Maximizing retention in long-term clinical trials of a weight loss agent: use of a dietitian support team.

OBJECTIVE: High-attrition rates have been observed in long-term clinical trials of weight loss agents. We evaluated the impact of an innovative retention programme on 1-year retention. METHODS: Three Phase 3 global multicentre clinical trials evaluated the efficacy and safety of a CB1 receptor antagonist in subjects with BMI ≥ or = 27 kg/m2. The impact of a multifaceted retention programme including a dietitian screening interview, a comprehensive culturally adapted lifestyle modification programme, and a dietitian support system to maximize lifestyle adherence, was evaluated in 4,410 subjects from four subpopulations (non-US English-speaking, non-English-speaking, US-without dietitian screening and US-with dietitian screening) comprising 208 centres from 15 countries. RESULTS: The median proportion retained over the first year among subjects in three protocols was 82%. Non-English-speaking countries showed higher retention rates (89%) compared with the USA (73%) and non-US English-speaking (81%) countries. Within the USA, behavioural screening was associated with 29% reduction in dropout rate; for every five monthly teleconferences attended above 11, there was a 32% decrease in dropout rate. CONCLUSIONS: This novel retention programme greatly improved upon reported retention rates of studies conducted with other weight loss agents in long-term clinical trials. Its effectiveness should be confirmed in future trials.

A randomized, comparative study of buserelin with DES/orchiectomy in the treatment of stage D2 prostatic cancer patients.

This multicenter, randomized study compared the LH-RH agonist buserelin with diethylstilbestrol (DES)/orchiectomy in the treatment of patients with stage D2 prostatic carcinoma. Subjects were randomized to treatment with buserelin or DES/orchiectomy in a 2:1 ratio. Data from 160 subjects were available for analysis: 105 buserelin subjects (89 s.c. and 16 i.n.), 41 DES-treated subjects, and 14 orchiectomized subjects. Either subcutaneous (200 micrograms q.d.) or intranasal (400 micrograms t.i.d.) maintenance doses of buserelin suppressed serum testosterone values to below castrate levels (less than 100 ng/dl) by week 3 and maintained suppression for over 24 months. Times to treatment failure for specific reasons were analyzed and compared between treatment groups. There was a significant difference between treatment groups in favor of buserelin in the time to treatment failure due to an adverse event (p less than or equal to 0.05). There were no statistically significant differences between the treatment groups in the progression-free survival, best response, and life survival analyses. In addition, buserelin treatment improved quality of life parameters such as pain, performance status, and genitourinary symptoms. With the exception of symptoms of androgen deficiency, few side effects were reported in the buserelin subjects and most were of a minor nature. The incidence of severe side effects was significantly higher among the DES/orchiectomy subjects.

Buserelin treatment of advanced prostatic carcinoma. Long-term follow-up of antitumor responses and improved quality of life.

The safety and efficacy of buserelin, a luteinizing hormone-releasing hormone (LH-RH) agonist, was tested in 33 evaluable patients with Stages C or D adenocarcinoma of the prostate. With a minimum follow-up duration of 10 months, there was one complete response and 22 partial responses (69%) by National Prostatic Cancer Project criteria, with a median duration greater than 18 months. Six patients (18%) had stable disease, median duration greater than 25 months, and only 12 patients have progressed. Performance status improved in 67%, patient-scored pain improved in 75%, and quality of life improved in 58%. Symptoms occurring during treatment consisted of hot flashes, loss of libido, and impotence. Buserelin produces a high frequency of durable objective and subjective responses in patients with advanced prostatic carcinoma.

Buserelin as primary therapy in advanced prostatic carcinoma.

The effectiveness of buserelin, a luteinizing hormone-releasing hormone agonist, was tested in 28 patients with Stages C or D adenocarcinoma of the prostate. Of 24 evaluable patients, there were 13 partial responses (54%) by National Prostatic Cancer Project criteria, median duration greater than 6 months. Nine patients had stable disease (38%), median duration greater than 5 months, and only two patients progressed. Performance status improved in 38%, patient-scored pain improved in 46%, and quality of life improved in 57%. Symptoms occurring during treatment consisted of hot flashes, loss of libido, and impotence. A flare of symptoms was observed in only one patient, despite a transient 25% increase in testosterone in 36% of patients. Buserelin is an effective treatment for inducing frequent and meaningful remissions in advanced prostatic cancer.

Protection of germinal epithelium with luteinizing hormone-releasing hormone analogue.

A dog model for chemotherapy and radiation-induced testicular damage was created to study the protective potential of superactive analogue of luteinizing hormone-releasing hormone, buserelin. Buserelin appeared to offer protection of the canine germinal epithelium against cyclophosphamide, cisplatinum and radiation. Clinical trials with buserelin in patients of reproductive age undergoing treatment for cancer should be encouraged.

Benzenesulfenamides as antihypertensive agents. Substituted piperidine and 1-arylpiperazine derivatives.

The synthesis and antihypertensive activity of several piperidinebenzenesulfenamides related to the previously reported potent hypotensive agents 1 and a series of 1-arypiperazine-4-benzenesulfenamides 7 are described. A number of the latter compounds exhibit marked antihypertensive properties. The most interesting of these compounds, 7a and 7k, have been evaluated in several other animal models. In addition, benzenesulfinamides 9a and 9b and benzensulfonamides 10a and 10b have been prepared for comparison purposes.

Synthesis and antihypertensive activity of 2-benzamido-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizines.

The synthesis and antihypertensive activity of a series of 2-benzamido-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]-quinolizines are reported. A number of these compounds exhibit extremely potent hypotensive properties (e.g., N-methylbenzamides 42, 48, and 50 and N-ethylbenzamide 53 cause drops of 110, 103, 79, and 83 mmHg, respectively, in systolic blood pressure in the spontaneous hypertensive rat at the screening dose of 50 mg/kg po). Structure-activity relationships for the entire series are discussed.

Synthesis of spiro[isobenzofuran-1(3H),4'-piperidines] as potential central nervous system agents. 5. Conformationally mobile analogues derived by furan ring opening.

Synthesis and antitetrabenazine activity of 4-[2-(arylmethyl)phenyl]piperidines and 4-(benzyloxy)-4-phenylpiperidines, prepared as simplified and possibly more readily synthesized analogues of 3-phenylspiro[isobenzofuran-1 (3H),4'-piperidine], are reported. Several 4-[2-(arylmethyl)phenyl]piperidines display antitetrabenazine activity comparable to imipramine or amitriptyline but are two- to fourfold less active than analogous 3-arylspiro[isobenzofuran-1(3H),4'-piperidines]. Structure--activity relationships for 4-[2p(arylmethyl)phenyl]piperidines are generally similar to the profile established for 3-arylspiro[isobenzofuran-1(3H),4'-piperidines]. Significant antitetrabenazine activity is associated only with derivatives where the arylmethyl group is ortho to the piperidine ring. 4-(Benzyloxy)-4-phenylpiperidines and 4-[2-(arylmethyl)phenyl]-4-piperidinols and the corresponding methyl ethers and esters display weak to modest antitetrabenazine activity. 4-[2-(Arylmethyl)phenyl]-1,2,3,6-tetrahydropyridine derivatives, at best, exhibit modest antitetrabenazine activity, with the exception of 4-[2-(phenylmethyl)phenyl]-1,2,3,6-tetrahydropyridine which is approximately equipotent with amitriptyline. The results of these investigations allow certain speculations to be made with respect to the role of the furan ring in the 3-arylspiro[isobenzofuran-1(3H),4'-piperidines] and antitetrabenazine activity.

Spiro[isobenzofuran-1(3H),4'-piperidines]. 3. Diuretic and antihypertensive properties of compounds containing a sulfur attached to nitrogen.

The synthesis and antihypertensive and diuretic activity of several N-sulfur derivatives of 3-phenylspiro[isobenzofuran-1(3H),4'-piperidine] are reported. Benzenesulfenamide 3 possessed marked, species-specific diuretic and antihypertensive activity in rats.

Synthesis of spiro[isobenzofuran-1(3H),4'-piperidines] as potential central nervous system agents. 2. Compounds containing a heteroatom attached to nitrogen.

The synthesis and antitetrabenazine activity of a series of N-heteroatom derivatives of 3-phenylspiro[isobenzofuran-1,4'-piperidines] are reported. Optimal antitetrabenazine activity is associated with compounds containing a sterically unhindered, basic nitrogen. Hydroxylamines 6, 11, 12, and 13 possess the most significant activity with ED50's of 1.4, 3.5, 4.7, and 4.0, respectively.

Synthesis of spiro[isobenzofuran-1(3H),4'-piperidines] as potential central nervous system agents.

Synthesis of 1'-methyl-3-phenylspiro[isobenzofuran-1(3H),4'-piperidine] (7a, HP 365) and the demethyl analogue 9a (HP 505) was prompted by recognition of an aminoalkyl(aryl)isobenzofuran moiety common to the antidepressants talopram (Lu 3-010) and trans-10,11-dihydro-5,10-epoxy-5-[3-(methylamino)propyl]-5H-dibenzo[a,d]cyclohepten-11-ol (MK-940). Convenient laboratory synthesis of 7a was provided by lithiation of 2-bromobenzhydryl methyl ether, followed by addition of 1-methyl-4-piperidone and acid-catalyzed cyclization. N-Dealkylation by standard methods afforded 9a. Synthesis of analogues was stimulated by discovery of marked inhibition of tetrabenazine-induced ptosis for lead compounds 7a and 9a. Optimal antitetrabenazine activity is associated with the 3-phenylspiro-[isobenzofuran-1(3H),4'-piperidine] moiety where nitrogen is basic. Modification of this moiety by introduction of large nitrogen substituents or a C-3 substituent greater than H significantly reduced antitetrabenazine activity. A series of analogues with aromatic substituents was investigated; however, few of these compounds were significantly more active than 7a and 9a. Compound 9a was selected for additional studies.