The Safety of Dronabinol and Nabilone: A Systematic Review and Meta-Analysis of Clinical Trials

Dronabinol, a natural cannabinoid, and its semi-synthetic derivative, nabilone, are marketed as medicines in several countries. The aim of our work was to systematically evaluate the frequency of adverse events related to dronabinol or nabilone treatment compared to placebo. Scientific databases were searched for placebo-controlled clinical studies of patients receiving either dronabinol or nabilone therapy with placebo control groups. This meta-analysis was reported following the PRISMA guidelines using the PICO format, and it was registered with the PROSPERO register. There were 16 trials included in the meta-analysis. In the nabilone studies, drowsiness was more than 7 times as frequent in patients treated with nabilone than in the placebo group (OR: 7.25; 95% CI: 1.64–31.95), and the risk of dizziness (OR: 21.14; 95% CI: 2.92–152.75) and dry mouth was also higher (OR: 17.23; 95% CI: 4.33–68.55). The frequency of headache was not different in the two groups. In case of dronabinol, the frequency of dry mouth (OR: 5.58; 95% CI: 3.19–9.78), dizziness (OR: 4.60 95% CI: 2.39–8.83) and headache (OR: 2.90; 95% CI: 1.07–7.85) was significantly higher in the dronabinol groups, whereas in case of nausea, drowsiness and fatigue there was no difference. The severity of adverse events was typically mild-to-moderate and transient. In a risk-benefit assessment, these adverse effects are acceptable compared to the achievable benefit. However, considering the diversity of the adverse effects, more studies are needed to provide a more accurate assessment on the side effect profiles of these two compounds.

Onset of normal cycles in postpartum anovulatory dairy cattle treated with kisspeptin

The efficacy of a long-acting synthetic derivative of kisspeptin (Kp) to initiate normal estrous cycles was tested in 24 mixed-aged, Holstein-Friesian cows that were 18 to 25 d postpartum on day of treatment (D0). Groups of eight received saline (Sal) vehicle by intramuscular injection at 0800 and 1600 h (Sal-Sal), Kp at 800 h and vehicle at 1600 h (Kp-Sal) or Kp on both occasions (Kp-Kp). The Kp dose was 15 nmol per 60 kg body weight. The cows ovaries were examined daily by ultrasonography between D-4 and D14. Blood samples were collected from a tail vessel 0, 2, 4, 8, 10 and 12 h relative to the time of first injection for LH and FSH assay. Additional samples were collected daily from D-4 until D14 and D19, 22, 26 and 29 for progesterone assay. An LH surge-like response were observed in cows treated with Kp at 0800 h. Ovulation was consistently induced by Kp within 48 h when there was a dominant follicle of at least 10 mm in diameter on the ovaries (8/14), but in no cases (6/14) during a new wave of ovarian follicular development consisting of follicles <10 mm diameter. The subsequent ovulatory cycle was of normal length in most cases, as compared with short 8 to 12 d cycles observed in spontaneously ovulating cows. We conclude that Kp treatment can induce ovulation in postpartum dairy cows, with ensuing estrous cycles of normal length, if administered when a mature dominant follicle is present on the ovaries.

Flavaglines: Discovery From Plants Used in Traditional Chinese Medicine, Synthesis and Drug Development against Cancer and Immune Disorders

: Flavaglines, a family of compounds coming from plants used in Traditional Chinese Medicine, exhibit a broad range of biological effects including anticancer, antiviral, cardioprotectant and anti-inflammatory activities. They exert their action by targeting the scaffold proteins called prohitins-1 and-2, and the mRNA helicases eIF4A and DDX3. Flavaglines are densely functionalized cyclopenta[b]benzofurans that have attracted the attention of some of the most eminent organic chemists. This review provides an overview of the biosynthesis, total synthesis and pharmacological activities of flavaglines, which recently culminated with the entrance of a synthetic derivative, Zotatifin, into clinical trials against advanced solid tumors refractory or intolerant to standard treatments.

Thermo-Analytical and Compatibility Study with Mechanistic Explanation of Degradation Kinetics of Ambroxol Hydrochloride Tablets under Non-Isothermal Conditions

Ambroxol hydrochloride (AMB), used as a broncho secretolytic and an expectorant drug, is a semi-synthetic derivative of vasicine obtained from the Indian shrub Adhatoda vasica. It is a metabolic product of bromhexine. The paper provides comprehensive and detailed research on ambroxol hydrochloride, gives information on thermal stability, the mechanism of AMB degradation, and data of practical interest for optimization of formulation that contains AMB as an active compound. Investigation on pure AMB and in commercial formulation Flavamed® tablet (FT), which contains AMB as an active compound, was performed systematically using thermal and spectroscopic methods, along with a sophisticated and practical statistical approach. AMB proved to be a heat-stable and humidity-sensitive drug. For its successful formulation, special attention should be addressed to excipients since it was found that polyvinyl pyrrolidone and Mg stearate affect the thermal stability of AMB. At the same time, lactose monohydrate contributes to faster degradation of AMB and change in decomposition mechanism. It was found that the n-th order kinetic model mechanistically best describes the decomposition process of pure AMB and in Flavamed® tablets.

Novel Secondary Metabolites from New Zealand Marine Sponges

<p>The isolation and structure elucidation of 12 new compounds from four different genera of marine sponge is described. Continued work with the marine sponge Raspailia topsenti resulted in the isolation of two clerodane diterpenes, raspailodanes F (40) and G (41). Raspailodane F contains a novel tricyclo[5.4.0.0]undecane scaffold including a cyclopropyl ring. A nonadecanoic acid derivative, petrosianoic acid (122), was isolated from an unknown species of the genus Petrosia. It is believed that 122 is only the third nonadecanoic acid derivative reported from the marine environment. The marine sponge Dendrilla rosea was examined for the presence of new spongian diterpenes. While no new diterpenes were discovered, the acetylenic nitrile dendronitrile (158) was isolated along with two known diterpenes and a known steroid. Dendronitrile is the first acetylenic nitrile discovered from the marine environment and only the third ever reported. Seven new lamellarins and one new dictyodendrin were isolated from Dictyodendrilla dendyi alongside one known lamellarin and two known dictyodendrins. Lamellarins Θ (187) and κ (188) are related to known lamellarins. The remaining five lamellarins are sulfated derivatives, lamellarin Θ 4'',4'''-disulfate (190), lamellarin O 4'''-sulfate (191), lamellarin O 4'',4'''-disulfate (192), lamellarin κ 4'''-sulfate (193), and lamellarin κ 4'',4'''- disulfate (194). Dictyodendrin F (195) is a new natural product previously only reported as a semi-synthetic derivative of known dictyodendrins. Lamellarin shows moderate cytotoxic activity. The biological activity of the remaining compounds, particularly the sulfated derivatives, is under investigation. The screening protocol used to analyse crude sponge extracts was refined and a number of advances were made towards the automated analysis of the spectra generated. A method was devised to extract peak data from screen HSQC spectra and by combining these data, to produce a software-based mask of known correlations. The application of this mask was demonstrated in three different ways to three different screen HSQC spectra. To aid in the identification of interesting correlations identified by the mask, a database of HSQC correlations was compiled from literature and in-house sources. A new method of describing the chemical environment of a given position was developed to suit the needs of the database. At present, the database contains 91 compounds and represents over 2500 individual HSQC correlations. Development of both the software screening technique and the HSQC correlation database is ongoing.</p>

Novel Secondary Metabolites from New Zealand Marine Sponges

<p>The isolation and structure elucidation of 12 new compounds from four different genera of marine sponge is described. Continued work with the marine sponge Raspailia topsenti resulted in the isolation of two clerodane diterpenes, raspailodanes F (40) and G (41). Raspailodane F contains a novel tricyclo[5.4.0.0]undecane scaffold including a cyclopropyl ring. A nonadecanoic acid derivative, petrosianoic acid (122), was isolated from an unknown species of the genus Petrosia. It is believed that 122 is only the third nonadecanoic acid derivative reported from the marine environment. The marine sponge Dendrilla rosea was examined for the presence of new spongian diterpenes. While no new diterpenes were discovered, the acetylenic nitrile dendronitrile (158) was isolated along with two known diterpenes and a known steroid. Dendronitrile is the first acetylenic nitrile discovered from the marine environment and only the third ever reported. Seven new lamellarins and one new dictyodendrin were isolated from Dictyodendrilla dendyi alongside one known lamellarin and two known dictyodendrins. Lamellarins Θ (187) and κ (188) are related to known lamellarins. The remaining five lamellarins are sulfated derivatives, lamellarin Θ 4'',4'''-disulfate (190), lamellarin O 4'''-sulfate (191), lamellarin O 4'',4'''-disulfate (192), lamellarin κ 4'''-sulfate (193), and lamellarin κ 4'',4'''- disulfate (194). Dictyodendrin F (195) is a new natural product previously only reported as a semi-synthetic derivative of known dictyodendrins. Lamellarin shows moderate cytotoxic activity. The biological activity of the remaining compounds, particularly the sulfated derivatives, is under investigation. The screening protocol used to analyse crude sponge extracts was refined and a number of advances were made towards the automated analysis of the spectra generated. A method was devised to extract peak data from screen HSQC spectra and by combining these data, to produce a software-based mask of known correlations. The application of this mask was demonstrated in three different ways to three different screen HSQC spectra. To aid in the identification of interesting correlations identified by the mask, a database of HSQC correlations was compiled from literature and in-house sources. A new method of describing the chemical environment of a given position was developed to suit the needs of the database. At present, the database contains 91 compounds and represents over 2500 individual HSQC correlations. Development of both the software screening technique and the HSQC correlation database is ongoing.</p>

Actions of Camptothecin Derivatives on Larvae and Adults of the Arboviral Vector Aedes aegypti

Mosquito-borne viruses including dengue, Zika, and Chikungunya viruses, and parasites such as malaria and Onchocerca volvulus endanger health and economic security around the globe, and emerging mosquito-borne pathogens have pandemic potential. However, the rapid spread of insecticide resistance threatens our ability to control mosquito vectors. Larvae of Aedes aegypti were screened with the Medicines for Malaria Venture Pandemic Response Box, an open-source compound library, using INVAPP, an invertebrate automated phenotyping platform suited to high-throughput chemical screening of larval motility. We identified rubitecan (a synthetic derivative of camptothecin) as a hit compound that reduced A. aegypti larval motility. Both rubitecan and camptothecin displayed concentration dependent reduction in larval motility with estimated EC50 of 25.5 ± 5.0 µM and 22.3 ± 5.4 µM, respectively. We extended our investigation to adult mosquitoes and found that camptothecin increased lethality when delivered in a blood meal to A. aegypti adults at 100 µM and 10 µM, and completely blocked egg laying when fed at 100 µM. Camptothecin and its derivatives are inhibitors of topoisomerase I, have known activity against several agricultural pests, and are also approved for the treatment of several cancers. Crucially, they can inhibit Zika virus replication in human cells, so there is potential for dual targeting of both the vector and an important arbovirus that it carries.

A Review on Meropenem

Meropenem is a new Carbapenem antibacterial agent with wide spectrum of activity for intravenous administration. It is synthetic derivative of Thienamycin. Three analogues of Meropenem are evaluated and active against 18 bacterial strains. Meropenem causes rapid bacterial cell death by covalently binding to penicillin binding proteins (PBS). Structural modification at C-2 position, produced double promoiety prodrug of Meropenem and increases bioavailability of oral administration. Other forms of drug such as liposome and nanoparticles are also available with enhanced absorption. 14C labelled Meropenem prepared from 14C Dimethylamine hydrochloride is used for the analysis of M. tuberculosis transpeptidase. ICI213,689 is the only metabolite of Meropenem and it is inactive. Meropenem penetrates well into the body fluids and tissues including cerebrospinal fluid. Its bioavailability is 100% on intravenous administration. Hence it is used in the treatment of meningitis, febrile neutropenia, anthrax and various other skin and skin structure infections. Dosage reduction is required in patient with reduced renal function but not in hepatic impairment. Seizures, gastrointestinal haemorrhage are observed in patients. Vabmoere is the combination of Meropenem and Vaborbactam which is active against the Carbapenem resistant Enterobacteriacea. Meropenem is an effective broad-spectrum antibacterial drug for the treatment of wide range of infection including polymicrobial infection in both children and adult.

Actions of camptothecin derivatives on larvae and adults of the arboviral vector Aedes aegypti

Mosquito-borne viruses including dengue, Zika and Chikungunya viruses as well as parasites such as malaria and Onchocerca volvulus endanger health and economic security around the globe and emerging mosquito-borne pathogens have pandemic potential. However, the rapid spread of insecticide resistance threatens our ability to control mosquito vectors. Larvae of Aedes aegypti (New Orleans strain) were screened with the Medicines for Malaria Venture Pandemic Response Box, an open-source compound library, using INVAPP, an invertebrate automated phenotyping platform suited to high-throughput chemical screening of larval motility. Of the 400 compounds screened, we identified rubitecan (a synthetic derivative of camptothecin) as a hit compound that significantly reduced Ae. aegypti larval motility compared to DMSO controls. Both rubitecan and camptothecin displayed concentration dependent reduction in larval motility with estimated EC50s of 25.5 ± 5.0 μM and 22.3 ± 5.4 μM respectively. We extended our investigation to adult mosquitoes and found that camptothecin increased lethality when delivered in a blood meal to Ae. aegypti adults at 100 μM and 10 μM and completely blocked egg laying when fed at 100 μM. Camptothecin and its derivatives, inhibitors of topoisomerase I, have known activity against several agricultural pests and are also approved for the treatment of several cancers. Crucially, they can inhibit Zika virus replication in human cells, so there is potential for dual targeting of both the vector and an important arbovirus that it carries. Both humans and mosquitoes express the highly conserved topoisomerase I target, however, the design of derivatives with differing pharmacokinetic properties may offer a promising route towards the development of insect-specificity of this chemistry.