Oral Administration of Cannabis and Δ-9-tetrahydrocannabinol (THC) Preparations: A Systematic Review.

BACKGROUND AND OBJECTIVE: Changes in cannabis legalization regimes in several countries have influenced the diversification of cannabis use. There is an ever-increasing number of cannabis forms available, which are gaining popularity for both recreational and therapeutic use. From a therapeutic perspective, oral cannabis containing Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is a promising route of administration but there is still little information about its pharmacokinetics (PK) effects in humans. The purpose of this systematic review is to provide a general overview of the available PK data on cannabis and THC after oral administration. METHODS: A search of the published literature was conducted using the PubMed database to collect available articles describing the PK data of THC after oral administration in humans. RESULTS: The literature search yielded 363 results, 26 of which met our inclusion criteria. The PK of oral THC has been studied using capsules (including oil content), tablets, baked goods (brownies and cookies), and oil and tea (decoctions). Capsules and tablets, which mainly correspond to pharmaceutical forms, were found to be the oral formulations most commonly studied. Overall, the results reflect the high variability in the THC absorption of oral formulations, with delayed peak plasma concentrations compared to other routes of administration. CONCLUSIONS: Oral THC has a highly variable PK profile that differs between formulations, with seemingly higher variability in baked goods and oil forms. Overall, there is limited information available in this field. Therefore, further investigations are required to unravel the unpredictability of oral THC administration to increase the effectiveness and safety of oral formulations in medicinal use.

[Hyperammonemic encephalopathy in multiple myeloma]. / Hyperammonämische Enzephalopathie bei multiplem Myelom.

HISTORY AND CLINICAL FINDINGS: A 54-year old man had suffered from advanced multiple myeloma for two years. After initially good response the myeloma was refractrory to treatment with dexamethasone, cyclophosphamide, bortezomibe, zoledronate and additionally doxorubicine. The patient then complained of dyspnea without clinical signs of cardiopulmonary disease. INVESTIGATIONS: Arterial blood gas analysis showed hyperventilation with respiratory alkalosis and normal alveolo-arterial gradient as the reason for the dyspnea. With a normal MRI of the brain and lumbal puncture, a neurological disease could be excluded. Serum calcium, creatinine and serum viscosity were normal. Eventually, serum ammonia levels were found to be substantially elevated (144 µmol/l) and hyperammonemic encephalopathy was diagnosed. TREATMENT AND COURSE: Therapy with bortezomib and high dose dexamethason was repeated, and the patient also received bendamustin. Despite this treatment, he lost consciousness and died after two weeks because of aspiration pneumonia. CONCLUSION: The existence of respiratory alkalosis and multiple myeloma should prompt a search for hyperammonemia.

Bendamustine versus chlorambucil for the first-line treatment of chronic lymphocytic leukemia in England and Wales: a cost-utility analysis.

OBJECTIVES: To evaluate the cost-effectiveness of bendamustine compared with chlorambucil as first-line treatment for patients with chronic lymphocytic leukemia who would be considered unsuitable for treatment with fludarabine combination chemotherapy regimens. METHODS: A semi-Markov approach was used to estimate time in each health state. The model was parameterized primarily by using data from a phase III randomized, open-label trial comparing bendamustine with chlorambucil. It captured the increased progression-free survival and improved response rates with bendamustine, and the cost and quality of life impacts of postprogression treatments. The analysis was conducted from the perspective of the National Health Service in England and Wales. A lifetime (35-year) time horizon was used. Deterministic sensitivity analyses, probabilistic sensitivity analyses, and subgroup analyses in older patients and patients with poor performance status were carried out. RESULTS: The estimated incremental cost-effectiveness ratio was £ 11,960 per quality-adjusted life-year. None of the deterministic sensitivity analyses increased the incremental cost-effectiveness ratio by more than £ 2000. Subgroup analyses showed that bendamustine remained cost-effective across different patient groups. Probabilistic sensitivity analysis showed that at the £ 20,000 threshold, bendamustine has a 90% probability of being cost-effective. CONCLUSIONS: Bendamustine represents good value for first-line treatment of patients with chronic lymphocytic leukemia who are unsuitable for treatment with fludarabine combination chemotherapy. The incremental cost-effectiveness ratio is below the thresholds commonly applied in England and Wales (£ 20,000-£ 30,000 per quality-adjusted life-year).

Salvage therapy with single agent bendamustine for recurrent glioblastoma.

The treatment of recurrent glioblastoma (GBM) remains challenging notwithstanding the recent approval of bevacizumab for this indication. Bendamustine has a bifunctional mechanism of action including alkylation, penetrates the CNS and does not show cross resistance to other alkylator chemotherapies. In a single institution phase 2 trial, patients with recurrent GBM were treated with bendamustine (100 mg/m(2)/day administered intravenously for two consecutive days every 4 weeks). The primary study endpoint was 6-month progression free survival (PFS-6). An interim analysis for futility was conducted according to a Simon two-stage minimax design. Complete blood counts were obtained bimonthly, clinical evaluations and brain imaging every month for the first cycle and bimonthly thereafter. Treatment responses were based upon MacDonald criteria. Sixteen patients were enrolled (nine men; seven women), with a median age of 53 years (range 36-68) and a median Karnofsky performance status of 90 (range 70-100). Nine patients were treated at first relapse and seven at second relapse (five patients were bevacizumab failures). A total of 25 cycles of bendamustine were administered with a median of 1 (range 1-6). Bendamustine-related toxicity was seen in eight patients; lymphopenia in seven (5 grade 3; 2 Grade 4), thrombocytopenia in two (1 Grade 3; 1 Grade 4), and neutropenia in one (1 Grade 3). Fourteen patients have died due to disease progression, two patients are alive and on alternative therapies. Only one patient was progression-free at 6 months, triggering the stopping rule for futility. Bendamustine was reasonably well tolerated but failed to meet the study criteria for activity in adults with recurrent GBM.

Sézary syndrome: a summary.

Sézary syndrome is the leukemic form of primary cutaneous T-cell lymphoma. It is an aggressive disease, with the lowest reported median survival of all cutaneous lymphomas. Patients with Sézary syndrome live with the awareness that they are suffering from an incurable disease. Having to cope daily with extensive skin care regimens, these patients can benefit tremendously from the expertise of dermatology nurses, who can teach them skin selfcare and who are aware of the psychologic impact of this disease. The symptoms, treatments, and emotional distress related to Sézary syndrome are summarized.

Thiazolidinyl- and perhydrothiazinylphosphamidesters: toxicity and preliminary antitumour evaluation.

Aldophosphamide thiazolidine (NSC 613060) and aldophosphamide perhydrothiazine (NSC 612567), which hydrolyse spontaneously to 4-hydroxycyclophosphamide (4-OH-CP) in aqueous solution, were synthesised. These substances are prototypes of a new class of prodrugs for activated oxazaphosphorines. They were developed according to our hypothesis on the mechanism of action of oxazaphosphorine cytostatics. According to this hypothesis, toxicity and canceroselectivity are the results of phosphoramide mustard (PAM) release from 4-OH-CP catalysed by two classes of phosphodiesterase. 4-OH-CP toxicity results (a) from oxazaphosphorine-specific toxicity due to reactivity of the hemiaminal group with thiol groups of membrane proteins and (b) from PAM release catalysed by ubiquitous phosphodiesterases present in blood and tissues. Specific cytotoxicity suitable for antitumour therapy is based on specific PAM release in the vicinity of the target molecule DNA by the exonuclease subsites of DNA polymerases delta and epsilon. To unfold this specific core, which, we assume, improves efficacy in cancer treatment, low, long-lasting concentrations of OH-CP have to be guaranteed beneath the affinity range of the ubiquitous phosphodiesterase. This goal is facilitated by the rapid transfer of 4-OH-CP released from the perhyrothiazine derivative NSC 612567 to protein SH groups, as shown by protein-binding studies. Half-lives of hydrolysis and dissociation constants of the thiazolidine and perhydrothiazine derivatives, in which the reactivity of the hemiaminal group is inactivated by inclusion into the thiazolidine or perhydrothiazine ring, were determined to be 23 h and 6.0 x 10(-6) mol/l for NSC 613060 and 1.5 h and 1.1 x 10(-4) mol/l for NSC 312567. Accordingly the compounds guarantee low but long-lasting steady-state concentrations of 4-OH-CP. The acute toxicity determined in mice was 2400 mg/kg for NSC 613060 and 1900 mg/kg for NSC 612567. Except for a 30% decrease in leucocytes, daily i.p. injections of 260 mg/kg NSC 612567 (15% of LD50) were tolerated without signs of toxicity over a period of 4 weeks. In contrast, equitoxic doses of cyclophosphamide caused severe signs of toxicity, only five daily applications were tolerated. In mice treated repeatedly with NSC 613060, oxazaphosphorine toxicity was overlapped by thiazolidine toxicity. Scheduled activity tests in mice bearing P815 ascites tumour showed optimal therapeutic response when mice were treated daily. Repeated applications of 4% LD50 of NSC 613060 and 13% LD50 of NSC 612567 prevented tumour growth in mice with advanced, P388 lymphomas, implanted subcutaneously, without signs of overall toxicity to the host.

Evaluation of phthalmustine, a new anticancer compound. I. Effect on Dalton's ascitic lymphoma in mice.

The anticancer property of phthalmustine, a hitherto unknown compound containing N-mustard attached to the phthalimide ethyl chain was evaluated using a murine tumor model. The results indicate that the compound was effective in significantly restraining tumor growth. This was accompanied by marked improvement in host survival. No toxic reactions were apparent as reflected in skin and hair texture, body weight and behavioral pattern (food and water intake and activity). Blood picture showed a shift towards the normal following treatment. DNA synthesis in tumor cells was found to be affected as revealed by radioactive thymidine incorporation.

[Experimental study of the antitumor properties and mechanism of action of kortifen]. / Eksperimental'noe izuchenie protivoopukholevykh svoistv i mekhanizma deistviia kortifena.

Cortiphen, a newly developed hormonal cytostatic ester of 11-desoxy-17 alpha-hydroxycorticosterone and chlorophenacyl, is described. It was studied in transplantable, spontaneous and induced tumors of 7 sites: hemoblastosis (5), hepatoma (3), mammary gland (5), lung (2), gastrointestinal tract (3), sarcoma (2) and melanoma. Practically all the tumors were shown to respond to cortiphen action. Among the antitumor effects of the drug were: long-term inhibition of tumor growth or tumor regression, contribution to longer survival, antimetastatic action and sustained action during repeated courses of administration. Cortiphen was found to interact with glucocorticoid receptors in both animal and human tumors. The role of the hormonal component of the drug's molecule in the realization of its antitumor effect is discussed.

The logistics of broader pre-clinical evaluation of potential anti-cancer agents with reference to anti-tumour activity and toxicity of mitozolomide.

Anti-tumour responses with CCRG81010, M & B 39565, NSC 353451, 8-carbamoyl-3-(2-chloroethyl)imidazo [5,1-d]-1,2,3,5-tetrazin-4(3H)-one (Mitozolomide) in a panel of 4 murine colon tumours of varying growth characteristics and chemosensitivity and a spontaneous murine lymphoma are similar to those seen with standard nitrosoureas. The moderately well differentiated colon adenocarcinoma MAC 16 is nonresponsive to mitozolomide and methylCCNU. Responses in the other 4 lines studied are only achieved near to maximum tolerated dose and at this level there is severe host toxicity. Haemopoietic toxicity is clearly demonstrated by analysis of peripheral blood counts and by CFU-S assays and severe testicular and ovarian toxicity was also seen at dose levels necessary to achieve anti-tumour effects. Using mitozolomide as an example, the study has demonstrated the feasibility of conducting simple but thorough toxicity evaluation for the determination of the therapeutic index. This approach would provide invaluable guidelines for the selection for clinical trial of the most appropriate members of a series of new cytotoxic compounds.

Phase I trial of spiromustine (NSC 172112) and evaluation of toxicity and schedule in a murine model.

Phase I evaluation of spiromustine was performed using an every-3-week schedule and a weekly X 3 schedule. Neurotoxicity was the dose-limiting toxicity presenting as alterations in cortical integrative functions (orientation, language, coordination), leading to a decrease in the level of consciousness. Traditional criteria for grading neurotoxicity poorly characterized these toxicities. The maximum tolerated dose was 6 mg/m2 every 3 weeks and 3 mg/m2 weekly X 3. Concurrent murine studies confirmed spiromustine as a schedule independent drug with toxicity correlating with peak plasma levels. Physostigmine had little effect on decreasing neurotoxicity in the murine model. The solvating agent used was not responsible for the neurotoxicity. Injection of spiromustine on a split-dose schedule decreased the acute neurological toxicity in mice and allowed a larger total dosage to be delivered (compared to single bolus dosage). Based on these results a split-dose schedule is suggested for future clinical trials.

Activity and distribution studies of etoposide and mitozolomide in vivo and in vitro against human choriocarcinoma cell lines.

The in vivo antitumor activity of etoposide and mitozolomide was assessed in nude mice bearing a xenograft (CC3) of human gestational choriocarcinoma. Both agents demonstrated, at best, marginal activity observed as a delay in tumour growth. This lack of sensitivity suggests that the CC3 xenograft is not a good model for selection of agents for clinical evaluation in gestational choriocarcinoma. Plasma and tissue concentrations of etoposide and mitozolomide were measured in nude mice. Drug concentrations found in tumour tissue were 60% and 30% of plasma levels for mitozolomide and etoposide respectively. Etoposide and mitozolomide activity was also evaluated in vitro with another choriocarcinoma cell line (JAR). Maximum cell-kill was achieved after exposure to etoposide 0.05-1 microgram/ml for 3-24 h. In vitro response to etoposide demonstrates the importance of exposure time in determining cytotoxicity. In contrast, mitozolomide at concentrations from 1-100 micrograms/ml did not have a marked effect against JAR after exposure for 3-24 h.

[Potentiation by Rabdosia rubescens on chemotherapy of advanced esophageal carcinoma].

One hundred and fifteen patients with inoperable esophageal carcinoma were treated by either chemotherapy alone or chemotherapy plus Rabdosia rubescens. In group A, out of 31 patients treated with pingyangmycin (P) and nitrocaphane (N), 10 (32.3%) responded to the treatment. Among them, 2 showed partial response (greater than 50% tumor regression) and 8 minimal response (greater than 50% tumor regression). In group B, out of 84 patients treated with PN plus Rabdosia rubescens, 59 (70.2%) responded. Of them, 10 showed complete response (100% tumor regression), 16 partial response and 33 minimal response. the one-year survival rates of group A and B were 13.6% and 41.3%. Statistical significance was present in these two groups both in the response rate and one-year survival rate. As regards the drug toxicity, there was no significant difference between these two groups. Alopecia, anorexia, nausea and hyperpyrexia occurred in more than 30% of patients. Mild leukopenia and thrombocytopenia and interstitial pneumonia were noted in some patients, and two patients died of toxicity in the lungs.

In vivo studies with the novel anticancer agent mitozolomide (NSC 353451) on Lewis lung carcinoma.

Mitozolomide is one of the most effective drugs against Lewis lung carcinoma in the mouse. Two IP doses of 40 mg/kg (days 6 and 15 after IM transplantation of 3LL) or four doses of 20 mg/kg given at various intervals (starting from day 6) increased survival time by 100%. A single IP dose of 80 mg/kg was toxic, and 10 mg/kg was ineffective even when this dose was given on eight occasions. The pharmacokinetics of mitozolomide was investigated in 3LL-bearing mice by HPLC assay. Peak drug levels were achieved in tumor 15 min after IP treatment, after which they declined according to first-order kinetics, with a half-life of 80-100 min (the same as in plasma). No dose-dependent kinetics was observed. Flow cytometry studies showed an accumulation of 3LL cells in G2M 24 h after drug treatment. This cell cycle perturbation was reversed 96 h after the inactive dose of 10 mg/kg, but not after the effective dose of 40 mg/kg.

Further studies on the anti-neoplastic activity of 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam [p-[bis(2-chloroethyl)amino]-phenyl]acetate (NSC 290205).

The modified steroidal alkylating agent 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam [p-[bis(2-chloroethyl)amino]phenyl]acetate (NSC 290205) is active in treating the LX-1 lung and MX-1 breast xenografts as well as a number of rodent tumors. Of 13 tumors tested, activity has been shown in 10 systems. Two systems have not received adequate testing and negative results were recorded in 1 system.