Hoechst-Roussel Pharmaceuticals Research Articles

Magnetic resonance imaging in the evaluation of ureteropelvic junction obstructed kidney

Deaconess Medical Center and H&ard Medical ychool, Boston, Massachusetts Reprint requests: Mohammad R. Mostafavi, M.D., Beth Israel Deaconess Medical Center-, East Campus, UT-ology Department, 330 Brookline Avenue, Boston, MA 02215 Submitted: April 4, 1997, accepted: May 13, 1997 The patient presented with cholestatic jaundice during her pregnancy. An abdominal ultrasound demonstrated a severe right hydronephrosis. After delivery, an intravenous urogram (IVU) revealed a high-grade right ureteropelvic junction (UPJ) obstruction (Fig. 1). No calculi were observed on the scout film. MAG3 Lasix (Hoechst-Roussel Pharmaceuticals, Somerville, NJ) renal scan confirmed a high-grade right UPJ obstruction with 35% function of the right and 65% function of the left kidney. To determine whether there were any accessory vessels that would preclude her candidacy for endopyelotomy, magnetic resonance (MR) urography and angiography was performed. Anatomic MR urograms were obtained using heavily weighted imaging without contrast agent. The collecting system appeared bright (Fig. 2). Next, functional MR urography was performed by in-

Canda Submissions: A Retrospective Look at a Sponsor’s Experience

Computer assisted new drug applications (CANDAs) can be as simple as data submitted in electronic format such as ASCII files, or as complex and sophisticated as systems that enable the Food and Drug Administration (FDA) reviewer to access sponsor databases, case report form (CRF) images, listings, tables, and text. A CANDA application was submitted to the Division of Topical Drug Products of FDA for Loprox® Gel by Hoechst-Roussel Pharmaceuticals Inc. (now Hoechst Marion Roussel, Inc.) in December 1994. The software used for this submission, Integrated CANDA™ (ICANDA), was a data access, review, and reporting tool that enabled the FDA reviewer to access the clinical database, the CRF images, tables, and report text. The reviewer could create tables, listings, graphs, perform simple statistical analyses, and cut and paste from the generated output to his review document. The features of the software, contents of the submission, corresponding documention, validation, and advantages and disadvantages of this CANDA submission are presented.

The content and properties of the Caregiver Activities Time Survey (CATS): An outcome measure for use in clinical trial research on Alzheimer's disease

The CaregiverActivities Time Survey (CATS) was developed in 1990, pilot tested and revised twice before its use in a long-term study of Mentaneo (velnacrine maleate), conducted by Hoechst Roussel Pharmaceuticals Inc. (currently Hoechst Marion Roussel Pharmaceuticals). The instrument yields ratio level data and, by relying on caregivers' reports of minutes per task, is more objective and theoretically less ambiguous than other subjective ratings. Overall alpha of the informal scale is .51 suggesting modest internal consistency which is not surprising given that caregiving tasks are more discrete than items on scales presumed to tap one dimension. Test-retest reliability of individual items suggests good reproducibility of scores over a J0-week period Criterion-related validity was demonstrated by the strmng relationships shown between the CATS and several measures of cognitive functioning. Longitudinal data support the CATS'sensitivity to change in disease severity. Ratings by a panel of experts suggest very good to excellent content validity of both informal caregiving andformal or paid caregiving CATS scales

The influence of pentoxifylline (Trental) on the antifertility effect of intrauterine devices in rats

To test the hypothesis that the inflammatory response stimulated by intrauterine devices (IUDs) plays a role in the antifertility action of IUDs. We treated rats with pentoxifylline (Trental; Hoechst-Roussel Pharmaceuticals, Inc., Somerville, NJ) and evaluated its effect on the anti-implantation action of IUDs. The number of embryos in treated compared with untreated rats was determined. Breeder female Sprague-Dawley rats (Harlan Sprague Dawley, Indianapolis, IN) were randomized into one of five test groups (n = 20 per group). A monofilament nylon IUD was inserted transcervically into one horn of the bicornuate uterus in two groups. The IUD-bearing groups received either intraperitoneal (IP) injections of pentoxifylline (45 mg/kg per every 12 hours) or normal saline (NS). The two non-IUD-bearing groups received IP injections of pentoxifylline or NS. The non-IUD group was not injected. All injections were administered daily for 21 days and the animals then mated. Successful mating was determined by the presence of spermatozoa in vaginal washings. The injections of pentoxifylline or NS were continued until day 12 of pregnancy when the rats were killed. The total number of embryos in each uterine horn was determined. University research laboratory. Embryo numbers (1.0 +/- 0.6 [mean +/- SEM]) were reduced in the IUD horn compared with the contralateral non-IUD horn (6.4 +/- 1.0) and with the uterine horns from each of the four other test groups. The number of embryos were increased in the IUD horn (3.5 +/- 0.9) of the pentoxifylline-treated rats. Pentoxifylline appeared to reduce the contraceptive effectiveness of the IUDs in this model.

Preliminary disk diffusion susceptibility testing criteria for cefdaloxime (RU29246, HR-916 metabolite), a new orally administered cephalosporin.

Cefdaloxime (formerly RU29246; Hoechst-Roussel Pharmaceuticals Inc., Somerville, N.J.) a new active component of the HR-916 ester, was tested by dilution and two disk (10- and 30-micrograms) diffusion susceptibility tests against 391 clinical isolates. Interpretive criteria were proposed for three potential MIC breakpoints of less than or equal to 1, less than or equal to 2, and less than or equal to 4 micrograms/ml. Analyses by regression line and error rate bounding methods minimized false-susceptible (very major) errors and produced a greater than or equal to 90% absolute interpretive agreement between susceptibility test methods. The less than or equal to 2-micrograms/ml breakpoint seemed optimal when 10-micrograms disks and the available human pharmacokinetics were used. The following inhibition zone diameter criteria were proposed: susceptible, greater than or equal to 19 mm; resistant, less than or equal to 15 mm. These recommendations for clinical trials should remain tentative until additional information about cefdaloxime formulations, pharmacokinetics, and patient outcomes can be correlated with in vitro susceptibility test results.

Immunex sues Hoechst over marketing of drug

Immunex, a Seattle, Wash.-based biotechnology firm, is suing Hoechst A.G. and two of its subsidiaries over issues related to their marketing agreement on granulocyte macrophage-colony stimulating factor (GM-CSF)—a drug that stimulates growth of white blood cells, strengthening the immune system. In its Seattle Superior Court suit, Immunex alleges the two subsidiaries, Germany-based Behringwerke A.G. and U.S.-based Hoechst-Roussel Pharmaceuticals, engaged in unfair competition, business interference, and breach of contract. It charges Hoechst-Roussel undercut U.S. demand for Immunex's GM-CSF, and failed to market this product as required by agreements between the companies. Instead, Immunex claims, a Hoechst-Roussel giveaway program has flooded Immunex's customer base with free products—at least 10,000 vials—in an attempt to undermine Immunex's investment in GM-CSF and intimidate it in contract negotiations. Immunex says these actions have lowered its sales, causing it a net loss for the first quarter ...

Evaluation of HP 029 (Velnacrine Maleate) in Alzheimer's Diseasea

HP 029 (1,2,3,4-tetrahydro-9-aminoacridin-1-ol-maleate) is a cholinesterase inhibitor and one of a series of compounds synthesized at Hoechst-Roussel Pharmaceuticals Inc. (HRPI) as a potential therapeutic agent for senile dementia of the Alzheimer type (SDAT). An ongoing clinical development program for HP 029 (velnacrine maleate) reflects a rational, traditional progression from therapeutic concept through clinical evaluation. Prior to the initiation of outpatient studies, sufficient data had been obtained from normal volunteers and hospitalized patients to support the following conclusions: the pharmacokinetic profile of HP 029 in young and elderly normal men is predictable; tolerance and safety data for HP 029 using normal volunteers poorly correlates with experience in patients with SDAT; patients with SDAT exhibit marked intersubject variability in tolerance within a suspected therapeutic dose range; mandatory endpoints for drug discontinuation for outpatients can be reliably established in an inpatient environment. Subsequently, Protocol 201 was initiated as a multicenter, multistage investigation of HP 029 in patients with probable SDAT (NINCDS-ADRDA criteria). A dose-ranging component determined patient eligibility for a subsequent dose-replication phase based upon explicit safety and efficacy criteria defined within protocol. One a priori specified interim analysis was conducted by the sponsor (HRPI) for administrative purposes after completing approximately 50% of the planned sample (September 1989). Results suggested that (1) beneficial effects of HP 029 existed on key and secondary measures for the approximately 30% of enrolled patients; (2) interim results would provide an accurate reflection of the results at the conclusion of the study (1991); (3) HP 029-induced hepatocellular injury appeared to be a reversible, predominantly dose-related event; and (4) cholinergically mediated adverse events are infrequent and clinically inconsequential at dosages less than or equal to 225 mg/day. Post hoc hypotheses based on the interim dataset suggest that: (1) carry-over effects of HP 029 exist within a dose-ranging/dose-replication paradigm that militate against the utility of an "enriched population" design; (2) beneficial effects are more robust on initial exposure to HP 029 with effects discerned on both memory and arousal; (3) patient characteristics associated with toxicity or response are not identified; (4) dosage reduction in subsequent efficacy trials may reduce hepatocellular injury and yield clinically unimportant differences in overall efficacy results.

RU-486: Hoechst-Roussel (US), Hoechst AG, Roussel Uclaf SA, and Hoechst-Roussel Pharmaceuticals Inc

To the Editor. — I am writing to clarify an inaccurate and misleading statement that appears in the Regelson et al Commentary, Beyond 'Abortion': RU-486 and the Needs of the Crisis Constituency.1In this Commentary, Dr Regelson and colleagues incorrectly associate Hoechst-Roussel Pharmaceuticals Inc with the compound RU-486 (mifepristone). RU-486 was developed in France by the company Roussel Uclaf SA, a minority shareholder of Hoechst-Roussel. Hoechst-Roussel has absolutely no connection with this compound—it did not develop the compound, nor does it manufacture or market RU-486.

4978663 5-(1-aminocyclohexyl) 2(1H)-pyridinone compounds which have pharmaceutical utility: Richard Effland, David M Fink assigned to Hoechst-Roussel Pharmaceuticals Inc

4978663 5-(1-aminocyclohexyl) 2(1H)-pyridinone compounds which have pharmaceutical utility: Richard Effland, David M Fink assigned to Hoechst-Roussel Pharmaceuticals Inc

4963537 Labdane compounds, pharmaceutical compositions and use: Raymond W Kosley, Robert J Cherill assigned to Hoechst-Roussel Pharmaceuticals Inc

4963537 Labdane compounds, pharmaceutical compositions and use: Raymond W Kosley, Robert J Cherill assigned to Hoechst-Roussel Pharmaceuticals Inc

Pharmacological Alleviation of Combined Cholinergic/Noradrenergic Lesion-Induced Memory Deficits in Rats

Data derived from a number of preclinical studies examining the effects of combined cholinergic and noradrenergic lesions in a rat model of Alzheimer's disease are reviewed. Results from these studies indicated that a nucleus basalis of Meynert (nbM) lesion combined with a lesion of the ascending noradrenergic bundle (ANB) did not exacerbate 72-h passive avoidance retention deficits beyond the degree of impairment produced by nbM lesions alone. However, the addition of an ANB lesion did block the efficacy of two choiinomimetics (physostigmine and oxotremorine) to reverse the lesion-induced memory impairment. Memory in combined lesioned rats was restored when cholinomimetic therapy was administered in combination with low doses of clonidine. Studies investigating a number of Hoechst-Roussel Pharmaceuticals compounds have produced memory-enhancing effects in animals prepared with combined nbM/ANB lesions without the need for clonidine supplementation. These compounds include P128, P86-7493, and P87-8184. Moreover, these compounds have also been shown to be effective in reversing passive avoidance memory deficits in animals with nbM lesions and treated with the noradrenergic toxin DSP-4. Implications for pharmacotherapeutic approaches for the treatment of Alzheimer's disease are discussed.

Clinical experience with a cholinesterase inhibitor (HP 029) in the treatment of Alzheimer's disease: Can it make a difference? : ∗R.W. Richter, M.F. Murphy and C. Dobson. University of Oklahoma and St. John's Hospital, 1705 East 19th Street, Tulsa, OK and Hoechst-Roussel Pharmaceuticals Inc., Somerville, NJ

Clinical experience with a cholinesterase inhibitor (HP 029) in the treatment of Alzheimer's disease: Can it make a difference? : ∗R.W. Richter, M.F. Murphy and C. Dobson. University of Oklahoma and St. John's Hospital, 1705 East 19th Street, Tulsa, OK and Hoechst-Roussel Pharmaceuticals Inc., Somerville, NJ

Implications of normal volunteer compared to patient studies in the early evaluation of compounds for Alzheimer's disease (AD) : ∗N.R. Cutler, M.F. Murphy, R.J. Nash, J.J. Sramek. California Clinical Trials, Beverly Hills, CA, and Hoechst-Roussel Pharmaceuticals, Sommerville, NJ

Implications of normal volunteer compared to patient studies in the early evaluation of compounds for Alzheimer's disease (AD) : ∗N.R. Cutler, M.F. Murphy, R.J. Nash, J.J. Sramek. California Clinical Trials, Beverly Hills, CA, and Hoechst-Roussel Pharmaceuticals, Sommerville, NJ

Ovarian suppression induced with Buserelin or danazol in the management of endometriosis: a randomized, comparative study

The effectiveness of Buserelin (Hoechst-Roussel Pharmaceuticals, Inc., Somerville, NJ) (0.2 mg subcutaneously [SC] or 1.2 mg intranasally [IN] per day) and danazol (800 mg per day) in inducing ovarian suppression for the management of endometriosis was compared in a prospective randomized study. During 6 months of treatment, peripheral follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol concentrations were suppressed to a similar degree in both groups. Symptomatic improvement and laparoscopically assessed regression of endometriotic lesions also were comparable. After treatment, 8 of 18 infertile women treated with Buserelin and 5 of 8 treated with danazol conceived. General and hypoestrogenic side effects were similar in both groups, while androgenic and anabolic were more frequent with danazol. High density lipoprotein (HDL)-cholesterol increased in the Buserelin and decreased in the danazol group. The study indicates that at the dose tested, buserelin and danazol induce a similar degree of ovarian suppression resulting in a comparable clinical improvement and regression of endometriotic lesions.

Effect of a luteinizing hormone-releasing hormone agonist (Buserelin ) on steroidogenesis of cultured human preovulatory granulosa cells

In order to ascertain whether there is a direct effect of luteinizing hormone-releasing hormone (LH-RH) agonists on ovarian steroidogenesis, human preovulatory granulosa cells were cultured in the presence of an LH-RH agonist (Buserelin, Hoechst Roussel Pharmaceuticals, Paris, France). Cultures were performed without serum but with precursors of estrogens and progestins. In basal conditions, Buserelin, at 1 ng/ml, increased estradiol and progesterone (P) secretion, while at concentrations of 10 and 100 ng/ml, no effect was observed. In the presence of follicle-stimulating hormone (FSH) or LH, Buserelin at 1 and 10 ng/ml did not modify the cell's steroidogenesis. However, at a concentration of 100 ng/ml, Buserelin decreased LH stimulation of P secretion. These results suggest that LH-RH agonists, at concentrations in the range of those obtained in clinical use, can modulate ovarian steroidogenesis by direct action.

Videotape standardization of the Hamilton depression rating scale during clinical developement of new chemical entities: Michael Francis Murphy Hoechst-Roussel Pharmaceuticals Inc., Somerville, New JerseyP36)

Videotape standardization of the Hamilton depression rating scale during clinical developement of new chemical entities: Michael Francis Murphy Hoechst-Roussel Pharmaceuticals Inc., Somerville, New JerseyP36)

Automated liquid chromatography for non-isothermal kinetic studies

An automated liquid chromatography workstation was developed to facilitate data collection in non-isothermal kinetics studies. Operation of this system was validated by studying the degradation of cefotaxime sodium (Claforan, Hoechst-Roussel Pharmaceuticals), a moderately stable Cephalosporin antibiotic. As in a previous paper (Kipp, 1985), two data treatment methods were applied, a derivative and an integral approach, which provided similar results.

4562186 (1,2,4-oxadiazol-3-yl)arylmethanones, compositions and pharmaceutical use: John J Tegeler, Craig J Diamond assigned to Hoechst-Roussel Pharmaceuticals Inc

4562186 (1,2,4-oxadiazol-3-yl)arylmethanones, compositions and pharmaceutical use: John J Tegeler, Craig J Diamond assigned to Hoechst-Roussel Pharmaceuticals Inc

4562187 (Isoxazol-3-yl)arylmethanones, compositions and pharmaceutical use: John J Tegeler, Craig J Diamond assigned to Hoechst-Roussel Pharmaceuticals Inc

4562187 (Isoxazol-3-yl)arylmethanones, compositions and pharmaceutical use: John J Tegeler, Craig J Diamond assigned to Hoechst-Roussel Pharmaceuticals Inc

Altered Vascular Responsiveness to Norepinephrine Following Withdrawal of Verapamil in Rabbits

Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania, U.S.A. * Hoechst-Roussel Pharmaceuticals, Inc., Somerville, New Jersey, U.S.A.