A Review on the Pharmacological Importance of PDE5 and Its Inhibition to Manage Biomedical Conditions

Phosphodiesterase type 5 (PDE5) is a cyclic GMP (cGMP) specific protein. It hydrolyzes the phosphodiesterase linkage and catalyzes the conversion of cGMP to 5’ GMP, which controls different physiological activities of the body. PDE5 is associated with biomedical conditions like neurological disorders, pulmonary arterial hypertension, cardiomyopathy, cancer, erectile dysfunction, and lower urinary tract syndrome. Inhibition of PDE5 has now been proven pharmaceutically effective in a variety of therapeutic conditions. Avanafil, tadalafil, sildenafil, and vardenafil are the most commonly used PDE5 inhibitors (PDE5i) today which are often used for the management of erectile dysfunction, lower urinary tract syndromes, malignancy, and pulmonary arterial hypertension. However, these synthetic PDE5i come with a slew of negative effects. Some of the most common side effects include mild headaches, flushing, dyspepsia, altered color vision, back discomfort, priapism, melanoma, hypotension and dizziness, non-arteritic anterior ischemic optic neuropathy (NAION), and hearing loss. In light of the potential negative effects of this class of medications, there is a lot of room for new, selective PDE5 inhibitors to be discovered. We have found 25 plant botanical compounds effectively inhibiting PDE5 which might be useful in treating a variety of disorders with minimal or no adverse effects.

Subacute toxicity of anilofos, a new organophosphorus herbicide in male rats: effect on lipid peroxidation and ATPase activity.

Effects of anilofos on lipid peroxidation--an index of oxidative stress, ATPase activity--an integral part of active transport mechanisms for cations, GSH level and GST activity were evaluated in blood (erythrocyte/plasma), brain and liver of male rats after daily oral exposure to 50, 100 or 200 mg/kg for 28 days. None of the doses increased lipid peroxidation. The lowest dose, rather, produced marginally significant decrease in peroxidation in liver. Different doses of anilofos decreased GSH content and activities of GST and ATPases. Inhibition of total ATPase (34-44%) and Na+-K+-ATPase (45-52%) activities was maximum in liver, while that of Mg2+-ATPase (46-56%) was more in erythrocyte. Results indicate that anilofos may not cause oxidative damage to cell membrane in repeatedly exposed animals and may cause neuronal/cellular dysfunction by affecting ionic transport across cell membrane.

Subacute toxicity of anilofos, a new organophosphorus herbicide, in male rats: effect on some physical attributes and acetylcholinesterase activity.

In acute toxicity study, rats showed dose-dependent signs of cholinergic hyperactivity and behavioural alterations. Maximum intensity of symptoms was not associated with mortality. Oral LD50 was 1681 mg/kg. In subacute toxicity study, rats were orally administered 50, 100 or 200 mg/kg of anilofos once daily for 28 days. Signs and symptoms were observed mainly with 200mg/kg. At this dose, anilofos induced hypothermia and progressive weight loss. None of the anilofos-treated rats died. Weight of brain, lung, testis was not altered, while of liver, heart, spleen and kidney increased. Anilofos inhibited cholinesterase (ChE) activities of erythrocyte (41-67%), plasma (36%), blood (37-64%), brain (63-73%) and liver (28-48%). Total protein was decreased in plasma and liver. Results indicate moderate toxic potential of anilofos in mammals, substantial contribution of CNS-mediated effects in causing anilofos toxicity and no direct relationship between hypothermia and level of ChE inhibition.

HIV infection among the high risk groups of Upper Assam.

Serum samples of 9350 individuals belonging to different high risk groups were tested for HIV Infection by ELISA and western blot technique. 9 samples were found to be positive. Two of them belonged to indigenous people of Assam and the infection was transfusion/transplant associated and acquired outside the state during the course of medical treatment. Two were IDUs from Nagaland requiring treatment in a local hospital at Dibrugarh, Assam. Five were from floating population temporarily residing in Assam with history of heterosexual promiscuity. Overall seropositivity rate was 0.97/1000. It is felt that HIV infection in Upper Assam has not penetrated deeply and is at a manageable level and the spread of infection can be prevented through IEC programmes.