The efficacy and safety profile of capsaicin 8% patch versus 5% Lidocaine patch in patients with diabetic peripheral neuropathic pain: a randomized, placebo-controlled study of south Asian male patients.

AIMS: Diabetic peripheral neuropathy affects up to 60% of individuals and often leads to foot ulceration and eventual amputation. When oral therapy has failed to achieve pain relief, the first line local treatment is the 5% lidocaine-medicated plaster which provides local relief. Capsaicin 8% patch is considered a promising topical treatment for diabetic peripheral neuropathy. The present study investigated the efficacy, safety and tolerability of capsaicin 8% patch vs 5% lidocaine patch treatments over 24 weeks in South Asian male diabetic patients with established peripheral diabetic neuropathy. METHODS: Analgesic effectiveness was assessed by observing any change in the Numeric Pain Rating Scale (NPRS) score, Brief Pain Inventory (BPI) for painful diabetic peripheral neuropathy (BPI-DPN question 4) and Patient Global Impression of Change (PGIC). All patients received 4% lidocaine gel/cream for 60 min prior to patch application. The trial was probably underpowered, taking into account the smaller than expected number of participants from the calculated 350 sample size required for the whole study. Two hundred ninety-one individuals were divided into three groups based on treatment regimen; Group LL (Lidocaine + Lidocaine), Group LP (Lidocaine + Placebo), Group LC (Lidocaine + Capsaicin). The treatment procedure was conducted once initially and then repeated once at 12 weeks. The patients were followed up on alternate weeks till 24 weeks after the initial treatment. RESULTS: Group LC experienced a more significant reduction in the average pain intensity (p < 0.05) during the last twenty-four hours. Group LC showed more significant reduction of pain compared to control (p < 0.01), a baseline score of 5.4 ± 1.2 dropped to 3.2 ± 1.5 by week 24 of treatment. The change in mean daily pain intensity was - 2.2 ± 1.5 [95% CI: -2.45, -1.5]. Group LL and LC experienced a significant overall improvement (slightly, much or very much) in the health status during the study. After the second week of the treatment, patient satisfaction scores were 2.1 ± 1.1 in Group LL which increased to 3.2 ± 1.2 by week 24 of treatment. The capsaicin 8% patch appears to be reasonably well tolerated since there were no discontinuations because of serious drug-related treatment emergent adverse event (TEAEs). CONCLUSIONS: The aim of the present study was to assess the efficacy, safety and tolerability of the 8% capsaicin patch in patients with established painful diabetic neuropathy. There was a sustained treatment response to the initial and repeat treatment of the capsaicin 8% patch over the 24 weeks. The study population was very specific so further studies are required to investigate the generalizability of the results for patients experiencing painful diabetic neuropathy. The patch could be considered as an effective long-term treatment option in individuals with painful diabetic neuropathy, particularly those experiencing inadequate pain relief or side effects from systemic therapies.

The clinical significance of statins-macrolides interaction: comprehensive review of in vivo studies, case reports, and population studies.

The objectives of this article were to review the mechanism and clinical significance of statins-macrolides interaction, determine which combination has the highest risk for the interaction, and identify key patients' risk factors for the interaction in relation to the development of muscle toxicity. A literature review was conducted in PubMed and Embase (1946 to December 2018) using combined terms: statins - as group and individual agents, macrolides - as group and individual agents, drug interaction, muscle toxicity, rhabdomyolysis, CYP3A4 inhibitors, and OAT1B inhibitors, with forward and backward citation tracking. Relevant English language in vivo studies in healthy volunteers, case reports, and population studies were included. The interaction between statins and macrolides depends on the type of statin and macrolide used. The mechanism of the interaction is due to macrolides' inhibition of CYP3A4 isoenzyme and OAT1B transporter causing increased exposure to statins. The correlation of this increased statin's exposure to the development of muscle toxicity could not be established, unless the patient had other risk factors such as advanced age, cardiovascular diseases, renal impairment, diabetes, and the concomitant use of other CYP3A4 inhibitors. Simvastatin, lovastatin, and to lesser extent atorvastatin are the statins most affected by this interaction. Rosuvastatin, fluvastatin, and pravastatin are not significantly affected by this interaction. Telithromycin, clarithromycin, and erythromycin are the most "offending" macrolides, while azithromycin appears to be safe to use with statins. This review presented a clear description of the clinical significance of this interaction in real practice. Also, it provided health care professionals with clear suggestions and recommendations on how to overcome this interaction. In conclusion, understanding the different characteristics of each statin and macrolide, as well as key patients' risk factors, will enable health care providers to utilize both groups effectively without compromising patient safety.

A sedge plant as the source of Kangaroo Island propolis rich in prenylated p-coumarate ester and stilbenes.

Propolis samples from Kangaroo Island, South Australia, were investigated for chemical constituents using high-field nuclear magnetic resonance spectral profiling. A type of propolis was found containing a high proportion of prenylated hydroxystilbenes. Subsequently, the botanical origin of this type of propolis was identified using a beehive propolis depletion method and analysis of flora. Ligurian honey bees, Apis mellifera ligustica Spinola, were found to produce propolis from resin exuded by the Australian native sedge plant Lepidosperma sp. Montebello (Cyperaceae). The plants, commonly known as sword sedge, were found to have resin that matched with the propolis samples identified as the most abundant propolis type on the island containing C- and O-prenylated tetrahydroxystilbenes (pTHOS) in addition to a small amount of prenylated p-coumarate. The isolation of five pTHOS not previously characterized are reported: (E)-4-(3-methyl-2-buten-1-yl)-3,4',5-trihydroxy-3'-methoxystilbene, (E)-2,4-bis(3-methyl-2-buten-1-yl)-3,3',4',5-tetrahydroxystilbene, (E)-2-(3-methyl-2-buten-1-yl)-3-(3-methyl-2-butenyloxy)-3',4',5-trihydroxystilbene, (E)-2,6-bis(3-methyl-2-buten-1-yl)-3,3',5,5'-tetrahydroxystilbene and (E)-2,6-bis(3-methyl-2-buten-1-yl)-3,4',5-trihydroxy-3'-methoxystilbene. A National Cancer Institute 60 human cell line anticancer screen of three of these compounds showed growth inhibitory activity. The large Australasian genus Lepidosperma is identified as a valuable resource for the isolation of substances with medicinal potential.

Synthesis of C- and O-prenylated tetrahydroxystilbenes and O-prenylated cinnamates and their action towards cancer cells.

Synthesis of the naturally occurred C- and O-prenylated tetrahydroxystilbenes and O-prenylated cinnamates was carried out by decarbonylative Heck reaction and selenium dioxide catalysed oxidation, respectively. In the decarbonylative Heck synthetic route, fusion of benzoyl chloride and styrene derivatives was catalysed by an N-heterocyclic carbene system generated in situ by palladium acetate and 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride to form a E-tetrahydroxystilbene derivative. Formation of allyl ether was subsequently carried out by reaction of the deprotected OH in the A phenyl ring of the stilbene with 3,3-dimethylallyl bromide and a base (sodium hydride) to form O-prenylated tetrahydroxystilbene derivatives. [1,5]-Rearrangement of the isoprenyl unit from O- to C-position in the A ring was carried out at elevated temperature in the presence of magnesium silicate (Florisil) to form the corresponding C-prenylated tetrahydroxystilbene. Formation of O-prenylated cinnamate was first carried out by base catalysed allyl ether formation between 3,3-dimethylallyl bromide and hydroxycinnamic acid methyl ester. The methyl group of the isoprenyl unit was subsequently oxidized using selenium dioxide to form a terminal hydroxyl group. The prenylated tetrahydroxystilbenes and cinnamate synthesized in this study were novel derivatives of piceatannol and methyl 4-(3'-methylbut-2'-enyloxy)cinnamate isolated from propolis in Kangaroo Island, South Australia. The synthetic compounds were tested against K562 cancer cells and potent growth inhibitory activity was observed for E-1-[5-hydroxy-3-methoxy-2-(3-methyl-2-butenyl)phenyl]-2-[4-hydroxy-3-methoxyphenyl]ethene, IC50 = 0.10 µM.

Prenylated cinnamate and stilbenes from Kangaroo Island propolis and their antioxidant activity.

A prenylated cinnamic acid derivative as well as six prenylated tetrahydroxystilbenes were isolated from the ethyl acetate extract of propolis that originated from Kangaroo Island, Australia. Furthermore, six known stilbenes and two known flavanones were also identified from the same sample. Stilbenes are not common in propolis; therefore, Kangaroo Island propolis is considered a unique type of propolis that is rich in prenylated stilbenes. Stilbene propolis from Kangaroo Island showed a stronger scavenging activity towards DPPH free radical than Brazilian green propolis. This strong activity can be explained by the presence of large number of stilbenes, most of them showed strong free radical scavenging activity.

Propolis with high flavonoid content collected by honey bees from Acacia paradoxa.

Honey bees, Apis mellifera var ligustica, on Kangaroo Island, Australia, were found to collect propolis from the sticky exudate on the stem shoots and seed pods of an Australian endemic plant, Acacia paradoxa. Extracts of the plant stem shoots and seed pods, the propolis carried on the legs of bees and freshly collected propolis in hives contained major flavonoid components consisting of 2',3',4'-trimethoxychalcone, 2'-hydroxy-3',4'-dimethoxychalcone, 2',4'-dihydroxy-3'-methoxychalcone, 5,7-dihydroxy-2,3-dihydroflavonol 3-acetate (pinobanksin 3-acetate) and 5,7-dihydroxy-6-methoxy-2,3-dihydroflavonol 3-acetate, a substance not previously characterized. HPLC and (1)H NMR analyses of the propolis and plant extracts indicated smaller amounts of other flavonoids. A survey of propolis samples from 47 apiary sites widely distributed on Kangaroo Island showed that 15 samples from 6 sites were largely sourced from A. paradoxa.