- Prediction of Drug-Drug Interactions Between Opioids and Overdosed Benzodiazepines Using Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation. [Journal Article]Drugs R D 2019; 19(3):297-305DR
- CONCLUSIONS: Our results appear to indicate that pharmacodynamics may play a more important role than PKs in causing DDIs between opioids and benzodiazepines. This study also demonstrated that molecular modeling can be a very useful tool to mitigate the problem of "missing metabolic reaction parameters" in PK modeling and simulation.
- CYP3A4 Induction in the Liver and Intestine of Pregnane X Receptor/CYP3A-Humanized Mice: Approaches by Mass Spectrometry Imaging and Portal Blood Analysis. [Journal Article]Mol Pharmacol 2019; 96(5):600-608MP
- Induction of cytochrome P450 enzyme 3A (CYP3A) in response to pregnane X receptor (PXR) activators shows species-specific differences. To study the induction of human CYP3A in response to human PXR activators, we generated a double-humanized mouse model of PXR and CYP3A. CYP3A-humanized mice generated by using a mouse artificial chromosome (MAC) vector containing the entire genomic human CYP3A lo…
Induction of cytochrome P450 enzyme 3A (CYP3A) in response to pregnane X receptor (PXR) activators shows species-specific differences. To study the induction of human CYP3A in response to human PXR activators, we generated a double-humanized mouse model of PXR and CYP3A. CYP3A-humanized mice generated by using a mouse artificial chromosome (MAC) vector containing the entire genomic human CYP3A locus (hCYP3A-MAC mouse line) were bred with PXR-humanized mice in which the ligand-binding domain of mouse PXR was replaced with that of human PXR, resulting in double-humanized mice (hCYP3A-MAC/hPXR mouse line). Oral administration of the human PXR activator rifampicin increased hepatic expression of CYP3A4 mRNA and triazolam (TRZ) 1'- and 4-hydroxylation activities, CYP3A probe activities, in the liver and intestine microsomes of hCYP3A-MAC/hPXR mice. The plasma concentration of TRZ after oral dosing was significantly decreased by rifampicin treatment in hCYP3A-MAC/hPXR mice but not in hCYP3A-MAC mice. In addition, mass spectrometry imaging analysis showed that rifampicin treatment increased the formation of hydroxy TRZ in the intestine of hCYP3A-MAC/hPXR mice after oral dosing of TRZ. The plasma concentration of 1'- and 4-hydroxy TRZ in portal blood was also increased by rifampicin treatment in hCYP3A-MAC/hPXR mice. These results suggest that the hCYP3A-MAC/hPXR mouse line may be a useful model to predict human PXR-dependent induction of metabolism of CYP3A4 substrates in the liver and intestine. SIGNIFICANCE STATEMENT: We generated a double-humanized mouse line for CYP3A and PXR. Briefly, CYP3A-humanized mice generated by using a mouse artificial chromosome vector containing the entire genomic human CYP3A locus were bred with PXR-humanized mice in which the ligand-binding domain of mouse PXR was replaced with that of human PXR. Expression of CYP3A4 and metabolism of triazolam, a typical CYP3A substrate, in the liver of CYP3A/PXR-humanized mice were enhanced in response to rifampicin, a typical human PXR activator. Enhancement of triazolam metabolism in the intestine of CYP3A/PXR-humanized mice was firstly shown by combination of mass spectrometry imaging of sliced intestine and liquid chromatography with tandem mass spectrometry analysis of metabolite concentration in portal blood after oral dosing of triazolam.
- Human anxiety-specific "theta" occurs with selective stopping and localizes to right inferior frontal gyrus. [Journal Article]Behav Neurosci 2019BN
- Anxiety disorders have high prevalence and generate major disability. But they have poor treatment targeting because psychiatry lacks diagnostic biomarkers. Right frontal goal-conflict-specific-rhythmicity (GCSR) in the simple stop signal task appears homologous to hippocampal "theta" as an anxiety-process biomarker but is weak and transient. An anticipatory response inhibition task (ARIT) elicit…
Anxiety disorders have high prevalence and generate major disability. But they have poor treatment targeting because psychiatry lacks diagnostic biomarkers. Right frontal goal-conflict-specific-rhythmicity (GCSR) in the simple stop signal task appears homologous to hippocampal "theta" as an anxiety-process biomarker but is weak and transient. An anticipatory response inhibition task (ARIT) elicits strong subjective conflict and so might generate stronger GCSR. Healthy participants provided EEG during an ARIT, which allowed direct comparison of selective (left, SG; right, GS), and nonselective (both, SS) handed stopping. We assessed GCSR as intermediate versus the average of short and long delay stop-specific power. SG produced right frontal 5-12 Hz GCSR that, as in the SST: significantly correlated with trait anxiety and neuroticism; and was sensitive to pregabalin (75 mg), buspirone (10 mg), and perhaps triazolam (0.25 mg). GS and SS produced faster stopping and only 9-10Hz GCSR, which did not correlate significantly with trait anxiety or neuroticism and was sensitive to pregabalin and buspirone but not triazolam. Source localization suggested that GCSR, like stopping, involves multiple right frontal circuits that depend on response speed. Anxiolytic-sensitive GCSR generalizes from the speeded stop signal task to fixed-time anticipatory response inhibition tasks. GCSR, and the circuits engaged, vary with stop signal RTs conditions. Tasks with longer stop times may be optimal to generate GCSR homologous with rodent hippocampal theta as (a) the first direct anchor of a specific neural form of trait anxiety; (b) a single-dose screen in normal humans for novel anxiolytics; and (c) a potential clinical anxiety biomarker. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
- Patient Satisfaction with Oral versus Intravenous Sedation for Cataract Surgery: A Randomized Clinical Trial. [Journal Article]Ophthalmology 2019; 126(9):1212-1218O
- CONCLUSIONS: The use of oral sedation in cataract surgery has been suggested as a cost- and space-saving measure, potentially allowing the transition of some patients from an operating to procedure room or office-based setting. We report the noninferiority of oral compared with intravenous sedation for cataract surgery in a diverse patient population in terms of patient satisfaction.
- GABAA Receptor Subtypes and the Abuse-Related Effects of Ethanol in Rhesus Monkeys: Experiments with Selective Positive Allosteric Modulators. [Journal Article]Alcohol Clin Exp Res 2019; 43(5):791-802AC
- CONCLUSIONS: Our results confirm prior findings regarding the respective roles of α1GABAA and α5GABAA receptors in the discriminative stimulus effects of EtOH and, further, suggest a key facilitatory role for α3GABAA and potentially α2GABAA receptors in several abuse-related effects of EtOH in monkeys. Moreover, they reveal a potential role for these latter subtypes in EtOH's sedative effects.
- StatPearls: Prescription of Controlled Substances: Benefits and Risks [BOOK]StatPearls Publishing: Treasure Island (FL)BOOK
- One of the single most difficult challenges for any prescriber is to distinguish between the legitimate prescription of controlled substances versus the prescription potentially used for illegitimate purposes. To discern the difference prescribers need to understand the signs, symptoms, and treatment of acute and chronic pain as well as the signs and symptoms of patients using controlled substanc…
One of the single most difficult challenges for any prescriber is to distinguish between the legitimate prescription of controlled substances versus the prescription potentially used for illegitimate purposes. To discern the difference prescribers need to understand the signs, symptoms, and treatment of acute and chronic pain as well as the signs and symptoms of patients using controlled substances for non-legitimate purposes. A common reason people seek the care of medical professionals is pain relief. While many categories of pain medications are available, opioid analgesics are FDA-approved for moderate to severe pain. As such, they are a common choice for patients with acute, cancer-related, neurologic, and end-of-life pain. The prescribing of opioid analgesics for chronic pain is controversial and fraught with inconclusive standards. In the 1990s, due to the chronic failure of health professionals to undertreat severe pain, opioid analgesic prescribing was expanded. Unfortunately, this led to increased overuse, diversion of drugs, opioid use disorder, and overdose. The "Catch-22" seems to be either health professionals undertreat, and there is needless suffering, or they overtreat, with a potential to cause adverse effects like increased opioid analgesic use disorder and potential overdose. The prescription of opioid analgesics peaked in 2011, since then both prescribing and overdose has been declining; yet as a society, in both the lay and scientific literature, there are grave concerns that we are still in the middle of an opioid crisis. Perhaps the biggest challenge of caring for patients with pain is that individuals have different levels of tolerance and require variable opioid doses to obtain adequate pain relief. Patients may have a range of behavioral, cultural, emotional, and psychologic responses to pain versus a substance use disorder; often it is challenging to tell the difference. All health professionals engaged in pain management need an understanding of the treatment recommendations and safety concerns in prescribing opioid analgesics. Appropriate opioid prescribing requires a thorough patient assessment, short and long-term treatment planning, close follow-up, and continued monitoring. All providers need to be aware of not only appropriate patient assessment and treatment planning but also the possibility of use disorder, diversion, and potentially dangerous behavioral responses to controlled substances, e.g., opioid analgesics differ from pseudo-addiction and physical dependence. It is unfortunately clear that many clinicians know little about opioid use disorder; they do not understand it is a disease, and many believe opioid dependence is the same as opioid use disorder. Lack of a clear understanding results in clinicians confusing a chronic non-use disorder pain patient from the one who is misusing their prescribed opioid. Lack of training and educational deficits often interferes with the appropriate prescription of opioid analgesic agents. To prevent misuse of controlled substances, providers that prescribe controlled substances should learn prescribing practices that minimize or prevent adverse consequences. Definitions Addiction - according to the American Society of Addiction Medicine (ASAM) - "Addiction is a primary, chronic disease of brain reward, motivation, memory, and related circuitry. Dysfunction in these circuits leads to characteristic biologic, psychologic, social, and spiritual manifestations. This is reflected in an individual pathologically pursuing reward or relief by substance use and other behaviors." Addiction is now termed "use disorder," and is characterized by an inability to consistently abstain, craving, impairment in behavioral control, diminished ability to recognize significant problems with one's behaviors and interpersonal relationships, and a dysfunctional emotional response. Like other chronic diseases, use disorder often involves cycles of relapse and remission. Without treatment or engagement in recovery activities, use disorder is progressive and can result in disability or premature death." Appropriate opioid prescribing - providing pain control while minimizing use disorder or risk of same, and toxicity; and implementing safeguards to reduce drug diversion. Inappropriate opioid analgesic prescribing - non-, inadequate, excessive, or continued prescribing despite evidence of the lack of effective opioid treatment. Controlled substances - drugs or medications that possess the potential for being misused and are considered to be substances that have a substantially high risk of resulting in substance use disorder. Narcotics - comes from the Greek word for stupor and originally referred to drugs that dulled the senses and relieved pain, e.g., morphine. Also, narcotics were any drug that induced sleep. A more precise term for this class of drugs, with less uncertainty regarding its meaning, is opioid analgesics. Please note that the Drug Enforcement Administration (DEA, USA) uses the term narcotic to refer to drugs that are opioid analgesics. Five Characteristics of Addiction/Use Disorder (ASAM): 1. Craving for drug or reward. 2. Diminished recognition of significant problems in one's behavior. 3. Dysfunctional emotional response. 4. Impairment in behavioral control. 5. Inability to consistently abstain Drug Schedules of Controlled Substances All providers should be familiar with the guidelines and laws for each schedule which have as their basis the purpose of the drug and the risk of use disorder. In the United States, controlled substances are under strict regulation by both federal and state laws which guide their manufacture and distribution. Controlled substances have a high risk of resulting in an addiction and substance use disorder. As the schedules decrease, I-V, the drugs listed within each category have a lower potential to cause a substance use or addiction disorder. Controlled Substance Act In the United States, the Comprehensive Drug Abuse Prevention and Control Act was passed in 1970, and it included the Controlled Substance Act. The Controlled Substance Act covers drug: Classification and regulation, according to their content and purpose. Manufacturing. Distribution. Exportation and sale. The Controlled Substance Act established five drug schedules and classified them to control their manufacture and distribution. Part of regulation requires providers that prescribe scheduled drugs and pharmacists that fill them to obtain a license from the Drug Enforcement Administration. Health professionals licenses include specific license numbers allowing controlled substance prescriptions to be tracked and linked to a particular provider or distributor. Of the five schedules, each has parameters based on their medical value, the risk of addiction, and ability to cause harm. The schedules range from schedule I (most potential for addiction and use disorder) to schedule V (least potential for addiction/use disorder). Schedule I: Schedule I drugs possess the highest potential for use disorder and misuse. They have no medical use and are illicit or “street” drugs. Examples of Schedule I drugs include heroin, lysergic acid diethylamide, mescaline, methylenedioxymethamphetamine (MDMA), and methaqualone. Marijuana, which is legal in some states, is still classified as a Schedule I drug at the federal level as of this writing. Schedule II : Schedule II drugs have a reduced potential for use disorders than I. They are high risk for both physical and psychological dependence. They have a high capacity for both use disorder and misuse. They are typically prescribed to treat severe pain, anxiety, insomnia, and ADHD. Examples of Schedule II substances include fentanyl, hydromorphone, meperidine, methadone, morphine, oxycodone, fentanyl, dextroamphetamine, methylphenidate, methamphetamine, pentobarbital, and secobarbital. They previously had to be prescribed only via paper prescription, but now are permitted to be electronically transmitted. (Electronic Prescribing of Controlled Substances or EPCS). No refills are allowed. Schedule II drugs have the tightest regulations when compared to other prescription drugs. Schedule III : Schedule III drugs are those with a lower misuse potential than I and II. Drugs in this category may cause physical dependence but more commonly lead to psychological dependence. Medications in this category are often used for pain control, or anesthesia or appetite suppression. Examples of Schedule III substances include benzphetamine, ketamine, phendimetrazine, and anabolic steroids. Opioid analgesics in this schedule include products containing not more than 90 milligrams of codeine per dosage unit, and buprenorphine. Schedule III drugs are prescribable verbally over the phone, with a paper prescription, or via EPCS. Within a six-month time frame, refill requirements are such that the drug can only have five refills. Schedule IV: Schedule IV drugs have an even lower misuse potential than I, II, or III. They have a limited risk of physical or psychological dependence. Examples of Schedule IV substances include: alprazolam, carisoprodol, clonazepam, clorazepate, diazepam, lorazepam, midazolam, temazepam, tramadol, and triazolam. Drugs in this class may be utilized for pain control as long as the provider deems the drug to be medically necessary and that the patient would benefit. Schedule IV drugs are prescribable verbally over the phone, with a paper prescription, or via EPCS. Refills are permitted up to five times in a six-month timeframe from the issuance date. Schedule V: Schedule V drugs are the least likely controlled substances to be misused. They result in very limited physical dependence or psychological dependence. Examples include cough medicines with codeine, antidiarrheal medications that contain atropine/diphenoxylate, pregabalin, and ezogabine. Schedule V drugs despite their low abuse potential, still need to be managed appropriately and administered with care. When they contain codeine, it must have less than 200 mg of codeine per 100 mL. Partial prescription fills cannot occur more than six months after the date of issue. When a partial fill occurs, it is treated in the same manner and with the same rules as a refill of the drug. Drug Use Disorder, Abuse, and Misuse Use disorder of a drug differs from abuse and misuse of a drug. The drugs taken may be illicit street or stolen drugs or obtained via a legal prescription. Misusing a drug usually involves taking the drug in a harmful or detrimental way that results in personal, professional, or social problems. A patient that is abusing an opioid analgesic may no longer be appropriately interacting with their family, friends, or be able to perform their duties at work. Misuse of a controlled substance refers to the use of a prescribed drug in a way that was not intended. It may be deliberate or accidental. A negative result may or may not occur. Examples of misuse include taking too much of a drug, using an incorrect dose route, or using prescription drugs written for another person. Controlled substances include both prescription drugs and illicit drugs with no recognized medical value. Both have the potential to be abused or misused. While schedule I drug use is illegal, prescription drugs found in schedules II-V are also commonly abused and misused, and their misuse is a challenging problem that has increased over the last several years. The Centers for Disease Control and Prevention has declared prescription drug abuse is a problem of epidemic proportions. The CDC believes that absent checks and balances on the prescription and distribution of controlled substances, including those prescribed for medical use, the potential for abuse and misuse will continue to increase. Pill Shopping Unfortunately, a common practice among those that deliberately misuse controlled substances is to seek out multiple sources of drugs. They do this by seeing different health care providers, and they present with a different list of complaints that are often fictitious and different for each provider. The patient may be able to obtain multiple prescriptions and then fill them at different pharmacies. Many states have enacted systems that allow providers to see all of the prescriptions written for each patient. Use of these systems is gradually curbing "pill shopping." Diversion Some prescription drugs will sell on the street for as much as $50 a tablet. Diversion is when a patient sells their drugs as a method of earning money. Drugs may also be sold to buy food, pay expenses, or purchase more potent street drugs. Worse, in some cases, healthcare providers may divert drugs from patients for the providers own personal use or sell them to someone else. Some individuals use controlled substances in ways for which they were not originally intended. Rather than pain control, they may be used to stay awake, induce sleep, or get "high." Before the popularity of prescription drug diversion, the only method to obtain illicit drugs was to import from other countries or manufacture them in private labs. Today, law enforcement agencies have the tremendous challenge of dealing with prescription drugs sold by diversion as well as illicit drugs imported or manufactured. In both instances, these drug sales and usage result in increased criminal activity as well as dangerous overdoses and death. Methods of Obtaining Prescription Drugs A review of multiple studies demonstrates a variety of means individuals obtain prescription drugs. The following summarizes the studies' findings. 55% free from a friend or relative. 20% from a prescriber. 10% purchased from a friend or relative. 5% stolen from a friend or relative. 5% purchased from a drug dealer. 2% from multiple doctors. 1% from theft from medical practice or pharmacy. Less 1% from internet. Studies also reveal the source of the majority of these drugs was a single legal prescriber.
- A comparative study for detecting CYP3A induction by CYP3A probe drugs and endogenous markers in cynomolgus monkeys. [Journal Article]Biopharm Drug Dispos 2019; 40(2):81-93BD
- CYP3A probe drugs such as midazolam and endogenous markers, and plasma 4β-hydroxycholesterol (4β-OHC) and urinary 6β-hydroxycortisol-to-cortisol ratios (6β-OHC/C) have been used as markers of CYP3A induction in cynomolgus monkeys, as with humans. However, there is limited information on their sensitivity and ability to detect CYP3A induction, as most studies were evaluated only at a high dose of …
CYP3A probe drugs such as midazolam and endogenous markers, and plasma 4β-hydroxycholesterol (4β-OHC) and urinary 6β-hydroxycortisol-to-cortisol ratios (6β-OHC/C) have been used as markers of CYP3A induction in cynomolgus monkeys, as with humans. However, there is limited information on their sensitivity and ability to detect CYP3A induction, as most studies were evaluated only at a high dose of the inducer, rifampicin (RIF; 20 mg/kg). In the present study, the CYP3A induction by RIF over a range doses of 0.2, 2 and 20 mg/kg (n = 4) was examined using CYP3A probe drugs (midazolam, triazolam and alprazolam) and the plasma and urinary endogenous CYP3A markers (4β-OHC and 6β-OHC/C). The sensitivity and relationship for detecting CYP3A induction was compared among the markers. Four days repeated oral administration of rifampicin to cynomolgus monkeys reduced the area under the plasma concentration-time curve of all CYP3A probe drugs in a rifampicin dose-dependent manner. Although the endogenous CYP3A markers (4β-OHC and 6β-OHC/C) were also changed for the middle (2 mg/kg) and high (20 mg/kg) doses of rifampicin, the fold-changes were relatively small, and CYP3A induction could not be detected at the lowest dose of rifampicin (0.2 mg/kg). In conclusion, CYP3A probe drugs are more sensitive for detecting CYP3A induction than endogenous CYP3A markers in cynomolgus monkeys, even for a short experimental period.
- Assessment of Inhibitory Effects of Hypnotics on Acetylcholine-Induced Contractions in Isolated Rat Urinary Bladder Smooth Muscle. [Journal Article]Biol Pharm Bull 2019; 42(2):280-288BP
- The present study aimed to investigate the potential inhibitory effects of 21 clinically available hypnotics on acetylcholine (ACh)-induced contractions in rat urinary bladder smooth muscle (UBSM) in order to predict whether these hypnotics could induce voiding impairment. ACh-induced contraction in rat UBSM was inhibited only by diphenhydramine (a histamine H1 receptor antagonist) at a concentra…
The present study aimed to investigate the potential inhibitory effects of 21 clinically available hypnotics on acetylcholine (ACh)-induced contractions in rat urinary bladder smooth muscle (UBSM) in order to predict whether these hypnotics could induce voiding impairment. ACh-induced contraction in rat UBSM was inhibited only by diphenhydramine (a histamine H1 receptor antagonist) at a concentration that was clinically relevant. ACh-induced contraction was also significantly inhibited by flurazepam (a benzodiazepine hypnotic) and suvorexant (an orexin receptor antagonist), albeit at concentrations that substantially exceeded clinically achievable blood levels. These three drugs (at 10-5 M) also inhibited high-KCl (80 mM) Locke-Ringer solution-induced contractions. In contrast to the effects of the abovementioned hypnotics, ACh-induced contractions were not significantly affected by triazolam, etizolam, brotizolam, lormetazepam, estazolam, flunitrazepam, nitrazepam (benzodiazepine hypnotics), thiopental, thiamylal, pentobarbital, amobarbital, secobarbital, phenobarbital (barbiturate hypnotics), zolpidem (an imidazopyridine hypnotic), zopiclone (a cyclopyrrolone hypnotic), ramelteon (a melatonin receptor agonist), bromovalerylurea, and chloral hydrate. These findings suggest that most clinically used hypnotics are not likely to result in anticholinergic-induced dysuria within their clinically achievable blood concentration ranges. Diphenhydramine may, however, induce voiding impairment, an action attributable to diminished UBSM contractility within its clinical dose range.
- Orexin Receptor Blockade-Induced Sleep Preserves the Ability to Wake in the Presence of Threat in Mice. [Journal Article]Front Behav Neurosci 2018; 12:327FB
- Retention of the ability to wake from sleep in response to dangerous situations is an ideal characteristic of safe hypnotics. We studied the effects of a dual orexin receptor antagonist-22 (DORA-22) and the GABA-A receptor modulator, triazolam, on the ability to wake in response to aversive stimuli. We examined four modalities of sensory inputs, namely, auditory (ultrasonic sound), vestibular (tr…
Retention of the ability to wake from sleep in response to dangerous situations is an ideal characteristic of safe hypnotics. We studied the effects of a dual orexin receptor antagonist-22 (DORA-22) and the GABA-A receptor modulator, triazolam, on the ability to wake in response to aversive stimuli. We examined four modalities of sensory inputs, namely, auditory (ultrasonic sound), vestibular (trembling), olfactory (predator odor), and autonomic (hypoxia) stimuli. When the mice fell asleep, one of the four stimuli was applied for 30 s. In the case of auditory stimulation, latency to arousal following vehicle, DORA-22, and triazolam administration was 3.0 (2.0-3.8), 3.5 (2.0-6.5), and 161 (117-267) s (median and 25-75 percentile in the parentheses, n = 8), respectively. Latency to return to sleep after arousal was 148 (95-183), 70 (43-98), and 60 (52-69) s, respectively. Similar results were obtained for vestibular and olfactory stimulation. During the hypoxic stimulation, latencies for arousal and returning to sleep were not significantly different among the groups. The findings of this study are consistent with the distinct mechanisms of these sleep promoting therapies; GABA-A receptor activation by triazolam is thought to induce widespread central nervous system (CNS) suppression while DORA-22 more specifically targets sleep/wake pathways through orexin receptor antagonism. These data support the notion that DORA-22 preserves the ability to wake in response to aversive and consciousness-inducing sensory stimuli, regardless of modality, while remaining effective in the absence of threat. This study provides a unique and important safety evaluation of the potential for certain hypnotics.
New Search Next
- Expanded table: Some oral hypnotics for chronic insomnia. [Review]Med Lett Drugs Ther 2018; 60(1546):e209-e213ML