Browsing Pathways

Pyruvate Dehydrogenase (PDH) Deficiency is an X linked disease where individuals have a reduced number of functioning PDH complexes ultimately affecting the mitochondria’s energy metabolism. In a healthy individual, PDH complex catalyzes the conversion of pyruvate to acetyl coenzyme A, therefore PDH deficiency can cause the accumulation of excess pyruvate and lactic acid. PDH deficiency presents itself in a variety of ways, however since the brain obtains most of it’s energy from aerobic oxidation of glucose, all PDH deficient individuals have some degree of neurological impairment. Other symptoms range from fatal lactic acidosis in the newborns, chronic neurodegenerative conditions, brain lesions, cerebral atrophy and much more. Due to the fatal nature of the disease many with this condition do not live past childhood, however there are some that survive to adolescents and adulthood. Treatments have tried to minimize systemic lactic acid accumulation by feeding patients high fat/low carbohydrate diets. However, this does not reverse neurological structural damage already present and therefore does little to influence the end results.

Dihydromorphine (also known as Paramorfan or Paramorphan) is analgesic that can bind to mu-type opioid receptor to activate associated G-protein in the sensory neurons of central nervous system (CNS), which will reduce the level of intracellular cAMP by inhibiting adenylate cyclase. The binding of dihydromorphine acetate will eventually lead to reduced pain because of decreased nerve conduction and release of neurotransmitter. Hyperpolarization of neuron is caused by inactivation of calcium channels and activation of potassium channels via facilitated by G-protein.

The branched chain amino acid (BCAA) leucine is able to signal transduction pathways that modulate translation initiation for protein synthesis in skeleton muscles. In the presence of leucine, hyperphosphorylation of 4E-BP1 causes its affinity for eIF4E to be lowered. This allows eIF4F protein complexes to recognize, unfold and guide the mRNA to the 43S preinitiation complex thereby increasing translation initiation. In addition, leucine has a transient affect on the release of insulin and/or enhances sensitivity of muscle cells to insulin. A culmination of both signals at the mammalian target of rapamycin (mTOR) and perhaps other signaling, such as PKCδ, are needed for maximum translation initiation to occur.

Buprenorphine, trade name subutex, suboxone, zubsolv and bunavail, is a partial agonist of mu-opioid receptors and a kappa-opioid receptor antagonist and is prescribed for opioid addiction to prevent cravings and symptoms of withdrawal. The binding of these receptors causes hyperpolarization and decreased neuronal excitability. Buprenorphine has a longer duration of action due to its slow dissociation from the receptor. This long rate of action causes a long clinical effect and decreases physical dependence. Buprenorphine can also prevent opioid use by inhibiting exogenous opioid effects. This elimination of the rush from the opioid can block the reinforcing behaviour of the drug and may treat opioid addiction. Buprenorphine is available on its own or in combination with naloxone.

Levomethadyl acetate (also known as LAAM) is a synthetic synthetic opioid analgesic with multiple actions quantitatively similar to those as morphine, the most prominent of which involve the central nervous system and organs composed of smooth muscle. However, levomethadyl acetate is more active and more toxic than morphine. Levomethadyl acetate can bind to mu-type opioid receptor to activate associated G-protein in the sensory neurons of central nervous system (CNS), which will reduce the level of intracellular cAMP by inhibiting adenylate cyclase. The binding of levomethadyl acetate will eventually lead to reduced pain because of decreased nerve conduction and release of neurotransmitter. Therefore, methadyl acetate can reduce nerve conduction and decrease neurotransmitter release; so that perception of pain signals can be blocked. Levomethadyl acetate can also open calcium-dependent inwardly rectifying potassium channels (OP1 receptor agonist) to reduce neuronal excitability as well as lead to hyperpolarization.

Lincomycin is a lincosamid antibiotic that can effectively aganist aerobic gram-positive cocci, aerobic gram-positive bacilli as well as anaerobic gram-positive sporeforming bacilli in vitro. Lincomycin is derived from yeast Streptomyces lincolnensis. Lincomycin can bind and inhibit 50S subunits of bacterial ribosomes to prevent protein synthesis, which result in cell death.

The discovery of AIDS prompted the search for agents that block the HIV replication process. Zidovudine (AZT) is a nucleoside analogue of thymidine, and was shown to reduce considerably the mortality of patients with AIDS. Zidovudine is toxic to the hemtopoietic system, causing anemia and neutropenia. It is clear, however, that disease progression can occur during continued administration of zidovudine. Moreover, zidovudine is not effective in treating Kaposi sarcoma, a common complication of HIV infection. Zidovudine therapy is also associated with a high incidence of toxicity, primarily bone marrow suppression, that requires dosage reduction or discontinuation of the therapy.

Efavirenz (also known as Sustiva) is a nucleoside reverse transcriptase inhibitor (NRTI) for treating HIV infection by inhibiting the transcriptase reversibly. Efavirenz is phosphorylated to its active triphosphorylated form so that it can compete with deoxycytidine 5'-triphosphate to inhibit HIV-1 reverse transcriptase, which lead to early chain termination.

Quinapril (trade name: Accupril) belongs to the class of drugs known as angiotensin-converting enzyme (ACE) inhibitors and is used primarily to lower high blood pressure (hypertension). This drug can also be used in the treatment of congestive heart failure and type II diabetes. Quinapril is a prodrug which, following oral administration, undergoes biotransformation in vivo into its active form quinaprilat via cleavage of its ester group by the liver. Angiotensin-converting enzyme (ACE) is a component of the body's renin–angiotensin–aldosterone system (RAAS) and cleaves inactive angiotensin I into the active vasoconstrictor angiotensin II. ACE (or kininase II) also degrades the potent vasodilator bradykinin. Consequently, ACE inhibitors decrease angiotensin II concentrations and increase bradykinin concentrations resulting in blood vessel dilation and thereby lowering blood pressure.

Quinapril (trade name: Accupril) belongs to the class of drugs known as angiotensin-converting enzyme (ACE) inhibitors and is used primarily to lower high blood pressure (hypertension). This drug can also be used in the treatment of congestive heart failure and type II diabetes. Quinapril is a prodrug which, following oral administration, undergoes biotransformation in vivo into its active form quinaprilat via cleavage of its ester group by the liver. Angiotensin-converting enzyme (ACE) is a component of the body's renin–angiotensin–aldosterone system (RAAS) and cleaves inactive angiotensin I into the active vasoconstrictor angiotensin II. ACE (or kininase II) also degrades the potent vasodilator bradykinin. Consequently, ACE inhibitors decrease angiotensin II concentrations and increase bradykinin concentrations resulting in blood vessel dilation and thereby lowering blood pressure.