Tadalafil + Dapoxetine is a combination of two medicines, Tadalafil and Dapoxetine, which treat premature ejaculation. Tadalafil is a phosphodiesterase type 5 (PDE 5) inhibitor, increasing the blood flow to the penis during sexual stimulation and enables its erection following sexual stimulation.
Mechanism of action:
- Penile erection during sexual stimulation is caused by penile arterial relaxation and increased penile flow as a result of smooth muscle of the corpus covernosum. This reaction is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cyclic guanosine monophosphate (commonly known as cyclic GMP or GGMP) in smooth muscle cells. cGMP relaxes smooth muscle and increases blood flow to the corpus covarnosum. Inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cGMP. Tadalafil (and sildenafil and vardenafil) inhibits PDE5. However, because local penile release of nitric oxide requires sexual stimulation, tadalafil’s inhibition of PDA5 would have no effect without sexual stimulation.
- Dapoxetine is a potent selective serotonin reuptake inhibitor (SSRI) with IC50at 1.12 nm, while its major human metabolites, desmethyldapoxetine (IC50 <1.0 nM) and didesmethyldapoxetine (IC50 = 2.0 nM) are equivalent or low-potency (POPE). (IC50 = 282 nM)).
- Human ejaculation is primarily mediated by the sympathetic nervous system. The ejaculation pathway arises from a spinal reflex center, mediated by the stem of the brain, which is initially affected by multiple nuclei in the brain (medial prophylactic and paraventricular nuclei).
- The mechanism of action of dapoxinate in premature ejaculation is thought to be associated with the inhibition of neuronal burst of serotonin and subsequent potentiation of neurotransmitters at pre- and postsynaptic receptors.
Noncompartmental analyses of plasma concentration and actual sampling time data were performed using WinNonlin Professional® (Pharsight Corporation, Mountain View, CA, USA). The following parameters were calculated for tadalafil: maximum observed plasma concentration (Cmax); time of Cmax (tmax), terminal elimination rate constant (λz) and half‐life (t1/2), area under the plasma concentration–time curve extrapolated to infinite time (AUC), AUC within a 24‐h dosing interval (AUCτ), oral clearance (CL/F), and apparent volume of distribution during the terminal elimination phase (Vz/F).
Food and time of dosing (diurnal) effects were evaluated with a mixed‐effects linear model. Absence of an effect was declared if the 90% confidence interval (90% CI) for the ratio of least‐squares (LS) means lay entirely within a range of 0.80–1.25 for AUC and 0.70–1.43 for Cmax. These criteria were prespecified in the protocol based upon intrasubject coefficients of variation of 19.1% for AUC and 26.2% for Cmax. Values of tmax were analysed with the Wilcoxon signed‐rank test. Median differences and 90% CIs were calculated for each of the treatment comparisons.
Dose proportionality of selected parameters (PK) was assessed with a power model of the form:
ln(PK ij) = β · ln(dose ij) + si + tj +ɛij
where ln(PKij) is the log of the response, ln(doseij) is the log of the dose for the ith subject and jth observation, ti is the fixed effect of study period, and ɛij is random error. Ideal dose proportionality requires that β = 1 for dose‐dependent parameters (AUC and Cmax) or that β = 0 for dose‐independent parameters (CL/F and Vz/F). Dose proportionality (or dose independence) was concluded if the 95% CIs for β included 1 (or included 0). The increase for doubling of the dose (eln(2) × β) and the associated 95% CIs were calculated for AUC and Cmax.
In the integrated statistical analysis (ISA), a population average and 95% CI were computed for each single‐dose pharmacokinetic parameter of interest. The data were analysed using the procedure MIXED of SAS to fit linear mixed effects models describing the relationship between the parameters and covariates. Each parameter was evaluated separately, and was log‐transformed prior to evaluation (except for tmax). Categorical covariates were classed as fixed effects and the subject term was included as a random effect to allow estimation of between‐subject and within‐subject variability. The analysis was carried out using stepwise regression methods. Type III sums of squares were used so all model terms were adjusted for all other terms. The Wilcoxon rank sum test was used to compare tmax values between covariate subgroups.
Absorption: Dapoxetine is a white powdery substance and water-insoluble. Taken 1–3 hours before sexual activity, it is rapidly absorbed in the body. Its maximum plasma concentration (Cmax) is reached 1–2 hours after oral administration. The Cmax and AUC (area under the plasma vs. time curve) is dose dependent. The Cmax and Tm (time needed to obtain the maximum plasma concentration) after single doses of dapoxetine 30 mg and 60 mg are 297 and 498 ng/ml at 1.01 and 1.27 hours, respectively. A high-fat meal does reduce the Cmax slightly, but it is insignificant. In fact, food does not alter dapoxetine pharmacokinetics. It can be taken with or without food.
Distribution: Dapoxetine is absorbed and distributed rapidly in the body. Greater than 99% of dapoxetine is bound to the plasma protein. The mean steady-state volume is 162 L. Its initial half-life is 1.31 hours (30 mg dose) and 1.42 hours (60 mg dose), and its terminal half-life is 18.7 hours (30 mg dose) and 21.9 hours (60 mg dose).
Metabolism: Dapoxetine is metabolized extensively in the liver and kidney by multiple enzymes such as CYP2D6, CYP3A4, and flavin monooxygenase 1. The major product at the end of the metabolic pathway is circulating dapoxetine N-oxide, which is a weak SSRI and contributes no clinical effect. The other products presented less than 3% in the plasma are desmethyldapoxetine and didesmethydapoxetine. Desmethyldapoxetine is roughly equipotent to dapoxetine.
Excretion: The metabolites of dapoxetine are eliminated rapidly in the urine with a terminal half-life of 18.7 and 21.9 hours for a single dose of 30 mg and 60 mg, respectively.
- Tadalafil is used to treat male erectile dysfunction (impotence) and pulmonary arterial hypertension (PAH). Part of the physiological process of erectile dysfunction involves the release of nitric oxide (NO) in the corpus cavernosum. This enzyme then activates the gynylate cyclase resulting in increased cyclic guanosine monophosphate (cGMP) levels, thereby relaxing smooth muscle in the corpus cavernosum, resulting in increased blood growth and an erection. Tadalafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) responsible for the degradation of cGMP in the corpus cavernosum. This means that, with tadalafil on board, normal sexual arousal leads to an increase in the level of the corpus that occurs in the corpus cavernum which leads to better erections. Without sexual stimulation and without activation of the NO / cGMP system, tadalafil should cause an erection.
- Before using this medicine, tell your doctor or pharmacist your medical history, specifically: heart problems (such as heart attack or life-threatening irregular heartbeat in the past 6 months, chest pain / angina , Heart failure), stroke in the last 6 months, kidney disease, liver disease, high or low blood pressure, body water (dehydration), a severe loss of penis position (Such as angulation, fibrosis / scarring, pyroneic disease), history of painful / prolonged erection (priapism), conditions that may increase the risk of priapism (eg sickle cell anemia, leukemia, multiple myeloma), eye conditions Problems (eg retinitis pigmentosa, sudden loss of vision, NAION), bleeding disorders, active stomach ulcers.
- This medicine may make you dizzy. Alcohol or marijuana (cannabis) can make you dizzy. Do not drive, use machinery, or do anything that requires vigilance until you can do it safely. Limit alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis).
- Headache, stomach upset, backache, muscle aches, stuffy nose, puffiness or dizziness may occur. If any of these effects persist or worsen, tell your doctor or pharmacist immediately. To reduce the risk of dizziness and lighthouse, rise slowly when getting up from a sitting or lying position.
- Remember that your doctor has prescribed this medicine because he or she has decided that the benefit to you outweighs the risk of side effects. Many people using this medicine do not have serious side effects.
- The usual dose of this medicine is one tablet per day for one hour before sexual activity.
- Healthy subjects have been given a single dose of up to 500 mg, and patients have been given multiple daily doses of up to 100 mg. Adverse events were similar to those seen at low doses. In cases of overdose, standard supportive measures should be adopted as required. Hemodialysis carelessly contributes to tadalafil elimination.
- Trouble breathing or swallowing
- Swelling of your lips, throat or tongue.
- Eating grapefruit or drinking grapefruit juice can increase tadalfil levels in your blood. This increases your risk of side effects.
- Do not drink large amounts of alcohol while taking tadalafil. Both alcohol and tadalafil can widen your blood vessels. When used together, they can cause your blood pressure to drop.
Duration of action:
- It is effective for up to 36 hours, the generic, unbranded version of tadalafil cialis. It is proven to be clinically proven when you need it.
Drug- drug interactions:
- Drug interactions can change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription / non-prescription drugs and herbal products) and share them with your doctor and pharmacist. Do not start, stop, or change the dose of any medicine without your doctor’s approval.
- Most common adverse reactions (≥ 2%) include headache, indigestion, backpain, myalgia, nasal congestion, flushing, and limb pain.
- There has not been enough study in pregnant women using the drug for PAH to show whether the drug is a threat to the human fetus.
- Tadalafil had no adverse effect on spermatogenesis, as assessed by sperm concentration, per ejaculation, sperm count, sperm motility and normal morphology or serum reproductive hormones. Tadalafil was well tolerated. Common adverse events were headaches, indigestion, and back pain.
- Administration of tadalafil to patients who are using any form of organic nitrate is contraindicated.
- Store tadalafil at room temperature between 59 ° F and 86 ° F (15 ° C and 30 ° C).
- Keep this medicine away from high temperature.
- Do not store this medicine in moist or damp areas, such as bathrooms.
- It is not known if tadalafil passes into breast milk. If this happens, it can cause serious effects in a breastfed baby. If you are taking tadalafil and you want to breastfeed, talk to your doctor.