Oral administration of cannabis with lipids leads to high levels of cannabinoids in the intestinal lymphatic system and prominent immunomodulation

Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) have well documented immunomodulatory effects in vitro, but not following oral administration in humans. Here we show that oral co-administration of cannabinoids with lipids can substantially increase their intestinal lymphatic transport in rats. CBD concentrations in the lymph were 250-fold higher than in plasma, while THC concentrations in the lymph were 100-fold higher than in plasma. Since cannabinoids are currently in clinical use for the treatment of spasticity in multiple sclerosis (MS) patients and to alleviate nausea and vomiting associated with chemotherapy in cancer patients, lymphocytes from those patients were used to assess the immunomodulatory effects of cannabinoids. The levels of cannabinoids recovered in the intestinal lymphatic system, but not in plasma, were substantially above the immunomodulatory threshold in murine and human lymphocytes. CBD showed higher immunosuppressive effects than THC. Moreover, immune cells from MS patients were more susceptible to the immunosuppressive effects of cannabinoids than those from healthy volunteers or cancer patients. Therefore, administering cannabinoids with a high-fat meal or in lipid-based formulations has the potential to be a therapeutic approach to improve the treatment of MS, or indeed other autoimmune disorders. However, intestinal lymphatic transport of cannabinoids in immunocompromised patients requires caution

Is clarithromycin a potential treatment for cachexia in people with lung cancer?: a feasibility study

Clarithromycin may improve cachexia and survival in non-small cell lung cancer (NSCLC), but adequately controlled data are lacking. This study was undertaken primarily to inform the feasibility and scale of a phase III trial. Eligible consenting patients with stage IV NSCLC and cachexia were to be randomized to receive either clarithromycin 250 mg twice daily or placebo for eight weeks. Aspects of trial feasibility recorded included numbers eligible, approached and recruited, together with adherence and completion of treatment and assessments. Over 6 months, none of 125 patients identified fulfilled the entry criteria. The commonest reasons for ineligibility were the use of an excluded concurrent drug (45, 36%), brain metastases (22, 18%), poor performance status (21, 17%) and current chemotherapy (15, 12%). A phase III trial of clarithromycin using these entry criteria is not feasible in this setting. Other macrolides that have a lower risk of a drug–drug interaction may be more practical to pursue

Dietary fats and pharmaceutical lipid excipients increase systemic exposure to orally administered cannabis and cannabis-based medicines

There has been an escalating interest in the medicinal use of Cannabis sativa in recent years. Cannabis is often administered orally with fat-containing foods, or in lipid-based pharmaceutical preparations. However, the impact of lipids on the exposure of patients to cannabis components has not been explored. Therefore, the aim of this study is to elucidate the effect of oral co-administration of lipids on the exposure to two main active cannabinoids, ?9-tetrahydrocannabinol (THC) and cannabidiol (CBD). In this study, oral co-administration of lipids enhanced the systemic exposure of rats to THC and CBD by 2.5-fold and 3-fold, respectively, compared to lipid-free formulations. In vitro lipolysis was conducted to explore the effect of lipids on the intestinal solubilisation of cannabinoids. More than 30% of THC and CBD were distributed into micellar fraction following lipolysis, suggesting that at least one-third of the administered dose will be available for absorption following co-administration with lipids. Both cannabinoids showed very high affinity for artificial CM-like particles, as well as for rat and human CM, suggesting high potential for intestinal lymphatic transport. Moreover, comparable affinity of cannabinoids for rat and human CM suggests that similar increased exposure effects may be expected in humans. In conclusion, co-administration of dietary lipids or pharmaceutical lipid excipients has the potential to substantially increase the exposure to orally administered cannabis and cannabis-based medicines. The increase in patient exposure to cannabinoids is of high clinical importance as it could affect the therapeutic effect, but also toxicity, of orally administered cannabis or cannabis-based medicines

Can body composition be used to optimize the dose of platinum chemotherapy in lung cancer? A feasibility study

Purpose Current methods of dosing platinum-based chemotherapy are suboptimal. Potentially, taking lean body mass into account may help. To inform the design of a future study, we first examined the feasibility and acceptability of such an approach using dual-energy X-ray absorptiometry (DEXA) and explored aspects suggestive of over- and under-dosing. Methods Patients with lung cancer offered platinum-based chemotherapy over 1 year were identified and, if eligible, invited to take part in a prospective feasibility study. Questionnaires examined acceptability of the DEXA scan and of a future study that randomized between traditional dosing and one adjusted according to body composition. Dose-limiting toxicity (DLT) and a lack of neutropenia explored potential over- and under-dosing, respectively. Results Of the 173 patients offered chemotherapy, 123 (71%) were ineligible, mostly because of failing entry criteria (84, 49%). Of the 50 approached, 18 (36%) participated, most receiving carboplatin, with 17 providing data. All found a DEXA scan acceptable; other assessments were fully completed, except nadir and pre-chemotherapy blood counts. Most (94%) were prepared to take part in a future study, although the additional hospital visits for a nadir blood count were unpopular with some. Five (29%) patients experienced six episodes of DLT which resulted in discontinuation (3), dose reduction (2) or change to a less toxic regimen (1). Nine (60%) patients experienced either no (2) or inconsistent (7) neutropenia. Conclusions A randomized trial appears acceptable and feasible in patients receiving carboplatin. Adjustment of our entry criteria and avoiding a hospital visit for a nadir blood count should aid recruitment

Cediranib in patients with alveolar soft-part sarcoma (CASPS):a double-blind, placebo-controlled, randomised, phase 2 trial

Background Alveolar soft-part sarcoma (ASPS) is a rare soft-tissue sarcoma that is unresponsive to chemotherapy. Cediranib, a tyrosine-kinase inhibitor, has shown substantial activity in ASPS in non-randomised studies. The Cediranib in Alveolar Soft Part Sarcoma (CASPS) study was designed to discriminate the effect of cediranib from the intrinsically indolent nature of ASPS.Methods In this double-blind, placebo-controlled, randomised, phase 2 trial, we recruited participants from 12 hospitals in the UK (n=7), Spain (n=3), and Australia (n=2). Patients were eligible if they were aged 16 years or older; metastatic ASPS that had progressed in the previous 6 months; had an ECOG performance status of 0-1; life expectancy of more than 12 weeks; and adequate bone marrow, hepatic, and renal function. Participants had to have no anti-cancer treatment within 4 weeks before trial entry, with exception of palliative radiotherapy. Participants were randomly assigned (2:1), with allocation by use of computer-generated random permuted blocks of six, to either cediranib (30 mg orally, once daily) or matching placebo tablets for 24 weeks. Treatment was supplied in number-coded bottles, masking participants and clinicians to assignment. Participants were unblinded at week 24 or sooner if they had progression defined by Response Evaluation Criteria in Solid Tumors (version 1.1); those on placebo crossed over to cediranib and all participants continued on treatment until progression or death. The primary endpoint was percentage change in sum of target marker lesion diameters between baseline and week 24 or progression if sooner, assessed in the evaluable population (all randomly assigned participants who had a scan at week 24 [or sooner if they progressed] with target marker lesions measured). Safety was assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01337401; the European Clinical Trials database, number EudraCT2010-021163-33; and the ISRCTN registry, number ISRCTN63733470 recruitment is complete and follow-up is ongoing.Findings Between July 15, 2011, and July 29, 2016, of 48 participants recruited, all were randomly assigned to cediranib (n=32) or placebo (n=16). 23 (48%) were female and the median age was 31 years (IQR 27-45). Median follow-up was 34·3 months (IQR 23·7-55·6) at the time of data cutoff for these analyses (April 11, 2018). Four participants in the cediranib group were not evaluable for the primary endpoint (one did not start treatment, and three did not have their scan at 24 weeks). Median percentage change in sum of target marker lesion diameters for the evaluable population was -8·3% (IQR -26·5 to 5·9) with cediranib versus 13·4% (IQR 1·1 to 21·3) with placebo (one-sided p=0·0010). The most common grade 3 adverse events on (blinded) cediranib were hypertension (six [19%] of 31) and diarrhoea (two [6%]). 15 serious adverse reactions in 12 patients were reported; 12 of these reactions occurred on open-label cediranib, and the most common symptoms were dehydration (n=2), vomiting (n=2), and proteinuria (n=2). One probable treatment-related death (intracranial haemorrhage) occurred 41 days after starting open-label cediranib in a patient who was assigned to placebo in the masked phase.Interpretation Given the high incidence of metastatic disease and poor long-term prognosis of ASPS, together with the lack of efficacy of conventional chemotherapy, our finding of significant clinical activity with cediranib in this disease is an important step towards the goal of long-term disease control for these young patients. Future clinical trials in ASPS are also likely to involve immune checkpoint inhibitors.Funding Cancer Research UK and AstraZeneca

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life