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Tolterodine

Tolterodine is a muscarinic receptor antagonist. The chemical name of tolterodine ta...

Testosterone

Testosterone is a steroid hormone from the androgen group and is found in mammals, r...

Terazosin

Terazosin hydrochloride, USP an alpha-1-selective adrenoceptor blocking agent, is a q...

Tamsulosin

Tamsulosin is an antagonist of alpha1A adrenoceptors in the prostate. Tamsulosin hydr...

Potassium citrate

Potassium citrate is a potassium salt of citric acid with the molecular formula C6H5K3O7...

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Tolterodine is a muscarinic receptor antagonist. The chemical name of tolterodine tartrate is (R)-N,N- diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine L-hydrogen tartrate. The empirical formula of tolterodine tartrate is C26H37NO7, and its molecular weight is 475.6. The structural formula of tolterodine tartrate is represented below.

1. Clinical pharmacology

Tolterodine is a competitive muscarinic receptor antagonist. Both urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors. After oral administration, tolterodine is metabolized in the liver, resulting in the formation of the 5-hydroxymethyl derivative, a major pharmacologically active metabolite. The 5-hydroxymethyl metabolite, which exhibits an antimuscarinic activity similar to that of tolterodine, contributes significantly to the therapeutic effect. Both tolterodine and the 5-hydroxymethyl metabolite exhibit a high specificity for muscarinic receptors, since both show negligible activity or affinity for other neurotransmitter receptors and other potential cellular targets, such as calcium channels.

Tolterodine has a pronounced effect on bladder function. Effects on urodynamic parameters before and 1 and 5 hours after a single 6.4-mg dose of tolterodine immediate release were determined in healthy volunteers. The main effects of tolterodine at 1 and 5 hours were an increase in residual urine, reflecting an incomplete emptying of the bladder, and a decrease in detrusor pressure. These findings are consistent with an antimuscarinic action on the lower urinary tract.

2. Mode of action

Tolterodine belongs to a class of drugs called cholinergic (acetyl-choline) receptor blockers. It is used to treat disorders of the urinary bladder that affect urination.

The urinary bladder is a muscular "bag." Urine coming from the kidneys fills the bladder and causes it to stretch like a balloon. As it stretches, pressure in the bladder increases and, when the bladder reaches a certain level of stretch, a desire to urinate is felt. Nerves in the muscular wall of the bladder release acetyl- choline, a chemical that attaches to receptors on the muscle cells and causes the cells to contract (tighten). This contributes further to the increase in pressure within the bladder and the desire to urinate. At the appropriate time (e.g., when a toilet is available), there is conscious relaxation of the muscle at the outlet of the bladder, and the high bladder pressure forces urine out of the bladder.

Normally, urination is under conscious control; however, in some individuals normal control as well as normal sensation are lost. The desire to urinate may be felt when there is little urine in the bladder, and urination may occur without warning or control. By blocking the effect of acetyl-choline on the muscle cells, tolterodine slows the build-up of pressure in the bladder, reduces the sensation to urinate, and prevents uncontrolled urination. The FDA approved tolterodine in 1998. An extended release form of tolterodine, (Detrol LA) was approved by the FDA in 2001.

3. Pharmacokinetics

Absorption

In a study with 14C-tolterodine solution in healthy volunteers who received a 5-mg oral dose, at least 77% of the radiolabeled dose was absorbed. Cmax and area under the concentration-time curve (AUC) determined after dosage of tolterodine immediate release are dose-proportional over the range of 1 to 4 mg. Based on the sum of unbound serum concentrations of tolterodine and the 5-hydroxymethyl metabolite ("active moiety"), the AUC of tolterodine extended release 4 mg daily is equivalent to tolterodine immediate release 4 mg (2 mg bid). Cmax and Cmin levels of tolterodine extended release are about 75% and 150% of tolterodine immediate release, respectively. Maximum serum concentrations of tolterodine extended release are observed 2 to 6 hours after dose administration.

Distribution

Tolterodine is highly bound to plasma proteins, primarily α1-acid glycoprotein. Unbound concentrations of tolterodine average 3.7% ± 0.13% over the concentration range achieved in clinical studies. The 5-hydroxymethyl metabolite is not extensively protein bound, with unbound fraction concentrations averaging 36% ± 4.0%. The blood to serum ratio of tolterodine and the 5-hydroxymethyl metabolite averages 0.6 and 0.8, respectively, indicating that these compounds do not distribute extensively into erythrocytes. The volume of distribution of tolterodine following administration of a 1.28-mg intravenous dose is 113 ± 26.7 L.

Metabolism

Tolterodine is extensively metabolized by the liver following oral dosing. The primary metabolic route involves the oxidation of the 5-methyl group and is mediated by the cytochrome P450 2D6 (CYP2D6) and leads to the formation of a pharmacologically active 5-hydroxymethyl metabolite. Further metabolism leads to formation of the 5-carboxylic acid and N-dealkylated 5- carboxylic acid metabolites, which account for 51% ± 14% and 29% ± 6.3% of the metabolites recovered in the urine, respectively.

Excretion

Following administration of a 5-mg oral dose of 14C-tolterodine solution to healthy volunteers, 77% of radioactivity was recovered in urine and 17% was recovered in feces in 7 days. Less than 1% ( < 2.5% in poor metabolizers) of the dose was recovered as intact tolterodine, and 5% to 14% ( < 1% in poor metabolizers) was recovered as the active 5-hydroxymethyl metabolite.

4. Drug Interactions

Tolterodine follows a specific path through the liver in order to be eliminated from the body. Drugs that block this path may slow the elimination of tolterodine, raise tolterodine blood levels, and lead to side effects. No formal studies have been conducted showing such interactions, however.

The list of drugs that might possibly interfere with the elimination of tolterodine includes is erythromycin, clarithromycin (Biaxin), ketoconazole (Nizoral), itraconazole (Sporanox), and miconazole (Monistat, Micatin). The dose of tolterodine should be reduced to 1mg twice daily if taken with any of these drugs.

5. Adverse reactions

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using tolterodine and call your doctor at once if you have any of these serious side effects:

• chest pain, fast or uneven heart rate;

• confusion, hallucinations;

• urinating less than usual or not at all; or

• painful or difficult urination.

Less serious side effects may include:

• dry mouth, dry eyes;

• blurred vision;

• dizziness, drowsiness;

• constipation or diarrhea;

• stomach pain or upset;

• joint pain; or

• headache.

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Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands. It is the principal male sex hormone and an anabolic steroid.

In men, testosterone plays a key role in the development of male reproductive tissues such as the testis and prostate as well as promoting secondary sexual characteristics such as increased muscle, bone mass and the growth of body-hair. In addition, testosterone is essential for health and well-being as well as the prevention of osteoporosis.

On average, an adult human male body produces about ten times more testosterone than an adult human female body, but females are more sensitive to the hormone.

Testosterone is conserved through most vertebrates, although fish make a slightly different form called 11-ketotestosterone. Its counterpart in insects is ecdysone. These ubiquitous steroids suggest that sex hormones have an ancient evolutionary history.

1. Biochemistry

1.1 Biosynthesis

Like other steroid hormones, testosterone is derived from cholesterol (see figure to the right). The first step in the biosynthesis involves the oxidative cleavage of the sidechain of cholesterol by CYP11A, a mitochondrial cytochrome P450 oxidase with the loss of six carbon atoms to give pregnenolone.

In the next step, two additional carbon atoms are removed by the CYP17A enzyme in the endoplasmic reticulum to yield a variety of C19 steroids. In addition, the 3-hydroxyl group is oxidized by 3-β-HSD to produce androstenedione. In the final and rate limiting step, the C-17 keto group androstenedione is reduced by 17-β hydroxysteroid dehydrogenase to yield testosterone.

The largest amounts of testosterone (>95%) are produced by the testes in men. It is also synthesized in far smaller quantities in women by the thecal cells of the ovaries, by the placenta, as well as by the zona reticularis of the adrenal cortex in both sexes.

In the testes, testosterone is produced by the Leydig cells. The male generative glands also contain Sertoli cells which require testosterone for spermatogenesis. Like most hormones, testosterone is supplied to target tissues in the blood where much of it is transported bound to a specific plasma protein, sex hormone binding globulin (SHBG).

1.2 Regulation

[Fig.1]Hypothalamic-pituitary-testicular axis

In males, testosterone is primarily synthesized in Leydig cells. The number of Leydig cells in turn is regulated by luteinizing hormone (LH) and follicle stimulating hormone (FSH). In addition, the amount of testosterone produced by existing Leydig cells is under the control of LH which regulates the expression of 17-β hydroxysteroid dehydrogenase.

The amount of testosterone synthesized is regulated by the hypothalamic-pituitary-testicular axis (see figure to the right). When testosterone levels are low, gonadotropin-releasing hormone (GnRH) is released by the hypothalamus which in turn stimulates the pituitary gland to release FSH and LH. These later two hormones stimulate the testis to synthesize testosterone. Finally increasing levels of testosterone through a negative feedback loop act on the hypothalamus and pituitary to inhibit the release of GnRH and FSH/LH respectively.

Environmental factors affecting testosterone levels include:

• Loss of status or dominance in men may result in a decreased testosterone level.

• Implicit power motivation predicts an increased testosterone release in men.

• Aging reduces testosterone release.

• Hypogonadism

• Sleep (REM dream) increases nocturnal testosterone levels.

• Resistance training increases testosterone levels, however, in older men, that increase can be avoided by protein ingestion.

• Zinc deficiency lowers testosterone levels but over supplementation has no effect on serum testosterone.

• Licorice. The active ingredient in licorice root, glycyrrhizinic acid has been linked to small, clinically non-significant decreases in testosterone levels. In contrast, a more recent study found that licorice administration produced a substantial testosterone decrease in a small, female-only sample.

• Natural or man-made antiandrogens including spearmint tea reduce testosterone levels.

1.3 Metabolism

Approximately 7% of testosterone is reduced to 5α-dihydrotestosterone (DHT) by the cytochrome P450 enzyme 5α-reductase, an enzyme highly expressed in male accessory sex organs and hair follicles. Approximately 0.3% of testosterone is converted into estradiol by aromatase (CYP19A1) an enzyme expressed in the brain, liver, and adipose tissues.

DHT is a more potent form of testosterone while estradiol has completely different activities (feminization) compared to testosterone (masculinization). Finally testosterone and DHT may be deactivated or cleared by enzymes that hydroxylate at the 6, 7, 15 or 16 positions.

2. Physiological effects

In general, androgens promote protein synthesis and growth of those tissues with androgen receptors. Testosterone effects can be classified as virilizing and anabolic, although the distinction is somewhat artificial, as many of the effects can be considered both. Testosterone is anabolic, meaning it builds up bone and muscle mass.

• Anabolic effects include growth of muscle mass and strength, increased bone density and strength, and stimulation of linear growth and bone maturation.

• Androgenic effects include maturation of the sex organs, particularly the penis and the formation of the scrotum in the fetus, and after birth (usually at puberty) a deepening of the voice, growth of the beard and axillary hair. Many of these fall into the category of male secondary sex characteristics.

Testosterone effects can also be classified by the age of usual occurrence. For postnatal effects in both males and females, these are mostly dependent on the levels and duration of circulating free testosterone.

2.1 Prenatal

The prenatal androgen effects occur between 4 and 6 weeks of the gestation.

• Genital virilization (midline fusion, phallic urethra, scrotal thinning and rugation, phallic enlargement); although the role of testosterone is far smaller than that of Dihydrotestosterone.

• Development of prostate and seminal vesicles

• Gender identity

2.2 Early infancy

Early infancy androgen effects are the least understood. In the first weeks of life for male infants, testosterone levels rise. The levels remain in a pubertal range for a few months, but usually reach the barely detectable levels of childhood by 4–6 months of age. The function of this rise in humans is unknown.

It has been speculated that "brain masculinization" is occurring since no significant changes have been identified in other parts of the body. Surprisingly, the male brain is masculinized by testosterone being aromatized into estrogen, which crosses the blood-brain barrier and enters the male brain, whereas female fetuses have alpha-fetoprotein which binds up the estrogen so that female brains are not affected.

2.3 Pre-peripubertal

Pre- Peripubertal effects are the first observable effects of rising androgen levels at the end of childhood, occurring in both boys and girls.

• Adult-type body odour

• Increased oiliness of skin and hair, acne

• Pubarche (appearance of pubic hair)

• Axillary hair

• Growth spurt, accelerated bone maturation

• Hair on upper lip and sideburns.

2.4 Pubertal

Pubertal effects begin to occur when androgen has been higher than normal adult female levels for months or years. In males, these are usual late pubertal effects, and occur in women after prolonged periods of heightened levels of free testosterone in the blood.

• Enlargement of sebaceous glands. This might cause acne.

• Phallic enlargement or clitoromegaly

• Increased libido and frequency of erection or clitoral engorgement

• Pubic hair extends to thighs and up toward umbilicus

• Facial hair (sideburns, beard, moustache)

• Loss of scalp hair (Androgenetic alopecia)

• Chest hair, periareolar hair, perianal hair

• Leg hair

• Axillary hair

• Subcutaneous fat in face decreases

• Increased muscle strength and mass

• Deepening of voice

• Growth of the Adam's apple

• Growth of spermatogenic tissue in testicles, male fertility

• Growth of jaw, brow, chin, nose, and remodeling of facial bone contours

• Shoulders become broader and rib cage expands

• Completion of bone maturation and termination of growth. This occurs indirectly via estradiol metabolites and hence more gradually in men than women.

2.5 Adult

Adult testosterone effects are more clearly demonstrable in males than in females, but are likely important to both sexes. Some of these effects may decline as testosterone levels decrease in the later decades of adult life.

• Testosterone is necessary for normal sperm development. It activates genes in Sertoli cells, which promote differentiation of spermatogonia.

• Regulates acute HPA (Hypothalamic–pituitary–adrenal axis) response under dominance challenge

• Mental and physical energy

• Maintenance of muscle trophism

• Testosterone regulates the population of thromboxane A2 receptors on megakaryocytes and platelets and hence platelet aggregation in humans

• Libido as evinced in clitoral engorgement/penile erection frequency

• Testosterone does not cause or produce deleterious effects on prostate cancer. In people who have undergone testosterone deprivation therapy, testosterone increases beyond the castrate level have been shown to increase the rate of spread of an existing prostate cancer.

• Recent studies have shown conflicting results concerning the importance of testosterone in maintaining cardiovascular health. Nevertheless, maintaining normal testosterone levels in elderly men has been shown to improve many parameters which are thought to reduce cardiovascular disease risk, such as increased lean body mass, decreased visceral fat mass, decreased total cholesterol, and glycemic control.

• Under dominance challenge, may play a role in the regulation of the fight-or-flight response

• Falling in love decreases men's testosterone levels while increasing women's testosterone levels. It is speculated that these changes in testosterone result in the temporary reduction of differences in behavior between the sexes. It has been found that when the testosterone and endorphins in the ejaculated semen meet the cervical wall after sexual intercourse, females receive a spike in testosterone, endorphin, and oxytocin levels, and males after orgasm during copulation experience an increase in endorphins and a marked increase in oxytocin levels. This adds to the hospitable physiological environment in the female internal reproductive tract for conceiving, and later for nurturing the conceptus in the pre-embryonic stages, and stimulates feelings of love, desire, and paternal care in the male (this is the only time male oxytocin levels rival a female's).

• Recent studies suggest that testosterone level plays a major role in risk-taking during financial decisions.

• The administration of testosterone makes men selfish and more likely to punish others for being selfish towards them.

• Fatherhood also decreases testosterone levels in men, suggesting that the resulting emotional and behavioral changes promote paternal care.

• In animals (grouse and sand lizards), higher testosterone levels have been linked to a reduced immune system activity. Testosterone seems to have become part of the honest signaling system between potential mates in the course of evolution.

2.6 Brain

As testosterone affects the entire body (often by enlarging; men have bigger hearts, lungs, liver, etc.), the brain is also affected by this "sexual" differentiation; the enzyme aromatase converts testosterone into estradiol that is responsible for masculinization of the brain in male mice. In humans, masculinization of the fetal brain appears, by observation of gender preference in patients with congenital diseases of androgen formation or androgen receptor function, to be associated with functional androgen receptors.

There are some differences between a male and female brain (possibly the result of different testosterone levels), one of them being size: the male human brain is, on average, larger. In a Danish study from 2003, men were found to have a total myelinated fiber length of 176,000 km at the age of 20, whereas in women the total length was 149,000 km. However, women have more dendritic connections between brain cells.

A study conducted in 1996 found no immediate short term effects on mood or behavior from the administration of supraphysiologic doses of testosterone for 10 weeks on 43 healthy men. Another study found a correlation between testosterone and risk tolerance in career choice among women.

Literature suggests that attention, memory, and spatial ability are key cognitive functions affected by testosterone in humans. Preliminary evidence suggests that low testosterone levels may be a risk factor for cognitive decline and possibly for dementia of the Alzheimer’s type, a key argument in life extension medicine for the use of testosterone in anti-aging therapies. Much of the literature, however, suggests a curvilinear or even quadratic relationship between spatial performance and circulating testosterone, where both hypo- and hypersecretion (deficient- and excessive-secretion) of circulating androgens have negative effects on cognition and cognitively modulated aggressivity, as detailed above.

Contrary to what has been postulated in outdated studies and by certain sections of the media, aggressive behaviour is not typically seen in hypogonadal men who have their testosterone replaced adequately to the eugonadal/normal range. In fact, aggressive behaviour has been associated with hypogonadism and low testosterone levels and it would seem as though supraphysiological and low levels of testosterone and hypogonadism cause mood disorders and aggressive behaviour, with eugondal/normal testosterone levels being important for mental well-being. Testosterone depletion is a normal consequence of aging in men. One possible consequence of this could be an increased risk for the development of Alzheimer’s disease.

3. Mode of action

The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors.

Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5α-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5-alpha reductase. DHT binds to the same androgen receptor even more strongly than testosterone, so that its androgenic potency is about 5 times that of T. The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing the androgen effects.

Androgen receptors occur in many different vertebrate body system tissues, and both males and females respond similarly to similar levels. Greatly differing amounts of testosterone prenatally, at puberty, and throughout life account for a share of biological differences between males and females.

The bones and the brain are two important tissues in humans where the primary effect of testosterone is by way of aromatization to estradiol. In the bones, estradiol accelerates maturation of cartilage into bone, leading to closure of the epiphyses and conclusion of growth. In the central nervous system, testosterone is aromatized to estradiol. Estradiol rather than testosterone serves as the most important feedback signal to the hypothalamus (especially affecting LH secretion). In many mammals, prenatal or perinatal "masculinization" of the sexually dimorphic areas of the brain by estradiol derived from testosterone programs later male sexual behavior.

The human hormone testosterone is produced in greater amounts by males, and less by females. The human hormone estrogen is produced in greater amounts by females, and less by males. Testosterone causes the appearance of masculine traits (i.e., deepening voice, pubic and facial hairs, muscular build, etc.) Like men, women rely on testosterone to maintain libido, bone density and muscle mass throughout their lives. In men, inappropriately high levels of estrogens lower testosterone, decrease muscle mass, stunt growth in teenagers, introduce gynecomastia, increase feminine characteristics, and decrease susceptibility to prostate cancer, reduces libido and causes erectile dysfunction and can cause excessive sweating and hot flushes. However, an appropriate amount of estrogens is required in the male in order to ensure well-being, bone density, libido, erectile function, etc.

4. Therapeutic use

4.1 Routes of administration

There are many routes of administration for testosterone. Forms of testosterone for human administration currently available include injectable (such as testosterone cypionate or testosterone enanthate in oil), oral, buccal, transdermal skin patches, transdermal creams, gels, and implantable pellets. Roll-on methods and nasal sprays are currently under development.

4.2 Indications

The original and primary use of testosterone is for the treatment of males who have too little or no natural endogenous testosterone production—males with hypogonadism. Appropriate use for this purpose is legitimate hormone replacement therapy (testosterone replacement therapy [TRT]), which maintains serum testosterone levels in the normal range.

However, over the years, as with every hormone, testosterone or other anabolic steroids has also been given for many other conditions and purposes besides replacement, with variable success but higher rates of side effects or problems. Examples include reducing infertility, correcting lack of libido or erectile dysfunction, correcting osteoporosis, encouraging penile enlargement, encouraging height growth, encouraging bone marrow stimulation and reversing the effects of anemia, and even appetite stimulation. By the late 1940s testosterone was being touted as an anti-aging wonder drug (e.g., see Paul de Kruif's The Male Hormone). Decline of testosterone production with age has led to interest in androgen replacement therapy.

To take advantage of its virilizing effects, testosterone is often administered to transsexual men as part of the hormone replacement therapy, with a "target level" of the normal male testosterone level. Like-wise, transsexual women are sometimes prescribed anti-androgens to decrease the level of testosterone in the body and allow for the effects of estrogen to develop.

Testosterone patches are effective at treating low libido in post-menopausal women. Low libido may also occur as a symptom or outcome of hormonal contraceptive use. Women may also use testosterone therapies to treat or prevent loss of bone density, muscle mass and to treat certain kinds of depression and low energy state. Women on testosterone therapies may experience an increase in weight without an increase in body fat due to changes in bone and muscle density. Most undesired effects of testosterone therapy in women may be controlled by hair-reduction strategies, acne prevention, etc. There is a theoretical risk that testosterone therapy may increase the risk of breast or gynaecological cancers, and further research is needed to define any such risks more clearly.

4.3 Hormone replacement therapy

Testosterone levels decline gradually with age in human beings. The clinical significance of this decrease is debated (see andropause). There is disagreement about when to treat aging men with testosterone replacement therapy.

The American Society of Andrology's position is that:

"... testosterone replacement therapy in aging men is indicated when both clinical symptoms and signs suggestive of androgen deficiency and decreased testosterone levels are present."

The American Association of Clinical Endocrinologists says:

"Hypogonadism is defined as a free testosterone level that is below the lower limit of normal for young adult control subjects. Previously, age-related decreases in free testosterone were once accepted as normal. Currently, they are not considered normal. Patients with low-normal to subnormal range testosterone levels warrant a clinical trial of testosterone."

There is not total agreement on the threshold of testosterone value below which a man would be considered hypogonadal. (Currently there are no standards as to when to treat women.) Testosterone can be measured as "free" (that is, bioavailable and unbound) or more commonly, "total" (including the percentage which is chemically bound and unavailable). In the United States, male total testosterone levels below 300 ng/dL from a morning serum sample are generally considered low. Identification of inadequate testosterone in an aging male by symptoms alone can be difficult.

Replacement therapy can take the form of injectable depots, transdermal patches and gels, subcutaneous pellets, and oral therapy. Adverse effects of testosterone supplementation include minor side effects such as acne and oily skin, and more significant complications such as increased hematocrit which can require venipuncture in order to treat, exacerbation of sleep apnea and acceleration of pre-existing prostate cancer growth in individuals who have undergone androgen deprivation.

Another adverse effect may be significant hair loss and/or thinning of the hair. This may be prevented with Propecia (Finasteride), which blocks DHT (a byproduct of testosterone in the body), during treatment. Exogenous testosterone also causes suppression of spermatogenesis and can lead to infertility. It is recommended that physicians screen for prostate cancer with a digital rectal exam and PSA (prostate specific antigen) level before starting therapy, and monitor hematocrit and PSA levels closely during therapy.

4.4 Benefits

Appropriate testosterone therapy can prevent or reduce the likelihood of osteoporosis, type 2 diabetes, cardio-vascular disease (CVD), obesity, depression and anxiety and the statistical risk of early mortality. Low testosterone also brings with it an increased risk for the development of Alzheimer’s Disease.

A small trial in 2005 showed mixed results.

Large scale trials to assess the efficiency and long-term safety of testosterone are still lacking.

4.5 Adverse effects

Exogenous testosterone supplementation comes with a number of health risks. Fluoxymesterone and methyltestosterone are synthetic derivatives of testosterone. Methyltestosterone and Fluoxymesterone are no longer prescribed by physicians given their poor safety record, and testosterone replacement in men does have a very good safety record as evidenced by over sixty years of medical use in hypogonadal men.

A 2006 article in Official Journal of the American Urological Association - The Journal of Urology pointed out that: Prostate cancer may become clinically apparent within months to a few years after the initiation of testosterone treatment. [...] Physicians prescribing testosterone supplementation and patients receiving it should be cognizant of this risk, and serum PSA testing and digital rectal examination should be performed frequently during treatment.

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Terazosin hydrochloride, USP an alpha-1-selective adrenoceptor blocking agent, is a quinazoline derivative. The chemical name for Terazosin hydrochloride, USP is (RS)-piperazine, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(tetra-hydro-2-furanyl)carbonyl]-, monohydrochloride, dihydrate. It has the following structural formula:

Terazosin hydrochloride, USP is a white, crystalline substance, freely soluble in water and isotonic saline.

1. Clinical pharmacology

The symptoms associated with BPH are related to bladder outlet obstruction, which is comprised of two underlying components: a static component and a dynamic component. The static component is a consequence of an increase in prostate size. Over time, the prostate will continue to enlarge. However, clinical studies have demonstrated that the size of the prostate does not correlate with the severity of BPH symptoms or the degree of urinary obstruction.

The dynamic component is a function of an increase in smooth muscle tone in the prostate and bladder neck, leading to constriction of the bladder outlet. Smooth muscle tone is mediated by sympathetic nervous stimulation of alpha-1 adrenoceptors, which are abundant in the prostate, prostatic capsule and bladder neck.

The reduction in symptoms and improvement in urine flow rates following administration of terazosin is related to relaxation of smooth muscle produced by blockade of alpha-1 adrenoceptors in the bladder neck and prostate. Because there are relatively few alpha-1 adrenoceptors in the bladder body, terazosin is able to reduce the bladder outlet obstruction without affecting bladder contractility.

2. Mode of action

Terazosin belongs to a class of medications called alpha 1 blockers which relaxes the smooth muscles of the arteries, the prostate, and the bladder neck. Other alpha blockers in the same class of drugs include doxazosin (Cardura), alfuzosin (Uroxatral), tamsulosin (Flomax), and prazosin (Minipress).

Relaxing the smooth muscles of the arteries lowers blood pressure. Relaxing the smooth muscles around the bladder neck relieves urinary obstruction caused by an enlarged prostate (prostate hypertrophy).

3. Pharmacokinetics

Terazosin hydrochloride is essentially completely absorbed in man. Administration of terazosin hydrochloride immediately after meals had a minimal effect on the extent of absorption. The time to reach peak plasma concentration however, was delayed by about 40 minutes. Terazosin has been shown to undergo minimal hepatic first-pass metabolism and nearly all of the circulating dose is in the form of parent drug. The plasma levels peak about one hour after dosing, and then decline with a half-life of approximately 12 hours.

In a study that evaluated the effect of age on terazosin pharmacokinetics, the mean plasma half-lives were 14 and 11.4 hours for the age group ≥ 70 years and the age group of 20 to 39 years, respectively. After oral administration the plasma clearance was decreased by 31.7% in patients 70 years of age or older compared to that in patients 20 to 39 years of age.

The drug is 90 to 94% bound to plasma proteins and binding is constant over the clinically observed concentration range. Approximately 10% of an orally administered dose is excreted as parent drug in the urine and approximately 20% is excreted in the feces. The remainder is eliminated as metabolites. Impaired renal function had no significant effect on the elimination of terazosin, and dosage adjustment of terazosin to compensate for the drug removal during hemodialysis (approximately 10%) does not appear to be necessary. Overall, approximately 40% of the administered dose is excreted in the urine and approximately 60% in the feces. The disposition of the compound in animals is qualitatively similar to that in man.

4. Drug interactions

In controlled trials, terazosin has been added to diuretics, and several beta-adrenergic blockers; no unexpected interactions were observed. Terazosin has also been used in patients on a variety of concomitant therapies; while these were not formal interaction studies, no interactions were observed.

Terazosin has been used concomitantly in at least 50 patients on the following drugs or drug classes: 1) analgesic/anti-inflammatory (e.g., acetaminophen, aspirin, codeine, ibuprofen, indomethacin); 2) antibiotics (e.g., erythromycin, trimethoprim and sulfamethoxazole); 3) anticholinergic/sympathomimetics (e.g., phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride); 4) antigout (e.g., allopurinol); 5) antihistamines (e.g., chlorpheniramine); 6) cardiovascular agents (e.g., atenolol, hydrochlorothiazide, methyclothiazide, propranolol); 7) corticosteroids; 8) gastrointestinal agents (e.g., antacids); 9) hypoglycemics; 10) sedatives and tranquilizers (e.g., diazepam).

5. Adverse reactions

The incidence of treatment-emergent adverse events has been ascertained from clinical trials conducted worldwide. All adverse events reported during these trials were recorded as adverse reactions. The incidence rates presented below are based on combined data from six placebo-controlled trials involving once-a-day administration of terazosin at doses ranging from 1 to 20 mg.

Asthenia, postural hypotension, dizziness, somnolence, nasal congestion/rhinitis, and impotence were the only events that were significantly (p ≤ 0.05) more common in patients receiving terazosin than in patients receiving placebo. The incidence of urinary tract infection was significantly lower in the patients receiving terazosin than in patients receiving placebo. An analysis of the incidence rate of hypotensive adverse events adjusted for the length of drug treatment has shown that the risk of the events is greatest during the initial seven days of treatment, but continues at all time intervals.

Additional adverse events have been reported, but these are, in general, not distinguishable from symptoms that might have occurred in the absence of exposure to terazosin. The safety profile of patients treated in the long-term open-label study was similar to that observed in the controlled studies.

The adverse events were usually transient and mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In the placebo-controlled clinical trials, the rates of premature termination due to adverse events were not statistically different between the placebo and terazosin groups. The adverse events that were bothersome, as judged by their being reported as reasons for discontinuation of therapy by at least 0.5% of the

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Tamsulosin is an antagonist of alpha1A adrenoceptors in the prostate.

Tamsulosin hydrochloride is (-)-(R)-5-[2-[[2-(o-Ethoxyphenoxy) ethyl]amino]propyl]-2-methoxybenzenesulfonamide, monohydrochloride. Tamsulosin hydrochloride is a white crystalline powder that melts with decomposition at approximately 230°C.

It is sparingly soluble in water and methanol, slightly soluble in glacial acetic acid and ethanol, and practically insoluble in ether.

The empirical formula of tamsulosin hydrochloride is C20H28N2O5S •HCl. The molecular weight of tamsulosin hydrochloride is 444.98. Its structural formula is:

1. Clinical pharmacology

The symptoms associated with benign prostatic hyperplasia (BPH) are related to bladder outlet obstruction, which is comprised of two underlying components: static and dynamic.

The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate.

The dynamic component is a function of an increase in smooth muscle tone in the prostate and bladder neck leading to constriction of the bladder outlet. Smooth muscle tone is mediated by the sympathetic nervous stimulation of alpha1 adrenoceptors, which are abundant in the prostate, prostatic capsule, prostatic urethra, and bladder neck. Blockade of these adrenoceptors can cause smooth muscles in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in symptoms of BPH.

Tamsulosin, an alpha1 adrenoceptor blocking agent, exhibits selectivity for alpha1 receptors in the human prostate. At least three discrete alpha1-adrenoceptor subtypes have been identified: alpha1A, alpha1B and alpha1D; their distribution differs between human organs and tissue. Approximately 70% of the alpha1-receptors in human prostate are of the alpha1A subtype.

2. Mode of action

Tamsulosin is a drug for the treatment of men who are having difficulty urinating because of benign prostatic hyperplasia (BPH). In men, the tube which carries urine from the bladder to the penis (called the urethra) travels through the prostate gland. As men get older, the prostate gland enlarges, and the muscle cells within the prostate gland and the neck of the bladder (which control the flow of urine) tighten.

The combination of enlargement and tightening of muscles compresses the urethra and obstructs the flow of urine. This results in difficulty urinating and retention of urine within the bladder.

The tightening or contraction of the muscle cells is controlled by nerves. One type of nerve, the alpha adrenergic nerves, cause the muscle cells to tighten by releasing a chemical related to epinephrine (adrenalin). Tamsulosin blocks the effects of this chemical on the muscle cells and causes the muscles to relax. This results in a decrease in obstruction to the flow of urine.

3. Pharmacokinetics

The pharmacokinetics of tamsulosin hydrochloride have been evaluated in adult healthy volunteers and patients with BPH after single and/or multiple administration with doses ranging from 0.1 mg to 1 mg.

Absorption

Absorption of tamsulosin hydrochloride is essentially complete ( > 90%) following oral administration under fasting conditions. Tamsulosin hydrochloride exhibits linear kinetics following single and multiple dosing, with achievement of steady-state concentrations by the fifth day of once-a-day dosing.

Distribution

The mean steady-state apparent volume of distribution of tamsulosin hydrochloride after intravenous administration to 10 healthy male adults was 16 L, which is suggestive of distribution into extracellular fluids in the body.

Tamsulosin hydrochloride is extensively bound to human plasma proteins (94% to 99%), primarily alpha1 acid glycoprotein (AAG), with linear binding over a wide concentration range (20 to 600 ng/mL).

The results of two-way in vitro studies indicate that the binding of tamsulosin hydrochloride to human plasma proteins is not affected by amitriptyline, diclofenac, glyburide, simvastatin plus simvastatinhydroxy acid metabolite, warfarin, diazepam, propranolol, trichlormethiazide, or chlormadinone. Likewise, tamsulosin hydrochloride had no effect on the extent of binding of these drugs.

Metabolism

There is no enantiomeric bioconversion from tamsulosin hydrochloride [R(-) isomer] to the S(+) isomer in humans. Tamsulosin hydrochloride is extensively metabolized by cytochrome P450 enzymes in the liver and less than 10% of the dose is excreted in urine unchanged.

However, the pharmacokinetic profile of the metabolites in humans has not been established. Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6 as well as via some minor participation of other CYP isoenzymes. Inhibition of hepatic drug-metabolizing enzymes may lead to increased exposure to tamsulosin. The metabolites of tamsulosin hydrochloride undergo extensive conjugation to glucuronide or sulfate prior to renal excretion.

Excretion

On administration of the radiolabeled dose of tamsulosin hydrochloride to 4 healthy volunteers, 97% of the administered radioactivity was recovered, with urine (76%) representing the primary route of excretion compared to feces (21%) over 168 hours.

Following intravenous or oral administration of an immediate-release formulation, the elimination half-life of tamsulosin hydrochloride in plasma ranged from 5 to 7 hours. Because of absorption rate-controlled pharmacokinetics with extended-release formulation, the apparent half-life of tamsulosin hydrochloride is approximately 9 to 13 hours in healthy volunteers and 14 to 15 hours in the target population.

Tamsulosin hydrochloride undergoes restrictive clearance in humans, with a relatively low systemic clearance (2.88 L/h).

4. Drug interactions

Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6.

Concomitant treatment with ketoconazole (a strong inhibitor of CYP3A4) resulted in an increase in the Cmax and AUC of tamsulosin. The effects of concomitant administration of a moderate CYP3A4 inhibitor (e.g., erythromycin) on the pharmacokinetics of tamsulosin have not been evaluated.

Concomitant treatment with paroxetine (a strong inhibitor of CYP2D6) resulted in an increase in the Cmax and AUC of tamsulosin. A similar increase in exposure is expected in CYP2D6 poor metabolizers (PM) as compared to extensive metabolizers (EM). Since CYP2D6 PMs cannot be readily identified and the potential for significant increase in tamsulosin exposure exists when Tamsulosin is co-administered with strong CYP3A4 inhibitors in CYP2D6 PMs, tamsulosin should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole).

The effects of concomitant administration of a moderate CYP2D6 inhibitor (e.g., terbinafine) on the pharmacokinetics of tamsulosin have not been evaluated.

The effects of co-administration of both a CYP3A4 and a CYP2D6 inhibitor with tamsulosin have not been evaluated. However, there is a potential for significant increase in tamsulosin exposure when tamsulosin is co-administered with a combination of both CYP3A4 and CYP2D6 inhibitors

5. Adverse reactions

Signs and symptoms of orthostasis

In the two U.S. studies, symptomatic postural hypotension was reported by 0.2% of patients (1 of 502) in the 0.4 mg group, 0.4% of patients (2 of 492) in the 0.8 mg group, and by no patients in the placebo group. Syncope was reported by 0.2% of patients (1 of 502) in the 0.4 mg group, 0.4% of patients (2 of 492) in the 0.8 mg group and 0.6% of patients (3 of 493) in the placebo group. Dizziness was reported by 15% of patients (75 of 502) in the 0.4 mg group, 17% of patients (84 of 492) in the 0.8 mg group, and 10% of patients (50 of 493) in the placebo group. Vertigo was reported by 0.6% of patients (3 of 502) in the 0.4 mg group, 1% of patients (5 of 492) in the 0.8 mg group and by 0.6% of patients (3 of 493) in the placebo group.

Multiple testing for orthostatic hypotension was conducted in a number of studies. Such a test was considered positive if it met one or more of the following criteria: (1) a decrease in systolic blood pressure of ≥20 mmHg upon standing from the supine position during the orthostatic tests; (2) a decrease in diastolic blood pressure ≥10 mmHg upon standing, with the standing diastolic blood pressure <65 mmHg during the orthostatic test; (3) an increase in pulse rate of ≥20 bpm upon standing with a standing pulse rate ≥100 bpm during the orthostatic test; and (4) the presence of clinical symptoms (faintness, lightheadedness/lightheaded, dizziness, spinning sensation, vertigo, or postural hypotension) upon standing during the orthostatic test.

Following the first dose of double-blind medication in Study 1, a positive orthostatic test result at 4 hours post-dose was observed in 7% of patients (37 of 498) who received tamsulosin hydrochloride capsules 0.4 mg once daily and in 3% of the patients (8 of 253) who received placebo. At 8 hours post-dose, a positive orthostatic test result was observed for 6% of the patients (31 of 498) who received tamsulosin hydrochloride capsules 0.4 mg once daily and 4% (9 of 250) who received placebo (Note: patients in the 0.8 mg group received 0.4 mg once daily for the first week of Study 1).

In Studies 1 and 2, at least one positive orthostatic test result was observed during the course of these studies for 81 of the 502 patients (16%) in the tamsulosin hydrochloride capsules 0.4 mg once-daily group, 92 of the 491 patients (19%) in the tamsulosin hydrochloride capsules 0.8 mg once-daily group and 54 of the 493 patients (11%) in the placebo group.

Because orthostasis was detected more frequently in tamsulosin hydrochloride capsule-treated patients than in placebo recipients, there is a potential risk of syncope.

Abnormal ejaculation

Abnormal ejaculation includes ejaculation failure, ejaculation disorder, retrograde ejaculation and ejaculation decrease. As shown in Table 1, abnormal ejaculation was associated with tamsulosin hydrochloride capsules administration and was dose-related in the U.S. studies. Withdrawal from these clinical studies of tamsulosin hydrochloride capsules because of abnormal ejaculation was also dose-dependent with 8 of 492 patients (1.6%) in the 0.8 mg group, and no patients in the 0.4 mg or placebo groups discontinuing treatment due to abnormal ejaculation.

Laboratory tests

No laboratory test interactions with tamsulosin hydrochloride capsules are known. Treatment with tamsulosin hydrochloride capsules for up to 12 months had no significant effect on prostate-specific antigen (PSA).

Postmarketing experience

The following adverse reactions have been identified during post-approval use of tamsulosin hydrochloride capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors:

(1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to tamsulosin hydrochloride capsules.

Allergic-type reactions such as skin rash, urticaria, pruritus, angioedema and respiratory symptoms have been reported with positive rechallenge in some cases. Priapism has been reported rarely. Infrequent reports of palpitations, hypotension, skin desquamation, constipation and vomiting have been received during the postmarketing period.

During cataract surgery, a variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome (IFIS) has been reported in association with alpha1 blocker therapy

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Potassium citrate is a potassium salt of citric acid with the molecular formula C6H5K3O7. It is a white, slightly hygroscopic crystalline powder. It is odorless with a saline taste.

As a food additive, potassium citrate is used to regulate acidity. Medicinally, it may be used to control kidney stones derived from either uric acid or cystine.

1. Clinical pharmacology

Potassium Citrate is used for the treatment and management of various medical disorders, such as uric acid or cystine kidney stones, renal tubular acidosis, gout and hypokalemia (a condition where the blood has a low amount of potassium concentration). Potassium citrate is part of the urinary alkalinizer drug class, and is often administered to patients who must limit their potassium and sodium intake. It may also be administered to boost the effectiveness of a number of antibiotics.

Kidneys are responsible in making sure that the body maintains a healthy acid to base ratio. Their ability to discharge acid and alkaline via the urine is critical when it comes to the overall ability to uphold a stable body pH. Urine can turn more and more acidic as the quantity of sodium and surplus acid kept by the body increases. This is where potassium citrate demonstrates its effectiveness---helping the kidneys to neutralize and eliminate uric acid, thus preventing a number of conditions that can result from kidney disease and related problems.

2. Mode of action

As an alkalinizing agent, potassium citrate operates as a urinary pH modifier, making the urine less acidic by neutralizing some of its acid. The urine pH is utilized to categorize urine as being a base solution or a dilute acid. A lower pH level signifies the higher acidity of a solution, whereas a higher pH level indicates a greater alkalinity. On the pH scale, seven is considered to be neutral; contingent upon a person's acid-base rank, the pH level of their urine tends to span anywhere from 4.5 to 8.

3. Drug interactions

No one taking a medication classified as an anticholinergic agent should take potassium citrate, because anticholinergics cause dehydration and dehydrated people should not take potassium citrate. Commonly used anticholinergic agents include tolterodine (Detrol from Pfizer), oxybutynin (Ditropan from Ortho McNeil Janssen) and solifenacin (Vesicare from Astellas).

Other medications to avoid while taking potassium citrate include amiloride (e.g., Midamor from Paddock), spironolactone (e.g., Aldactone from Pfizer) and hydrochlorothiazide-triamterene (e.g., Dyazide from GSK). Amiloride, spironolactone and hydrochlorothiazide-triamterene are known as potassium-sparing diuretics; taking them at the same time as potassium citrate puts patients at risk for hyperkalemia.

4. Adverse reactions

As with any medication, potassium citrate can cause side effects, which may include nausea, vomiting, a tingling sensation in the hands and feet, stomach upset and diarrhea.

Adverse reactions to the medication include increased confusion or agitation, irregular heartbeat, continuous vomiting, trouble breathing, numbness of the mouth, stomach pain and muscle weakness.

Potassium citrate may adversely affect or interfere with other prescription medications and over-the-counter remedies. Prior to starting any medication, it's important to notify your doctor of any medications you're taking, preexisting medical conditions you have and allergies.

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CETRAXAL PLUS® Otic Soln.

Each bottle of 10 mL contains Ciprofloxacin 3 mg and Fluocinolone acetonide 0.25 ...