The pharmacokinetics of tranylcypromine enantiomers in healthy subjects after oral administration of racemic drug and the single enantiomers

The pharmacokinetics of the two enantiomers of tranylcypromine were evaluated in six healthy subjects after oral dosage of the racemate (20 mg of the sulphate) and the single enantiomers (10 mg of the sulphate) using an enantiospecific assay. Significant differences in AUC, Cmax, lambda(z), and CLR of the two enantiomers were observed both on administration of the racemate and of the individual enantiomers. The plasma concentrations and urinary excretion rates of (-)-tranylcypromine exceeded those of (+)-tranylcypromine. AUCs of the (-)-enantiomer [arithmetical means 197 ng ml(-1) h after the racemate, 130 ng ml(-1) h after the enantiomer] were greater than those of the (+)-enantiomer [26 ng ml(-1) h after the racemate, 28 ng ml(-1) h after the enantiomer] (P = 0.0001). No in vivo racemisation was detected. The power of the study was insufficient to establish any enantiomer-enantiomer interaction except for a possible interaction at the level of renal clearance (P = 0.013 for both enantiomers).     

Erworbene Bauchhöhlenmuskelstörungen

Zusammenfassung Die Bauchhöhle hat ein Faszienskelett, das durch ihren permanenten veränderhchen Ruhetonus verspannt gehalten wird. Zur Bauchhöhle gehören mit der seitlichen Bauchmuskulatur auch das Zwerchfell und der Beckenboden. Willkürliche und reflektorische Tonusänderungen bedingen ihre Verformung und ihren Verschluß oder ihre Eröffnung. Am Versuchstier haben wir diesen Ruhetonus schon in der Schwanzmuskulatur nachgewiesen, von der der Beckenboden des Menschen stammesgeschichtlich abstammt. Der Beckenboden bildet mit den Sphinkteren das anorektale Kontinenzorgan. Es ist, phylogenetisch erklärbar, bei der Frau viel schwächer entwickelt als beim Mann. Diese unterschiedliche Mächtigkeit ist his zu den Kernen des Rückenmarks, die diese Muskulatur steuern, zu verfolgen. Diese Asthenie des weiblichen Kontinenzorgans wird durch das Gebären und die Obstipation noch zusätzlich belastet. Das gleiche gilt für die Bauchdecke der Frau, die, wie hier nachgewiesen wird, nach einer Gravidität die gleichen, bleibenden Denervationserscheinungen ihrer Muskulatur erkennen läß t. Es sind die gleichen Schäden, die der Beckenboden mit den Sphinkteren erleidet. In schwereren Fällen ist neben der Inkontinenz also auch ein Schlotterbauch die Folge dieser Belastungen. Der ruhetonisierte Beckenboden kann das spastische Beckenbodensyndrom, die kontinente Obstipation, zur Folge haben. Sic kann psychotherapeutisch geheilt werden. Davon muß die inkontinente Obstipation unterschieden werden, die manchmal mit einem Mastdarmvorfall einhergeht. Bei ihr liegt das Hindernis im Darm. Sic kann in schweren Fällen durch eine Sigmaresektion gebessert werden. Die Denervationsinkontinenz ist am besten durch das operative Engerstellen des ganzen Levatortrichters zu bessern. Voraussetzung ist: Der gelähmte Beckenboden muß noch eine Restruheaktivität aufweisen.

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Acquired disturbances of muscles of the peritoneal cavity

The peritoneal cavity has a fascial skeleton that is kept under tension by permanent variable resting tone maintained by the abdominal muscles. The lateral abdominal muscles, the diaphragm and the pelvic floor are all components of this fasciomuscular support system. Voluntary and reflective changes in muscle tension allow the entry and exit of matter into and out of the spherical abdominal cavity by opening and closing of specialized wall segments called sphincters. We have previously demonstrated the existence of a resting tone in the tail muscles of mammals from which the human pelvic floor muscles are derived. The pelvic floor and its integrated sphincters form the anorectal organ of continence. This organ is much weaker in females than in males. The spinal centers that govern continence, contain in the female significantly fewer ganglion cells than the corresponding centers in the male. Childbirth and a commonly found tendency to develop constipation are additional stressors for the congenitally weaker female organ of continence. We explain in this paper why the abdominal wall and the pelvic floor may suffer stretch-induced denervation injuries during pregnancy and delivery. Such damage may persist in later life and can give rise to incontinence and flabby abdomen. Based on our work in this field, we found a new differentiation between continent and incontinent constipation. Continent constipation is caused by spasticity of the pelvic floor characterized by abnormally high sphincter activity. This spastic pelvic floor syndrome can be treated successfully by psychotherapeutic techniques. Incontinent constipation, in contrast, is always associated with subnormal activity of the sphincters and may be a cause of rectal prolapse. It can be treated successfully by anterior rectosigmoid resection. Incontinent constipation will also require operative approximation of the levators in many cases. Improvement cannot be expected to result from this procedure, however, unless the pelvic floor shows some residual resting activity.

Korrespondenz an: em. Prof. Dr. Dr. h. c. mult. F. Stelzner     

Parameters influencing piezoelectric shock wave lithotripsy of biliary calculi

A total of 225 human gallbladder stones were divided into sets of two, three, or four identical calculi (with maximum diameters of 6-26 mm) and submitted to piezoelectric shock wave lithotripsy in vitro in order to investigate the influence of the following parameters on stone disintegration: shock wave intensity, pulse frequency, and various physicochemical parameters such as the volume and viscosity of the fluid surrounding the stone, the hardness of the calculus, and its chemical composition. The fragmentation efficacy increased with enhanced shock wave energy (P less than 0.01). If the volume of the fluid (30 mL) surrounding the calculus was small, the disintegration end-point (defined by maximum fragment diameters less than or equal to 4 mm) was achieved after a lower number of pulses (median: 250 pulses) than in the case of a large fluid volume (80 mL) (500 pulses; P less than 0.01). On the other hand, however, factors such as the shock wave pulse rate (0.9 Hz vs 1.6 Hz), variations in viscosity of a water-jelly mixture surrounding the stone, the chemical composition of the stones as determined by X-ray diffractometry, and stone hardness were found to have no significant influence on the fragmentation efficacy.     

Detection and significance of glutathione-S-transferase pi in osteogenic tumors of dogs

In this study we describe a relationship between the percentage of tumor cells staining positive for GST pi and the response to cisplatin treatment in dogs with appendicular osteosarcoma. Clinical resistance to platinum compounds has been attributed to tumor cell resistance to the drug. An overexpression of glutathione-S-transferase pi has been implicated in the resistance of tumor cells in vitro to cisplatin. In this study, the relative concentration of GST pi was quantified immunohistochemically in formalin-fixed, paraffin-embedded histologic specimens obtained from dogs with appendicular osteosarcoma prior to cisplatin treatment. The percentage of tumor cells staining positive for GST pi was compared with patient response (remission and survival times) following treatment. Those osteosarcoma-bearing dogs having a low pre-treatment tumor expression of GST pi (<50%; n=13) had a significantly longer (p <0.01) median remission and survival time (24.0 and 33.7 weeks, respectively) than those dogs with a high pre-treatment tumor expression of GST pi (>50%; n=8; median remission and survival times 14.2 and 24.0 weeks, respectively). The relative staining of GST pi in primary canine bone tumors has therapeutic importance and warrants further evaluation as a therapeutic model for human osteosarcoma.     

Thorn-like prickles and heterophylly in Cyanea: adaptations to extinct avian browsers on Hawaii?

The evolution of thorn-like structures in plants on oceanic islands that lack mammalian and reptilian herbivores is puzzling, as is their tendency toward juvenile-adult leaf dimorphism. We propose that these traits arose in Cyanea (Campanulaceae) on Hawaii as mechanical and visual defenses against herbivory by flightless geese and goose-like ducks that were extirpated by Polynesians within the last 1600 years. A chloroplast DNA phylogeny indicates that thorn-like prickles evolved at least four times and leaf dimorphism at least three times during the last 3.7 million years. The incidence of both traits increases from Oahu eastward toward younger islands, paralleling the distribution of avian species apparently adapted for browsing. The effectiveness of visual defenses against avian browsers (once dominant on many oceanic islands, based on the vagility of their ancestors) may provide a general explanation for insular heterophylly: the other islands on which this previously unexplained phenomenon is marked (New Zealand, New Caledonia, Madagascar, Mascarene Islands) are exactly those on which one or more large flightless avian browsers evolved.     

Stress-induced C-fos expression in the rat locus coeruleus is dependent on neurokinin 1 receptor activation

These experiments examined the role of substance P-selective neurokinin 1 receptors in the restraint-induced activation of the rat locus coeruleus. Immunohistochemistry revealed high levels of neurokinin 1 receptor expression in the plasma membrane of tyrosine hydroxylase-positive locus coeruleus neurons. The selective neurokinin 1 receptor antagonists, RP 67580 (5 nmol) and L-760,735 (3.4 nmol), were administered intracerebroventricularly prior to restraint stress, and c-fos protein was measured as an index of locus coeruleus activation. Both antagonists attenuated the restraint-induced increase in locus coeruleus c-fos expression, whereas their inactive enantiomers were ineffective. These results suggest that neurokinin 1 receptors may mediate activation of locus coeruleus neurons during stress. Neurokinin 1 receptor antagonists may prove to be novel therapeutic compounds in the treatment of anxiety and depression.     

Internal derangements of the shoulder: decision tree and cost-effectiveness analysis of conventional arthrography, conventional MRI, and MR arthrography

Purpose. In a patient with internal derangement of the shoulder, the diagnostic method of choice is controversial. Conventional arthrography can diagnose most rotator cuff tears accurately; however, in many institutions MR arthrography is usually necessary to diagnose labral tears. We utilized decision tree methodology to compare the cost- effectiveness of conventional arthrography and conventional MRI with a hypothetical algorithm in which a patient underwent arthrography, performed with admixed gadolinium, which if negative, was followed by MRI. Design. The use of double-contrast arthrography alone, conventional MRI alone, and gadolinium-enhanced MRI used as an adjunct to conventional arthrography were modeled for the diagnosis of full-thickness rotator cuff tears (RCT), partial RCTs, labral tears, and the absence of cuff/labral tears using decision analysis methodology. English language medical publications were searched to determine the base probabilities for the accuracy of the diagnostic tests. The outcome utilities ranged from –1 to +1 to reflect the value of correct diagnostic evaluation. Charges for diagnostic tests and appropriate surgical treatments were based on 1997 Medicare reimbursement rates for professional fees and hospital charges in an outpatient setting. Sensitivity analyses were performed to evaluate the effects of uncertainty regarding the prevalence of each disease state and the accuracy of several diagnostic tests. Results. In the base-case analysis, the average effectiveness of double-contrast arthrography alone, MRI alone and arthrography selectively followed by MRI were 0.6610, 0.6715, and 0.7204, respectively. The average costs for each of these strategies were $1090, $2033, and $2339, respectively. Conclusion. Arthrography performed with admixed diluted gadolinium, which if negative is immediately followed by MRI, was somewhat more expensive than conventional MRI. However, because of much greater effectiveness, cost-effectiveness was significantly higher for our proposed algorithm. Conventional arthrography without gadolinium, although less expensive, had severely limited effectiveness. Received: 4 June 1999 Revision requested: 6 August 1999 Revision received: 30 August 1999 Accepted: 1 September 1999     

A novel sodium channel mutation in a family with hypokalemic periodic paralysis

OBJECTIVE: To identify the cause of hypokalemic periodic paralysis (HOKPP) in a family whose disease is not caused by a mutation in the dihydropyridine-sensitive (DHP) receptor alpha1-subunit gene (CACNA1S). BACKGROUND: Hypokalemic periodic paralysis is primarily caused by mutations within CACNA1S. Genetic heterogeneity for HOKPP has been reported, but no other locus has been identified. METHODS: Single-stranded conformational polymorphism (SSCP) analysis and PCR direct sequencing were used to screen the skeletal muscle alpha1-sodium channel gene (SCN4A) for a mutation in our family. RESULTS: SSCP analysis showed an abnormally migrating conformer in exon 12. Direct sequencing of the conformer showed a guanine to adenine transition at position 2006 in the cDNA sequence; this results in an amino acid substitution of a highly conserved arginine (Arg) to histidine (His) at position 669. This sequence alteration segregated only with the affected members of the kindred and was not found in a panel of 100 DNA samples from healthy controls. The amino acid substitution alters the outermost positive charge in the membrane spanning segment DII/S4, which is involved in voltage sensing. CONCLUSIONS: The first arginine in DII/S4 and in DIV/S4 within the skeletal muscle sodium channel and the L-type calcium channel genie CACNA1S appear to be critical for normal function. In all four cases, Arg to His mutations result in a disease phenotype. The identification of a mutation within the skeletal muscle sodium channel resulting in hypokalemic periodic paralysis represents a novel finding.     

Linkage analysis in alcohol dependence

Alcohol dependence often is a familial disorder and has a genetic component. Research in causative factors of alcoholism is coordinated by a multi-center program, COGA [The Collaborative Study on the Genetics of Alcoholism, Begleiter et al., 1995]. We analyzed a subset of the COGA family sample, 84 pedigrees of Caucasian ancestry comprising 745 persons, 339 of whom are affected according to DSM-III-R and Feighner criteria. Using parametric and nonparametric methods, evidence for linkage was found on chromosome 1 (near markers D1S532, D1S1588, and D1S534), as well as on chromosome 15 (near marker D15S642). Other regions of the genome showed suggestive evidence for contributing loci. Related findings are discussed in recent publications investigating linkage in humans [Reich et al., 1998] and mice [Melo et al., 1996].     

Long-term outcome of radical radiation therapy for prostatic carcinoma: 1967-1987

PURPOSE: This study was done to review long-term results of radical radiotherapy for prostate cancer. METHODS AND MATERIALS: The records of 674 patients with Stage T1a, T1b, T2a, T2b, T3, and any T,N1,M0 disease, treated with external beam radiotherapy between January 1, 1967 and December 1987, were reviewed. These patients were treated to an average total dose of 66 Gy, with an average fractional dose of 2.05 Gy, using megavoltage. The duration of follow-up for surviving patients ranged from a minimum of 7 years to more than 20 years. RESULTS: The survival for 151 Stage T1a,T1b patients was 98.5% at 5 years, 93.6% at 10 years, and 75.2% at 15 years. Survival for 346 Stage T2a,b patients was 94.4% at 5 years, 67.9% at 10 years, and 41.5% at 15 years. Survival for 92 Stage T3 patients was 87.3% at 5 years, 54% at 10 years, and 26.6% at 15 years. The survival for 85 any T,N1,M0 patients was 73.9% at 5 years, 34.4% at 10 years, and 8.5% at 15 years. At 15 years, 75.2% of Stage T1a,b patients, 41.5% of Stage T2a,b patients, 21.7% of Stage T3 patients, and 8.5% of Stage T,N1,M0 patients remained free of local recurrence and distant metastases. The elevation of prostatic acid phosphatase prior to radiotherapy was an unfavorable prognostic factor, with impact on both loco-regional recurrences and survival. CONCLUSIONS: The external beam radiotherapy for localized carcinoma of the prostate produced a good loco-regional control, NED, and overall survival. Patients with smaller tumors and low grade fared better than the ones with more aggressive and/or bulky tumors. The weakness of this study is the absence of serial prostate-specific measurements, which were not available during the period under study. The complication rate requiring surgical intervention was low, i.e. 0.4%.