Saliva vs. plasma bioequivalence of paracetamol in humans: validation of class I drugs of the salivary excretion classification system.

AIMS: To study saliva and plasma bioequivalence of paracetamol in healthy human volunteers, and to investigate the robustness of using saliva instead of plasma as surrogate for bioequivalence of class I drugs according to the salivary excretion classification system (SECS). METHODS: Saliva and plasma pharmacokinetic parameters were calculated by non compartmental analysis. Analysis of variance, 90% confidence intervals, intra-subject and inter-subject variability values of pharmacokinetic parameters were calculated after logarithmic transformation. Calculations were done using Kinetica program V5. Descriptive and comparative statistics were also calculated by Excel. RESULTS AND DISCUSSION: Paracetamol falls into class I (High permeability/High fraction unbound to plasma proteins) and was subjected to salivary excretion, with correlation coefficient of 0.99 between saliva and plasma concentrations and saliva/plasma concentrations ratios of 1.45-1.50. The 90% confidence limits of areas under curve (AUC(last) and AUC(∞)) showed similar trend and passed the 80-125% acceptance criteria in both saliva and plasma. On the other hand for maximum concentration (C(max)), the 90% confidence limits passed the acceptance criteria in plasma and failed in saliva. Inter and intra subject variability values in saliva were higher than plasma leading to need for higher number of subjects to be used in saliva. Saliva and plasma parameter ratios were not significantly different (P>0.05). CONCLUSIONS: Saliva instead of plasma can be used as surrogate for bioequivalence of class I drugs according to SECS when adequate sample size is used. Future work is planned to demonstrate SECS robustness in drugs that fall into classes II or III.

Different classes of CB2 ligands potentially useful in the treatment of pain.

The search of new drugs and targets to treat the pain is an intriguing challenge both for several companies and researchers from academia. In this context, since the modulation of the endocannabinoid system with the non selective phytocannabinoid Δ9-THC produces analgesia and potentiates opioid analgesia in animal models, CB2 ligands studies aimed to explore the involvement of endocannabinoid system in management of pain were started. Several selective CB2 receptor agonists exhibited analgesic activity in preclinical models of acute, inflammatory and neuropathic pain, therefore this class of modulators could be useful as analgesic agents for pain, migraine, inflammation and osteoarthritis. This review is an update of our previously manuscript "A survey of recent patents on CB2 agonists in the management of pain" and provides an overview of patents and advances in CB2 agonist studies in the treatment of pain.

[Pain therapy with antipyretic analgesics]. / Schmerztherapie mit antipyretischen Analgetika.

The pharmacotherapy of musculoskeletal pain remains of high importance in Western countries. The present review concentrates on the use of acidic (nonsteroidal anti-inflammatory drugs) and nonacidic (paracetamol, selective cyclooxygenase-2 inhibitors) antipyretic analgesics in the therapy of musculoskeletal pain disorders with particular emphasis on the diverse pharmacokinetic properties and unwanted side effects of these substances.

[Clinical pharmacology of analgesics: outlook and risks]. / Klinische Pharmakologie der Schmerzmittel. Chancen und Risiken.

Despite that many drugs are available for pain treatment, many patients are still suffering because of wrong choice or wrong use of analgesics. Both are determined by the degree and the nature of pain to be treated. Non-opioid drugs, especially COX-2-inhibitors are extensively evaluated. If treatment with these drugs is not sufficient, opioids have to be used. Their efficiency is outstanding and their side effects are appropriate. However, doctors and nurses are still reluctant to use opioids because of overestimation of respiratory depression and addiction.

The effects of drugs on thermoregulation.

Body temperature is a balance of the hypothalamic set point, neurotransmitter action, generation of body heat, and dissipation of heat. Drugs affect body temperature by different mechanisms. Antipyretics lower body temperature when the body's thermoregulatory set point has been raised by endogenous or exogenous pyrogens. The use of antipyretics may be unnecessary or may interfere with the body's resistance to infection, mask an important sign of illness, or cause adverse drug effects. Drugs may cause increased body temperature in five ways: altered thermoregulatory mechanisms, drug administration-related fever, fever from the pharmacologic action of the drug, idiosyncratic reactions, and hypersensitivity reactions. Certain drugs cause hypothermia by depression of the thermoregulatory set point or prevention of heat conservation. By affecting the balance of thermoregulatory neurotransmitters, drugs may prevent the signs and symptoms of hot flashes.

Public health issue brief: medical marijuana: year end report-2004.

During the last few years, the debate over the use of marijuana for medical purposes has moved from the legislative arena into the public forum. Thirty six states and the District of Columbia have had statutes that address the medical utility of marijuana within the past 26 years. However, several of those states have either repealed the laws or allowed them to sunset. Since 1996, 11 states have enacted laws that allow individuals to use marijuana with a doctor's consent.

Rational use of analgesic combinations.

Careful selection of an effective analgesic regimen based on the amount and type of pain the patient is expected to have can prevent the stress and anxiety associated with breakthrough pain. When analgesics fail, it is not unusual for patients to go to desperate lengths to seek relief. The clinician can and should develop a variety of effective, safe analgesic regimens based on estimates of anticipated pain intensity that apply sound pharmacologic principles.

New antidepressants in the treatment of neuropathic pain. A review.

Before 1980s, tricyclics (TCAs) were considered, between antidepressants, the standard in the treatment of different kinds of neuropathic pain, for their action on noradrenergic and serotoninergic pathways, thought the high incidence of side effects. In 1980s a new class of antidepressants has been introduced, the selective serotonin reuptake inhibitors (SSRI). We reviewed some publications, including trials comparing SSRIs with TCAs in pain management. The available literature did not show an effective superiority of the former on the latter, though improved side-effect profile. Recently new antidepressants were introduced in the clinical use, with a significant reduction in side effects and equivalent efficacy on mood disorders. These new drugs may be classified in three categories: Serotonin and Noradrenergic Reuptake Inhibitors (SNaRI), like venlafaxine and nefazodone; Noradrenergic and Specific Serotoninergic Antidepressants (NaSSA), like mirtazapine, and Noradrenaline Reuptake Inhibitors (NaRI), like reboxetine. In this review we present the available publications of their application in the treatment of neuropathic pain. Venlafaxine (SNaRI), the most investigated of these new drugs, was shown to be effective in the treatment of different kinds of pain, with side-effects profile significantly better than TCAs. The other new antidepressants have been less extensively studied, thus only anecdotal therapeutic results and experimental works have been found and reported. Existing data are surely insufficient to conclude which of these new classes of drugs has the best clinical profile and can be more effective in the treatment of neuropathic pain, but the lower incidence of side effects should be considered. Further evidence-based research in the safety and efficacy of these promising agents in pain relief, is warranted.

[Non-opioid analgesics--irreplaceable in cancer pain therapy? / Nicht-Opioid-Analgetika--unersetzlich in der Tumorschmerztherapie?

Sufficient therapy of pain is essential for the treatment of tumor patients. World Health Organisation (WHO)-guidelines recommend a combination of opioids with non-opioid-analgesics (NOA) for patients with medium to strong pain. Cancer pain is often a combination of pain caused by the tumor itself, tumor associated and pain caused by therapy. Various substances act by different mechanisms and therefore combinations may demonstrate superior effects. Opioids ("central analgesics") inhibit neuronal transduction within the spinal cord, enhance inhibiting function of midbrain nuclei on ascending pain transduction and influence pain perception via modulation of the limbic system. NOAs ("peripheral analgesics") inhibit cyclooxygenase hindering activation of the peripheral nociceptor-system. There are 2 different classes of NOAs: 1) non-acidic, antipyretic analgesics like pyrazolones (metamizol) and anilin-derivates (paracetamol) and 2) non-steroidal antirheumatics (NSAR) like salicylates (acetylsalicylic acid), derivates of propionic acid (ibuprofen, naproxen), acetate acid (indomethacin, diclofenac), enolic acid (piroxicam, meloxicam) and anthranil acid (mefenamin). Adjuvant therapy is necessary to control common NSAR-side-effects like dyspepsia, ulcer and gastrointestinal bleeding. Due to its exceptional analgesic, antipyretic and spasmolytic properties, metamizol is an essential substance in tumor therapy. As agranulocytosis-incidence of 1:1,000,000 is low, good gastrointestinal and renal tolerance makes metamizol an excellent alternative to NSAR. There is scientific evidence that adequate combinations of non-opioids, opioids and adjuvant drugs, considering adverse side effects, were effective and safe in the treatment of cancer pain.

Schedules of controlled substances: rescheduling of the Food and Drug Administration approved product containing synthetic dronabinol [(-) - [DELTA] less than 9 greater than - (trans)-tetrahydrocannabinol] in sesame oil and encapsulated in soft gelatin capsules from schedule II to schedule III. Department of Justice (DOJ), Drug Enforcement Administration (DEA). Final rule.

This is a final rule of the Deputy Administrator of the Drug Enforcement Administration (DEA) transferring a drug between schedules of the Controlled Substances Act (CSA) pursuant to 21 U.S.C. 811. With the issuance of this final rule, the Deputy Administrator transfers from schedule II to schedule III of the CSA the drug containing synthetic dronabinol [(-) - [DELTA] less than 9 greater than - (trans)-tetrahydrocannabinol] in sesame oil and encapsulated in soft gelatin capsules in a product approved by the Food and Drug Administration (FDA). This rule also designates this drug as a schedule III non-narcotic substance requiring an import/export permit. As a result of this rule, the regulatory controls and criminal sanctions of schedule III will be applicable to the manufacture, distribution, importation and exportation of this drug.