As we all know within the bodybuilding community Clenbuterol is the highly touted beta-2 agonist with pretty impressive fat burning effects. However, there is a downside to this incredible fat-burning effect. Clenbuterol does its job so well binding to the beta-2 receptor(That's involved in both the regulation of body temperature and protein synthesis), that it down-regulates the receptor in about 2 weeks(Assuming a dosing schedule of 60-120mcgs/day, on a 2 on/2 off day cycle). The aformentioned 2 on/2 off dosing schedule doesn't work because the half-life of clenbuterol Hydrochloride in the body is 48hrs, therefore it would still be present in the system during the "off" days, giving the beta-2 receptor no time to recuperate and up-regulate. What to do? Well, if we had a pretty benign compound that drastically increased cyclic-adenosine monophosphate(C-amp) within the cell this would up-regulate the elusive beta-2 receptor. You know what, it exists!, it's called Ketotifen(brand name Zaditen). This compund at a dosage of 6mg/ spread throughout the day will completely negate clenbuterol's down-regulating effects on the beta-2 receptor, due to the fact that it increases C-amp levels within the cell by an amazing 80%. Now, everybody is thinking: "Great, now I can take Clenbuterol forever"; however, there is a catch. While Ketotifen will keep the beta-2 receptor up-regulated, during the 4th or 5th week of clenbuterol use(depending on the person), active T3 levels within the body will decline and production of rT3 will increase(Due to the fact that Clen decreases T3 levels in the body). This will shut down Clenbuterol's fat-burning effects. However, there is a way one can combat this down-regulation of one's own T3 levels. The answer, is exogeneous T3(brand name cytomel). T3, at a dosage of 25mcgs daily will not shut down TSH to a large degree, so therefore could be taken for quite a while(6-8 weeks). This latter dosage will boost T3 levels back to normal, helping clenbuterol continue its fat-burning effects. So, now we have the optimal 10 week Clenbuterol cycle:

Can you site the studies?

In other words, can you back it up, my brother?

Effects of ketotifen and clenbuterol on beta-adrenergic receptor functions of lymphocytes and on plasma TXB-2 levels of asthmatic patients.

Huszar E, Herjavecz I, Boszormenyi-Nagy G, Slapke J, Schreiber J, Debreczeni LA

Experimental Physiological Research Unit of Koranyi National Institute for TB and Pulmonology, Budapest/Hungary.

Clinical observations indicate that beta-adrenergic drugs may increase bronchial reactivity in asthmatics. To find out possible reasons for this phenomenon the beta-adrenergic receptor function of isolated lymphocytes of asthmatic patients treated with clenbuterol alone or with ketotifen and clenbuterol together were studied. The cAMP levels of lymphocytes stimulated by different doses of isoproterenol were measured by radioimmunoassay and have been compared in the groups of healthies, and asthmatic patients after 3-months running of clenbuterol (Spiropent, Sandoz), as well as in the same asthmatics after one-week running of parallel administration of ketotifen and clenbuterol. There was no difference between the beta-adrenergic receptor function in asthmatic patients treated with clenbuterol alone vs. untreated healthies. Applying ketotifen and clenbuterol together the beta-adrenergic receptor function increased compared to the values obtained after application of clenbuterol alone (intraindividual-control) as well as vs. the group of healthies (control). Data presented support the view that therapeutic doses of selective beta 2-agonists do not lead to damage of the beta-adrenoceptor function. The improvement of receptor function after parallel administration of clenbuterol and ketotifen may be a consequence of the participation of ketotifen in the control of beta-adrenergic receptor system. Thus it seems unlikely that down-regulation of beta-adrenergic receptors is responsible for the beta-agonist induced bronchial hyperreactivity. That's why TXB-2 levels in the plasma of the same asthmatic patients and healthy volunteers were determined by RIA.

Effects of ketotifen on the responsiveness of peripheral blood lymphocyte beta-adrenergic receptors.

Polson JB, Lockey RF, Bukantz SC, Lowitt S, Krzanowski JJ Jr, Szentivanyi A

Department of Pharmacology and Therapeutics, College of Medicine, University of South Florida, Tampa.

The effects of ketotifen therapy on the responsiveness of lymphocyte beta-adrenergic receptors was evaluated by measuring cyclic AMP elevations caused by isoproterenol in cells isolated from patients treated with ketotifen for more than 1 year. Binding of 3H-dihydroalprenolol to beta-receptors was also evaluated. The isoproterenol-induced rise in cyclic AMP relative to each individual's baseline level was greater in patients on current ketotifen therapy than in other asthmatic patients or non-asthmatic subjects. Ketotifen therapy increased the apparent equilibrium dissociation constant for specific 3H-dihydroalprenolol binding to the receptors. Receptor numbers in symptomatic asthma patients on standard drug therapy were decreased. The results indicate that long term ketotifen therapy is associated with increased responsiveness of beta-receptors to stimulation by catecholamines and that this alteration may involve changes in the receptors themselves, their membrane environment, adenylate cyclase or components of the adenylate cyclase coupling system.

Effect of prednisolone and ketotifen on beta 2-adrenoceptors in asthmatic patients receiving beta 2-bronchodilators.

Brodde OE, Howe U, Egerszegi S, Konietzko N, Michel MC

Medizinische Klinik und Poliklinik, University of Essen, Federal Republic of Germany.

In 13 patients with bronchial asthma, who were on beta 2-adrenergic bronchodilator therapy, the effects of prednisolone and ketotifen on lymphocyte beta 2-adrenoceptor density and -responsiveness were investigated. The mean lymphocyte beta 2-adrenoceptor density and -responsiveness was significantly lower than in healthy controls, presumably due to the long-term beta 2-adrenergic bronchodilator treatment. Both prednisolone 100 mg i.v. and ketotifen 1 mg b.d.p.o. for 6 days rapidly improved lymphocyte beta 2-adrenoceptor function. 16 h after prednisolone and about 6 days after the first dose of ketotifen lymphocyte beta 2-adrenoceptor density and -responsiveness had risen to values within the range in normal volunteers. The improvement of lymphocyte beta 2-adrenoceptor function was accompanied by a significant increase in peak expiratory flow rate before and after inhalation of salbutamol. It is concluded that prednisolone and ketotifen may act beneficially on the recovery of beta 2-adrenoceptor responsiveness to beta 2-adrenergic bronchodilators in tolerant asthmatic patients.

Terbutaline-induced desensitization of beta 2-adrenoceptor in vivo function in humans: attenuation by ketotifen.

Brodde OE, Petrasch S, Bauch HJ, Daul A, Gnadt M, Oefler D, Michel MC

Department of Internal Medicine, University of Essen, Germany.

Use of beta-adrenoceptor agonists in long-term treatment of patients with chronic asthma bronchiale or heart failure is of limited value because beta-adrenoceptor desensitization develops. The antiallergic drug ketotifen prevents beta-adrenoceptor agonist-induced desensitization of rat and human pulmonary and lymphocyte beta 2-adrenoceptors. In 10 healthy volunteers in a double-blind, placebo-controlled study, we investigated whether ketotifen also prevents beta-adrenoceptor agonist-induced desensitization of beta 1- and/or beta 2-adrenoceptor-mediated physiologic in vivo effects. beta 1-Adrenoceptor-mediated effects were isoprenaline (ISO) infusion-induced increase in systolic blood pressure (SBP) and bicycle exercise-induced increase in heart rate (HR); beta 2-adrenoceptor-mediated effects were ISO infusion-induced increase in plasma norepinephrine (NE) and decrease in diastolic blood pressure (DBP); ISO infusion-induced increase in HR was assessed as mixed beta 1- and beta 2-adrenoceptor-mediated effect. These parameters were assessed before and after a 14-day treatment with the beta 2-adrenoceptor agonist terbutaline (5 mg three times daily) with or without simultaneous administration of ketotifen (1 mg twice daily). Terbutaline desensitized all in vivo effects involving beta 2-adrenoceptors (ISO-induced decrease in DBP and increase in plasma NE and, to a minor extent, the mixed beta 1- and beta 2-adrenoceptor-mediated increase in HR), but did not affect beta 1-adrenoceptor-mediated in vivo effects; concomitant treatment of the volunteers with ketotifen markedly blunted terbutaline-induced desensitization of beta 2-adrenoceptor in vivo function. We conclude that ketotifen prevents, or at least attenuates, beta-adrenoceptor agonist-induced desensitization of beta 2-adrenoceptor in vivo function.

Terbutaline-induced desensitization of human lymphocyte beta 2-adrenoceptors. Accelerated restoration of beta-adrenoceptor responsiveness by prednisone and ketotifen.

Brodde OE, Brinkmann M, Schemuth R, O'Hara N, Daul A

We investigated, in 36 healthy volunteers, the effects of prednisone and ketotifen on recovery of lymphocyte beta 2-adrenoceptor density (determined by (-)-125iodocyanopindolol binding) and responsiveness (assessed by lymphocyte cyclic AMP [cAMP] responses to 10 microM (-)-isoprenaline) after desensitization by the beta 2-agonist terbutaline. Terbutaline (3 X 5 mg/d) decreased lymphocyte beta 2-adrenoceptor density by approximately 40-50%; concomitantly, lymphocyte cAMP responses to 10 microM (-)-isoprenaline were significantly reduced. After withdrawal of terbutaline beta 2-adrenoceptor, density and responsiveness gradually increased, reaching predrug levels after 4 d. Prednisone (1 X 100 mg orally) accelerated beta 2-adrenoceptor recovery; only 8-10 h after administration of the steroid beta 2-adrenoceptor density and cAMP responses to (-)-isoprenaline had reached values not significantly different from pretreatment levels. Similar effects were obtained with ketotifen (2 mg; thereafter 2 X 1 mg/d for 4 d): 24 h after application of the drug beta 2-adrenoceptor density and cAMP responses to (-)-isoprenaline had reached pretreatment levels. Furthermore, ketotifen simultaneously applied with terbutaline completely prevented terbutaline-induced decrease in lymphocyte beta 2-adrenoceptor density and responsiveness. Prednisone (1 X 100 mg orally) or ketotifen (2 mg; thereafter 2 X 1 mg/d for 2 d) had no significant influence on lymphocyte beta 2-adrenoceptor density in healthy volunteers not pretreated with terbutaline, but shifted the ratio high-to-low affinity state of the lymphocyte beta 2-adrenoceptor toward high affinity state. We conclude that glucocorticoids as well as ketotifen can accelerate recovery of density and responsiveness of lymphocyte beta 2-adrenoceptors desensitized by long-term treatment with beta 2-agonists. Such an effect may have clinical implications for preventing tachyphylaxis of asthmatic patients against therapy with beta 2-agonists.

Effects of calcium channel blockers and ketotifen on beta 2 adrenergic receptor regulation in intact human lymphocytes.

Hui KK, Yu JL

Department of Medicine, UCLA School of Medicine, 90024.

Effects of three calcium channel blockers (nifedipine, NIF; verapamil, VER and diltiazem, DIL) and one antiallergic drug, ketotifen (KET) on isoproterenol (ISO)-induced beta 2 adrenergic receptor desensitization and resensitization have been studied with intact human lymphocytes in vitro. While incubation of lymphocytes with 1.0 microM NIF, VER, or DIL alone neither changed [3H]-CGP-12177 binding (Bmax) nor increased cAMP responsiveness to ISO, they all partially prevented 50 nM ISO-induced beta 2 adrenoceptor-adenylate cyclase uncoupling. VER and DIL also partially prevented beta 2 adrenoceptor down-regulation, but NIF did not. In contrast, 10 microM KET not only diminished ISO-induced desensitization but also accelerated subsequent resensitization. KET alone also induced an up-regulation of cell surface beta adrenergic receptors. The effects of these compounds on beta 2 adrenoceptor regulation may partially explain their potentiation of ISO-induced cAMP accumulation in lymphocytes.

PMID: 2571180, UI: 89387905