a sensitivity of 94% and a specificity of 70%. Median quantitative results showed a good correlation with semiquantitative URS readings for all parameters, but there was a wide range of URS scores. We concluded that URS sensitivity detect urinary abnormalities and thus may be used as a general screening method under field conditions when more specific methods cannot be performed.(ABSTRACT TRUNCATED AT 250 WORDS)

Congo↗

PubMed1992

Inter-observer variance in ultrasonographical assessment of Schistosoma mansoni-related morbidity in young schoolchildren.

49 Sudanese schoolchildren aged 6-9 years with Schistosoma mansoni infection were ultrasonographically examined by two independent observers in a double-blind fashion. The first observer recorded normal appearance of the liver in 23 cases, whereas the second observer recorded the appearance as normal in 33 cases. There were 23 concordant observations. For Grade I periportal fibrosis (PF), 13 observations were concordant. PF Grade II was rarely observed (2 versus 3 cases), and Grade III was not recorded at all. In total, 38 out of 49 observations were concordant (77.5%). These preliminary data from two ultrasound observers, from observations on a limited number of patients, can be seen as an indication of a potential inter-observer variation of around 20% for the distinction between the absence of PF and a low level of PF.

Child↗

PubMed1992

Ultrasonographical investigation of periportal fibrosis in children with Schistosoma mansoni infection: reversibility of morbidity twenty-three months after treatment with praziquantel.

In February 1987, 322 Sudanese school children were diagnosed for Schistosoma mansoni infection and treated randomly with praziquantel (either 20 mg/kg or 40 mg/kg body weight). A followup of these subjects was carried out in January 1989. This treatment resulted in a substantial reduction of egg output. Patients underwent complete abdominal ultrasonography and periportal fibrosis of the liver was graded into three degrees of severity. The proportion of patients with periportal fibrosis decreased from 36.6% in February 1987 to 21.7% in January 1989. At the time of followup, higher grades of periportal fibrosis (grades II and III) were encountered in only 4.3% and 0.3% of these patients, respectively, compared with 21.1% and 5.9%, respectively, before therapy. This was paralleled by a significant decrease in hepatomegaly from 10.9% to 7% of the patients. In contrast, the rate of splenomegaly showed a slight increase during the period of observation. The different dosage regimens of praziquantel did not result in a significantly different reversibility of periportal fibrosis or a decrease in egg excretion. The reversibility of specific liver lesions 23 months after antischistosomal therapy with praziquantel was substantial. The improvement was greater at 23 months than that obtained seven months after treatment.

Adolescent↗

PubMed1992

Ultrasound versus clinical examination as indication for Schistosoma mansoni associated morbidity in children.

In order to compare clinical versus ultrasound based diagnosis of Schistosoma mansoni induced periportal fibrosis (pF) 536 infected Sudanese schoolchildren underwent clinical and sonographical examination. A liver exceeding 3 cm in sternal line and a palpable spleen were considered pathological. Ultrasound criteria for age dependent organometry of a Central European cohort were used as reference. Based on clinical criteria 190 children (35.4%) had hepatomegaly, whereas according to ultrasound results the rate was only 11.4%. Splenomegaly was detected in 77 cases (14.4%) by clinical means, but in 196 by ultrasound (36.6%). The sensitivity of clinical parameters as indication of pF was around 50%. Results for ultrasound detected organomegaly were only slightly better. It was concluded that assessment of liver and spleen sizes was of limited value as an indication for pF and that a considerable discrepancy existed between clinical and ultrasound based assessment of hepato- and splenomegaly.

Adolescent↗

PubMed1992

An inside look at a small cell. Yeast Cell Biology sponsored by Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA, August 13-18, 1991.

It should be apparent from this review that new genes important for cell function are rapidly being discovered in yeast. In the not too distant future, the sequence of the yeast genome will provide us with a list of all of the proteins needed to make a cell. The challenge will then be to continue to develop biochemical and genetic approaches to uncover the function of these proteins. Clearly, yeast is going to play a major role in the future of cell biology and the power of this small eukaryote is just beginning to be tapped.

Biological Transport↗

PubMed1991

Malignant fibrous histiocytoma of the larynx.

Malignant fibrous histiocytomas of the upper respiratory tract are rare, aggressive mesenchymal neoplasms. We report a case of a glottic malignant fibrous histiocytoma of the larynx on a 54 year old man. Only a few have been reported in the English literature. The clinical behaviour and degree of malignancy of these tumours cannot be predicted. Wide, aggressive excision of the tumour with a margin of normal tissue appears to be the treatment of choice. About two years after total laryngectomy the patient is well and free of disease.

Histiocytoma, Benign Fibrous↗

PubMed1991

Aminoalkynyldithianes. A new class of calcium channel blockers.

Several dithiane derivatives, prepared as intermediates for compounds structurally related to the therapeutically useful antimuscarinic agent oxybutynin, were effective inhibitors of calcium ion induced contraction of guinea pig ileal strips and of KCl-induced calcium entry into neuronal cells. Although the first member of this series, 2-[5-(diethylamino)-3-pentynyl]-1,3-dithiane (2a), was only marginally effective, its condensation product with diphenyl ketone, i.e. 2-[5-(diethylamino)-3-pentynyl]-2-(a,a-diphenyl-a- hydroxymethyl)-1,3-dithiane (3a), demonstrated weak, but significant, calcium channel antagonist activity. As part of a structure-activity relationship (SAR) study, various structural analogues of 2a and 3a were prepared and examined for calcium antagonist properties. In addition to these structural types, ring bridged (tricyclic) congeners of 3, i.e. 4, related bicyclic compounds 5, dehydroxylated derivatives 6, some homologous 2-[[[(N,N-disubstituted-amino)methyl]2- phenyl-1,3-dithianes (7), and a series of 2-[6-[N,N-disubstituted-amino)methyl]-1-hydroxy-1-phenyl- 4-hexynyl]-1,3-dithianes (8) were prepared and studied for calcium channel blocking activity. In general, greatest potency was noted in the tricyclic series 4; however, a definitive SAR could not be established. A structural similarity between several potent calcium antagonists having the structures 7c, 8b, and 8d and the well-known calcium channel blockers verapamil and tiapamil suggests these compounds may act at the same site. Compounds in the other classes (2-6) failed to show clearly defined SAR and their potency differed markedly in two tests for calcium channel antagonist activity. These results may indicate that the dithiane derivatives 2-6 produce their effects in a manner differing from that of the calcium channel antagonists diltiazem, verapamil, and nitrendepine.

Animals↗

PubMed1991

Analogues of oxybutynin. Synthesis and antimuscarinic and bladder activity of some substituted 7-amino-1-hydroxy-5-heptyn-2-ones and related compounds.

Oxybutynin chloride [4-(diethylamino)-2-butynyl alpha-cyclohexyl-alpha-hydroxybenzeneacetate hydrochloride, Ditropan] is widely used for the relief of symptoms in neurogenic bladder. This is a result of its combined anticholinergic, antispasmodic, and local anesthetic activities. In a study directed toward development of agents possessing the beneficial properties of oxybutynin, but having a longer duration of action, a series of metabolically more stable keto analogues of the parent ester, i.e. substituted 7-amino-1-hydroxy-5-heptyn-2-ones along with some analogues and derivatives, was prepared and evaluated for in vitro and in vivo antimuscarinic action in guinea pig preparations. Several members of the series were potent antimuscarinics having a longer duration of activity than that of oxybutynin in a guinea pig cystometrogram model. On the basis of its in vitro and in vivo antimuscarinic activity, coupled with a 5-fold greater duration of action than that of oxybutynin, 1-cyclobutyl-7-(dimethylamino)-1-hydroxy-1-phenyl-5-heptyn-2-one (14b) was selected for clinical evaluation.

Alkynes↗