Therapeutic drug monitoring of patients with psoriasis during tumour necrosis factor (TNF)-α antagonist treatment using a novel interleukin-8 reporter cell line.

BACKGROUND: Tumour necrosis factor (TNF)-α antagonist therapy is currently used for moderate and severe psoriasis. However, this treatment has several drawbacks, including interindividual variability in clinical response and secondary loss of effectiveness. OBJECTIVES: To evaluate quantitatively the TNF-α-neutralizing activity of the plasma of patients with psoriasis during TNF-α antagonist therapy and to determine poor responders objectively. METHODS: We used a human interleukin-8 reporter monocyte cell line, THP-G8, that harbours a stable luciferase orange (SLO) gene under the control of the interleukin-8 promoter. After confirming its dose-dependent response to exogenous TNF-α, we examined the suppressive activity of TNF-α antagonists and of the patients' plasma during TNF-α antagonist therapy on TNF-α-induced SLO luciferase activity (TNF-SLO-LA). RESULTS: Pretreatment of TNF-α with TNF-α antagonists or with the plasma of patients with psoriasis who achieved 75% improvement in Psoriasis Area and Severity Index (PASI 75) dose dependently suppressed TNF-SLO-LA. There was a significant correlation between change in PASI and percentage suppression (inhibitory rate of a 1 : 2 dilution of patient plasma on TNF-SLO-LA). A percentage suppression of 50·3% has a positive predictive value of 87% of achieving PASI 75, with a sensitivity of 93% and a specificity of 80%. CONCLUSIONS: Therapeutic monitoring of patients with psoriasis during TNF-α antagonist therapy using THP-G8 can provide a useful tool to determine objectively the efficacy of the administered TNF-α antagonists.

Serotonin syndrome during clomipramine monotherapy: comparison of two diagnostic criteria.

Incidence of serotonin syndrome was determined by two different diagnostic criteria during clomipramine monotherapy. Incidence, determined by Sternbach's criteria, was 12.1% (8/66 patients), and that determined by the criteria of Dursun et al. was 3.0% (2/66 patients). The two patients who met the latter criteria also met the former criteria. The lower incidence with the latter was attributable to the fact that it does not include certain symptoms, such as tremors and diaphoresis, which are included in the former, and were seen in a relatively large number of patients; as well as the fact that the latter more strictly define certain symptoms. Both criteria have pros and cons. Sternbach's diagnostic criteria make it possible to diagnose serotonin syndrome in a wider range of patients, but they sometimes make it difficult to make it differential diagnosis in the presence of certain limited symptoms. In contrast, the criteria of Dursun et al. may make a more accurate diagnosis possible, though only in severe cases.

Development of hydrosalpinx during ovulation induction.

We have observed that hydrosalpinx develops in some patients undergoing ovulation induction as part of in vitro fertilization-embryo transfer and gamete intrafallopian transfer programs. Increased tubal secretions due to multihormonal stimulation causes a blocked tube to distend by the time of oocyte harvest. In a subset of women, hydrosalpinx was not identified on initial pelvic sonograms. Hydrosalpinx became apparent during serial sonography to monitor follicular development. We performed a retrospective chart review of these cases in order to confirm this finding with hysterosalpingography or laparoscopy. Nine of 316 women developed unilateral (eight cases) or bilateral hydrosalpinx (one case) during stimulation. Recognition of this sonographic finding is important to the referring physician because it has important therapeutic and outcome implications.

Effects of 8-OH-DPAT on corticosterone after acute and chronic administration of antidepressants.

1. Serotonin has a facilitary role in the role of corticosterone secretion. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT1A agonist, dose dependently (0.25- 1.0 mg/kg i.p.) increased rat plasma corticosterone concentration. 2. 3 days parachlorophenylalanine (PCPA) (150 mg/kg) administration did not effect the 8-OH-DPAT-induced corticosterone secretion. 3. Corticosterone responses to 8-OH-DPAT (0.5 mg/kg) were significantly attenuated by pretreatment with propranolol (5 mg/kg). Ketanserin (2 mg/kg), haloperidol (0.2 mg/kg), prazosin (0.1 mg/kg), and ICS-205930 (30 mu/kg) failed to antagonize the corticosterone response to 8-OH-DPAT. 4. 8-OH-DPAT-induced corticosterone were investigated in male rats after treatment with mianserin (2, 10 mg/kg), imipramine (5 mg/kg), desipramine (5 mg/kg), doxepine (5 mg/kg) for 1 day or 3 weeks. Chronic mianserin (10 mg/kg) and doxepine (5 mg/kg) did significantly increase 8-OH-DPAT-induced corticosterone response. Acute antidepressant, chronic imipramine, desipramine and mianserin (2 mg/kg) treatment did not change it. 5. These findings demonstrate that chronic treatment of some antidepressants potentiates 8-OH-DPAT-induced increase in plasma corticosterone, by actions at 5-HT-1A receptors located postsynaptically on 5-HT neurones.

A method for analyzing biological rhythms in healthy subjects and depressed patients.

Rectal temperature rhythms of healthy subjects and patients with depression were fitted to a waveform having cosine components of periods 8, 12, and 24 hours using the least squares method. The nadir was then used as an index of phase. The results suggest that this method gives more exact data than the conventional method of analyzing biological rhythms, which uses a least squares fit to a single, 24-hour-period cosine waveform.

[Adverse effects of antidepressants and anti-manics/mood stabilizers].

Information on the adverse effects of antidepressants and antimanics/mood stabilizers is presented. The adverse effects of antidepressants include pharmacological side-effects, toxic effects, interactions with other drugs, withdrawal syndrome and "jitteriness" syndrome. The most common adverse effects with lithium treatment are polyuriapoly-dipsia, hypothyroidism, gastrointestinal symptoms, psychological complaints and ECG changes. The adverse effects of carbamazepine and valproate are mild and readily manageable, however problems associated with the hepatic system, the hematopoietic system and the thyroid gland, are important. It seems that no major deficits have been identified in studies of tricyclic antidepressant teratogenicity. Lithium, carbamazepine and valproate carry significant teratogenic effects.

The effect of chronic administration of antidepressants and electroconvulsive shock on the 5-HT1A receptor mediated hypothermic response induced by 8-OH-DPAT in the rat.

1. The effect of chronic administration of antidepressants and electroconvulsive shock (ESC) on the hypothermic response (HTR) induced by 8-hydroxy-2-(di-n-propyramino) tetralin (8-OH-DPAT) as an index of the function of 5-HT1A receptors was investigated in the rat. 2. 8-OH-DPAT dose-dependently decreased the rectal temperature. 3. Pretreatment with parachlorophenylalanine increased HTR. 4. Chronic administration of the antidepressants, trazodone, imipramine, amitriptyline, and fluoxetine had no effect on HTR, whereas administration of clorgyline attenuated HTR significantly. 5. Repeated ECS had no effect on HTR. 6. These results suggest that the action site of 8-OH-DPAT is post-synaptic 5-HT1A receptors and that the chronic administration of some antidepressants and ECS has no direct action on these receptors. 7. Therefore, the antidepressant effects of these drugs are not produced by direct action on postsynaptic 5-HT1A receptors.

Effects of chronic mianserin administration on serotonin metabolism and receptors in the 5-hydroxytryptophan depression model.

1. To further investigate a previous postulate that increased serotonergic activity may cause depression, the effects of chronic mianserin administration on 5-HT, its metabolites, and the subtypes of 5-HT receptors were studied. 2. The levels of 5-HT, 5-hydroxyindoleacetic acid, 5-HTP, 5-HT turnover and their response to 5-HTP administration all exhibited no change following mianserin treatment. 3. The Bmax value of the high affinity site of the 5-HT-1A receptor increased and the Bmax value of 5-HT-2 receptor decreased with no change in the low affinity site of the 5-HT-1A receptor nor in the 5-HT-1B receptor. 4. The response to 5-HTP administration showed no change in any of these receptors. 5. These results suggest that the chronic mianserin administration might block both the 5-HT-2 and 5-HT-1A receptors in the 5-hydroxytryptophan depression model.

Effect of IAP and chronic antidepressant administration on the 5HT1A receptor in rat cortical membranes.

1. A possible coupling of the rat cerebral cortex 5-hydroxytryptamine (5HT)-1A receptors to isletactivating protein (IAP, pertussis toxin) sensitive Gi protein was investigated by studying the effects of a guanosine 5'-triphosphate (GTP) and IAP injection to the rat ventricle. 2. Scatchard analysis showed that Bmax value of the high-affinity componentin [3H]8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) binding was decreased by pretreatment with IAP. 3. GTP caused a significant decreased Bmax of the high affinity site for [3H]8-OH-DPAT binding. It was noted that the IAP suppressed the cyclic AMP production by 5HT, VIP and Forskolin. 4. These results suggest that the rat cortex 5HT-1A receptors are linked to the Gi protein. 5. After 3 weeks chronic administration of amitriptyline (5mg/kg), desipramine (5mg/kg), imipramine (5mg/kg), doxepin (5mg/kg) and trazodone (10mg/kg), the receptor binding assay was carried out on 5HT-1A receptors. 6. It was observed that all the antidepressant drugs except for imipramine increased the number of high-affinity sites of the 5HT-1A receptors in the frontal cortex. 7. These results suggested that the increase of the Bmax for the 5HT-1A receptor might be related to the effectiveness of the antidepressant drugs.

Animal study on the role of serotonin in depression.

1. In our series of experiments the role of serotonin in human depression was studied by using animal models of depression. 2. The results of these studies support the hypothesis that some types of human depression may be primarily due to an excessive transmission of serotonin at the synapse.

Circadian rhythm of serotonin receptor in rat brain.

Bmax and Kd for the serotonin receptors (5-HT-1) as well as the ratios of 5-HT-1A and 5-HT-1B receptors were assessed at 3-hour intervals over a 24-hour period in the cortex of rats that were housed under a 12-hour lighting cycle, with the light turned on at 18:00. The circadian rhythm of the Bmax for the high- and low-affinity sites in 5-HT-1 receptor became evident. The peak of the Bmax for the high- and low-affinity sites occurred between 21:00 and 00:00. No circadian rhythm was observed for Kd at each site for the 5-HT-1 receptors. The ratios of Bmax for the high- and low-affinity sites of the 5-HT-1 receptors were constant at 8.6 +/- 1.4% and 91.4 +/- 1.4% respectively over the test period. The ratios of 5-HT-1A and 5-HT-1B receptors were constant at 36.8 +/- 1.3% and 63.2 +/- 1.2% respectively over the test period. No circadian rhythm was observed for Kd. These results suggest that the Bmax for the 5-HT-1 receptors may have the same circadian rhythm as high- and low-affinity sites and the Bmax for the 5-HT-1A and 5-HT-1B receptors may also have circadian rhythm.

[Second report of ofloxacin: clinical study].

We previously reported a study on the antimicrobial action of a chemically synthesized drug, ofloxacin (OFLX) and on its transfer in. This paper describes the results of our clinical study on OFLX. 1. Only small fractions of intra-blood OFLX were transported into female organs such as uterus, ovary and fallopian tube. Our study with the normal delivery method shows that umbilical cord blood concentrations of OFLX is a third to a sixth of maternal blood concentrations and is achieved through trans-placental transfer. Its transfer into amniotic fluid, however, is very low. 2. Forty-one cases, including cases of female intrapelvic inflammation, urinary tract infection, puerperal mastitis, etc., were administered with OFLX at levels of 200 approximately 400 mg/day for 3 approximately 10 days. OFLX were found to be effective in 35 cases. 3. We observed 113 cases to which OFLX was administered, and found only 4 cases of gastrointestinal disturbance and 1 case of suspicion of drug eruption as side effects. Laboratory tests showed no abnormalities due to OFLX in blood, serum biochemical or urine value in the cases examined (26 to 51 cases depending on test).

[Per rectal administration of antibiotics. Clinical use of ampicillin in respiratory tract infection in children].

As one of our clinical studies on per rectal administration of antibiotics, children who suffered respiratory tract infection (RTI) were administered with ampicillin (ABPC) through this route. Our conclusions drawn from this study are as follows: 1. One hundred and eighty strains of aerobic bacteria which were isolated by us in 1984-1985 were tested for the sensitivity to ABPC using plate-disk method. MIC's of ABPC for all the strains of Streptococcus pyogenes were lower than 0.024 micrograms/ml. MIC's for all the strains of Streptococcus haemolyticus were 0.05-0.20 microgram/ml. MIC's for 88% of the strains tested of Haemophilus influenzae were 0.10-0.78 microgram/ml. 2. Bacterial flora in the respiratory tract of 97 cases of children, who suffered RTI, were cultured. Almost half of them were Gram-positive cocci, the rest belonged to Gram-negative groups. This indicates that broad-spectrum antibiotics should be chosen first even before the diagnosis of causative organisms is established. 3. Soon after a per rectal administration of ABPC to children, high blood concentrations of the drug were observed by paper-disk method. 4. Eleven cases, which included 2 cases of pneumonia, of 15 children who suffered RTI and were given this antibiotic were greatly improved within 3-10 days. No serious side effects were observed. 5. Our brief study reported here indicates that ABPC administration by rectal route is safe and useful for the clinical treatment of RTI of children.