The storage of household long guns: the situation in Quebec.

This survey on the storage of household firearms in Quebec was conducted in 1994. At that time, 35% (175/504) of survey participants who kept long guns in their homes had failed to comply with Canadian firearm storage regulations. In most cases (85%; n=149), this was because at least one stored long gun was found to be both operable and accessible. Thirty-seven per cent of participants stated that no one, including themselves, had used their firearm(s) in the 12 months preceding the survey. These findings point to two possible ways of dealing with long guns kept in the home: render these weapons inoperable or inaccessible, which would increase the level of compliance with the regulations, and dispose of those no longer in use. The results of this survey have never been published before, and constitute the only information of this kind with respect to Quebec.

Activation of EGFP expression by Cre-mediated excision in a new ROSA26 reporter mouse strain.

Reporter mouse strains are important tools for monitoring Cre recombinase-mediated excision in vivo. In practice, excision may be incomplete in a given population due to threshold level or variegated expression of Cre. Hence, it is desirable in many experimental contexts to isolate cells that have undergone excision to assess the consequences of gene ablation. To generate alternative reporter mice, an enhanced green fluorescent protein (EGFP) gene was targeted to the retroviral-trapped ROSA26 locus. Upon Cre-mediated excision of "Stop" sequences, EGFP was expressed ubiquitously during embryogenesis and in adult tissues (including T cells, B cells, and myeloid cells). Using this new reporter strain, separation of excised from nonexcised cells in vitro was achieved in thymocytes in a noninvasive manner based on activated EGFP expression. This new EGFP reporter strain should facilitate a variety of conditional gene-targeting experiments, including the functional studies of hematopoietic cells in lineage-specific knockout mice.

Measuring perceived barriers to condom use: psychometric evaluation of the Condom Barriers Scale.

A programmatic series of three studies developed and evaluated the Condom Barriers Scale (CBS), an instrument measuring women s perceived barriers to condom use for prevention of HIV and other sexually transmitted diseases. Following item generation and selection, Study 1 evaluated the CBS in a sample of minority women (N = 178), reduced the number of items, assessed the factor structure, evaluated the internal consistency, and explored the convergent validity of the CBS. In Study 2, the CBS was administered to a cross-validation sample (N = 278). Confirmatory factor analysis and internal consistency were compared against the original sample and construct, criterion, and discriminant validity were assessed. In Study 3 (N = 30), temporal stability of the CBS was evaluated. The resulting instrument appears to have sound psychometric properties and can be used to measure a key construct in the leading theoretical models of health behavior for which a measure with known psychometric properties previously has not been available.

Safety and safety promotion: conceptual and operational aspects.

After illustrating the main difficulties usually encountered in efforts to prevent injuries and improve the safety of populations, this paper will propose a frame of reference on the subject of safety promotion. It applies to the prevention of non-intentional injuries as well as to the problem of violent crimes and suicide. This framework should facilitate dialogue among those involved in these issues by encouraging better integration of the various prevention models used. It should also improve both the implementation and effectiveness of interdisciplinary and intersectorial interventions.

Estradiol activates p60src, p53/56lyn and renatured p50/55 protein tyrosine kinases in the dog prostate.

Protein tyrosine kinases (PTKs) are key enzymes implicated in signal transduction pathways regulated by growth factors (GFs). We have previously shown by immunohistochemistry that the level of phosphotyrosine (pY) proteins is increased in prostatic basal epithelial cells following estrogen treatment in castrated dogs. In this study, we investigated if this treatment increases the level and distribution of prostatic PTK activity, and more specifically, if it alters the expression and/or activity of the Src family members p60src and p53/56lyn. Prostates from normal and hyperplastic dog prostates, as well as those from castrated dogs treated with androgens, were also examined. Only the glands obtained from estrogen-treated dogs had a significantly increased total and specific PTK activity, observed uniquely in the particulate extract, as compared to the other types of prostates studied. In addition, this increased activity was correlated upon gel filtration chromatography with the presence of an additional peak of activity with an apparent molecular weight of 130 kDa, which was absent in other prostate fractions presenting only 50 kDa peaks. Using antibodies, we demonstrate that active p60src and pp53/56lyn kinases accounted for 81% of the activity in this 130 kDa peak. On the other hand, in situ renaturation also revealed the presence of still uncharacterized 50/55 kDa PTKs in the 130 kDa peak. Altogether, these findings raise the possibility that these PTKs contribute to the transmission of mitogenic signals originating directly or indirectly from estrogen stimulation of the basal cell layer of the prostate.

Firearms injury prevention and gun control in Canada.

Firearms cause more than three deaths daily in Canada. The rate of mortality from gunshot wounds varies among provinces and territories, ranging from 5.7 to 21.2 per 100,000 people. Most deaths from gunshot wounds occur in the home, with more occurring in rural areas than in cities, and are inflicted with legally acquired hunting guns. The cost of the consequences of the improper use of firearms in Canada has been estimated at $6.6 billion per year. There is a correlation between access to guns and risk of death. The mere presence of a firearm in a home increases the risk of suicide, homicide and "accidental" death. It is estimated that, in one third of all households in Quebec that have a firearm, it is not safely, or even legally, stored. To prevent deaths and injuries from firearms, education is not enough. Environmental, technological and legislative measures are also needed. In this spirit, the Quebec Public Health Network has taken a position supporting better controls on access to firearms, including the licensing and registration of all firearms and their ownership, to prevent deaths and injuries. The network believes that licensing and registration will reduce the problems related to firearms by making owners accountable for the use of their firearms, improving public safety, helping to control the import and circulation of firearms, reinforcing research and education, and reducing access to firearms in homes. Licensing and registration do not interfere with legitimate firearm use, their cost is acceptable in light of the advantages they provide, and they are desired by most Canadians.

Focal adhesion kinase (pp125FAK) expression, activation and association with paxillin and p50CSK in human metastatic prostate carcinoma.

pp125FAK, a protein tyrosine kinase (PTK) co-localized with integrins in focal adhesion plaques, is known to transduce signals involved in the regulation of cell adhesion and motility as well as the anchorage-independent growth of transformed cells. We investigated whether pp125FAK could be part of a signalling pathway that contributes to the progression of human prostate carcinoma (PCa). Up-regulation of pp125FAK expression, its activation by phosphorylation on tyrosine and its association with paxillin and p50csk were preferentially observed in PCa tissues from patients with metastases, whereas normal and hyperplastic prostates and localized PCa tissues showed undetectable or low levels of both FAK mRNA and protein and an absence of pp125FAK signalling complexes. The increase in expression and activation of pp125FAK in metastatic PCa tissues was also corroborated by our findings in human PCa cell lines. Indeed, higher levels of pp125FAK and FAK mRNA were observed in highly tumorigenic PC-3 cells as was the presence of activated pp125FAK, as opposed to an inactive form in LNCaP cells, which have a lower tumorigenic ability. In addition, pp125FAK formed signalling complexes with both paxillin and p50csk in PC-3 cells as in metastatic PCa tissues. Together, our results show that an increase in FAK mRNA and protein, as well as pp125FAK activation and association with signalling proteins, correlates with progression and invasion in human PCa tissues and cells.

Regulation and activation of focal adhesion kinase and paxillin during the adhesion, proliferation, and differentiation of prostatic epithelial cells in vitro and in vivo.

Focal adhesion kinase (pp125FAK) is a nonreceptor protein tyrosine kinase transducing signals initiated through integrin activation triggered by cell/extracellular matrix (ECM) interactions. To examine its role in epithelial cell adhesion, proliferation, and differentiation, we have studied pp125FAK expression, activity, and association with paxillin in two canine prostate models in which these functions can be selectively regulated: in vitro by vitronectin (VN) and serum factors, and in vivo by sex steroids. Kinetic studies revealed that the adhesion and spreading of prostatic epithelial cells in primary culture was regulated by serum VN and a natural ECM containing VN produced by prostate cells. While barely detectable in freshly isolated prostate cells, proliferating cells, after 72 h in culture, expressed higher levels of FAK mRNA (8-fold), pp125FAK (50-fold), and paxillin (50-fold). In prostate cells with a reduced growth rate after 2 weeks in culture, we observed a decrease in pp125FAK (4-fold) and its transcript (3-fold), but no change in paxillin. In vivo, both proteins were undetectable in normal and hyperplastic glands composed of a well differentiated epithelium, and in prostates restored by androgen supplementation. In contrast, pp125FAK and paxillin were up-regulated by androgen deprivation (castration) and further increased by estrogen treatment, which yielded metaplastic prostates mostly composed of proliferating basal epithelial cells. Moreover, both proteins were constitutively phosphorylated on tyrosine in the metaplastic prostate, as well as in proliferating cultured cells. Together, these results demonstrate that pp125FAK expression is regulated at the protein and mRNA levels and forms active signaling complexes with paxillin when epithelial cells in contact with ECM proteins are induced to proliferate in vivo and in vitro.

Radiation inactivation and in situ renaturation of protein tyrosine kinases reveal a major 50-kDa enzyme as part of a membrane complex present in dividing but not in resting prostatic epithelial cells.

Because protein tyrosine kinases play a crucial role in the regulation of cell division and carcinogenesis, we have herein measured such enzyme activities (specific activity and subcellular distribution) and compared their characteristics with respect to hydrodynamic properties and radiation inactivation sizes as well as renaturation after electrophoresis in denaturing conditions in canine prostatic epithelial cells either in a resting (freshly isolated) or in a dividing (cultured cells) state. In quiescent cells, most protein tyrosine kinase activity was expressed by soluble proteins with a Stokes' radius (Rs) of 3.05 nm, a sedimentation coefficient (S20,w) of 4.0 S, and a molecular mass of 50 kDa. By contrast, in dividing cells (three days in primary culture), the specific activity was higher and the enzyme was mainly membrane bound. The use of a detergent (Triton X-100) allowed the extraction of most of that enzyme; its partial specific volume, S20,w and Rs were then 0.883 cm3/g, 4.0 S, and 5.6 nm, respectively, hence yielding a molecular mass of 215 kDa, which decreased to 125-145 kDa when corrected for detergent binding. Probing these chromatography-peak fractions, 50 kDa from cytosol of resting cells and 215 kDa from membrane extracts of dividing cells, with a phosphotyrosine antibody following their incubation with ATP and electrophoresis in denaturing conditions revealed the presence of a common 50-kDa phosphotyrosylated protein along with three other bands (130, 75, and 40 kDa) in the high-Mr peak of enzyme. However, the radiation inactivation size for protein tyrosine kinases expressed in both resting and dividing cells were similar, 47.2 +/- 8.7 and 44.5 +/- 6.1 kDa, respectively. Furthermore, by renaturation after electrophoresis in denaturing conditions, major protein tyrosine kinase polypeptides of 50 kDa were identified in both cell populations. Taken together, these results indicate that, in dividing prostatic epithelial cells, membrane-bound protein tyrosine kinases of low molecular weight with properties similar to those of monomeric soluble forms present in quiescent cells are part of high-molecular weight complexes. This activation process may be critical for hormone-independent proliferation of prostatic epithelial cells.

Phosphotyrosine antibodies preferentially react with basal epithelial cells in the dog prostate.

PURPOSE: Considering the hypothesis that androgen-independent but growth factor dependent epithelial cell division may be important in the development and progression of prostate cancer and that protein tyrosine kinases and phosphotyrosine protein phosphatases are key enzymes modulating the levels of specific phosphotyrosylated proteins implicated in several growth factor regulated signal transduction pathways, our aim was to study the cellular distribution of phosphotyrosine proteins in normal and hyperplastic dog prostates as well as in those of castrated dogs supplemented with either androgens or estrogens in order to modify the relative proportion of basal versus secretory epithelial cells. MATERIALS AND METHODS: Following the determination of optimal conditions to specifically detect phosphotyrosine proteins by a rabbit polyclonal antibody directed against phosphotyrosine, immunohistochemistry was performed on prostate tissue sections from these experimental animals. In addition to morphological criteria, an antibody to high molecular weight cytokeratins and antisera against arginine esterase were used to selectively identify basal and secretory cells. Since prostatic acid phosphatase may be involved in the local regulation of phosphotyrosine proteins, its distribution was also evaluated with a human prostatic acid phosphatase antiserum. RESULTS: In all prostatic tissues examined, basal epithelial cells were preferentially and specifically stained with antiphosphotyrosine. The staining intensity per basal cell was highest in the estrogen-supplemented dogs. In addition, basal cells were numerically increased and all were highly immunoreactive for high molecular weight cytokeratins. In prostates displaying a well-differentiated glandular epithelium, the number of positive basal cells and their staining intensity varied in the following order: normal < hyperplastic < androgen-supplemented dogs. At all times, the levels of phosphotyrosine proteins in prostatic acid phosphatase and arginine esterase positive cells (secretory) remained low. Fibroblasts and smooth muscle cells were unreactive to antiphosphotyrosine, even though estrogen supplementation increased the prostatic stromal volume. CONCLUSIONS: The preferential localization of phosphotyrosine proteins in basal cells, their increased level per cell and the number of positive cells in the different experimental animals support the concept that basal cells represent the stem cells of the prostate. The sex steroid-mediated up-regulation of protein phosphorylation on tyrosine residues in these cells suggests that their proliferation is likely to involve growth factor regulated signal transduction pathways. In this respect, the lack of maturation of basal cells and the differentiation of secretory cells induced by androgen deprivation, combined with estrogen stimulation, favors the activation of these pathways and cell growth. On the other hand, the activation of glandular cell differentiation and the increase of stromal volume do not alter the threshold level of protein tyrosine kinase and phosphatase activities in secretory cells, fibroblasts and smooth muscle cells.

Activation of a serine/threonine kinase signaling pathway by transforming growth factor type beta.

Transforming growth factor type beta (TGF-beta) is a multifunctional factor that regulates proliferation and differentiation of many cell types. TGF-beta mediates its effects by binding to and activating cell surface receptors that possess serine/threonine kinase activity. However, the intracellular signaling pathways through which TGF-beta receptors act remain largely unknown. Here we show that TGF-beta activates a 78-kDa protein (p78) serine/threonine kinase as evidenced by an in-gel kinase assay. Ligand-induced activation of the kinase was near-maximal 5 min after TGF-beta addition to the cells and occurred exclusively on serine and threonine residues. This kinase is distinct from TGF-beta receptor type II, as well as several cytoplasmic serine/threonine kinases of similar size, including protein kinase C, Raf, mitogen-activated protein kinase kinase kinase, and ribosomal S6 kinase. Indeed, these kinases can be separated almost completely from p78 kinase by immunoprecipitation with specific antibodies. Furthermore, using different cell lines, we demonstrate that p78 kinase is activated only in cells for which TGF-beta can act as a growth inhibitory factor. These data raise the interesting possibility that protein serine/threonine kinases contribute to the intracellular relay of biological signals originating from receptor serine/threonine kinases such as the TGF-beta receptors.

The enhancement by pervanadate of tyrosine phosphorylation on prostatic proteins occurs through the inhibition of membrane-associated tyrosine phosphatases.

The relapse of prostate cancer during endocrine therapies is attributed to the proliferation of growth factor (GF)-dependent epithelial cells. Such cells are present but in a quiescent state in the normal adult human and dog (experimental model) prostates. GF-signaling pathways involve the activation of protein tyrosine kinases (PTK) whose action is also modulated by phosphotyrosine protein phosphatases (PTPs). To that effect, we have previously reported that dividing canine prostatic epithelial cells exhibited high levels of phosphotyrosyl-(pY)-proteins which were greatly enhanced when incubated in the presence of vanadate. The aim of this study, performed with pervanadate (pV), was to determine whether pV acts either directly by stimulating prostatic PTKs or indirectly by inhibiting PTPs. Upon fractionation, most of the PTK activity was found in membranes of dividing cells and pV selectively increased its activity. This was due to an inhibition of intrinsic PTPs, as demonstrated by dephosphorylation of endogenous pY-proteins which was abolished by pV. This activity was very sensitive to pV (IC50: 150 nM) and was due to non-secreted forms of prostatic acid phosphatase (PAP), a pV inhibited-enzyme, as well as to PTP-1 B, as demonstrated by gel filtration, isoelectric focusing and probing with antibodies. These enzymes were also detected in membranes from human hyperplastic/neoplastic prostates but only PTP-1 B was present in those of prostatic carcinoma PC3 cells. These PTPs, bound to membranes of dividing cells (normal vs neoplastic) where activated PTKs are also located, may be of importance in the development and progression of prostatic proliferative diseases.

Transforming growth factor beta down-regulates Src family protein tyrosine kinase signaling pathways.

Transforming growth factor beta (TGF beta) inhibits the proliferation of a wide range of cell types through interaction with its cell surface receptor (R-TGF beta). R-TGF beta possesses serine/threonine kinase activity rather than the tyrosine kinase activity normally associated with peptide growth factor receptors; nevertheless, TGF beta triggers a signaling pathway that leads to the repression of transcription factors, which appear to mediate the action of receptor tyrosine kinases within the nucleus. Accumulating evidence has also shown that the nonreceptor protein tyrosine kinases of the Src family play essential roles in the signal transduction pathways that regulate cell proliferation, differentiation, and function. Here, we investigate whether signals initiated by R-TGF beta are transduced, at least in part, through members of the Src family of tyrosine kinases. Treatment of the responsive human prostate carcinoma cell line PC3 with TGF beta induces a rapid and specific decrease in cellular levels of pp60Src and pp53/56Lyn and a corresponding decrease in their protein kinase activity when the assays were performed in vitro using the exogenous substrate enolase. Consistent with suppression of pp60Src and pp53/56Lyn kinase activity, TGF beta also caused a substantial intracellular accumulation of the unphosphorylated form of SH2-containing protein (SHC), a substrate of the Src family kinases. This was paralleled by decreased formation of a complex between the adaptor protein known as growth factor receptor-bound protein 2 and SHC. These results suggest, for the first time, that TGF beta induces down-regulation of Src family kinases, leading to disruption of the SHC-growth factor receptor-bound protein 2 complex. These events may play a crucial role in the negative regulation of Ras, as well as in the control of downstream effector molecules involved in the regulation of cell growth.

150-kDa proteins in dog serum bind 1.5-kDa growth-promoting factors for androgen-independent canine prostatic epithelial cells.

Fractions obtained by gel filtration or ultrafiltration of dog serum were tested for their mitogenic activity on canine prostatic epithelial cells: two prostatic growth factor (PGF) entities were found, a major one of 150 kDa (PGF-I) and a minor one of 1.5-2.0 kDa (PGF-II). Treatment and/or extraction with acetic acid, hydrochloric acid, or acidified-ethanol or preparations enriched in PGF-I obtained either by ion-exchange chromatography, acetone precipitation, or retention by ultrafiltration membrane (cut-off 30 kDa) resulted, upon gel filtration, in the detection of a mitogenic activity eluting mainly at the position of PGF-II. Acid hydrolysis and proteolysis of PGF-II led to a loss of activity. It is proposed that, in dog serum, mitogenic peptides for prostatic epithelial cells of 1.5 kDa (PGF-II) are found in their free form and/or in association with proteins of 150 kDa (PGF-I).

Estrogen and interrupted progestin: a new concept for menopausal hormone replacement therapy.

OBJECTIVE: We tested a new hormone replacement formulation based on the hypothesis that interrupted administration of progestin in the presence of continuous estrogen would result in receptor up-regulation and resensitization of target tissues to both estrogen and progestin. As a result, symptom control might be possible with lower doses of steroids and in the absence of withdrawal bleeding. STUDY DESIGN: Forty postmenopausal women were entered in a 6-month pilot study, including an 18-month extension. They received piperazine estrone sulfate 0.75 mg daily. Norethindrone 0.35 mg daily was added in 3-day phases, alternating with progestin-free phases of 3 days. There was no steroid-free withdrawal period. We examined symptom control, bleeding patterns, endometrial protection, and lipid profiles in the women over the 24 months of the study. RESULTS: Hot flushes were completely eliminated in 76% of women, and 80% had no bleeding by 6 months. There were three dropouts. Thirty-three women elected to continue after the first 6 months and completed 24 months on therapy for a compliance rate of 82.5%. No endometrial hyperplasia was seen on serial biopsies, and no changes occurred in lipids except for a small but statistically significant decrease in high-density lipoproteins and triglycerides at 24 months. CONCLUSION: Our preliminary results of low bleeding rates, good symptom control, and endometrial protection suggest that hormone replacement with low-dose estrogen and interrupted progestin is effective and may lead to improved compliance in menopausal women.

Protection of islets of Langerhans from antibodies by microencapsulation with alginate-poly-L-lysine membranes.

Microencapsulation of islets has been proposed to prevent their immune destruction following transplantation. An indirect immunofluorescence technique has been developed and used to study the permeability of the alginate-poly-L-lysine microcapsules to antibodies. Wistar rat islets were incubated with the R2D6 monoclonal mouse IgM antibody against rat islets, microencapsulated, and incubated with fluorescein-labeled goat IgG antibodies against mouse IgG and IgM. For the negative controls, the first antibody was omitted or both antibodies were omitted. The positive controls included islets incubated with both antibodies before they were encapsulated. Our study demonstrated that the alginate-poly-L-lysine membranes are not permeable to IgG when poly-L-lysine of molecular weights ranging from 21,000 to 390,000 are used. This simple immunofluorescence technique demonstrated the nonpermeability of the microcapsules to IgG, and could be useful for the initial evaluation of new types of membranes.

Identification of cytosolic protein tyrosine kinases of human prostate by renaturation after SDS/PAGE.

The identification of protein tyrosine kinases (PTKs) was successfully achieved by renaturation in gels after SDS/PAGE. To this effect, samples were mixed with a PTK substrate, namely the polydispersed co-polymer of glutamic acid and tyrosine [poly(Glu, Tyr), M(r) from 30,000 to 94,000], and were simultaneously submitted to electrophoresis. Following guanidine hydrochloride denaturation, renaturation and phosphorylation with [gamma-32P]ATP, kinase activity was detected by autoradiography. When applied to cytosol from human hyperplastic prostate, eleven protein kinases were detected, among which one major (M(r) 50,000) and two minor proteins (M(r) 40,000 and 38,000) were identified as PTKs by the presence of phosphotyrosine. Incubation of the gel in hot alkali after glutaraldehyde cross-linking almost completely eliminated the detection of non-PTK enzymes. On the other hand, in the absence of poly(Glu,Tyr), no PTK activity was detected. Partial purification of cytosolic PTKs indicates that the native M(r) of the major phosphotransferase was 44,000, as estimated by gel filtration following ammonium sulphate precipitation and anion-exchange chromatography. Upon renaturation after electrophoresis, this fraction showed only one major band active on poly(Glu,Tyr) which was associated with the polypeptide of M(r) 50,000. This enzyme was also identified following two-dimensional electrophoresis and renaturation in the presence of poly(Glu,Tyr), allowing the determination of a pI in the range 7.5-7.8. Thus PTKs can be easily renatured following electrophoresis and rapidly identified on the basis of their M(r) and pI in both crude or partially purified preparations. With the crucial role played by PTKs in the activation of cell function and carcinogenesis, this procedure could be useful in the identification of such enzymes and in distinguishing them from their substrates in gels.

[Promoting airbags:Evaluation of a public health intervention aimed at federal election candidates]. / La promotion du coussin gonflable: Evaluation d'une intervention de santé publique auprès de candidats aux élections fédérales

During the 1988 federal election campaign, the Directors of Community Health Departments throughout Québec met with the candidates of the three national political parties. The objectives of this intervention were to inform the candidates on the importance of regulating the installation of airbags in motor vehicles and to elicit from them a commitment to take initiatives in that direction once elected into office. This report assesses the effect of this intervention on the candidates of the Québec City region. After the intervention, two-thirds of candidates had developed a strongly favourable opinion of airbags. A majority, including 11 of the 13 Conservatives who were elected, committed themselves in writing to lobby in support of airbags. Despite this commitment, these Members of Parliament made little progress during the year following the election.

Comparative contraceptive efficacy and mechanism of action of the norgestimate-containing triphasic oral contraceptive.

Norgestimate (NGM), a derivative of 19-nortestosterone with very specific affinity for the progesterone receptor, has been used in combination with ethinyl estradiol (EE) at low doses in both monophasic and triphasic oral contraceptives (OCs). An open-label comparative clinical trial was conducted with 4,234 healthy women using comparative clinical trial was conducted with 4,234 healthy women using triphasic levonorgestrel (LUG)/EE and NGM/EE through a total of 22,312 menstrual cycles. Contraceptive (LUG)/EE and NGM/EE through a total of 22,312 menstrual cycles. Contraceptive efficacy was excellent with both preparations, with no statistically significant between-regimen differences in pregnancy rates. The theoretical Pearl index was the NGM/EE triphasic, and 0.34 for the LNG/EE triphasic. Adverse experiences in groups were typical of those that may occur among women taking low-dose OC agents. was similar with the two preparations: 8.6% for the NGM/EE triphasic and 6.8% for the LNG/EE triphasic. In a separate mechanism of action study, specific endocrine parameters were investigated in 20 subjects using the NGM/EE triphasic for 4 cycles. Ovulation suppression was demonstrated in statistically significant decreases from pretreatment values in serum levels of luteinizing hormone, follicle-stimulating hormone, progesterone, and estradiol. Significant on-treatment increases in serum levels of sex hormone binding globulin evidenced minimal androgenicity. All hormonal values returned to or toward normal in the post-treatment cycle. The study results support those obtained in large noncomparative studies of the NGM/EE triphasic. This phased-dose combination suppresses ovulation and is a very effective, minimally androgenic contraceptive agent with a good safety profile.

PIP: Norgestimate (NGM), a derivative of 19-nortestosterone with very specific affinity for the progesterone receptor, has been used in combination with ethinyl estradiol (EE) in low doses in both monophasic and triphasic oral contraceptives (OCs). An open-label comparative clinical trial was conducted with 4234 healthy women using triphasic levonorgestrel (LNG)/EE and NGM/EE through a total of 22,312 menstrual cycles. Contraceptive efficacy was excellent with both preparations with no statistically significant between-regimen differences in pregnancy rates. The theoretical Pearl index was 0.12 for the NGM/EE triphasic, and 0.34 for the LNG/EE triphasic. Adverse experiences in both groups were typical of those which could occur among women taking low-dose OCs. The % of subjects who discontinued treatment due to use-related adverse experiences was similar among the 2 preparations; 8.6% for the NGM/EE triphasic and 6.8% for the LNG/EE triphasic. In a separate mechanism of action study, specific endocrine parameters were investigated in 20 subjects who used the NGM/EE triphasic for 4 cycles. Ovulation suppression was demonstrated in statistically significant decreases from pretreatment values in serum levels of luteinizing hormone, follicle stimulating hormone, progesterone, and estradiol. Significant on-treatment increases in serum levels of sex hormone binding globulin evidenced minimal androgenicity. All hormonal values returned to or toward normal in the posttreatment cycle. The study results support those obtained in large noncomparative studies of the NGM/EE triphasic. This phased-dose combination suppresses ovulation and is a very effective, minimally androgenic contraceptive with good safety profile.