The development of Byetta (exenatide) from the venom of the Gila monster as an anti-diabetic agent

The development of Byetta (synthetic exendin-4; exenatide) as a treatment of diabetes arose from two, parallel lines of investigation. The development of the ‘incretin concept’ which hypothesised that hormones from the gut contributed to the insulin secretion in response to meals, led to the identification of glucagon-like peptide 1 (GLP-1) as an important ‘incretin’ hormone. GLP-1 not only increases insulin secretion but increases β-cell proliferation and survival, suppresses glucagon secretion, delays gastric emptying and suppresses appetite, all of these actions contributing to a potential anti-diabetic effect. However, GLP-1 has a very short half due to its rapid breakdown by dipeptidyl peptidase IV and ectopeptidases. A systematic investigation of the composition and activity of venom from the Gila monster, Heloderma suspectum, led to the isolation of a 39-amino acid peptide, designated exendin-4, showing 53% structural homology with GLP-1(7-36). Exendin-4 mimicked GLP-1 through stimulating the GLP-1 receptor. The much greater stability of exendin-4 led to its experimental and clinical evaluation as an anti-diabetic agent and its introduction to the market in 2005.     

Effects of VIP and related peptides and Gila monster venom on genitourinary smooth muscle

The pharmacological effects of peptide histidine isoleucine (PHI), glucagon and secretin were compared with vasoactive intestinal polypeptide (VIP) on rabbit urethra and anococcygeus muscle. VIP and PHI dose-dependently inhibited induced contractions of both smooth muscle preparations. Cross-tachyphylaxis between VIP and PHI was demonstrated in the urethra preparation, suggesting that their activity is mediated via a common receptor or second messenger. Glucagon and secretin were without effect on either preparation. Radioimmunoassays demonstrated substantial concentrations of VIP and PHI in both urethra and anococcygeus tissue extracts. These observations suggest that PHI is an additional candidate together with VIP to mediate relaxation of rabbit urethra and anococcygeus muscle. When compared with VIP, Gila monster venom was found to inhibit both smooth muscle preparations, producing concentration-response curves parallel to those produced by VIP.     

Exenatide.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and dosage and administration of exenatide are discussed. SUMMARY: Exenatide, derived from a compound found in the saliva of the Gila monster, is an incretin mimetic agent that enhances glucose-dependent insulin secretion and has several other antihyperglycemic actions. The drug is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus who are taking metformin, a sulfonylurea, or both but who have not achieved adequate glycemic control. Peak plasma concentration following subcutaneous administration of exenatide is attained in 2.1 hours. The mean apparent volume of distribution after administration of a single subcutaneous dose is 28.3 L. The terminal half-life of the drug is 2.4 hours. Based on animal studies, the bioavailability of exenatide after subcutaneous injection has been estimated to be between 65% and 75%. The drug is predominantly eliminated by glomerular filtration followed by proteolytic degradation. Clinical trials have shown that exenatide given subcutaneously twice daily significantly reduced glycosylated hemoglobin values when maximum doses of a sulfonylurea, metformin, or both were ineffective. The most common adverse effects are nausea, vomiting, diarrhea, jitteriness, dizziness, headache, and dyspepsia. Drug-drug interactions with digoxin, lovastatin, lisinopril, and acetaminophen have been documented. The recommended starting dosage is 5 microg subcutaneously twice daily within one hour before the morning and evening meals. CONCLUSION: Exenatide offers a novel treatment option for patients with type 2 diabetes mellitus who are refractory to metformin or sulfonylurea therapy or both.     

Isolation and cloning of exendin precursor cDNAs from single samples of venom from the Mexican beaded lizard (Heloderma horridum) and the Gila monster (Heloderma suspectum).

Reptile venoms are complex cocktails of bioactive molecules, including peptides. While the drug discovery potential of most species remains unrealized, many are endangered and afforded protection under international treaties. In this study, we describe how potential clinically important bioactive peptides and their corresponding mRNAs can be structurally characterized from single, small samples of reptile venom. The potential type-2 diabetes therapeutics, exendin-3 and exendin-4, from the Mexican beaded lizard (Heloderma horridum) and the Gila monster (Heloderma suspectum), respectively, have been characterized at both protein and nucleic acid levels to illustrate the efficacy of the technique and its contribution to biodiversity conservation.     

Jurisprudent pharmacy as a new pharmacy--feedback from litigation to pharmacy

Risk management in the medical field is said to be entering into the third generation. By definition, the first generation covers the period until some 10 years ago when medical errors themselves used to be regarded as inconceivable and therefore as something of a taboo. The second generation is a period in which those concerned with medical treatment grappled squarely with this issue of medical errors and compiled manuals of "near miss" cases in an effort to prevent errors. After that, such an idea has come into existence that even the deepest carefulness threatens errors that could develop into the disputes among those involved. The thought of this kind has resulted in the deepening of understanding of the importance of risk management. As a result, the point of view on this issue has been getting broader to cover not only prevention of errors but also prevention of disputes. This type is called third-generation risk management. In this sense jurisprudent pharmacy or legal pharmacy, which is a kind of pharmacy that constitutes medical pharmacy, is aimed at feeding back the lessons learned from litigations to pharmacy to improve and develop it as a practical science and contributing to the realization of "patient-centered medical science."     

Privacy in the pharmacy environment: Analysis of observations from inside the pharmacy

ObjectiveTo measure the extent to which pharmacist–patient conversations are private.DesignCross sectional.SettingNew York State, April to June 2007.ParticipantsNo individual participants were enrolled; the study consisted of observations of the pharmacy environment and pharmacy patient–staff interactions.InterventionMeasurement of privacy-related distances in the pharmacy.Main outcome measuresDistance between patients at the pharmacy counter and staff behind the counter, distance between patient waiting area and pharmacy counter, and distance that a pharmacy counter conversation was audible.ResultsObservational data were recorded from 597 pharmacy staff–patient interactions in 282 pharmacies across New York State. Of the 597 interactions, 167 occurred while a second patient was within 6 ft. Of the 282 pharmacies, pharmacy staff–patient conversations were audible to observers more than 6 ft away in 229 pharmacies; 142 could be heard more than 15 ft away.ConclusionMost staff–patient conversations in the pharmacy setting are not private and, as a result, have a high potential for incidental protected health information disclosures.     

From community pharmacy to healthy living pharmacy: Positive early experiences from Portsmouth,England

BackgroundResearch has shown the potential for community pharmacies to promote better health and prevent disease by providing individual services in a limited range of settings. In the UK, the healthy living pharmacy (HLP) framework has been developed to allow pharmacies to provide a portfolio of such services tailored to local need. This paper reports an evaluation of the uptake and success of HLP introduction in Portsmouth, the original pathfinder site for a national program.ObjectivesTo assesses the impact on service provision and staff engagement at an early stage in HLP program development.MethodsQuantitative data, derived from pharmacy records, on service provision by HLPs (n = 17) and non-HLPs (n = 19) during April 2011–March 2012 was evaluated for trends and differences. Face-to-face interviews were conducted during November 2011 and February 2012, to gauge staff opinion on HLP development and sustainability, using interpretative phenomenological analysis.ResultsSignificantly more clients per pharmacy were seen in HLPs than non-HLPs for the following services: targeted respiratory medicine use reviews (medians: 29 vs 11; P = 0.0167); smoking cessation at initiation (62 vs 18; P < 0.001) and at 4-week (26 vs 10; P < 0.001) and 12-week (5 vs 1; P = 0.023) follow-ups. Medians for alcohol awareness and weight management were appreciably higher in HLP pharmacies, but the differences did not reach statistical significance. Medians for clients seeking emergency hormonal contraception were comparable. Interviews with 38 staff from 32 pharmacies revealed a positive impact on service development in HLPs, largely engineered through revision of skill mix and additional training of non-pharmacist staff to become healthy living champions. Obstacles to HLP development were managing the increased workload, raising awareness of clients and other healthcare professionals of the services available, and receiving remuneration for service provision.ConclusionsThese data point to a largely successful introduction of the HLP program in Portsmouth and the potential for improving client health. Staff interviews suggest that adoption and sustainability of the scheme depend on achieving the right skill mix, including the introduction of healthy living champions, motivation of the entire staff team and the provision of adequate funding for services offered.     

Exenatide. Amylin/Eli Lilly

Amylin Pharmaceuticals Inc and Eli Lilly & Co are co-developing exenatide (AC-2993; synthetic exendin-4), a 39-amino acid, glucagon-like peptide-1 agonist derived from the venom of the Gila monster lizard (Heloderma suspectum) as a potential injectable treatment for type 2 diabetes. The first phase III trial (exenatide as a monotherapy) was initiated in December 2001. In January 2002 the second phase III trial, of exenatide in conjunction with sulfonylureas, was initiated and in March 2002, Amylin initiated the third phase III trial, of exenatide in combination with metformin and sulfonylureas.