Biomedical subjects
Publications and source records attributed to M Philipp.
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Thrombin, the blood-clotting enzyme, is a serine proteinase with trypsin-like specificity and is able to cleave Arg-Xaa peptide bonds but only in a very limited number of substrates (and sites therein). For the prevention and treatment of thrombosis the control of thrombin activity is a key target, and a variety of synthetic inhibitors have been introduced recently, all of which have a positive charge at the P1 site. We report the synthesis of the first example of a new class of inhibitor containing a neutral side chain at the P1 site, the peptide benzyloxycarbonyl-D-Phe-Pro- methoxypropylboroglycine. The peptide is a potent inhibitor of thrombin [Ki (limiting) = 7 nM] and is highly selective for its target enzyme in respect of other serine proteinases. This may be expected to confer considerable advantage in terms of specificity of action and reduced toxicity over conventional, positively charged, inhibitors.
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Psychotropic drugs have been integrated into the management of chronic pain syndromes for more than 30 years. Numerous open and controlled studies have taken place evaluating especially the antinociceptive efficacy of antidepressive drugs. This survey comprises the results of clinical reports, open clinical studies, placebo-controlled studies, and comparative studies of different substances. It will be shown that antidepressants are by far the best evaluated psychopharmacological substances, showing superiority against placebo in 70% of a total of 67 placebo-controlled studies. The synopsis of controlled comparison studies of different antidepressants tends to demonstrate a superiority of clomipramine; however, the number of comparative studies is too small to draw final conclusions, especially because a number of methodological shortcomings reduce the comparability of different studies. The literature is concerning the pharmacological mechanisms and the interaction of antidepressive and antinociceptive effects of antidepressants is reviewed. Finally, treatment guidelines are formulated, which summarize the recommendations of the international literature.
A double-blind parallel-group comparison study of moclobemide versus doxepin in 237 patients with major depression confirmed that moclobemide was equal in efficacy and better tolerated than doxepin. It was less sedating and caused fewer anticholinergic adverse events as measured by the UKU side-effect rating scale. Unexpectedly, moclobemide therapy more often than doxepin resulted in increased sexual desire. An exploratory analysis of UKU-measured symptoms of impaired sexual function prior to commencement of the study revealed that moclobemide more often than doxepin led to an improvement of reduced libido and impaired erection, ejaculation and orgasm. This finding is compatible with the assumption that there is a greater likelihood that the anticholinergic reuptake inhibitor doxepin has a higher risk of impairing sexual function than the non-anticholinergic RIMA moclobemide. A single case report of moclobemide-induced sexual hyperarousal supports the alternative assumption that moclobemide has a specific sexually stimulative effect in depression.
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The alcohol withdrawal syndrome consists of autonomic, neurological and mental symptoms. For its assessment, these symptoms have to be rated in a quantitative and valid manner. We developed a new rating scale for mild and moderate alcohol withdrawal states. Difficulty, discrimination coefficient, internal consistency, and the principal component analysis were assessed. External validation was tested on a separate sample of inpatients. Eight of 12 original items fulfilled test-theoretical criteria. From these a psychosensory and an autonomic factor have been extracted. This instrument can be used repeatedly for clinical assessment as well as for evaluation of the alcohol withdrawal syndrome in clinical drug studies.
Though the concept of Major Depression was generated by clinicians using depressed inpatients as models, a polydiagnostic study in 600 psychiatric inpatients with heterogenous psychological disturbances revealed that all six competing operational definitions of Major Depression (including DSM-III-R and ICD-10) were too restrictive to serve as a general concept of depression. Another polydiagnostic study in 500 primary care outpatients showed that more than two-thirds of all non-chronic depressed cases were below the severity threshold of Major Depression: these patients are classified as Depression Not Otherwise Specified (NOS) by DSM-III-R. Loosening of the over-restrictive time criteria would broaden the concept of Major Depression so as to meet the requirements of a general concept of depression, while the definition of Minor Depression below the threshold of Major Depression would add to a reduction of cases of NOS Depression by more than 80%. For the evaluation of antidepressant drugs in outpatient samples, we propose that patients with these modified definitions of Major and Minor Depression be included, provided they meet a minimum severity criterion of 13 or more points on the Hamilton Depression Scale; four-fifths of the modified Major Depression group and one-third of the Minor Depression group do in fact meet this criterion.
Patterns of expression of surface-associated antigens were analyzed in the filarial nematode Brugia malayi immediately prior, and during development in the vertebrate host. Two surface-associated protein molecules, i.e., accessible to surface radioiodination and soluble in aqueous buffers, were investigated: Mrs 29-30,000 and 16,000, both of which are antigenic in infected animals. The Mr 29-30,000 glycoprotein is expressed in a surface-associated manner by adult worms and by fourth-stage larvae, but is not detectable in preparasitic third-stage larvae. The 16,000 component, which appears not to be glycosylated, is surface-associated in adult worms and fourth-stage larvae. In contrast to the 29-30,000 glycoprotein, the 16,000 protein is also expressed both by pre- and postparastic third-stage larvae. However, it becomes surface-associated only after infection. Thus, immediately prior, and during development within the vertebrate host, B. malayi displays at least two different patterns of expression of surface-associated antigens: (i) de novo, intiated either immediately after infection (phase specific) or during genesis of the fourth-stage larva (stage specific); (ii) continuous, but with phase-dependent surface exposure of previously cryptic antigens, during the transition from intermediate to definitive host.
The effect of the calcium channel blocker, nimodipine, in acute alcohol withdrawal was investigated in a randomized, placebo controlled, double blind study. Thirty-two male patients with a history of alcohol dependence according to DSM-III criteria, but no other substance abuse, were included. A new rating instrument which fulfilled theoretical test criteria was applied to determine the severity of the alcohol withdrawal state. The patients received nimodipine or a placebo on four separate occasions (4 x 60 mg) and, in addition, clomethiazole, according to a standardized procedure. Our investigation has shown that, in the first 48-72 h of alcohol withdrawal, both groups consumed similar amounts of additional clomethiazole medication. Thus, no significant effect of nimodipine on the acute alcohol withdrawal state could be demonstrated. There was some tendency for nimodipine to ameliorate psychosensory dysfunction.
The phylum Nematoda consists of over half a million species of worms that inhabit astoundingly diverse environments. Nematodes can live as obligatory parasites of plants and animals, or alternate a parasitic with a free-living life style. The fact that the vast majority of species are strictly free living often surprises parasitology students, for obviously the highest research priorities in this field have involved parasites of medical, veterinary and agricultural importance. Here Samuel Politz and Mario Philipp contend that some basic questions concerning the biology of the parasite cuticle can be investigated more easily and in greater depth in the free-living nematode Caenorhabditis elegans than in the parasites themselves.
TEPC-15 is a phosphorylcholine-binding mouse myeloma protein which reacts with an ester-containing phosphorylcholine, the p-nitrophenyl ester of 6-(phosphorylcholine)hexanoic acid (PEPCH). The rate of nitrophenolate release mediated by the antibody is pH-dependent and increases with increasing pH. The antibody becomes inactive during the reaction with the ester. The inactive antibody is not reactivated even after treatment with hydroxylamine. Antibody activity is associated with the Fab' fragment. These observations together with the pH profile of the reaction suggest that the ester acylates a lysine side chain near the antibody-binding site.
All operationalized diagnostic systems contain a diagnostic category, which corresponds to the concept of major depression. Yet, these corresponding definitions are not identical. Up to now, no comprehensive comparisons of the competing diagnoses have been published. We will therefore present a series of studies, describing six different operational definitions of major depression according to their content and construction and empirically comparing them in large inpatient and outpatient samples. This first paper presents a descriptive comparison of the definitions given in the Feighner Diagnostic Criteria, the Research Diagnostic Criteria, the Diagnostic and Statistical Manual of Mental Disorders, third edition and third edition, revised, and in two developmental drafts of the ICD-10 diagnostic criteria for research (draft April 1987-I87; draft April 1989-I89). The descriptive comparison will demonstrate that there are many similarities, especially concerning the symptom-criteria of major depression. Classificatory relevance could only be assumed for those differences found for cut-offs, for time criteria and especially for exclusion criteria. Whether these differences are negligible and whether patients classified by different diagnostic systems are really comparable will be examined in subsequent publications.
Six operational definitions of the concept of major depression were submitted to empirical evaluation in 600 psychiatric inpatients. Special attention was given to the comparison of major depression in DSM-III-R and ICD-10. The data base created by a polydiagnostic interview revealed relevant classificatory differences between the six definitions under study. Sources of different diagnostic base rates were: inclusion or omission of anhedonia as an obligatory mood criterion; minimal number of syndrome criteria required for the syndrome diagnosis; different width and reference points of time criteria; exclusion rules for co-existing schizophrenic symptoms and for previous nonaffective and manic episodes. The empirically evaluated overlap between pairs of diagnostic definitions was less than excellent in most of the diagnostic definitions under study; only the DSM-III and DSM-III-R definitions agreed with each other to a highly comparable degree. The relatively good agreement of the 1989 draft definition of ICD-10 for major depression ("mild depression") with the other five operational definitions (kappa = 0.69) led us to expect that this definition should receive sufficient international acceptance.
The comparative validity of six operational diagnoses of major depression was evaluated in 600 psychiatric inpatients using the independently assessed clinical ICD-9 diagnoses as a yardstick. Agreement with, and positive predictive value for the ICD-9 categories of pure (endogenous and psychogenic) depression served as validation criteria; sensitivity of major depression diagnoses for detecting ICD-9 bipolar depressions was additionally used for examining the adequacy of width, time and exclusion criteria of the competing operational definitions. Three essential results were found. First, the "old" diagnostic definitions of RDC and FDC are superior to all newer definitions because they define the time criteria and the schizophrenic exclusion criteria more adequately than, for example, both DSM-III and DSM-III-R definition. Secondly, the current ICD-10 definition of 1989 ("mild", "moderate" or "severe" depression) comes closer to the concurrent validity of RDC and FDC than DSM-III, DSM-III-R and the previous ICD-10 definition of 1987. Thirdly, using the criterion of identifying a high proportion of ICD-9 bipolar depressions, all six competing diagnostic systems are too restrictive. Evaluations of predictive and criterion-related validity will be needed to substantiate these findings.
The endogenous/non-endogenous distinction of unipolar major depression is widely accepted, as is the family study approach to the validation of diagnostic distinctions. Rates of affective disorders were examined in 689 first-degree relatives of 184 patients with unipolar major depression and were compared with 312 first-degree relatives of 80 healthy controls. Only unipolar depression and alcoholism were more common in families of depressed probands compared with families of healthy controls. As a variety of diagnostic definitions of endogenous depression have been proposed, probands and relatives were diagnosed in a polydiagnostic manner. None of the five diagnostic definitions of endogenous depression was able to identify patients with an increased familial risk of unipolar depression.
Five hundred general practice patients with functional complaints were studied with the Polydiagnostic Interview (PODI) to see whether DSM-IIIR criteria were able to specify affective disorders satisfactorily. Almost one third of the patients received the diagnosis of depression not otherwise specified (NOS). When Research Diagnostic Criteria were applied to these patients more than 70% received specific diagnoses. A modification of DSM-IIIR algorithms enabled us to further specify diagnoses in subjects with depression NOS. On the 17-item Hamilton Depression Scale many of these patients reached scores of 13 or more which is severe enough to justify a therapy trial with antidepressants.