Novel Δ(9) -tetrahydrocannabinol formulation Namisol® has beneficial pharmacokinetics and promising pharmacodynamic effects

AIMS

Among the main disadvantages of currently available Δ⁹-tetrahydrocannabinol (THC) formulations are dosing difficulties due to poor pharmacokinetic characteristics. Namisol® is a novel THC formulation, designed to improve THC absorption. The study objectives were to investigate the optimal administration route, pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of Namisol®.

METHODS

This first in human study consisted of two parts. Panel I included healthy males and females (n = 6/6) in a double-blind, double-dummy, randomized, crossover study with sublingual (crushed tablet) and oral administration of Namisol® (5 mg THC). Based on these results, male and female (n = 4/5) participants from panel I received oral THC 6.5 and 8.0 mg or matching placebo in a randomized, crossover, rising dose study during panel II. PD measurements were body sway; visual analogue scales (VAS) mood, psychedelic and heart rate. THC and 11-OH-THC population PK analysis was performed.

RESULTS

Sublingual administration showed a flat concentration profile compared with oral administration. Oral THC apparent t_1/2 was 72–80 min, t_max was 39–56 min and C_max 2.92–4.69 ng ml⁻¹. THC affected body sway (60.8%, 95% CI 29.5, 99.8), external perception (0.078 log mm, 95% CI 0.019, 0.137), alertness (−2.7 mm, 95% CI −4.5, −0.9) feeling high (0.256 log mm, 95% CI 0.093, 0.418) and heart rate (5.6 beats min^–1, 95% CI 2.7, 6.5). Namisol® was well tolerated.

CONCLUSIONS

Oral Namisol® showed promising PK and PD characteristics. Variability and t_max of THC plasma concentrations were smaller for Namisol® than reported for studies using oral dronabinol and nabilone. This study was performed in a limited number of healthy volunteers. Therefore, future research on Namisol® should study clinical effects in patient populations.     

Diagnostic performance of the platelet function analyzer (PFA-100) for the detection of disorders of primary haemostasis in patients with a bleeding history-a systematic review and meta-analysis

The Platelet Function Analyzer (PFA-100) is increasingly being used in the workup of patients with a bleeding diathesis. A profound knowledge of the possible diagnostic performance of this test is essential in order to make sound clinical decisions based on its results. It was the aim of this study to systematically review the published literature and provide valid estimates of the diagnostic performance of the PFA-100 for detecting disorders of primary haemostasis in newly presenting patients with a bleeding diathesis. A comprehensive literature search was performed for studies published between January 1994 and February 2006. Studies were eligible for the systematic review if they provided data supposed to be applicable to the determination of the diagnostic performance of the PFA-100. Furthermore, they were included in a meta-analysis if study reporting allowed calculation of sensitivity and specificity and if study quality ensured minimized biases of these estimates for the described clinical setting. Pooled weighted sensitivity, specificity and diagnostic odds ratio were calculated applying random effects modelling and constructing summary operator characteristic curves. This was done separately for the available test modifications using either collagen/epinephrine (PFA-EPI) or collagen/adenosine-diphosphate (PFA-ADP) for platelet activation. Thirty-six articles were included in the systematic review. Six studies met our eligibility criteria for a meta-analysis. The major reason for exclusion from the meta-analysis was a case-control design. A total of 1486 and 1259 patients were included in the meta-analysis of the diagnostic performance of the PFA-EPI and PFA-ADP, respectively. Pooled weighted sensitivity and specificity of the PFA-EPI/PFA-ADP in detecting a disorder of primary haemostasis were: 82.5/66.9% (95%-confidence interval (95%-CI): 76.0-88.9%/57.9-75.9%), and 88.7/85.5% (95%-CI: 84.3-93.1%/82.0-89.1%). 83/75% of patients with a positive PFA-EPI/PFA-ADP result do have a disorder of primary haemostasis whereas 88/79% with a negative PFA-EPI/PFA-ADP result do not. The PFA-EPI appeared to have a higher sensitivity and better predictive values than the PFA-ADP in detecting disorders of primary haemostasis, although a rigorous gold standard definition for a disorder of primary haemostasis, particularly for platelet disorders, was not applied in most studies. The majority of the studies lacked important requirements for quality and reporting, precluding a more precise and definitive characterization of the clinical utility of the PFA-100. This emphasizes the need for an evidence-based critical appraisal of diagnostic studies in haemostasis research in order to promote the conducting of studies that produce clinically relevant results.     

Clinical features of chromosome 22q11.2 microdeletion syndrome in 208 Chilean patients

Patients with chromosome 22q11 deletion syndrome exhibit significant phenotypic variability. Epidemiologic data suggest a higher incidence in Hispanics, but limited clinical information is available from Latin-American patients. We describe the clinical features of Chilean patients with 22q11 deletion syndrome and compare their findings with those reported in large European, Japanese and US series. Data were obtained from 208 patients from five medical centers. Mean age at diagnosis was 5.2 years, with a median of 2.3 years. Congenital heart defects were present in 59.6%, lower than other large series that averaged 75.8%. Palate abnormalities were present in 79%, higher than previous reports averaging 56%. Patients with congenital heart disease were diagnosed earlier (median 0.3 years of age) than those without heart defects (median 5.6 years) and had greater mortality attributable to the syndrome (9.8% vs 2.4%, respectively). The differences in frequencies of major anomalies may be due to growing awareness of more subtle manifestations of the syndrome, differences in clinical ascertainment or the presence of modifier factors. These observations provide additional data useful for patient counseling and for the proposal of health care guidelines.     

Musculoskeletal disease burden of hereditary hemochromatosis

Objective

To determine the prevalence, clinical picture, and disease burden of arthritis in patients with hereditary hemochromatosis.

Methods

In this cross‐sectional observational study of 199 patients with hemochromatosis and iron overload, demographic and disease‐specific variables, genotype, and organ involvement were recorded. The prevalence, intensity, and localization of joint pain were assessed, and a complete rheumatologic investigation was performed. Radiographs of the hands, knees, and ankles were scored for joint space narrowing, erosions, osteophytes, and chondrocalcinosis. In addition, the number and type of joint replacement surgeries were recorded.

Results

Joint pain was reported by 72.4% of the patients. Their mean ± SD age at the time of the initial joint symptoms was 45.8 ± 13.2 years. If joint pain was present, it preceded the diagnosis of hemochromatosis by a mean ± SD of 9.0 ± 10.7 years. Bony enlargement was observed in 65.8% of the patients, whereas synovitis was less common (13.6%). Joint space narrowing and osteophytes as well as chondrocalcinosis of the wrist and knee joints were frequent radiographic features of hemochromatosis. Joint replacement surgery was common, with 32 patients (16.1%) undergoing total joint replacement surgery due to severe OA. The mean ± SD age of these patients was 58.3 ± 10.4 years at time of joint replacement surgery. Female sex, metacarpophalangeal joint involvement, and the presence of chondrocalcinosis were associated with a higher risk of early joint failure (i.e., the need for joint replacement surgery).

Conclusion

Arthritis is a frequent, early, and severe symptom of hemochromatosis. Disease is not confined to involvement of the metacarpophalangeal joints and often leads to severe damage requiring the replacement of joints.

     

Therapeutic action and underlying mechanisms of a combination of two pentacyclic triterpenes, α- and β-amyrin,in a mouse model of colitis

Background and purpose:

α- and β-amyrin are pentacyclic triterpenes found in plants and are known to exhibit pronounced anti-inflammatory effects. Here, we evaluated the effects of a 1:1 mixture of α- and β-amyrin (α,β-amyrin) on an experimental model of colitis in mice.

Experimental approach:

Colitis was induced in Swiss male mice by trinitrobenzene sulphonic acid (TNBS) and followed up to 72 h; animals were treated systemically with α,β-amyrin, dexamethasone or vehicle. Macro- and microscopic damage, myeloperoxidase activity and cytokine levels were assessed in colons. Histological sections were immunostained for cyclooxygenase-2 (COX-2), vascular endothelial growth factor, phospho-p65 nuclear factor-κB (NF-κB) and phospho-cyclic AMP response element-binding protein (CREB)

Key results:

TNBS-induced colitis was associated with tissue damage, neutrophil infiltration and time-dependent increase of inflammatory mediators. Treatment with α,β-amyrin (3 mg·kg⁻¹, i.p.) or dexamethasone (1 mg·kg⁻¹, s.c.) consistently improved tissue damage scores and abolished polymorphonuclear cell infiltration. α,β-Amyrin, like dexamethasone, significantly diminished interleukin (IL)-1β levels and partially restored IL-10 levels in colon tissues 72 h after colitis induction, but only α,β-amyrin reduced vascular endothelial growth factor expression by immunohistochemistry. The colonic expression of COX-2 at 24 h and that of phospho-NF-κB and phospho-CREB (peaking at 6 h) after colitis induction were consistently inhibited by both α,β-amyrin and dexamethasone.

Conclusions and implications:

Systemic administration of α,β-amyrin exerted a marked and rapid inhibition of TNBS-induced colitis, related to the local suppression of inflammatory cytokines and COX-2 levels, possibly via inhibition of NF-κB and CREB-signalling pathways. Taken together, our data suggest a potential use of α,β-amyrin to control inflammatory responses in bowel disease.     

Schussverletzungen durch Flinten/“shotgun injuries“

Shotguns are smooth bore long firearms which commonly fire many small sized lead pellets. The special characteristics of the firearm, such as choke bore and of the ammunition, such as secondary ejecta or shotgun slugs are explained. Shotguns are generally used for hunting small but moving game from shooting distances <50 m. The low mass of the single pellets reduces the effective range as well as the penetration depth in tissue. The shotgun pellet spread (dispersion) in front of the muzzle is used for estimating the firing distance. The morphological characteristics of the entrance wound also depend on the pellet spread and thus on the shooting distance and a corresponding scheme is presented. For shotguns fired from less than 5–10 m, the so-called billiard effect causes pronounced dispersion of the pellets within tissue, thus producing large and funnel-shaped injuries. Sawn-off shotguns and the forensic investigation of cases involving shotguns are reviewed.     

15The effect of Lower Esophageal Sphincter (LES) electrical stimulation on LES pressure

Background: Electrical stimulation (ES) of the stomach has been shown to modulate LESP. Electrical stimulation, using neural high frequency stimulation (NGES) can induce contractions of the smooth muscle of the gut. The purpose of this study was to determine if electrical stimulation of the LES can affect LESP. Methods: Four female hound dogs, weight: 20–25 kg, underwent an esophagostomy that allowed the introduction of a sleeve manometry catheter into the esophagus. They were also implanted with a pair of electrodes along the longitudinal axis of the LES. After 3 weeks of recovery, they underwent esophageal manometry recording during control and ES, performed randomly on separate days, using 4 different stimulations: 1‐Low frequency: freq: 6 cycles/min, pulse: 350 milisec, amp: 5 mAmp; 2 High‐frequency: freq: 50 Hz, pulse: 1 milisec, amp: 5 mAmp; 3‐ NGES: freq: 50 Hz, pulse:20 milisec, amp:10 volts; 4‐ High‐frequency, circular: freq: 20 Hz, pulse:1 milisec, amp:5 mAmp. All recordings were performed 1 hour after consumption of 3 ounces of canned dog food, to prevent fluctuations in LESP and under mild sedation (acepromazine 0.5 mg kg^­1). Tests consisted, during ES days, of 3 periods of 20 minutes each: control , stimulation and post stimulation. The effect of NGES was also tested under anesthesia and following administration of L‐NAME 50 mg kg^­1 IV. and also atropine 0.05 mg kg^­1 IV. Analysis: area under the curve (AUC) and pressure were compared among the 3 periods. Data shown as mean ± SD, ANOVA and t‐test, p < 0.05. Results: Sustained increase in LESP was observed during low frequency stimulation, 32.1 ± 12.8 vs. 42.4 ± 18.0 vs. 50.1 ± 23.6, control vs. stimulation vs. post stimulation respectively, p = 0.013. AUC also significantly increased during and after stimulation, 39,320.3 ± 15,722 vs. 51,294 ± 21,826 vs. 59,823.6 ± 28,198.4 mmHgxsec, control vs. stimulation vs. post stimulation respectively, p = 0.01. There was no significant change with other types of ES. NGES induced an initial rise in LESP followed within few seconds by relaxation with slow resumption of pressure over a 1 minute period. L‐NAME increased LESP and augmented the initial rise in LESP following NGES but markedly diminished or abolished the relaxation phase. Atropine lowered LESP and abolished the initial rise in LESP induced by NGES. Conclusions: Low frequency ES of the LES increases LESP in conscious dogs. NGES has dual effect on LESP: an initial stimulation, cholinergically mediated, followed by relaxation mediated by nitric oxide.     

Simple and rapid purification of alphaherpesviruses by chromatography on a cation exchange membrane

A simple and rapid method is described for the purification of two alphaherpesviruses, pseudorabies virus (PrV) and bovine herpesvirus 1, by chromatography on a cation exchange membrane. Cell culture supernatants were passed over a sulfonic-acid modified filter membrane and virions were eluted with a potassium chloride-containing buffer. Over 85% of the virus was eluted within a single fraction and specific infectivity of the resulting virus preparation was over 10-fold higher than that of sucrose gradient-purified virions. Cation exchange was also used for purification of PrV mutants deleted in several glycoproteins which grow in cell culture to titers 10- to 100-fold lower than those obtained by wildtype PrV. For PrV, the presence of non-essential glycoprotein gC, which mediates interaction of virions with cell surface heparin sulfate during attachment, was crucial for the successful purification by cation exchange.     

Unusual self-inflicted injuries simulating a criminal offence

A total of 14 cases with self-inflicted injuries intended to simulate a criminal offence are reported. Typical characteristics of self-infliction such as superficiality, localisation at the anterior aspect, parallel course or avoidance of areas with high sensitivity to pain are substantiated by most of the cases analysed. However, the majority of cases also comprised atypical features including large hematomas of the extremities, a gaping cut wound, lip laceration, hematoma of the eyelids, concussion of the brain, large burn injuries and signs of bonding. Therefore, atypical injuries, which are either found in isolation or in combination with typical injury patterns, cannot exclude self-infliction. Initially, most “victims” did not intend to report the matter to the police but the persons whose affection was to be obtained made the report. Psychopathological motivations are predominant but rational motives such as attempted insurance fraud also occur. Received: 1 March 1997 / Accepted: 4 April 1997