Δ9-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for nonreceptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15–30 minutes, and taper off within 2–3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30–90 minutes, reach their maximum after 2–3 hours and last for about 4–12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial. They are reported to be low in humans and do not preclude legitimate therapeutic use of cannabis-based drugs. Properties of cannabis that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, sedation, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and induction of apoptosis in cancer cells.

Pharmacokinetics and Pharmacodynamics of Cannabinoids

Aminoglycoside Modifying Enzymes

Endogenous melatonin is synthesized from tryptophan via 5-hydroxytryptamine. It is considered an indoleamine from a biochemical point of view because the melatonin molecule contains a substituted indolic ring with an amino group. The circadian production of melatonin by the pineal gland explains its chronobiotic influence on organismal activity, including the endocrine and non-endocrine rhythms. Other functions of melatonin, including its antioxidant and anti-inflammatory properties, its genomic effects, and its capacity to modulate mitochondrial homeostasis, are linked to the redox status of cells and tissues. With the aid of specific melatonin antibodies, the presence of melatonin has been detected in multiple extrapineal tissues including the brain, retina, lens, cochlea, Harderian gland, airway epithelium, skin, gastrointestinal tract, liver, kidney, thyroid, pancreas, thymus, spleen, immune system cells, carotid body, reproductive tract, and endothelial cells. In most of these tissues, the melatonin-synthesizing enzymes have been identified. Melatonin is present in essentially all biological fluids including cerebrospinal fluid, saliva, bile, synovial fluid, amniotic fluid, and breast milk. In several of these fluids, melatonin concentrations exceed those in the blood. The importance of the continual availability of melatonin at the cellular level is important for its physiological regulation of cell homeostasis, and may be relevant to its therapeutic applications. Because of this, it is essential to compile information related to its peripheral production and regulation of this ubiquitously acting indoleamine. Thus, this review emphasizes the presence of melatonin in extrapineal organs, tissues, and fluids of mammals including humans.

Extrapineal melatonin: sources, regulation, and potential functions.

Melatonin, the major hormone produced by the pineal gland, displays characteristic daily and seasonal patterns of secretion. These robust and predictable rhythms in circulating melatonin are strong synchronizers for the expression of numerous physiological processes in photoperiodic species. In mammals, the nighttime production of melatonin is mainly driven by the circadian clock, situated in the suprachiasmatic nucleus of the hypothalamus, which controls the release of norepinephrine from the dense pineal sympathetic afferents. The pivotal role of norepinephrine in the nocturnal stimulation of melatonin synthesis has been extensively dissected at the cellular and molecular levels. Besides the noradrenergic input, the presence of numerous other transmitters originating from various sources has been reported in the pineal gland. Many of these are neuropeptides and appear to contribute to the regulation of melatonin synthesis by modulating the effects of norepinephrine on pineal biochemistry. The aim of this review is firstly to update our knowledge of the cellular and molecular events underlying the noradrenergic control of melatonin synthesis; and secondly to gather together early and recent data on the effects of the nonadrenergic transmitters on modulation of melatonin synthesis. This information reveals the variety of inputs that can be integrated by the pineal gland; what elements are crucial to deliver the very precise timing information to the organism. This also clarifies the role of these various inputs in the seasonal variation of melatonin synthesis and their subsequent physiological function.

Generation of the Melatonin Endocrine Message in Mammals: A Review of the Complex Regulation of Melatonin Synthesis by Norepinephrine, Peptides, and Other Pineal Transmitters

Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways.

In vivo and in vitro studies on modulation of the pineal endocrine function by L-acetyl-carnitine in the rat.

Penetration of pefloxacin and ciprofloxacin into lung tissue.

Twenty-four patients, hospitalized in order to undergo radical gynaecological surgery, were orally administered cefatrizine in a single dose of 1 g at different times before surgery. The tissue levels determined in the organs considered (uterus, ovary, tubae, vagina) proved that cefatrizine possesses good absorption in the genital tract, reaching concentrations near to the MICs of most gram-negative and gram-positive sensitive bacteria lasting even 12 h after administration.

Kinetics of Cefatrizine Penetration into Gynaecological Tissues after Oral Administration

To determine the efficacy in vivo of pefloxacin and ciprofloxacin in the treatment of acute infectious bron-chopneumopathies, 90 patients, suffering from acute exacerbation of chronic bronchitis and with no known allergies to quinolones, were admitted to the study.Patients were randomly divided into three groups of 30; the first group was dosed with pefloxacin 800 mg i.v. every 24 hours; the second group with pefloxacin 800 mg per os every 24 hours and the third with 500 mg per os of ciprofloxacin every 12 hours.Blood and bronchial secretion samples were simultaneously collected 2, 4, 8, 12, 14 and 24 hours after the first daily dose of antibiotic.Serum and bronchial secretion concentrations of pefloxacin and ciprofloxacin were determined by using a microbiological agar disk diffusion assay, employing Escherichia coli Kp 712 as test organism.Eradication of responsible microorganisms (Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis) were achieved in 98% of patients around 72 ho...

Comparative Activities of Pefloxacin and Ciprofloxacin in the Treatment of Chronic Respiratory Tract Infections

The pharmacokinetic disposition of buflomedil was compared in humans after oral administration of solution, tablets and film tablets. Six healthy male volunteers received a single oral dose of the three different dosage formulations. Blood and urine samples were taken before dosing and at selected times over 24 h and 72 h, resp., after dosing. The concentration of the drug in samples was measured by gas-chromatography with nitrogen detector. The absorption of buflomedil was faster after solution administration, while other plasma parameters did not show any major differences. Also the amount of drug excreted in urines was higher with solution dosing.

F. Fraschini

Papers

In vivo and in vitro studies on modulation of the pineal endocrine function by L-acetyl-carnitine in the rat.

Penetration of pefloxacin and ciprofloxacin into lung tissue.

Kinetics of Cefatrizine Penetration into Gynaecological Tissues after Oral Administration

Comparative Activities of Pefloxacin and Ciprofloxacin in the Treatment of Chronic Respiratory Tract Infections

Pharmacokinetics of buflomedil after various dosage forms.