The need for a transparent, ethical, and successful relationship between academic scientists and the pharmaceutical industry: a view of the Group for the Respect of Ethics and Excellence in Science (GREES).

UNLABELLED: This paper provides recommendations for fair and unbiased relationship between academic scientists and the pharmaceutical industry. INTRODUCTION: Real or perceived problems in the relationship between academics and the industry have been the subject of much recent debate. It has been suggested that academic clinicians should sever all links with the industry-a view that is rarely challenged. METHODS: Academic experts and members of the pharmaceutical industry were invited to an expert consensus meeting to debate this topic. This meeting was organized by the Group for the Respect of Ethics and Excellence in Science. Conflict of interest, competing interest, right and duties of academic scientist, authorship, and staff and student education were discussed. RESULTS: Guidelines for a transparent, ethical, strong, and successful partnership between the academic scientist and the pharmaceutical industry have been provided. CONCLUSIONS: The Group support interactions between the industry and clinicians provided that it is transparent and ethical.

EEG discharges in WR 1-5 HIV-seropositive hemophiliacs.

Human immunodeficiency virus (HIV)-seropositive patients show involvement of the central and/or peripheral nervous system. We present here the results of electroencephalographic (EEG) findings in stage WR 1-5 HIV-seropositive hemophiliacs from a total of 184 who attended our clinic prior to October 1987.

Randomized, double-blind, one-year study of the safety and tolerability of cyclosporine microemulsion compared with conventional cyclosporine in renal transplant patients. International Sandimmun Neoral Study Group.

BACKGROUND: A microemulsion formulation of cyclosporine, Neoral, has been developed to overcome the problems associated with the poor and variable absorption of the traditional oil-based oral formulation, Sandimmune. The present study was conducted to compare the safety and tolerability of Neoral versus Sandimmune in maintenance renal transplant recipients over 1 year, and to assess the number of dose adjustments necessary to maintain trough cyclosporine concentrations within the desired therapeutic range. METHODS. Patients on Sandimmune were randomized to be converted to Neoral (n=373) or remain on Sandimmune (n=93) for 12 months. RESULTS: The proportion of patients needing dose increases to maintain cyclosporine trough levels within the desired range was significantly higher in the Sandimmune group during the first 3 months of the study, whereas the number of patients needing dose reductions was similar in both groups throughout the study period. There were no differences between the groups in terms of changes in blood pressure, serum creatinine levels, or other laboratory parameters. No significant differences in the incidence of adverse events known to be related to cyclosporine were observed between the treatment groups. More adverse events were causally related to Neoral than to Sandimmune by the investigators. However, overall, there were no clinically relevant differences between the treatment groups in the main safety and tolerability variables. CONCLUSIONS: The results of this study in maintenance renal transplant patients suggest that the improved pharmacokinetic characteristics of the microemulsion formulation of cyclosporine, Neoral, may facilitate the clinical management of cyclosporine immunosuppression, compared with the traditional formulation, Sandimmune. Furthermore, there is no evidence that the average improved bioavailability of Neoral has a negative impact on the main safety and tolerability variables, as no significant differences in graft function, the incidence of rejections, and most adverse events were seen.

Evidence for earlier stabilization of cyclosporine pharmacokinetics in de novo renal transplant patients receiving a microemulsion formulation.

Sequential cyclosporine pharmacokinetic assessments were performed at four centres within the context of a double-blind, multicenter clinical trial comparing the safety and tolerability of the conventional formulation with cyclosporine for microemulsion in de novo renal transplant patients. The initial average daily oral dose was 9.3 mg/kg given in two divided doses every 12 hr with subsequent dose reductions individually titrated to maintain trough concentrations within the target therapeutic range. Pharmacokinetic profiles were assessed at week 2, once between weeks 4-6, and at week 12 in 12 patients on the conventional formulation and 9 patients on the microemulsion. Over the study duration, cyclosporine daily doses were comparable in both study arms and were reduced in parallel from 9.2 to 6.9 to 4.7 mg/kg/day at the three successive pharmacokinetic visits. Dose-normalized peak and area-under-the-curve (AUC) increased between the week 2 and week 4-6 assessments for both formulations. Thereafter, these parameters continued to increase for the conventional formulation but exhibited a high degree of within-in patient stability for the microemulsion between week 4-6 and week 12. Between-formulation comparisons indicated that the rate and extent of cyclosporine absorption from the microemulsion were significantly higher over the study duration. Specifically, at week 2, 4-6 and 12, dose-normalized AUC was 49%, 63%, and 32% higher for the microemulsion. Intrasubject coefficients of variability for pharmacokinetic parameters of the conventional formulation ranged from 26.3% to 68.2%. Corresponding values for the microemulsion were reduced by approximately half, ranging from 13.1% to 38.7%. The correlation between predose trough concentration and AUC was stronger for the microemulsion (r(2)0.819 vs. 0.635) over the full range of systemic exposures attained throughout the study. These results provide initial evidence that, as doses are reduced with time posttransplant, the cyclosporine dose-exposure relationship from the microemulsion may stabilize earlier than that from the conventional formulation, allowing increased pharmacokinetic control over cyclosporine use in this critical posttransplant period.

QEEG in hemophiliacs with HIV infection.

Conventional visual analysis of the EEG was performed on 320 hemophiliacs infected with HIV, who spanned the range of the Walter Reed (WR) system for classifying clinical stage of HIV infection, and on 50 HIV seronegative hemophiliac controls. Intermittent or paroxysmal slowing was the conventional EEG abnormality most commonly seen in early stages of HIV infection (stages WR1 and 2), with increased focal epileptiform activity and generalized slowing appearing in patients with the full clinical syndrome of AIDS (WR6). Slowing of the manually measured alpha rhythm was noted in stages WR2 and above. Quantitative EEG (qEEG) was obtained in a subset of 103 male HIV seropositive male hemophiliacs and 35 male HIV seronegative hemophiliac controls. The principal findings were a progressive relative increase in theta power with a tendency towards an anterior topographic distribution, and a progressive decline of spectral power in fast alpha relative to slow alpha with increasing severity of HIV disease. Significant qEEG differences from controls were apparent in WR2 subjects (seropositive with lymphadenopathy and without other constitutional symptoms), and were relatively greater in WR3-6 subjects. These results suggest sensitivity of qEEG to early CNS involvement with HIV infection.

[Course and diagnosis of pulmonary Kaposi sarcoma in patients with AIDS]. / Verlauf und Diagnose des pulmonalen Kaposi-Sarkoms bei Patienten mit AIDS.

Diagnosis of pulmonary Kaposi's sarcoma can be difficult. Clinical findings and chest X-rays are non-specific and endobronchial diagnostic in about 50% of cases. Additional concomitant infectious complications are frequent. Symptomatic pulmonary Kaposi's sarcoma most oftenly is progressive and has a poor prognosis. Preliminary data suggest effective palliation with radio- and chemotherapy and an improved survival time in selected cases. We present six cases of proven pulmonary Kaposi's sarcoma and discuss clinical course and diagnostic difficulties. Based on this view we propose a diagnostic approach to warrant therapeutic success.

[Tuberculosis and atypical mycobacterioses in HIV infection. Results from the Bonn Center 1985 to 1989]. / Tuberkulose und atypische Mykobakteriosen bei HIV-Infektion. Ergebnisse des Zentrums Bonn 1985 bis 1989.

485 HIV-positive patients have been treated at our institution in Bonn during 1985 to 1989. Mycobacterial infections occurred in twelve (2.5%) HIV-positive patients. Of 166 AIDS-manifestations according to CDC, eleven (6.6%) were mycobacterial infections. There occurred one case of miliary tuberculosis, six cases of extrapulmonary, one of disseminated tuberculosis and four cases of atypical mycobacteriosis. Mycobacteriosis other than tuberculosis (MOTT) were caused three times by Mycobacterium kansasii and once by Mycobacterium scrofulaceum. Tuberculosis was seen less often in haemophiliacs. Disseminated tuberculosis and atypical mycobacteriosis developed in late stages of HIV-infection with underlying severe immunodeficiency. The lung was the main target organ of tuberculosis. MOTT most often affected the gastrointestinal tract additionally. Noninvasive materials, first of all sputum and gastric acid, were reliably diagnostic but available with delay in particular cases. In those cases histologic studies proved helpful. Application of five-fold regimen (INH, RMP, EMB, PZA and SM) always succeeded in negative cultures in a mean of 15 days in all cases of tuberculosis. Two cases of atypical mycobacteriosis with Mycobacterium kansasii were treated with a five-fold regimen (one case with ciprofloxacin additionally) and culture-negative after six resp. 28 weeks of therapy.

Safety and tolerability of a new oral formulation of cyclosporin A, Sandimmun Neoral, in renal transplant patients.

The current therapy with Sandimmun has been improved by the development of a new oral formulation of its active ingredient, Cyclosporine A and which is called Sandimmun Neoral. This new galenical formulation is based on the microemulsion technology and offers consistent oral absorption and pharmacokinetic predictability. In two studies of a 12 weeks duration each and including 466 stable renal transplant patients and 86 new renal transplant patients it was shown that Sandimmun Neoral is as well tolerated and as safe as Sandimmun. Stable renal transplant patients currently receiving Sandimmun can safely be switched to Sandimmun Neoral on a 1:1 dose level basis. However, as a result of the more consistent absorption of Sandimmun Neoral, poor absorbers with Sandimmun will become normal absorbers and than will need a considerable dose reduction to reach the same Cyclosporine A exposure. In new renal transplant patients kidney function seems to improve better and faster when Sandimmun Neoral is given as shown by creatinine and creatinine clearance values. In the Sandimmun Neoral group less patients experienced a rejection episode and time free of rejection was longer, this may reflect a better maintenance of immunosuppression. In addition, considerably lower doses (16% on average) are required for Sandimmun Neoral to achieve comparable cyclosporine A blood trough levels and these patients are also sooner stabilized in terms of Cyclosporine a therapy.

Cyclosporine microemulsion increases drug exposure and reduces acute rejection without incremental toxicity in de novo renal transplantation. International Sandimmun Neoral Study Group.

BACKGROUND: The new oral microemulsion formulation of cyclosporine (Neoral) possesses superior pharmacokinetics to the conventional formulation, Sandimmun (SIM), providing more complete and predictable absorption, and less pharmacokinetic variability. METHODS: The safety and tolerability of Neoral, together with the incidence of acute rejection episodes and graft survival, were compared to the conventional cyclosporine formulation, SIM, in a prospective, randomized, double-blind multicenter trial. A total of 167 patients who received a first or second cadaveric renal transplant in 21 participating centers in six countries were randomized equally to two treatment groups and followed for three months after transplantation. Outcomes were analyzed across treatment, center and regional groups. In addition, a nested pharmacokinetic study was performed in four of these centers throughout the period of follow-up. RESULTS: No difference was detected between the safety or tolerability of the two formulations. Kidney function and other laboratory parameters remained comparable in Neoral- and SIM-treated patients throughout the study. However, the number of patients experiencing acute rejection was significantly reduced for the Neoral group (44.2% vs. 60.5%; P = 0.044), and significantly fewer patients experienced multiple episodes of rejection (12.8% vs. 22.2%, P = 0.028). The proportion of patients free of rejection at three months was significantly higher in patients treated with Neoral than in those receiving SIM (Kaplan-Meier estimated probability of remaining rejection-free at 3 months = 55% for the Neoral group, compared with 39% for the SIM group, P = 0.046, log rank test). Similar results were obtained when acute rejection, graft loss and death were used as a combined endpoint (Kaplan-Meier estimated probability for Neoral group = 54%, compared with 38% for the SIM group, P = 0.047, log rank test). Comparison of results by center or regional groups did not show any significant treatment interaction. A nested pharmacokinetic evaluation (four centers; 28 subjects) showed that the bioavailability of cyclosporine from Neoral was significantly higher than from SIM at all assessment times. Specifically, at weeks 2, 4 to 6, and 12, dose-normalized AUC was 49%, 63% and 32% higher for Neoral. Dose-normalized peak cyclosporine blood concentrations and AUC stabilized by weeks 4 to 6 in patients receiving Neoral, whereas these values increased slowly in SIM-treated patients without reaching the levels achieved in the Neoral group. CONCLUSIONS: These results suggest that the superior pharmacokinetic characteristics of the microemulsion formulation of cyclosporine lead to more efficient immunosuppression during the first critical months after transplantation, without a deleterious impact on clinical safety.

Pigeon breeders' lung lacking detectable antibodies.

Whereas fifteen pigeon fanciers suffering from extrinsic allergic alevolitis from avian dust had high titres of antibodies against pigeon antigens, antibodies were not demonstrable, even by immunofluorescence, in the serum of a symptomatic individual exposed to minimal amounts of avian dust. Following exposure to larger quantities of pigeon dust inhalation challenges, a low titre of antibodies appeared, but disappeared again after avoidance of the allergen. Cell-mediated immunity was elevated in the lymphocyte transformation test and also decreased after avoidance of allergen contact. Therefore, it seems likely that the antibody is not the only mediator of pigeon breeder's lung. Inhalation challenges and T cell-dependent immune reactivity may reveal more avian dust sensitive individuals suffering from fibrosis without the typical history of extrinsic allergic alevolitis and without detectable antibodies.

Clinical development of a cyclosporine microemulsion in transplantation.

Current clinical difficulties in the use of cyclosporine in transplantation are in part due to its narrow therapeutic window between effective immunosuppression and adverse events and in part due to suboptimal absorption associated with wide pharmacokinetic variability. Under the assumption that the latter aspects are largely formulation-related, a clinical development program was undertaken to compare the conventional formulation (Sandimmun) with a new microemulsion preconcentrate (Neoral). After oral administration, Neoral immediately forms a microemulsion in aqueous gastrointestinal fluids yielding a homogeneous dispersion from which cyclosporine is more readily absorbed. Single-dose crossover studies in healthy subjects were initially performed to document improved bioavailability and dose linearity, lower intrasubject pharmacokinetic variability, and reduced food effect with Neoral. In a subsequent phase of the development program, questions that could only be assessed in transplant patients at steady state were addressed in small, open-label studies under a trough concentration-guided strategy. This approach was necessary to maintain effective immunosuppression while determining appropriate and safe guidelines for converting between formulations, assessing the trough: area under the curve correlation and exploring for potential differences in metabolism. Multicenter, double-blind, randomized investigations were then performed to compare the formulations in stable and de novo transplant populations. In this context, the conversion approach, the safety/tolerability profile, and the attendant pharmacokinetic advantages of the microemulsion formulation were confirmed in larger populations under clinical conditions. It is anticipated that the more precise pharmacokinetic control possible with Neoral will provide a firmer base from which to elucidate the relationship between cyclosporine exposure and graft survival to optimize cyclosporine-based immunosuppressive regimens.