Efficacy of 17α-ethynylestradiol-3-sulfate for severe hemorrhage in minipigs in the absence of fluid resuscitation.

BACKGROUND: Of the potentially survivable US battlefield deaths from 2001 to 2011, 80% to 91% were caused by severe hemorrhage. We subjected minipigs to acute severe blood loss, administered a single dose of 17α-ethynylestradiol-3-sulfate (EE-3-SO4) without resuscitative fluids, and determined survival as well as cardiovascular, biochemical, and physiologic response parameters. METHODS: Following controlled removal of 60% circulating blood volume over 1 hour, minipigs received EE-3-SO4 at 0, 1, 3, or 5-mg/mL saline per kilogram of body weight in Experiment 1 (n = 25) and 0-, 0.1-, 0.3-, or 1-mg/mL saline per kilogram in Experiment 2 (n = 23). Survival times and response parameters were recorded for the next 6 hours. RESULTS: Median survival times of the minipigs receiving 1 mg/kg (257 minutes and 360 minutes) were 1.8 times and 5 times those of the control group (140 minutes and 65 minutes) in Experiments 1 and 2, respectively. For both experiments combined, the log-rank p value was 0.0002, and the number of animals alive at 6 hours was 6 (50%) of 12 in the 1-mg/kg groups versus 0 (0%) of 12 in the control groups. Early increases in glucose, lactate, potassium, and phosphate as well as decreases in bicarbonate and mean arterial pressure correlated with shorter survival times. CONCLUSION: Administration of a single dose of 1-mg/kg EE-3-SO4 in 1-mL/kg of saline following severe hemorrhage increased survival in 60% acutely bled minipigs by 3.5-fold. Slightly elevated blood pressure values, more physiologic values of oxidative phosphorylation parameters, and lower elevations of possible tissue necrosis parameters correlated with longer survival time. These results support the further product development of EE-3-SO4 for the indication of severe hemorrhage when standard resuscitative fluids are not available.

Challenges in the development of prescription opioid abuse-deterrent formulations.

Opioid analgesics remain the cornerstone of effective management for moderate-to-severe pain. In the face of persistent lack of access to opioids by patients with legitimate pain problems, the rate of prescription opioid abuse in the United States has escalated over the past 15 years. Abuse-deterrent opioid products can play a central role in optimizing the risk-benefit ratio of opioid analgesics--if these products can be developed cost-effectively without compromising efficacy or creating new safety issues for the target treatment population. The development of scientific methods for assessing prescription opioid abuse potential remains a critical and challenging step in determining whether a claim of abuse deterrence for a new opioid product is indeed valid and will thus be accepted by the medical, regulatory, and reimbursement communities. To explore this and other potential impediments to the development of prescription opioid abuse-deterrent formulations, a panel of experts on opioid abuse and diversion from academia, industry, and governmental agencies participated in a Tufts Health Care Institute-supported symposium held on October 27 and 28, 2005, in Boston, MA. This manuscript captures the main consensus opinions of those experts, and also information gleaned from a review of the relevant published literature, to identify major impediments to the development of opioid abuse-deterrent formulations and offer strategies that may accelerate their commercialization.

Impact of formulation on the abuse liability, safety and regulation of medications: the expert panel report.

A scientific meeting was held in April 2005 to consider how the formulation of medications might impact on their potential for abuse. The background papers prepared for this meeting, as well as abstracts of volunteered presentations, are published in this supplemental issue of Drug and Alcohol Dependence. This paper is the Expert Panel Report summarizing the discussions held following the formal presentations and including the suggested recommendations for additional research that emerged from these discussions. There was overwhelming consensus that formulation does play a role in prescription drug abuse, i.e., a formulation of an abused substance can be developed that will decrease its abuse potential, and several examples were cited. Nevertheless, it is imperative that new formulations have similar efficacy and in no way compromise medication access to doctors and patients. However, there was also consensus that a great deal of research and discussion was needed to fully implement a program of risk management through reformulation of existing products or tailoring the formulation of new products to retain clinical efficacy and safety while minimizing potential for abuse. Those who need to take part in this discussion include scientific groups, pharmaceutical companies, as well as governmental and regulatory agencies. The areas where more research is needed include development of standards for assessing tamper-resistance, improved animal models that can address formulation-related variables (e.g., onset, duration), the redesign of human laboratory studies providing appropriate models for comparing formulations, and improved post-marketing surveillance. Finally, knowledge and experience are needed to translate scientific work into a predictable, transparent and reliable regulatory process.

Involving the pharmaceutical and biotech communities in medication development for substance abuse.

Pharmacotherapy as adjunctive treatment is an integral part of the strategy for treating substance abuse. Although there are several approved drugs for the treatment of opioid, alcohol, and nicotine dependence, the pharmaceutical industry, for a variety of reasons, has been reluctant to enter this area to develop medications for substance abuse indications. Therefore, in 1990, a Medication Development Program was established by NIDA to carry out and assist in stimulating development of new pharmacotherapies. It is vital for NIDA to provide clear leadership and establish a collaborative working relationship with the pharmaceutical industry, providing scientific, development, and financial assistance, depending on the size, resources, and expertise of the company. An important NIDA role in this effort is setting standards, such as establishing Target Product Profiles (TPPs), predictive decision trees for selection of clinical candidates, and animal models to evaluate safety and potential effectiveness prior to human studies. NIDA can further establish standards for clinical studies, including Proof of Concept (PoC), Phase 2 (or Learning) trials to establish initial proof of safety and effectiveness, and Phase 3 (or Confirming) trials to validate Phase 2 findings. NIDA and other government agencies need to work to improve industry incentives to participate in medication development for substance abuse. Specific incentives, such as market exclusivity and patent extension, as provided in BioShield and pediatric drug legislation, should be strongly considered. NIDA can further assist industry to navigate the regulatory and, if needed, controlled substance scheduling processes, by establishing a true Federal partnership between NIDA, FDA, and DEA.

Postmarketing drug dosage changes of 499 FDA-approved new molecular entities, 1980-1999.

PURPOSE: Risks and benefits of marketed drugs can be improved by changing their labels to optimize dosage regimens for indicated populations. Such postmarketing label changes may reflect the quality of pre-marketing development, regulatory review, and postmarketing surveillance. We documented dosage changes of FDA-approved new molecular entities (NMEs), and investigated trends over time and across therapeutic groups, on the premise that improved drug development methods have yielded fewer postmarketing label changes over time. METHODS: We compiled a list of NMEs approved by FDA from 1 January 1980 to 31 December 1999 using FDA's website, Freedom of Information Act request, and PhRMA (Pharmaceutical Research and Manufacturers of America) database. Original labeled dosages and indicated patient populations were tracked in labels in the Physician's Desk Reference. Time and covariate-adjusted risks for dosage changes by 5-year epoch and therapeutic groups were estimated by survival analysis. RESULTS: Of 499 NMEs, 354 (71%) were evaluable. Dosage changes in indicated populations occurred in 73 NMEs (21%). A total of 58 (79%) were safety-motivated, net dosage decreases. Percentage of NMEs with changes by therapeutic group ranged from 27.3% for neuropharmacologic drugs to 13.6% for miscellaneous drugs. Median time to change following approval fell from 6.5 years (1980-1984) to 2.0 years (1995-1999). Contrary to our premise, 1995-1999 NMEs were 3.15 times more likely to change in comparison to 1980-1984 NMEs (p = 0.008, Cox analysis). CONCLUSIONS: Dosages of one in five NMEs changed, four in five changes were safety reductions. Increasing frequency of changes, independent of therapeutic group, may reflect intensified postmarketing surveillance and underscores the need to improve pre-marketing optimization of dosage and indicated population.