Clinical, genomic and immune microenvironmental determinants of nivolumab response in head and neck squamous cell carcinoma.

Background: In view of improving biomarkers predicting the efficacy of immunotherapy for head and neck squamous cell carcinoma (R/M HNSCC), this multicenter retrospective study aimed to identify clinical, tumor microenvironmental, and genomic factors that are related to therapeutic response to the anti- Programmed cell death protein 1 (PD-1) antibody, nivolumab, in patients with R/M HNSCC. Methods: The study compared 53 responders and 47 non-responders, analyzing formalin-fixed paraffin-embedded samples using 14-marker multiplex immunohistochemistry and targeted gene sequencing. Results: Of 100 patients included, responders had significantly lower smoking and alcohol index, higher incidence of immune related adverse events, and higher PD-1 ligand (PD-L1) expression in immune cells as well as PD-L1 combined positive score (CPS) than non-responders. The frequency of natural killer cells was associated with nivolumab response in patients with prior cetuximab use, but not in cetuximab-naïve status. Age-stratified analysis showed nivolumab response was linked to high CPS and lymphoid-inflamed profiles in patients aged ≥ 65. In contrast, lower NLR in peripheral blood counts was associated with response in patients aged < 65. Notably, TP53 mutation-positive group had lower CPS and T cell densities, suggesting an immune-excluded microenvironment. Patients with altered tumor suppressor gene pathways, including TP53, CDKN2A, and SMAD4 mutations, had lower CPS, higher smoking index, and were associated with poor responses. Conclusion: Nivolumab treatment efficacy in HNSCC is influenced by a combination of clinical factors, age, prior treatment, immune environmental characteristics, and gene mutation profiles.

Efficacy of endoscopic surveillance for pharyngeal mucosa during endoscopic resection for pharyngeal carcinoma: a multicenter prospective study.

INTRODUCTION: Since patients with pharyngeal squamous cell carcinoma (SCC) often have multiple pharyngeal lesions, evaluation of pharyngeal lesions before endoscopic resection (ER) is important. However, detailed endoscopic observation of the entire pharyngeal mucosa under conscious sedation is difficult. We examined the usefulness of endoscopic surveillance with narrow band imaging (NBI) and lugol staining for detection of pharyngeal sublesions during ER for pharyngeal SCC under general anesthesia (endoscopic surveillance during treatment; ESDT). METHODS: From January 2021 through June 2022, we examined 78 patients who were diagnosed with superficial pharyngeal SCC and underwent ER. They underwent the ESDT and for patients who were diagnosed with new lesions of pharyngeal SCC or high-grade dysplasia (HGD) that were not detected in the endoscopic examination before treatment, ER were performed simultaneously for new lesions and the main lesions. The primary endpoint of this study was the detection rate of new lesions of pharyngeal SCC or HGD in the ESDT. RESULTS: Fifteen of the 78 patients were diagnosed as having undetected new pharyngeal lesions in the ESDT and 10 (12.8%) (95% CI 6.9-22.2%) were histopathologically confirmed to have new lesions of pharyngeal SCC or HGD. Among the 13 lesions of SCC or HGD, 8 were found by NBI observation; however, 5 were undetectable using NBI but detectable by lugol staining. All of the 13 lesions had endoscopic findings of pink color sign on lugol staining. CONCLUSIONS: Endoscopic surveillance for pharyngeal sublesions during ER for pharyngeal SCC is feasible and useful.

Artificial Nerve Conduit for Recurrent Laryngeal Nerve Reconstruction in Thyroid Surgery.

OBJECTIVE: Oncological reconstruction of the recurrent laryngeal nerve (RLN) is sometimes necessary for RLN invaded by thyroid cancer. There have been no case reports of RLN reconstruction using artificial nerve conduits, which are often used for peripheral nerves. In this study, we retrospectively evaluate the feasibility, safety, and efficacy of a collagen conduit with collagen filaments for RLN reconstruction cases at our hospital. METHODS: Artificial nerve conduits were used in seven cases of RLN reconstruction. Two patients had preoperative unilateral vocal cord paralysis with severe vocal cord atrophy, and two had vocal cord paresis without atrophy. The remaining three patients had functional vocal cords before surgery that had to be resected via surgery due to thyroid cancer infiltration of the RLN. Reconstruction was performed using RENERVE®, which is a collagen conduit. Voice examination and laryngeal endoscopy were performed 1, 3, and 12 months after surgery. RESULTS: There was no improvement in the phonetics of the two patients with vocal cord atrophy before surgery. In the remaining five cases, three with functional vocal cords improved to preoperative values, and two with vocal cord paresis improved to greater than preoperative values. CONCLUSION: We report the first case series using an artificial nerve conduit for human RLN reconstruction. In cases of RLN resection when the patient has good voice quality pre-operatively, reconstruction of the RLN using an artificial nerve may be a favorable option in cases where direct anastomosis or ansa cervicalis to RLN anastomosis cannot be performed. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:1773-1779, 2023.

Outcomes of long-term nivolumab and subsequent chemotherapy in Japanese patients with head and neck cancer: 2-year follow-up from a multicenter real-world study.

BACKGROUND: We have previously reported the effectiveness and safety of nivolumab in patients with head and neck cancer (HNC) in real-world clinical practice in Japan. Here, we report long-term outcomes from this study in the overall population and subgroups stratified by subsequent chemotherapy. METHODS: In this multicenter, retrospective observational study, Japanese patients with recurrent or metastatic (R/M) HNC receiving nivolumab were followed up for 2 years. Effectiveness endpoints included overall survival (OS), OS rate, progression-free survival (PFS), and PFS rate. Safety endpoints included the incidence of immune-related adverse events (irAEs). RESULTS: Overall, 256 patients received a median of 6.0 doses (range: 1-52) of nivolumab over a median duration of 72.5 days (range: 1-736). Median OS was 9.5 months [95% confidence interval (CI) 8.2-12.0] and median PFS was 2.1 months (95% CI 1.8-2.7). A significant difference between 2-year survivors (n = 62) and non-2-year survivors was observed by median age (P = 0.0227) and ECOG PS (P = 0.0001). Of 95 patients who received subsequent chemotherapy, 54.7% received paclitaxel ± cetuximab. The median OS and PFS from the start of paclitaxel ± cetuximab were 6.9 months (95% CI 5.9-11.9) and 3.5 months (95% CI 2.3-5.5), respectively. IrAEs were reported in 17.2% of patients. Endocrine (7.0%) and lung (4.3%) disorders were the most common irAEs; kidney disorder (n = 1) was newly identified in this follow-up analysis. CONCLUSIONS: Results demonstrated the long-term effectiveness of nivolumab and potential effectiveness of subsequent chemotherapy in patients with R/M HNC in the real-world setting. Safety was consistent with that over the 1-year follow-up.

Evaluation of the risk of metachronous multiple squamous cell carcinoma of the head and neck after transoral surgery based on the genetic polymorphisms of alcohol dehydrogenase 1B and aldehyde dehydrogenase 2.

Patients with superficial head and neck squamous cell carcinoma (HNSCC) can be completely treated by techniques of transoral surgery (TOS). The aim of this study was to evaluate the risk of metachronous multiple HNSCC arising after TOS based on alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2). We registered patients who underwent TOS for superficial HNSCC. Buccal cell samples were obtained by using a cotton swab to examine two single nucleotide polymorphisms in ADH1B and ALDH2 genotyping. We used Cox proportional hazards models to examine the risk of metachronous HNSCC. A total of 198 patients who underwent TOS for HNSCC were evaluated. In multivariate analysis, risks for second HNSCC were ADH1B*1/*1 [hazard ratio (HR), 1.88; 95% confidence interval (CI), 1.11-3.19; P = 0.02], ALDH2*1/*2 (HR, 2.11; 95% CI, 1.00-5.16; P = 0.048) and alcohol consumption before TOS (HR, 1.17; 95% CI, 1.06-1.27; P = 0.01). The 5-year incidence rates of second primary HNSCC in the temperance group and the non-temperance group were 20.8 and 46.5%, respectively (HR, 0.54; 95% CI, 0.31-0.92; P = 0.02). Cumulative development rates of third HNSCC in the temperance group and non-temperance group at 10 years were 11.3 and 36.1%, respectively (HR, 0.19; 95% CI, 0.03-0.65; P = 0.006). ADH1B*1/*1, ALDH2*1/*2 and moderate or heavy alcohol consumption before treatment are independent risk factors of metachronous HNSCC. Since it was shown that temperance decreased the incidences of second and third metachronous HNSCC, advice to discontinue alcohol drinking is necessary.

Transoral surgery for superficial head and neck cancer: National Multi-Center Survey in Japan.

Head and neck cancers, especially in hypopharynx and oropharynx, are often detected at advanced stage with poor prognosis. Narrow band imaging enables detection of superficial cancers and transoral surgery is performed with curative intent. However, pathological evaluation and real-world safety and clinical outcomes have not been clearly understood. The aim of this nationwide multicenter study was to investigate the safety and efficacy of transoral surgery for superficial head and neck cancer. We collected the patients with superficial head and neck squamous cell carcinoma who were treated by transoral surgery from 27 hospitals in Japan. Central pathology review was undertaken on all of the resected specimens. The primary objective was effectiveness of transoral surgery, and the secondary objective was safety including incidence and severity of adverse events. Among the 568 patients, a total of 662 lesions were primarily treated by 575 sessions of transoral surgery. The median tumor diameter was 12 mm (range 1-75) endoscopically. Among the lesions, 57.4% were diagnosed as squamous cell carcinoma in situ. The median procedure time was 48 minutes (range 2-357). Adverse events occurred in 12.7%. Life-threatening complications occurred in 0.5%, but there were no treatment-related deaths. During a median follow-up period of 46.1 months (range 1-113), the 3-year overall survival rate, relapse-free survival rate, cause-specific survival rate, and larynx-preservation survival rate were 88.1%, 84.4%, 99.6%, and 87.5%, respectively. Transoral surgery for superficial head and neck cancer offers effective minimally invasive treatment. Clinical trials registry number: UMIN000008276.

Effectiveness of nivolumab affected by prior cetuximab use and neck dissection in Japanese patients with recurrent or metastatic head and neck cancer: results from a retrospective observational study in a real-world setting.

BACKGROUND: To examine the effect of prior use of cetuximab and neck dissection on the effectiveness of nivolumab, we conducted a large-scale subgroup analysis in Japanese patients with recurrent/metastatic head and neck cancer. METHODS: Data on the effectiveness of nivolumab were extracted from patient medical records. All patients were analyzed for effectiveness by prior cetuximab use. In the analyses for prior neck dissection, only patients with locally advanced disease were included. RESULTS: Of 256 patients analyzed, 155 had received prior cetuximab. Nineteen of 50 patients with local recurrence underwent neck dissection. The objective response rate was 14.7 vs 17.2% (p = 0.6116), median progression-free survival was 2.0 vs 3.1 months (p = 0.0261), and median overall survival was 8.4 vs 12 months (p = 0.0548) with vs without prior cetuximab use, respectively. The objective response rate was 23.1 vs 25.9% (p = 0.8455), median progression-free survival was 1.8 vs 3.0 months (p = 0.6650), and median overall survival was 9.1 vs 9.9 months (p = 0.5289) with vs without neck dissection, respectively. CONCLUSIONS: These findings support the use of nivolumab for patients with recurrent/metastatic head and neck cancer regardless of prior cetuximab use or neck dissection history. TRIAL REGISTRATION NUMBER: UMIN-CTR (UMIN000032600), Clinicaltrials.gov (NCT03569436).

Evaluation of Pharyngeal Background Mucosa in Patients with Superficial Hypopharyngeal Carcinoma.

OBJECTIVES/HYPOTHESIS: Transoral surgery (TOS) has become increasingly popular for patients with superficial hypopharyngeal squamous cell carcinoma (SCC). However, the number of patients in whom metachronous multiple SCC of the head and neck (HNSCC) occurs has also increased. In this study, we investigated whether multiple lugol-voiding lesions (LVLs) in the pharyngeal background mucosa observed during TOS would be a biomarker of metachronous HNSCC. STUDY DESIGN: Retrospective study. METHODS: We examined 362 patients who underwent TOS for superficial hypopharyngeal carcinoma. Endoscopic images were reviewed in a blinded fashion by two endoscopists. LVLs in the pharyngeal mucosa were graded as follows: A, no lesions; B, 1 to 4 lesions; and C, ≥5 lesions per endoscopic view. RESULTS: Cumulative incidence curves of secondary HNSCC in the groups of grades A, B, and C revealed 3-year incidence rates of 14.4%, 18.8%, and 29.3%, respectively (P = .001 for A vs. C and P = .002 for B vs. C). Cumulative incidence curves of third HNSCC in the groups of grades A, B. and C revealed 5-year incidence rates of 3.9%, 9.8%, and 19.6%, respectively (P = .001 for A vs. C and P = .006 for B vs. C). Cumulative incidence curves of fourth HNSCC in the groups of grades A, B, and C revealed 7-year incidence rates of 0%, 2.3%, and 13.2%, respectively (P = .025 for A vs. C and P = .009 for B vs. C). CONCLUSIONS: Multiple LVLs in the pharyngeal mucosa increase the risk of development of metachronous multiple HNSCC. LEVEL OF EVIDENCE: 3 (nonrandomized, controlled cohort/follow-up study) Laryngoscope, 131:2036-2040, 2021.

Effectiveness and safety of nivolumab in patients with head and neck cancer in Japanese real-world clinical practice: a multicenter retrospective clinical study.

BACKGROUND: To fill the data gap between clinical trials and real-world settings, this study assessed the overall effectiveness and safety of nivolumab in patients with head and neck cancer (HNC) during Japanese real-world clinical practice. METHODS: This was a multicenter, retrospective study in Japanese patients with recurrent or metastatic HNC who received nivolumab for the first time between July and December 2017. Data on the clinical use, effectiveness, and safety of nivolumab were extracted from patient medical records. RESULTS: Overall, 256 patients were enrolled in this study. The median duration of nivolumab treatment was 72.5 days, with patients receiving a median of 6.0 (range 1-27) doses. Median overall survival (OS) was 9.5 (95% confidence interval [CI] 8.2-12.0) months and the estimated 12-month OS rate was 43.2%. The objective response rate (ORR) was 15.7% overall and 21.1%, 7.1%, and 13.6% in patients with primary nasopharynx, maxillary sinus, and salivary gland tumors, respectively, who had been excluded from CheckMate 141. Grade ≥ 3 immune-related adverse events occurred in 5.9% of patients. No new safety signals were identified compared with adverse events noted in CheckMate 141. CONCLUSIONS: The effectiveness and safety of nivolumab in real-world clinical practice are consistent with data from the CheckMate 141 clinical trial. Therapeutic response was also observed in the groups of patients excluded from CheckMate 141. TRIAL REGISTRATION NUMBER: UMIN-CTR (UMIN000032600), Clinicaltrials.gov (NCT03569436).

[Efficacy of Neoadjuvant Endocrine Therapy for Prostate Ductal Carcinoma with Large Multiple Cysts Prior to Robot-Assisted Laparoscopic Radical Prostatectomy].

A 71-year-old man with gross hematuria and urinary retention showed a 7×8 cm polycystic mass compressing the prostate on the right ventral side on pelvic magnetic resonance imaging (MRI). The prostate specific antigen (PSA) level was 6.47 ng/ml. Prostate biopsy histopathology was consistent with prostate ductal carcinoma. Considering the difficulty of surgical therapy, endocrine therapy was undertaken prior to surgery for seven months. Almost all of the cyst disappeared ; robot-assisted laparoscopic radical prostatectomy was then successfully performed. Prostate ductal carcinoma is a relatively rare pathology for which radical prostatectomy plays an important role if the disease is localized. However, when ductal carcinoma involves large cysts, surgical treatment may be difficult. This report discusses the usefulness of neoadjuvant endocrine therapy to reduce the size of the cystic lesions.

Larynx-preserving hybrid surgery with endoscopic laryngopharyngeal surgery and open surgery for cervical esophageal cancer invading pharynx.

Larynx preserving hybrid surgery with endoscopic laryngopharyngeal surgery and open surgery (HELPS) was created for resectable cervical esophageal cancer (CEC) invading the hypopharynx. This study aimed to verify the effectiveness and to evaluate the feasibility of the new HELPS treatment method. Between 2014 and 2018, 19 patients with CEC invading the hypopharynx were treated with HELPS. The postoperative complications and survival rates were reviewed. Postoperative recurrent laryngeal nerve paralysis occurred in four patients. All patients consumed food orally without a feeding tube at the time of the discharge. The median follow-up period was 27 months. The 2- and 3-year overall survival rates were 94.7 and 71.5%, respectively. HELPS, a new surgical treatment method that utilizes endoscopic surgery, is effective, feasible and beneficial for preserving the larynx in patients with CEC even if the tumor invaded the pharynx.

Fabrication of Fe-Co Magnetostrictive Fiber Reinforced Plastic Composites and Their Sensor Performance Evaluation.

The inverse magnetostrictive effect is an effective property for energy harvesting; the material needs to have large magnetostriction and ease of mass production. Fe-Co alloys being magnetostrictive materials have favorable characteristics which are high strength, ductility, and excellent workability, allowing easy fabrication of Fe-Co alloy fibers. In this study, we fabricated magnetostrictive polymer composites, in which Fe-Co fibers were woven into polyester fabric, and discussed their sensor performance. Compression and bending tests were carried out to measure the magnetic flux density change, and the effects of magnetization, bias magnetic field, and the location of the fibers on the performance were discussed. It was shown that magnetic flux density change due to compression and bending is related to the magnetization of the Fe-Co fiber and the bias magnetic field. The magnetic flux density change of Fe-Co fiber reinforced plastics was larger than that of the plastics with Terfenol-D particles.

Synopsis of transoral endoscopic laryngopharyngeal surgery for superficial pharyngeal cancers.

BACKGROUND: Endoscopic laryngopharyngeal surgery (ELPS) was developed for superficial pharyngeal cancers in Japan. In this study, we present our results of ELPS for superficial pharyngeal cancers. METHODS: From November 2009 to December 2015, 258 patients with superficial pharyngeal cancers underwent ELPS. Results, including survival rates, postoperative complications, and vocal function, are reviewed. RESULTS: The median follow-up period of 258 patients was 31 months. The overall and cause-specific survival rates over 3 years were 85.7% and 100%, respectively. Only 3 patients incurred local recurrences and were successfully salvaged by re-ELPS. Regarding postoperative complications, 4 patients required reoperation because of postoperative bleeding. As for the postoperative quality of life, no patients developed vocal fold paralysis. Every patient was able to consume meals at preoperative levels. CONCLUSION: ELPS is a feasible and minimally invasive treatment for superficial pharyngeal cancers with impressive quality of life results.

Efficient, effective, safe procedure to identify nonrecurrent inferior laryngeal nerve during thyroid surgery.

BACKGROUND: The nonrecurrent inferior laryngeal nerve (NRILN) is always associated with the aberrant subclavian artery. CT images can detect this vascular anomaly, which predicts an NRILN. The purpose of this study was to report our procedure to identify the NRILN in patients with the aberrant subclavian artery. METHODS: Four of 730 patients undergoing thyroid operation in our hospital were preoperatively diagnosed with aberrant subclavian artery by CT of the neck. To avoid vocal cord paralysis, we approached the vagal nerve first before dissecting the paratracheal region to discover the separation point of the NRILN from the vagal nerve. RESULTS: The NRILN was identified without difficulty in all 4 patients. No patients showed vocal cord paralysis. CONCLUSION: Approaching the vagal nerve first before dissecting the paratracheal region is an efficient, effective, and safe procedure to identify an NRILN in patients who are preoperatively diagnosed as having the aberrant subclavian artery.

Global Trends in Alzheimer Disease Clinical Development: Increasing the Probability of Success.

PURPOSE: Alzheimer disease (AD) is a growing global health and economic issue as elderly populations increase dramatically across the world. Despite the many clinical trials conducted, currently no approved disease-modifying treatment exists. In this commentary, the present status of AD drug development and the grounds for collaborations between government, academia, and industry to accelerate the development of disease-modifying AD therapies are discussed. METHODS: Official government documents, literature, and news releases were surveyed by MEDLINE and website research. FINDINGS: Currently approved anti-AD drugs provide only short-lived symptomatic improvements, which have no effect on the underlying pathogenic mechanisms or progression of the disease. The failure to approve a disease-modifying drug for AD may be because the progression of AD in the patient populations enrolled in clinical studies was too advanced for drugs to demonstrate cognitive and functional improvements. The US Food and Drug Administration and the European Medicines Agency recently published draft guidance for industry which discusses approaches for conducting clinical studies with patients in early AD stages. For successful clinical trials in early-stage AD, however, it will be necessary to identify biomarkers highly correlated with the clinical onset and the longitudinal progress of AD. In addition, because of the high cost and length of clinical AD studies, support in the form of global initiatives and collaborations between government, industry, and academia is needed. IMPLICATIONS: In response to this situation, national guidance and international collaborations have been established. Global initiatives are focusing on 2025 as a goal to provide new treatment options, and early signs of success in biomarker and drug development are already emerging.

MK-801-induced deficits in social recognition in rats: reversal by aripiprazole, but not olanzapine, risperidone, or cannabidiol.

Deficiencies in social activities are hallmarks of numerous brain disorders. With respect to schizophrenia, social withdrawal belongs to the category of negative symptoms and is associated with deficits in the cognitive domain. Here, we used the N-methyl-D-aspartate receptor antagonist dizocilpine (MK-801) for induction of social withdrawal in rats and assessed the efficacy of several atypical antipsychotics with different pharmacological profiles as putative treatment. In addition, we reasoned that the marijuana constituent cannabidiol (CBD) may provide benefit or could be proposed as an adjunct treatment in combination with antipsychotics. Hooded Lister rats were tested in the three-chamber version for social interaction, with an initial novelty phase, followed after 3 min by a short-term recognition memory phase. No drug treatment affected sociability. However, distinct effects on social recognition were revealed. MK-801 reduced social recognition memory at all doses (>0.03 mg/kg). Predosing with aripiprazole dose-dependently (2 or 10 mg/kg) prevented the memory decline, but doses of 0.1 mg/kg risperidone or 1 mg/kg olanzapine did not. Intriguingly, CBD impaired social recognition memory (12 and 30 mg/kg) but did not rescue the MK-801-induced deficits. When CBD was combined with protective doses of aripiprazole (CBD-aripiprazole at 12 : or 5 : 2 mg/kg) the benefit of the antipsychotic was lost. At the same time, activity-related changes in behaviour were excluded as underlying reasons for these pharmacological effects. Collectively, the combined activity of aripiprazole on dopamine D2 and serotonin 5HT1A receptors appears to provide a significant advantage over risperidone and olanzapine with respect to the rescue of cognitive deficits reminiscent of schizophrenia. The differential pharmacological properties of CBD, which are seemingly beneficial in human patients, did not back-translate and rescue the MK-801-induced social memory deficit.

Lymph node metastasis in t4 maxillary sinus squamous cell carcinoma: incidence and treatment outcome.

BACKGROUND: The purpose of this study was to evaluate the incidence of lymph node metastasis among patients with T4 maxillary sinus squamous cell carcinoma (MS-SCC) as well as the delayed metastasis rate and the treatment outcome for untreated N0 neck in patients with T4 MS-SCC. METHODS: Consecutive series of all patients (n = 128) with previously untreated T4 maxillary sinus SCC between 2006 and 2007 were obtained from 28 institutions belonging to or cooperating in the Head and Neck Cancer Study Group of the Japan Clinical Oncology Group. RESULTS: Of the 128 patients, 28 (21.9 %) had lymph node metastasis, and six patients (4.7 %) had distant metastasis at diagnosis. Among the 111 patients who were treated with curative intent, 98 had clinically N0 neck disease and did not receive prophylactic neck irradiation. A total of 11 patients (11.2 %) subsequently developed evidence of lymph node metastasis, of whom eight were among the 83 patients with an N0 neck and had not received elective neck treatment. There were 15 patients who received an elective neck dissection as part of the initial treatment, of whom three had pathologically positive for lymph node metastases. Of 11 patients, six patients with nonlateral retropharyngeal lymph node metastasis without primary or distant disease were successfully salvaged. CONCLUSIONS: This study identified the incidence of lymph node metastasis among patients with T4 MS-SCC as well as the delayed metastasis rate and the treatment outcome for untreated N0 neck in patients with T4 MS-SCC. These results will be of assistance in selecting treatment strategy for T4 MS-SCC in the future.

Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour.

RATIONALE: Phytocannabinoids are useful therapeutics for multiple applications including treatments of constipation, malaria, rheumatism, alleviation of intraocular pressure, emesis, anxiety and some neurological and neurodegenerative disorders. Consistent with these medicinal properties, extracted cannabinoids have recently gained much interest in research, and some are currently in advanced stages of clinical testing. Other constituents of Cannabis sativa, the hemp plant, however, remain relatively unexplored in vivo. These include cannabidiol (CBD), cannabidivarine (CBDV), Δ(9)-tetrahydrocannabivarin (Δ(9)-THCV) and cannabigerol (CBG). OBJECTIVES AND METHODS: We here determined pharmacokinetic profiles of the above phytocannabinoids after acute single-dose intraperitoneal and oral administration in mice and rats. The pharmacodynamic-pharmacokinetic relationship of CBD (120 mg/kg, ip and oral) was further assessed using a marble burying test in mice. RESULTS: All phytocannabinoids readily penetrated the blood-brain barrier and solutol, despite producing moderate behavioural anomalies, led to higher brain penetration than cremophor after oral, but not intraperitoneal exposure. In mice, cremophor-based intraperitoneal administration always attained higher plasma and brain concentrations, independent of substance given. In rats, oral administration offered higher brain concentrations for CBD (120 mg/kg) and CBDV (60 mg/kg), but not for Δ(9)-THCV (30 mg/kg) and CBG (120 mg/kg), for which the intraperitoneal route was more effective. CBD inhibited obsessive-compulsive behaviour in a time-dependent manner matching its pharmacokinetic profile. CONCLUSIONS: These data provide important information on the brain and plasma exposure of new phytocannabinoids and guidance for the most efficacious administration route and time points for determination of drug effects under in vivo conditions.