KLP IVKLP IV

Preterm labor is a multifactorial problem. The currenttreatment options are symptomatic, rather thancausally directed. Preventive treatment withprogesterone can lower the rate of preterm birth inhigh-risk groups by more than 30%. TocolysisTocolysis –– thethe uterineuterine relaxantsrelaxants effecteffect ofof β2β2--

adrenoceptoradrenoceptor agonistsagonists (terbutaline,(terbutaline, fenoterol)fenoterol) cancan bebeusedused toto preventprevent prematurepremature laborlabor

Preterm labor is a multifactorial problem. The currenttreatment options are symptomatic, rather thancausally directed. Preventive treatment withprogesterone can lower the rate of preterm birth inhigh-risk groups by more than 30%. TocolysisTocolysis –– thethe uterineuterine relaxantsrelaxants effecteffect ofof β2β2--

adrenoceptoradrenoceptor agonistsagonists (terbutaline,(terbutaline, fenoterol)fenoterol) cancan bebeusedused toto preventprevent prematurepremature laborlabor

Pathophysiology prematur Labor

Contraction Mechanism

Mechanisms of action of tocolytic drugs

Betamimetics are the best-studied tocolytic drugs; they inhibit myometrialcontractions by raising the intracellular concentration of cAMP. Fenoterol hasbeen approved for this purpose only in Germany and Austria, where it is used in95% of hospitals. In other countries, ritodrine and terbutaline are used.

There is no drug of first choice. The tocolytic agentthat is most effective and has the least side effects isselected individually for each patient. Because these drugs activate the sympathetic nervous

system, nearly all patients who take them suffer fromtachycardia, sweating, tremulousness, nausea, orheadaches in the first few hours of use. Betamimeticshave the highest side-effect rates of all tocolytic drugs.

There is no drug of first choice. The tocolytic agentthat is most effective and has the least side effects isselected individually for each patient. Because these drugs activate the sympathetic nervous

system, nearly all patients who take them suffer fromtachycardia, sweating, tremulousness, nausea, orheadaches in the first few hours of use. Betamimeticshave the highest side-effect rates of all tocolytic drugs.

Selective estrogen receptor modulators (SERMs)exhibit a pharmacologic profile characterized byestrogen agonist activity in some tissues with estrogenantagonist activity in other tissues. These compoundswere initially called “antiestrogens”.

Selective estrogen receptor modulators (SERMs)exhibit a pharmacologic profile characterized byestrogen agonist activity in some tissues with estrogenantagonist activity in other tissues. These compoundswere initially called “antiestrogens”.

DHT

Androgen-receptor signaling in prostate cancer. Hormone-dependent androgen signaling takes place through DHT stimulation of the AR (leftpanel). Hormone-refractory prostate cancer cells survive through stimulation of multiple signaling pathways, including the PI3K and the MAPKpathways. These culminate in androgen-receptor signaling, or alternate pathways that lead to cell proliferation, migration and survival (rightpanel). aHSP90-inhibitor-sensitive protein or pathway. Abbreviations: AKT, protein kinase B; GF, growth factor; IGF1, insulin-like growthfactor 1; IL-6, interleukin 6; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; MEK, upstream kinases of mitogen-activated proteinkinases, also known as MAP2Ks; P13K, phosphatidylinositol 3 kinase; mRNA, messenger RNA; STAT3, signal transducer and activator of transcription3; TK, tyrosine kinase.

Growth factors that are ligands for receptor tyrosinekinases including epidermal growth factor (EGF),insulin-like growth factor (IGF), vascular endothelialgrowth factor (VEGF) and transforming growthfactor (TGFB), can initiate a signaling cascade thatculminates in AR activation. While the initiatingsignaling event differs, all of these mechanismsemploy a phosphorylation cascade, including thewell known AKT and MAPK path- ways

Growth factors that are ligands for receptor tyrosinekinases including epidermal growth factor (EGF),insulin-like growth factor (IGF), vascular endothelialgrowth factor (VEGF) and transforming growthfactor (TGFB), can initiate a signaling cascade thatculminates in AR activation. While the initiatingsignaling event differs, all of these mechanismsemploy a phosphorylation cascade, including thewell known AKT and MAPK path- ways

Dutasterid DHT, the primary prostatic androgen, is

transformed from T by types 1 and 2 5 -reductase. Thepredominant isoenzyme in normal prostate is type 2 5-reductase. The two 5 -reductase inhibitors currently available for

clinical use are finasteride and dutasteride DHT and other androgens are hypothesized to con-

tribute to the maintenance of homeostasis betweenthe processes of cell proliferation and (penurunan) celldeath (ie, apoptosis)

DHT, the primary prostatic androgen, istransformed from T by types 1 and 2 5 -reductase. Thepredominant isoenzyme in normal prostate is type 2 5-reductase. The two 5 -reductase inhibitors currently available for

clinical use are finasteride and dutasteride DHT and other androgens are hypothesized to con-

tribute to the maintenance of homeostasis betweenthe processes of cell proliferation and (penurunan) celldeath (ie, apoptosis)

Cell proliferation and apoptosis are androgen-dependent mechanisms affected by intermediaries setin motion by the binding of DHT to the androgenreceptor. DHT indirectly mediates expression ofgenes that control cellular proliferation and death bycontrolling the expression and secretion of growthfactors Androgen receptor (AR) is a member of the super-

family of nuclear hormone receptors which actsas a ligand- activated transcription factor

Cell proliferation and apoptosis are androgen-dependent mechanisms affected by intermediaries setin motion by the binding of DHT to the androgenreceptor. DHT indirectly mediates expression ofgenes that control cellular proliferation and death bycontrolling the expression and secretion of growthfactors Androgen receptor (AR) is a member of the super-

family of nuclear hormone receptors which actsas a ligand- activated transcription factor

). Ligand-binding positively or negatively controls gene expressions of target genes byAR through switching of co-regulators; most of them form histone-modifying enzymecomplexes, together with histone remodeling by ATP-dependent chromatin remodellingcomplexes

Diagrammatic representation of factors involved in maintaining homeostasis between cellular proliferationand cellular death in the prostate. DHT dihydrotestosterone; EGF epidermal growth factor; IGFs insulinlike growth factors; KGF keratinocyte growth factor; TGF- transforming growth factor– .

Raloxifene SERMs also have differing effects on the female genital

tract. Raloxifene acts as a complete estrogen antagonistin its effects on uterine wet weight in estrogen repleteovariectomized rats. In human studies, raloxifene doesnot cause any increase in vaginal bleeding nor does itsignificantly increase endometrial thickness asassessed by transvaginal ultrasonography. The effects of raloxifene on bone and the determinants

of bone strength (turnover, quantity, and quality)

SERMs also have differing effects on the female genitaltract. Raloxifene acts as a complete estrogen antagonistin its effects on uterine wet weight in estrogen repleteovariectomized rats. In human studies, raloxifene doesnot cause any increase in vaginal bleeding nor does itsignificantly increase endometrial thickness asassessed by transvaginal ultrasonography. The effects of raloxifene on bone and the determinants

of bone strength (turnover, quantity, and quality)

. The first, which depends on the activation of itsbinding to the ligand, appears to indicate that thisdrug is capable of decreasing osteoclastic resorptiveactivity by up to 50%, interleukin-6 (IL-6)production, and up to 30% of the pro- duction oftumor necrosis factor (TNF- ) at 6 months in vitroas well as in vivo . Both of these latter sub- stancesconstitute important mediators of bone resorption The second, which depends in this case on the

activation of the RRE, suggests that raloxifene iscapable of increasing the production oftransforming growth factor 3 (TGF- 3), therebydecreasing the number of osteoclasts as well as theirresorptive activity

. The first, which depends on the activation of itsbinding to the ligand, appears to indicate that thisdrug is capable of decreasing osteoclastic resorptiveactivity by up to 50%, interleukin-6 (IL-6)production, and up to 30% of the pro- duction oftumor necrosis factor (TNF- ) at 6 months in vitroas well as in vivo . Both of these latter sub- stancesconstitute important mediators of bone resorption The second, which depends in this case on the

activation of the RRE, suggests that raloxifene iscapable of increasing the production oftransforming growth factor 3 (TGF- 3), therebydecreasing the number of osteoclasts as well as theirresorptive activity