Quetiapine in combination with citalopram in patients with unipolar psychotic depression.

This 6-week, open-label, multicenter study evaluated the efficacy and safety of quetiapine in combination with citalopram in adult patients (n=25) with ICD-10/DSM-IV unipolar psychotic depression. The primary endpoint was change from baseline to Week 6 in the Hamilton Depression Rating Scale (HAM-D-21) score. Secondary endpoints were change from baseline to Week 6 in the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression (CGI) Scale scores. Spontaneously reported adverse events (AEs), the Simpson Angus Scale (SAS), and the Udvalg for Kliniske Undersogelser (UKU) side effects rating scale scores were recorded. Patients' average age was 51.4 years and baseline weight was 72.6 kg. Quetiapine (50-750 mg/day, mean dose+/-SD: 303+/-118 mg/day), in combination with citalopram (20-60 mg/day, mean dose+/-SD: 34+/-12 mg/day), provided significant improvements in depression. Mean (+/- SD) HAM-D-21 was reduced to 13.25+/-10.87 at Week 6 from a baseline value of 31.21+/-5.18. Significant improvement of psychotic symptoms (mean+/-SD) was indicated by the decrease from baseline (59.25+/-6.60) to Week 6 (35.25+/-15.60) in BPRS scores. No serious AEs occurred. The mean change in weight was +2.1 kg. Mean (+/- SD) weight at visit 1 was 72.72 (+/-16.34) kg and mean (SD) weight at visit 4 was 74.79 (+/-18.69) kg. Quetiapine in combination with citalopram appears to be effective and is well tolerated in the treatment of unipolar psychotic depression. Further studies of larger, double-blind, parallel-group design are warranted to confirm these findings.

Hyaluronidase additional to standard chemotherapy improves outcome for children with malignant brain tumors.

Ex vivo experiments with vital brain tumor samples show that hyaluronidase enhances the permeation of carboplatin into tumor tissue with a matrix rich in hyaluronic acid. We achieved long-lasting second remissions for children with relapsed malignant brain tumors treated with carboplatin, etoposide and this enzyme. Thereafter, we initiated a pilot study where we added hyaluronidase to the first line standard therapy to prevent the deadly relapses right from the beginning. All 19 patients with malignant brain tumors admitted to our pediatric neurooncological center from 1992 to 1994 were included in the study. Kaplan-Meier estimation of event-free survival and overall survival after 3 years follow-up indicates a significantly better outcome for the hyaluronidase-treated group. The children receiving supportive hyaluronidase suffered significantly less relapses (P = 0.034) and had a significantly better chance for survival (P = 0.045) compared to the historical control of 21 children treated with the same standard regimen but without supportive hyaluronidase (product limit analysis and the log-rank test, P < 0.05). Children aged >3 years receiving hyaluronidase together with primary treatment seemed to gain the most benefit.

Dose intensification of epidoxorubicin and cyclophosphamide in metastatic breast cancer: a randomised study with two schedules of granulocyte-macrophage colony stimulating factor.

A randomised phase II/III study was conducted in patients with advanced breast cancer to determine the dose intensity achievable through an acceleration of administration of chemotherapy with epidoxorubicin and cyclophosphamide (EC) alone, as compared with the combination of this regimen with two different schedules of granulocyte-macrophage colony stimulating factor (GM-CSF). 73 patients received EC intravenous (i.v.) (epidoxorubicin 100 mg/m2, cyclophosphamide 600 mg/m2) on day 1 (group A), or the same chemotherapy plus sub-cutaneous (s.c.) GM-CSF (5 micrograms/kg/day) either from days 3 to 12 (group B) or from days -6 to -3 (group C). The primary objective of the study was the investigation of dose intensity delivered in the three treatment arms, whereas the secondary objective was response rate. A significant increase (P = 0.006) in dose intensity of 21% was observed for treatment group B, whereas the increase in dose intensity achieved in group C (7%) was not significant (P = 0.086). Response rates (complete response (CR) + partial response (PR)) of 56% were observed in group A, 65% in group B, and 57% in group C, respectively. This difference in response rates did not reach statistical significance (P = 0.271). We thus conclude that an acceleration of the EC regimen over the standard schedule could be accomplished with postchemotherapeutic GM-CSF support, leading to an increase in dose intensity, whereas pretherapeutic short-term GM-CSF administration did not reach this goal.

Estrogen suppression as a pharmacotherapeutic strategy in the medical treatment of benign prostatic hyperplasia: evidence for its efficacy from studies with mepartricin.

Estrogen suppression has been introduced as a pharmacotherapeutic strategy in the medical treatment of benign prostatic hyperplasia. Recent negative results obtained in placebo-controlled trials with the aromatase inhibitor atamestane raised doubts about the efficacy of estrogen reduction. However, inhibition of aromatase not only reduces estrogens but also increases androgens which promote prostatic growth. In order to reevaluate the therapeutic efficacy of estrogen suppression, we summarize clinical trials investigating the therapeutic effects of mepartricin in the treatment of uncomplicated benign prostatic hyperplasia. Mepartricin has been reported to lower the levels of circulating estrogens without causing changes in other hormones such as androgens. By applying stringent inclusion criteria, 23 studies (including 7 placebo-controlled trials, 3 post-marketing surveillance studies, and 13 open trials) published between 1982 and 1996 were selected to be included in this report. In 79.9% of 4635 patients treated with mepartricin, its therapeutic effect was rated "good" or "excellent". In 6 out of 7 placebo-controlled trials, the therapeutic efficacy of mepartricin was significantly superior to that of placebo. Comparison of these data with results obtained with alpha 1-adrenoceptor antagonists or with the 5 alpha-reductase inhibitor finasteride indicates that mepartricin is as efficient as these widely accepted medical treatments for benign prostatic hyperplasia. Since mepartricin acts selectively upon estrogens, the present results show that estrogen suppression may be considered an efficient pharmacotherapeutic strategy in the medical treatment of uncomplicated benign prostatic hyperplasia.

Efficacy of intranasally applied dimethindene maleate solution as spray in adult volunteers with symptoms of seasonal allergic rhinitis in the Vienna challenge chamber.

Twelve asymptomatic subjects (4 female, 8 male), being allergic to grass pollen proved by positive anamnesis, positive Prick-test and positive nasal provocation test, were challenged under controlled conditions with purified airborne grass pollen of Dactylis glomerata in the Vienna Challenge Chamber (VCC), located at the Universitätsklinik für Hals-Nasen-Ohrenheilkunde, Allgemeines Krankenhaus (AKH), der Stadt Wien, Vienna (Austria) by means of a double-blind, randomised, cross-over design, with 2 weeks wash-out periods between. Efficacy and safety of 2 concentrations of dimethindene (dimethindene maleate; DMM, CAS 3614-69-5, Fenistil resp. Foristal) 0.025% DMM, 0.1% DMM) were tested vs placebo as negative control and vs 0.1% azelastine as positive control, as topical nasal sprays. The tested nasal sprays were applied as single doses in the morning (2 puffs = 0.28 ml of the respective solution) to each nostril 15 min before the start of the 4 h lasting provocation procedure in the VCC, thus representing a total daily dose of 0.14 mg resp. 0.56 mg DMM and 0.56 mg azelastine, respectively. Compared to placebo, the objective variables nasal flow (150 Pa., measured by active anterior rhinomanometry) and nasal secretion (g), showed similar onset of antiobstructive and antisecretory effects in the nose after 0.1% DMM and 0.1% azelastine, respectively. The same applied for the subjective nasal symptom complex and for nasal symptom scores, evaluated by Visual Analog Scale (VAS): Time curves showed statistically significant and clinically relevant superiority of 0.1% DMM and 0.1% azelastine vs placebo, during the 4 h lasting provocation period. 0.025% DMM was not significantly different from placebo. No systemic adverse events were reported after the 4 tested preparations. Only a total of 3 subjects reported very slight local irritations (1 subject after placebo, 1 subject after 0.025% DMM and 1 subject after 0.1% azelastine). However, after 0.1% DMM no local adverse events were reported. It is concluded from this study that 0.1% DMM as nasal spray, is an efficient and safe galenical formulation for nasal spray application for patients suffering from seasonal allergic rhinitis (SAR).

Comparison of the bioavailability of dexibuprofen administered alone or as part of racemic ibuprofen.

Two bioavailability studies of S(+)-ibuprofen (dexibuprofen) were conducted in healthy volunteers to define the relationship between the bioavailability of the drug after administration of dexibuprofen alone or as part of ibuprofen racemate. Enantioselective plasma drug analysis was used throughout. In the first study, the bioavailability of dexibuprofen from a 400 mg tablet formulation was compared with that from 400 mg in aqueous solution. The tablet formulation did not influence the bioavailability of the drug and dexibuprofen was well absorbed from the gastro-intestinal tract. The second study was divided into three identical parts. Bioavailability of dexibuprofen 200, 400 and 600 mg was compared with its bioavailability from ibuprofen racemate 400, 800 and 1200 mg. The second study showed that the mean relative bioavailability of dexibuprofen to ibuprofen racemate was 0.66, thus enabling the estimation of clinically useful dexibuprofen doses from the usual doses of the racemate. The 95% confidence interval limits did not include 0.5, leading to the conclusion that administering half of the racemate dose would not provide patients with an adequate amount of therapeutically active drug.

Controlled exposure to mite allergen for a dose-finding of dimethindene maleate (DMM).

The aim of the study was to develop a laboratory system to challenge mite allergic patients with physiological concentrations of Der p I in order to evaluate the efficacy of antiallergic drugs in mite allergic patients. A double-blind, placebo-controlled, cross-over study was designed with three consecutive sessions. Twelve patients with proven sensitivity to dust mite were treated with a single dose of dimethindene maleate in a FOAD formulation (4 and 8 mg vs. placebo) 12 h before a long-term challenge with mite allergen Der p I in the Vienna challenge chamber. Challenge was performed with a constant concentration of 40 ng Der p I per cubic meter of air for 4 h. Nasal parameters were recorded at 15 min intervals during long-term challenge. In comparison to placebo, dimethindene leads to a statistically significant reduction (p < 0.05) of the nasal response at both concentrations tested. The house-dust mite model in the Vienna challenge chamber thus proved to be a useful tool for drug investigations in mite allergies.

Dose-related control of allergic rhinitis symptoms by a H1-receptor antagonist. Finding the proper doses [correction of dosis] of dimethindene maleate in patients with allergic rhinitis.

The aim of the study was to evaluate the efficacy and duration of two doses of dimethindene, in a sustained release pellet formulation, with a standardized grass pollen provocation model (Vienna Challenge Chamber, VCC). The study of 12 grass pollen-allergic volunteers (verified by case history, skin prick test and RAST) was carried out in a placebo-controlled, double-blind, cross-over design. 12 h before a 4-hour continuous challenge with permanent 1,000 Dactylis grass pollen/m3 of air in the VCC, 4 or 8 mg of dimethindene (Fenistil pellets) or an identically appearing placebo was administered in three sessions. Nasal flow and resistance, nasal secretion and subjective symptoms were recorded at 15-min intervals during this long-term challenge under reproducible conditions. In comparison to placebo, dimethindene leads to a statistically significant reduction (p < 0.05) in nasal response and clinical symptoms for at least 16 h after treatment. The efficacy of 8 mg dimethindene was superior to that of 4 mg dimethindene; however, the differences between both active treatments were not statistically significant. Therefore 4 mg dimethindene once a day is adequate for usual pollinotic disease conditions.

Pharmacodynamic dose finding of dimetindene in a sustained release formulation.

A sustained release form of dimetindene (dimethindene maleate, Fenistil, CAS 3614-69-5) was developed based on a micropellet technique. Aim of the study was to evaluate the efficacy and duration of two doses of dimetindene in a sustained release pellet formulation with a standardised grass pollen provacation model (Vienna Challenge Chamber; VCC). The study with 12 grass pollen allergic volunteers--verified by case history, skin prick test (SPT), and radio allergo sorbent test (RAST)--was carried out in a placebo controlled, double blind, cross-over design. 12 h before a 4-h-lasting continuous challenge with permanent 1000 dactylis grass pollen in the VCC, administration of dimetindene (Fenistil R Pellets) in doses of 4 mg, 8 mg or identically appearing placebo was scheduled in three sessions. Nasal flow and resistance, nasal secretion and subjective symptoms were recorded at 15-min intervals during this long-term challenge under reproducible conditions. In comparison to placebo, dimetindene leads to a statistically significant reduction (p < 0.05) of nasal response and clinical symptoms for at least 16 h after treatment. The efficacy of 8 mg dimetindene was pronounced over 4 mg, however, the differences between both active treatments were not statistically significant. Therefore 4 mg dimetindene once a day is the adequate treatment for usual pollinotic disease conditions.

Bioavailability and pharmacokinetics of D-penicillamine.

The absolute and the relative bioavailability of D-penicillamine, available from different dosage forms and products, was studied in 10 healthy volunteers. Plasma levels and urine excretion of D-penicillamine were determined up to 8 h after administration by high performance liquid chromatography after intravenous administration of 250 mg and after oral administration of 250 mg (2 products) and 150 mg (1 product) D-penicillamine. The absolute bioavailability on oral administration was 50-70%. No statistical difference was found between the relative bioavailabilities of the different dosage forms tested.