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In this pilot study carried out in two centres, six male and two female patients with severe active rheumatoid arthritis (RA) (average duration over 10 years) were treated with thymopentin 50 mg in the form of prolonged i.v. injection (over 10 min), 3 times weekly for 3 to 20 weeks. Two of these patients were subsequently treated with different s.c. doses of thymopentin in a crossover fashion for more than two years, including periods without any treatment or treatment with placebo. The overall clinical efficacy was judged by assessing pain patterns and joint status and the functional stage of the patients according to Steinbrocker; in addition, the sedimentation rate was measured before and after the therapy. Seven out of eight patients showed definite improvement in their clinical status as assessed by the Steinbrocker scale. Most of the symptoms, particularly pain, capsular swelling, tenderness and morning stiffness, were remarkably reduced within 3 weeks of thymopentin treatment. Sedimentation rate decreased in five out of eight patients. Prolonged i.v. injections seemed to have somewhat better effects than s.c. administration; in the latter group the highest dose (3 X 100 mg/week or higher) produced the best results. During placebo treatment and during the medication-free intervals both groups of patients got worse. No side-effects occurred during the study.

Samples from two pools were sent 10 times to 27 laboratories for assay of digoxin. One pool contained digoxin 2.60 nmol/l in normal plasma (SP); the other was pooled plasma from patients treated with digoxin (PP). Ten radioimmunoassay (RIA) methods were used. The mean of SP assays was 2.59 nmol/l, not significantly different from 2.60 nmol/l. The mean of PP determinations was 2.46 nmol/l. Within each of the 10 assay rounds, the concentrations showed an almost twofold variation and S.D. averaged 0.33 nmol/l and 0.31 nmol/l for SP and PP respectively. Significant differences (P less than 0.001) were found between mean concentrations obtained for the pools at various laboratories (SP range 2.15-2.85 nmol/l; PP range 2.12-2.72 nmol/l). The laboratory means obtained for SP and PP correlated significantly (P less than 0.001). Nevertheless, significant (P less than 0.01) variations between laboratories were found also concerning the mean difference between SP and PP concentrations. The interassay SD of the assays differed significantly between laboratories (range 0.05-0.61 nmol/l. Between and within groups of laboratories using the same RIA method and between various types of laboratories, differences were also found concerning both accuracy and precision of the assays. It is concluded that a better control of digoxin assay is needed.

The acetylation of procaine amide has been studied by means of gas liquid chromatography in 33 healthy human volunteers. The acetylator phenotype was determined by measuring unchanged and acetylated sulphapyridine in urine. Slow acetylators of sulphapyridine excreted significantly less procaine amide in acetylated from in the urine than rapid acetylators (9 plus or minus 1% against 19 plus or minus 4%). Hence, it is suggested that the acetylation of procaine amide is subject to the same genetic polymorphism as that of isoniazid and some sulfonamides.

The efficacy of oral acyclovir in a twice-daily treatment regime was demonstrated in an open long-term study in 8 patients with frequently relapsing genital herpes type II infections. The treatment was well tolerated and no side effects were noted during the medication period of 6-21 months. No signs of decreased sensitivity for acyclovir appeared.

During some hot summer-days in 1973 about 70 cases of acute feet dermatitis were reported among soldiers from one regiment. They had used newly laundered socks from the same batch. The socks were disinfected with a solution containing TBTO and a quarternary ammonium compound, but by mistake a roughly 7 times too high concentration of the solution had been used. Patch tests with TBTO, quarternary ammonium compound and standard substances were negative. There was no suspicion of phototoxicity in these cases, but according to the literature TBTO may be photodynamic and several case reports relate specifically to sunny summerdays. We consider our cases to be due to the primary irritant properties of TBTO. As the span between optimal concentration for disinfection and the primary irritant concentration is narrow, we consider it inappropriate to use this substance for disinfection of textiles which are to be in direct contact with the skin until it has been established whether, for example, sweat may extract TBTO from treated fibres.

The efficacy of thioguanine in the treatment of severe cases of psoriasis is demonstrated. This treatment is valuable in selected cases of severe psoriasis in whom other treatment is ineffective or impossible due to side effects. The effect of thioguanine on psoriasis lesions appears to run parallel with depression of the bone marrow. The bone marrow toxicity has to be considered. Patients previously treated with methotrexate are very sensitive to thioguanine and close follow up is mandatory with adjustment of the thioguanine dose according to blood white cell and thrombocyte levels.

The phagocytic ability of neutrophil leucocytes was found to be impaired in patients suffering from pustulosis palmaris et plantaris (PPP). This ability was studied with the aid of the yeast particle method. In 78% of 27 patients whose PPP was in a static phase, the phagocytic function was enhanced, while the PPP abated concomitantly and the pustules disappeared. Impaired phagocytosis and the beneficial effect of clofazimine signify the pathogenic importance of defective neutrophils in PPP.

1 A specific gas-chromatographic method was developed for determination of N-acetylprocaine amide in plasma and urine, using 4-amino-N-(2-piperidinoethyl)benzamide as an internal standard. The investigation was performed in 50 cardiac patients who had reached steady-state plasma concentrations of procaine amide. 2 The plasma concentrations of the acetylated metabolite varied between 1.0 and 15.0 μg/ml and were thus of the same order of magnitude as those of the parent drug. Especially high plasma levels of the metabolite were seen in patients with poor kidney function. 3 The urinary excretion of the metabolite varied markedly between individuals and ranged between 6 and 52% of the administered daily dose. There was a clear tendency towards higher rates of acetylation of procaine amide in patients with short plasma half-lives of isoniazid, i.e. the phenotype rapid acetylators. Because of coexisting therapy with other drugs and impaired renal function in some patients studies are required in healthy human volunteers to ascertain whether the acetylation of procaine amide and isoniazid are mediated by the same enzyme system.

Optothermal infrared spectrometry (OTIS) is a recently introduced method for specific measurement, in vivo, of water in the skin. In the present study the method proved well suited to register the increase in water content in stratum corneum following application of emollients. The results were compared with those obtained with a commercial instrument, the Corneometer, and the two methods were found to match very closely. Neither method indicated any difference in hydration of normal skin between young and elderly women. Evaporimetry was used to detect any influence on the water barrier function of the skin following application of emollients; even though the water content of the skin was significantly higher after emollient treatment, the transepidermal water loss remained unchanged.

The metabolism of procaine amide was studied in 41 cardiac patients who had achieved steady state plasma concentrations of the drug. Acetylated procaine amide accounted for 31 +/- 12% (range 16-63%) of the overall urinary recovery of the drug and is therefore a main metabolite in man. Plasma levels of the metabolite were usually lower but sometimes exceeded those of the parent compound with variations between 1 and 15 mug/ml. The metabolite had a weaker effect than procaine amide on the maximal electrical driving velocity of isolated atrial strips from guinea pig.

The Scandinavian Mycosis Fungoides Study Group have treated 19 patients with mycosis fungoides in tumour stage by systemic chemotherapy. Nine patients were treated with Bleomycin 15 mg i.m. twice weekly for 7 weeks and 10 patients with the same dose of Bleomycin in combination with Methotrexate 15 mg i.m. per m2 body surface each week for 7 weeks. No maintenance treatment was given. The immediate therapeutic effect of Bleomycin alone was considered good in half of the patients. Bleomycin and Methotrexate together produced a better initial effect. In both treatment series the remission was short-lived in the absence of maintenance therapy. The mortality rate was high, especially in combination treatment. Lethal complications occurred in 6 patients during the treatment, 3 of which were thromboembolic, one pancytopenia, one lung fibrosis with pulmonary insufficiency, and one bronchopneumonia. The conclusion is that these two forms of therapy cannot be recommended.

Fifteen patients with spontaneous systemic lupus erythematosus (SLE) have been phenotyped by determination of plasma isoniazid (INH) half-life. Seven patients had signs of renal insufficiency. Of the 15 patients, 13 were slow and only 2 rapid acetylators. No correlation was found between the plasma INH half-lives and the renal function. Thus, there is the same marked predominance of slow acetylators in patients with spontaneous SLE as in patients with the drug-induced SLE-like syndrome.

Twenty-four patients suffering from longstanding severe recurrent herpes simplex, who had not responded to prior therapy, were treated with s.c. thymopentin injections 50 mg, three times weekly, over a period of six weeks. They were followed up at weekly intervals over this period and then six weeks later. Moreover, the longest relapse-free period observed in the year after the treatment was recorded in the investigator's documentation. Thirteen of the 14 patients with labial herpes simplex and 10 of the 13 patients with genital herpes simplex improved markedly as shown by a decrease in the relapse rate of at least 50%, shorter episodes of relapse and improvement of symptoms such as pain and itching. Fourteen of these 27 patients experienced no relapse for a period longer than four months after cessation of the therapy. No serious side-effects were observed. Laboratory examinations before, during and after thymopentin did not reveal significant alterations except for an increase in the T-helper/T-suppressor ratio. The effect of thymopentin is assumed to be due to T-helper cell activation resulting in enhanced interleukin-2 production with subsequent proliferation of cytotoxic T lymphocytes and natural killer cells which are capable of producing immune interferon.

Thirty-nine patients with mycosis fungoides in various stages or Sézary syndrome were treated with isotretinoin and 29 with etretinate as single drug therapy. Complete remission within 2 months was obtained with isotretinoin in 8 cases (21%) and partial remission in another 15 cases (38%). Etretinate induced complete remission in 5 cases (21%) and partial remission in 11 (46%). Only 1 case with Sézary syndrome went into partial remission. The first sign of remission occurred in 2 to 4 weeks. During continued treatment remissions could not always be maintained. Isotretinoin and etretinate were considered to be of equal potency in the treatment of mycosis fungoides.

The concentrations of digoxin in plasma and urine samples obtained from three healthy male volunteers, who received 1.2 mg of labeled digoxin perorally and intravenously, were simultaneously measured by a commercially available radioimmunoassay (RIA) and by a combined column thin-layer chromatographic assay (CA). The CA method, previously shown to assay digoxin specifically, was also used to monitor the individual digoxin metabolites. The results of this investigation showed that digoxin was significantly metabolized, particularly after peroral administration. The lower level of sensitivity of the RIA in plasma was 0.4 ng/mL. There were highly significant positive linear correlations between the values of the following parameters of digoxin as obtained by the RIA and CA methods: the concentrations in plasma and urine, the AUCs, and the cumulatively excreted amounts in urine. The two assays did not give completely identical results either with plasma or urine; the slopes of the regression lines deviated from unity in a significant number of cases. However, there was no relationship between the magnitude of the slopes of the regression lines and the extent of metabolism. It was concluded that the commercially available RIA evaluated was specific for digoxin and that the presence of digoxin metabolites did not affect the determinations.

We studied the interference of the sample matrix on digoxin radioimmunoassays using four commercial kits. Plasma samples from non-digitalized patients of the following categories were assayed: uncomplicated essential hypertension treated with spironolactone, uremia, and acute myocardial infarction (AMI). Digoxin 2.50 nmol/L was added to all samples. Digoxin in plasma from patients on spironolactone was overestimated by two of the kits (means 2.77 and 2.68 nmol/L, respectively; p less than 0.01) and underestimated in samples from uremic patients by one kit (2.32 nmol/L; p less than 0.01). The digoxin content of AMI plasma was overestimated by one kit (2.62 nmol/L; p less than 0.05). Significant differences were found between radioimmunoassays when estimating digoxin concentration in the same category of patient and within individual methods used for different categories. Precision expressed as 95% confidence intervals ranged from 0.43 to 0.80 nmol/L for the kits. Thus, deviations in recorded digoxin concentrations from the true values found, but were of secondary importance because of the relatively low precision of the assays.

The acetylator phenotype of 35 healthy, drug-free volunteers and 21 patients with cardiac and/or renal disease has been assessed using oral sulphapyridine. Comparative evaluation of a simplified and a more selective method of sulphapyridine analysis was performed. Thirteen of the patients were also phenotyped by determination of plasma isoniazid half-life. 81% of the patients were slow acetylators, compared with only 51% of the volunteers. When phenotyping healthy, drug-free subjects the analytical procedure, involving a direct estimation of sulphapyridine in urine with the Bratton-Marshall procedure, was satisfactory. On the other hand, in patients receiving concomitant drug therapy the more selective analytical procedure was necessary in order to diminish the risk of methodological interference.

Epipodophyllotoxin (VP-16-213) was administered to 9 patients with mycosis fungoides in various stages, most of them in the advanced tumour stage. In 4 of the patients VP-16 was combined with cyclophosphamide. VP-16 alone or in combination with cyclophosphamide was capable of inducing remission initially in all cases, complete in 2, partial in 3 and improvement to a lesser degree in the remaining 5 patients, but it was unable to maintain the remission. The induced remission has to be upheld by other agents, possibly added to VP-16.

The case histories of 2 patients with chronic Trichophyton rubrum infections are presented. Both subjects had previously been treated systemically with griseofulvin, but had to be dropped from therapy due to adverse reactions. Topical treatment alone yielded unsatisfactory results. Thymopentin, 50 mg, administered subcutaneously three times weekly for a period of 6 weeks, induced rapid improvement within 3 weeks and almost complete remission 3 weeks later, although the fungi were still present on the skin. This beneficial effect lasted for up to 7 months after cessation of thymopentin therapy. Reinstitution of treatment produced the same response pattern. The clinical and immunological implications of these findings are briefly discussed; thymopentin is believed to enhance the suggested impaired cellular immunity in patients with chronic T. rubum infections.

Sulfasalazine and its active components, 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP), are potent modulators of inflammatory reactions but with somewhat different modes of action. Investigating the effect of these compounds on normal human polymorphonuclear leukocytes in vitro, we show inhibition of different stages in the phagocytic process, such as migration (sulfasalazine and SP), superoxide production (sulfasalazine and SP), myeloperoxidase-mediated iodination and cytotoxicity (5-ASA and SP). It is thus suggested that sulfasalazine is not just a vehicle for delivering its active components in the colon, but that its therapeutic effect is ulcerative colitis and other inflammatory reactions is a result of the concurrent action of the three compounds.

The Scandinavian Mycosis Fungoides Study Group includes dermatologic clinics in Denmark, Norway, and Sweden. The results of the first three years of activity are presented herein. In plaque stage, topical nitrogen mustard was highly effective. Preceding intravenous tolerance induction seems to be of no value. PUVA induced equally high remission rates. Both modalities were also highly effective in cutaneous tumor stage. In advanced tumor stage and in case of extracutaneous involvement systemic chemotherapy was given. Topical treatment alone was more effective on the cutaneous lesions including tumors than systemic chemotherapy alone. Therefore a combination of topical and systemic treatment is recommended in advanced stages of mycosis fungoides.

Eight patients had pyoderma gangrenosum. They were given a phendimetrazine tartrate derivative, clofazimine (Lamprene [Britain]), which is a chemotherapeutic agent used mainly in certain mycobacterial infections and which also has phagocytosis-enhancing properties. The effect of this drug was remarkably good, with rapid healing of the lesions commencing 3 to 14 days after treatment was started. The mechanism for the effect of clofazimine in pyoderma gangrenosum is not known.

The Scandinavian Mycosis Fungoides Study Group has treated 21 patients with mycosis fungoides in plaque stages with topical, whole-body application of nitrogen mustard, 20 mg in 40 ml water per square metre. Ten patients were treated after previous attempts at intravenous tolerance induction ad modum van Scott & Kalmanson and eleven without. Complete remission was initially achieved in 10 patients and partial remission in 9 patients. Contact dermatitis to nitrogen mustard developed in 2/10 after tolerance induction and in 1/11 without tolerance induction. It is concluded that topical, whole-body application of nitrogen mustard gives high remission rates. In this series, however, many relapses occurred, due to inadequacy of the maintenance treatment. Tolerance induction has not been found of any value.

Sixty-nine patients with mycosis fungoides, plaque stage, were treated in an open study with photochemotherapy (PUVA) or the combination of oral retinoids and PUVA (RePUVA). The response rate of Re-PUVA was equal to that of PUVA, with complete remission in 73% and 72%, respectively. Remissions were obtained with fewer PUVA sessions, and with a lower UVA dosage, if PUVA was combined with retinoids. A lower UVA dosage was needed if treatment was given four times weekly in stead of twice weekly. The duration of the remissions tended to be prolonged if retinoids were given as maintenance therapy.

Four commercial radioimmunoassay (RIA) kits for digoxin varied in precision (coefficient of variation, CV within-assays 5-14%) and accuracy (up to 40%). Thus it seems that such commercial RIA-kits can reach at best a CV within-assay of 5% and a similar variation between assays. Without a good control of the performance, the variation can increase 5-6 times. We found that the precision of digoxin RIA as performed at 27 Swedish laboratories using 10 different methods varied from 0.05 to 0.61 nmol/L in between-assay SD for a pool of 2.60 nmol/L. Up to 100% deviations between the highest and lowest reported concentration of a spiked plasma pool may occasionally occur. Such deviations mostly depend on the laboratory, but there are contributions from the kit and effects of the matrix as well. Matrix effects were observed in plasma samples from patients with uremia, acute myocardial infarction and treated with spironolactone to which digoxin was added to a concentration of 2.50 nmol/L. We found 10% underestimation by one method, 10% overestimation by two methods and 5% overestimation by a fourth method, respectively, with the above described samples. For a good judgement of a found plasma concentration value, calculation of a confidence interval is useful. This can be done by computer fitting of the standard curve after duplicate runs of standards and samples in random order. One source of error in RIA appears to be the use of inaccurate standards. We found that standards provided with different RIA-kits for digoxin varied up to 30%. Various physicochemical properties of cardiac glycosides, which could influence the assays were studied. Both digitoxin and digoxin are sparsely soluble in water (5.1 and 36 mumol/L, respectively). Methanol is a much better solvent, which dissolves 6.9 mmol/L of digoxin and 20-24 mmol/L of digitoxin. Chloroform is a good solvent for digitoxin (29-34 mmol/L) but not for digoxin (0.42 mmol/L). Partition of cardenolides between chloroform and water reflected their lipophilic or hydrophilic character. Thus, digitoxin had a high affinity to the organic phase (distribution constant KD = 10(3.65)), while the hydrophilic deslanoside was preferentially found in the aqueous phase (KD = 10(-3.08). Interestingly, the sugar moiety digitoxose in the digoxin molecule turned out to be a substituent that increased lipophilicity. Adsorption of cardiac glycosides occurs to plastics and glass from aqueous solutions. To overcome losses at low concentrations, the solutions must contain plasma, albumin, alcohol or similar solubility-increasing ingredients.(ABSTRACT TRUNCATED AT 400 WORDS)

A method for evaluation of radioimmunoassay results is described. The order of the single tubes in each assay run is randomized. A polynomial is fitted to untransformed data (y = counts per minute; x = concentration of curve.A confidence interval is calculated for each sample, taking into account the variance of the standard curve and that of the actual duplicate assay jointly.

Histamine release from rat peritoneal mast cells was evaluated during interaction with IgG, C3b-bi and Concanavalin A-opsonized yeast particles and activated neutrophils. In contrast to others we could show no phagocytic uptake of yeast particles attaching to Fc, or Concanavalin A receptors on the mast cell. Attached yeast particles opsonized with C3b/bi were also poorly ingested (less than 10% of the attached particles.) Neither could we detect any significant histamine release. If, however, neutrophils were added to the mast cell-yeast particle complex, histamine release was induced particularly in the presence of Concanavalin A-yeast. We furthermore showed that phorbol myristate acetate-activated neutrophils and eosinophils initiated mast cell degranulation and histamine release. This release is not dependent on myeloperoxidase, but on other oxidative metabolites, since myeloperoxidase-deficient neutrophils also induce histamine release. These experiments show that mast cells exposed to immune complexes and activated neutrophils or eosinophils may augment the inflammatory response.

A young woman suffering from recurrent erythema multiforme associated with relapsing gluteal herpes simplex is presented, in whom long-term treatment with oral acyclovir prevented herpes episodes as well as erythema multiforme.

The effect of the sulfone compound 4,4'-diaminodiphenyl sulfone (dapsone) on normal human polymorphonuclear leukocytes (PMNL) has been investigated in vitro. The drug has a dramatically beneficial effect in dermatitis herpetiformis in which the PMNL and immune complexes has been stressed to be of importance for the development of the skin lesions. Pruritus disappears and the inflammatory eruptions clear within a few days of starting therapy. The effect of dapsone has been evaluated on the different stages of phagocytosis. Using dapsone concentrations (1-30 mug/ml) comparable with those found after therapeutic doses, we have found that the drug interferes primarily with the myeloperoxidase (MPO)-H(2)O(2)-halide-mediated cytotoxic system in the PMNL. No effect was observed on random locomotion, chemotaxis, phagocytic ingestion, oxidative metabolism, or the release of lysosomal enzymes. Kinetic studies in a cell-free system with purified MPO revealed a competitive type of inhibition using varying concentrations of NaI. Furthermore, the inhibition resulted in reduced candidicidal activity during phagocytosis of Candida albicans, and reduced cytotoxicity to adjacent mammalian cells measured as the (51)Cr release from virus-induced lymphoma cells. Because the MPO-H(2)O(2)-halide system not only fulfills the antimicrobial activity but is suggested to be a modulator of the inflammatory reaction as well, the action of dapsone in dermatitis herpetiformis may in part be explained by its effect on this system.

Human neutrophils harvested from skin chambers containing autologous serum in psoriatic patients were compared with peripheral blood neutrophils by examining migration, phagocytosis, and oxidative activation. Random migration was reduced in exudate cells, whereas the chemotactic response to yeast-activated serum was evident not only in blood neutrophils, but also in exudate cells. The metabolic activation of exudate neutrophils, when stimulated with formyl-methionyl-leucyl-phenylalanine and measured as chemiluminescence, was enhanced by 50-400% compared to blood neutrophils. The chemiluminescence response to phorbol myristate acetate was on the other hand reduced to 35%. In the phagocytic assay, using C3bi- and IgG-opsonized yeast particles, exudate neutrophils from non-psoriatic healthy controls showed enhanced uptake of C3bi-coated yeast compared to blood neutrophils. In psoriatics, the blood neutrophils showed enhanced C3bi-mediated phagocytosis compared to non-psoriatic control cells. No further increase in C3bi-mediated phagocytosis was then seen in exudate cells from these patients. IgG-mediated phagocytosis was in contrast to C3bi similar between blood and exudate neutrophils in psoriatics and non-psoriatic controls. These experiments show that during exudation priming of different receptor-mediated processes can occur. However, no significant difference was observed between different functional capacities in exudate neutrophils from psoriasis patients and non-psoriatic controls.

The content of 21 elements (As, Au, Br, Ca, Cd, Co, Cr, Cs, Cu, Fe, Hg, K, La, Mo, P, Rb, Sb, Sc, Se, W and Zn) in normal epidermis has been determined with the aid of neutron activation analysis. The dermal loss of these elements via desquamation has been calculated in view of its possible importance in balance studies. For the bulk elements Ca, K and P, the calculated daily loss is considered to be negligible. For some of the trace elements, however, the loss may be appreciable. The daily loss of Fe by desquamation may be as much as one fourth of the daily urinary iron excretion; the corresponding fraction for Co, Cu, and Zn is one tenth.