AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Venomous drugs from spiders

 Uncategorized  Comments Off on Venomous drugs from spiders
Jul 192013
 

 

Spiders are nature’s pest controllers. These eight-legged, web-forming arachnid predators are equipped with two venom glands full of valuable chemicals designed to kill insect prey. Such compounds, from small organic molecules to complex structures such as acylpolyamines, neuropeptides and enzymes, are precious ligands that target several biological receptors. Since insect receptors are not substantially different from those of humans and other mammals, the majority of the molecules contained in spider venom could also target human receptors.

 

Spider

The potential medical uses of spider venoms are largely due to their selectivity and affinity for ion channels.

The potential medical uses of spider venoms are largely due to their selectivity and affinity for ion channels [proteins that allow ions to cross cell membranes] and other receptors. This makes them suitable for studying cell function and for designing therapeutic drugs. As an example, the venom of the theraphosid Grammostola spatulata from South America contains a peptide, GsMtx-4, that blocks stretch-activated ion channels. These channels are sensitive to muscle contraction and blood pressure and play an important role in coordinating a heartbeat. Potentially, GsMtx-4 could be used to prevent atrial fibrillation after a heart attack and to treat cardiac patients.

 

LIPID BOUND Like related peptide toxins, GsMTx4 has a highly hydrophobic face (green). The cysteines that make up the protein’s core are colored yellow, and positive and negative residues are shown in blue and red, respectively.
NATURE ©2004

“Peptides make up a substantial part of spider venom and modulate ionic currents across calcium, sodium or potassium ion channels.”

Peptides make up a substantial part of spider venom, and modulate ionic currents across Ca2+, Na+, or K+ ion channels. Some spider peptides can discriminate between ion channel subtypes and several will inhibit peripheral neurons, the nerve cells that are associated with supplying sensation to the skin and skeletal muscles. Spider toxins that block the neuronal Ca2+ ion channel could prove important for the treatment of chronic pain.

A special group of the spider peptides have a mixed hydrophilic-hydrophobic nature – they are amphipathic. These form alpha-helical structures that insert into cell membranes to form pores, resulting in loss of cell function. Although most of these peptides will destroy red blood cells, they could potentially be used in topical applications, such as antibacterial coatings for medical implants, in inhibiting the growth of oral bacteria associated with tooth decay and early plaque formation and in treating skin infections.

Venom peptides contain a common basic structure called a ‘cysteine knot,’ a tangle of protein chains and disulfide bridges that gives them an excellent molecular stability. Also, the small organic components of spider venom, such as organic acids, amines, nucleic acids and amino acids, are thought to stabilise the mixture and enhance the delivery and effectiveness of the peptides.

 

“The acylpolyamines represent the vast majority of the molecules in the mixture. These have been shown to suppress epileptic activity in brain tissue.”

Of all the venom components, the acylpolyamines represent the vast majority of the molecules in the mixture. These have been shown to suppress epileptic activity in brain tissue. They can also act as pain-killers, by blocking capsaicin receptor channels, non-selective cation channels in sensory neurons that respond to pain-causing stimuli. Moreover, brain damage caused by restricted blood flow, for example during a stroke, can be prevented with acylpolyamines. The compounds work by blocking Ca2+ voltage-gated ion channels or preventing glutamate release, both of which are implicated in neuronal death.

Finally, enzymes and large protein components of spider venoms are of special medical importance. For example, the neurotoxic protein alpha-latrotoxin, from the black widow spider, causes massive neurotransmitter release. Similarly, an active enzyme in the venom of the brown recluse spider is sphingomyelinase D, which degrades cell membranes and causes painful lesions to develop. Another component of brown recluse spider venom, hyaluronidase, belongs to a family of compounds that have shown medical potential as tumour treatments.

 

“Most spider species are harmless to humans, so peptides or drug molecules from these spiders are likely to be safe.”

Most spider species are harmless to humans, so peptides or drug molecules from these spiders are likely to be safe. By modifying the molecular surfaces and active sites of peptides and enzymes from spiders, whilst keeping the spider scaffold, it is possible to gain specificity and/or affinity for a given receptor. Therefore, acylpolyamines, peptides and enzymes from spider venoms represent an interesting source of molecules for the design of novel pharmaceutical drugs.

References

Spider venoms: a rich source of acylpolyamines and peptides as new leads for CNS drugs

G Estrada, E Villegas and G Corzo, Nat. Prod. Rep., 2007,

DOI10.1039/b603083c

Applications of Spider Venom

Interest in potential agricultural and medical uses of spider venom is largely due to its selectivity in species and site of action.  Current research centres around exploring the development of pesticides and drugs for treating cardiac patients.

Pesticides

Cotton crop

Components in the neurotoxic venom of an Australian funnel-web spider have been found to be specific for insects such as cockroaches, crickets, fruit-flies and the Helicoverpa armigera moth which destroys cotton crops.  Targeting specific species prevents the accidental killing of other insects.  This selectivity also means that the pesticide is harmless to other organisms so there would be no danger if it entered the food chain.  The compounds in venom are environmentally friendly and the development of resistance to a spider venom pesticide would be slow.  Traditional chemical pesticides do not tend to be species specific, are toxic to humans in large amounts and insects develop resistance towards them relatively fast so it is easy to see why pesticides based on spider venom are attractive.

Prevention of Atrial Fibrillation

Heart

The venom of the Chile Rose tarantula (Grammostola spatulata) from South America contains an active protein, GsMtx-4, which blocks ion channels that are stretch activated.  These channels are therefore sensitive to muscle contraction and blood pressure and play an important role in co-ordinating a heartbeat.  A heart attack causes these ion channels to open and release chemicals which interfere with the heart rhythm leading to atrial fibrillation.  Fibrillation is when the upper heart chambers (the atria) contract rapidly and prevent sufficient blood from entering the lower chambers (the venticles).  It is fibrillation which often causes the death of a heart attack victim, not the attack itself so GsMtx-4 could be utilised in a potentially life-saving drug which prevents fibrillation.  GsMtx-4 is ineffective on the normal unstretched heart so side effects should be small or even non-existent.  The venom from the Chile Rose spider is also harmless to humans which constitutes an extra safety precaution.

Prevention of Brain Damage

Brain

Oxygen deprivation caused by events such as stroke or excessive smoke inhalation can result in nerve cell damage in the brain.  Glutamate is a neurotransmitter in the human brain and large amounts of it are released by these damaged neurons causing the death of neighbouring nerve cells.  The Holena curta funnel-web spider produces a venom containing the active ingredient HF-7 which blocks receptors on the nerve cell membranes and prevents glutamate production.  A drug developed using this compound could therefore limit brain damage for stroke victims.

 

 

Share

Sugammadex sodium-agent for reversal ofneuromuscular blockade by the agent rocuronium in general anaesthesia

 Uncategorized  Comments Off on Sugammadex sodium-agent for reversal ofneuromuscular blockade by the agent rocuronium in general anaesthesia
Jul 192013
 

File:Sugammadex sodium.svg

Sugammadex sodium

Sugammadex (designation Org 25969, tradename Bridion) is an agent for reversal ofneuromuscular blockade by the agent rocuronium in general anaesthesia. It is the firstselective relaxant binding agent (SRBA) and was discovered at the Newhouse research site in Scotland. These scientists who discovered Sugammadex worked for the pharmaceutical company, Organon. Organon was acquired by Schering-Plough in 2007; Schering-Plough merged with Merck in 2009. Sugammadex is now owned and sold by Merck.

On January 3, 2008, Schering-Plough submitted a New Drug Application to the US Food and Drug Administration for sugammadex, but the FDA rejected the application on August 2008. It was approved for use in the European Union on July 29, 2008.

Sugammadex incapsulating a molecule of rocuronium

Sugammadex is a modified γ-cyclodextrin, with a lipophilic core and a hydrophilic periphery. This gamma cyclodextrin has been modified from its natural state by placing eight carboxyl thio ether groups at the sixth carbon positions. These extensions extend the cavity size allowing greater encapsulation of the rocuronium molecule. These negatively charged extensions electrostatically bind to the quaternary nitrogen of the target as well as contribute to the aqueous nature of the cyclodextrin. Sugammadex’s binding encapsulation of rocuronium is one of the strongest among cyclodextrins and their guest molecules. The rocuronium molecule (a modified steroid) bound within sugammadex’s lipophilic core, is rendered unavailable to bind to the acetylcholine receptor at theneuromuscular junction.

Schematic diagram of sugammadex encapsulating a rocuronium molecule
Sugammadex sodium 3D three quarters view.png
Left: Schematic of a sugammadex molecule encapsulating a rocuronium molecule.
Right: Space-filling model of a sugammadex sodium molecule in the same orientationSugammadex also has some affinity for other aminosteroid neuromuscular blocking agents such as vecuronium and pancuronium. Though sugammadex’s affinity for vecuronium is lower than its affinity for rocuronium, reversal of vecuronium is still effective because fewer vecuronium molecules are present in vivo for equivalent blockade. Vecuronium is approximately seven times more potent than rocuronium and overall requires fewer molecules to induce blockade. Sugammadex encapsulates with a 1:1 ratio and therefore will adequately reverse vecuronium as there are fewer molecules to bind compared to rocuronium. Shallow Pancuronium blockade has been successfully reversed by sugammadex in phase III clinical trials.
A study was carried out in Europe looking at its suitability in rapid sequence induction. It found that sugammadex provides a rapid and dose-dependent reversal of neuromuscular blockade induced by high-dose rocuronium.

A Cochrane systematic review on sugammadex has been recently published by Abrishami et al. This review article included 18 randomized controlled trials on the efficacy and safety of sugammadex. The trials included a total of 1321 patients. The review concluded that “sugammadex was shown to be more effective than placebo (no medication) or neostigmine in reversing muscle relaxation caused by neuromuscular blockade during surgery and is relatively safe. Serious complications occurred in less than 1% of the patients who received sugammadex. The results of this review article (especially the safety results) need to be confirmed by future trials on larger patient populations”.

Share

Curis has obtained the conditional approval for Erivedge (vismodegib) in EU

 Uncategorized  Comments Off on Curis has obtained the conditional approval for Erivedge (vismodegib) in EU
Jul 192013
 

VISMODEGIB

Oncology-focused drug development company Curis has obtained the conditional approval for Erivedge (vismodegib) to treat adult patients with symptomatic metastatic basal cell carcinoma (BCC) or locally advanced BCC inappropriate for surgery or radiotherapy in the European Union (EU)

http://regulatoryaffairs.pharmaceutical-business-review.com/news/curis-obtains-conditional-approval-of-erivedge-in-eu-170713

Vismodegib (trade name Erivedge) is a drug for the treatment of basal-cell carcinoma(BCC). The approval of vismodegib on January 30, 2012, represents the first Hedgehog signaling pathway targeting agent to gain U.S. Food and Drug Administration (FDA) approval. The drug is also undergoing clinical trials for metastatic colorectal cancer,small-cell lung cancer, advanced stomach cancerpancreatic cancermedulloblastomaand chondrosarcoma as of June 2011. The drug was developed by the biotechnology /pharmaceutical company Genentech, which is headquartered at South San Francisco, CaliforniaUSA.

Share
Follow

Get every new post on this blog delivered to your Inbox.

Join other followers: