DL-Centchroman (67/20; INN: Ormeloxifene) synthesized at the Central Drug Research Institute, Lucknow, is a nonsteroidal once-a-week oral contraceptive. It was introduced in Delhi in July, 1991, marketed in India in 1992 as Saheli and Choice-7 (Hindustan Latex Ltd., Thiruvananthapuram) and Centron (Torrent Pharmaceuticals India Ltd., Ahmedabad), and included in the National Family Welfare Programme in 1995.5 According to post-marketing surveillance, approximately 100,000 women were using this pill and approximately 1100,000 menstrual cycles were covered until 1996. It is a unique need-oriented contraceptive being effective when taken immediately after coitus or routinely as a weekly pill and has the advantage of less frequent administration. Its contraceptive action is quickly reversible. It has long terminal serum halflife of 168 hr in women and exhibits duration of anti-implantation/estrogen antagonistic action of 120 hr, despite a short (24.1 hr) serum halflife, in the rat. In lactating women, it is excreted in milk in quantities considered unlikely to cause any deleterious effect on suckling babies. In phase II and III multicentric trials as a contraceptive, children born of method-and-user failure pregnancies showed normal milestones, without any congenital anomaly. Reports of its promising action in the management of certain hormone-related clinical disorders are available. It has an excellent therapeutic index and is considered safe for chronic administration.
The management of pancreatic ductal adenocarcinoma (PDAC) is extremely poor due to lack of an efficient therapy and development of chemoresistance to the current standard therapy, gemcitabine (GEM). Recent studies implicate the intimate reciprocal interactions between epithelia and underlying stroma due to paracrine Sonic hedgehog (SHH) signaling in producing desmoplasia and chemoresistance in PDAC. Herein, we report for the first time that a nonsteroidal drug, ormeloxifene (ORM), has potent anti-cancer properties and depletes tumor-associated stromal tissue by inhibiting the SHH signaling pathway in PDAC. We found that ORM inhibited cell proliferation and induced death in PDAC cells, which provoked us to investigate the combinatorial effects of ORM with GEM at the molecular level. ORM caused potent inhibition of the SHH signaling pathway via downregulation of SHH and its related important downstream targets such as Gli-1, SMO, PTCH1/2, NFκB, p-AKT and Cyclin D1. ORM potentiated the anti-tumorigenic effect of GEM by 75% in PDAC xenograft mice. Further, ORM depleted tumor-associated stroma in xenograft tumor tissues by inhibiting the SHH cellular signaling pathway and mouse/human collagen I expression. Xenograft tumors treated with ORM in combination with GEM restored the tumor suppressor miR-132, and inhibited stromal cell infiltration into the tumor tissues. Additionally, invasiveness of tumor cells co-cultivated with TGFβ-stimulated human pancreatic stromal cells was effectively inhibited by ORM treatment alone or in combination with GEM. We propose that ORM has high therapeutic index and in a combination therapy with GEM it possesses great promise as a treatment of choice for PDAC/pancreatic cancer.
Schizophrenics maintained on a cereal grain-free and milk-free diet and receiving optimal treatment with neuropleptics showed an interruption or reversal of their therapeutic progress during a period of "blind" wheat gluten challenge. The exacerbation of the disease process was not due to variations in neuroleptic doses. After termination of the gluten challenge, the course of improvement was reinstated. The observed effects seemed to be due to a primary schizophrenia-promoting effect of wheat gluten.
In a double-blind, cross-over study, the comparative therapeutic effects of 6-week courses of two prototypic neuroleptics--haloperidol and chlorpromazine--and the reversal of those effects with benztropine were investigated in a group of 18 schizophrenics. Periodic measurements were made for 32 dimensions of psychopathology, social participation, span of attention, sleeplessness, pulse rate and neurological side effects. The results showed that haloperidol was generally a more effective drug over the period studied. This was particularly apparent in terms of social and emotional responsiveness, communicativeness and cognitive processes. The only superiority of chlorpromazine seemed to be that patients felt less dysphoric on it than they did on haloperidol. Haloperidol also proved to be more rapid in its action. The data failed to support the clinical validity of the distinction often made between "sedative" and "activating" neuroleptics. Consistent with previous reports, benztropine had the effect of diminishing therapeutic response to both neuroleptics. However, haloperidol again proved less susceptible to this effect. The slowness and lesser therapeutic efficiency of chlorpromazine and its greater susceptibility to benztropine reversal were all considered to be due to its built-in anti-cholinergic properties acting in opposition to its antipsychotic activity. The low potency of chlorpromazine-like drugs was attributed to their inherent anticholinergic characteristics. It was suggested that one of the factors determining potency difference among neuroleptics may be the degree of built-in anticholinergic activity.
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