1 In decerebrated, spinalized and paralyzed rabbits, intravenous administration of the 5-HT 1A -receptor agonists (+)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 3 ± 300 nmol kg 71 , cumulative) and esinoxan (22 ± 2200 nmol kg 71 , cumulative) signi®cantly increased the short latency re¯ex evoked in gastrocnemius medialis motoneurones by electrical stimulation of all myelinated a erents (Ab and Ad ®bres) of the sural nerve. Re¯exes increased to median values of 198% (inter-quartile range (IQR) 148 ± 473%) and 296% (IQR 254 ± 522%) of pre-drug values with the highest doses of 8-OH-DPAT and esinoxan, respectively. The enhancement of re¯exes induced by 5-HT 1A -receptor agonists was not reversed by the selective 5-HT 1A -receptor antagonist (S)WAY-100135 (2.05 mmol kg 71 ).2 The e ects of 8-OH-DPAT were tested after pretreatment with (S)WAY-100135 (2.05 mmol kg 71 ), its more potent analogue WAY-100635 (185 nmol kg 71 ), and the 5-HT 2 /5-HT 1D -/5-HT 7 -receptor ligand ritanserin (1.67 mmol kg 71 ). 8-OH-DPAT (300 nmol kg 71 single dose) signi®cantly increased gastrocnemius re¯ex responses in the presence of (S)WAY-100135 and WAY-100635, to median values of 260% (IQR 171 ± 295%) and 165% (IQR 136 ± 170%) of pre-drug levels, respectively. These values were not signi®cantly di erent from each other, or from the e ects of 8-OH-DPAT given alone. When 8-OH-DPAT was given after ritanserin, re¯exes were a median of 102% (IQR 76 ± 148%) of pre-drug values: i.e. there was no signi®cant increase in responses. Neither WAY-100635 nor ritanserin had any e ects on re¯exes per se. 3 WAY-100635 (185 nmol kg 71 ) and ritanserin (1.67 mmol kg 71 ) were given after 8-OH-DPAT (300 nmol kg 71 ). The agonist increased re¯exes to a median value of 184% (IQR 135 ± 289%), after which WAY-100635 signi®cantly reduced responses to 165% (IQR 130 ± 254%) and ritanserin further decreased re¯exes to a median of 107% (IQR 100 ± 154%) of pre-drug levels, i.e. not signi®cantly di erent from controls. 4 Previous studies have shown that re¯exes evoked by large myelinated axons tend to be suppressed, rather than enhanced, by 5-HT 1A -receptor agonists. When tested against re¯exes evoked by stimulation of the sural nerve at strengths between 1.5 and 2.5 times threshold, 8-OH-DPAT (3 ± 300 nmol kg 71 , cumulative) and¯esinoxan (22 ± 2200 nmol kg 71 , cumulative) signi®cantly reduced gastrocnemius responses to median values of 36% (IQR 15 ± 75%) and 17% (IQR 12 ± 38%) of pre-drug levels, respectively. This inhibition was fully reversed by (S)WAY-100135 (2.05 mmol kg 71 ). 5 These data show that drugs that are agonists at 5-HT 1A -receptors increase polysynaptic spinal re¯exes evoked by moderate to high stimulus intensities and depress responses to very low intensity stimuli. The inhibitory e ects of these drugs were mediated through 5-HT 1A -receptors as they were abolished by a selective antagonist for these sites. However, the facilitatory e ects of 8-OH-DPAT could be completely blocked only by a combination of ritanserin, which has no signi®can...
Basal cell carcinoma (BCC) is the most common cutaneous malignancy in humans. One of the most efficacious drugs used in the management of basal cell carcinoma BCC is the immunomodulator, imiquimod. However, imiquimod has physiochemical properties that limit its permeation to reach deeper, nodular tumour lesions. The use of microneedles may overcome such limitations and promote intradermal drug delivery. The current work evaluates the effectiveness of using an oscillating microneedle device Dermapen ® either as a pre or post-treatment with 5% w/w imiquimod cream application to deliver the drug into the dermis. The effectiveness of microneedles to enhance the permeation of imiquimod was evaluated ex vivo using a Franz cell set up. After a 24-hour permeation experiment, sequential tape strips and vertical cross-sections of the porcine skin were collected and analysed using time-of-flight secondary ion mass spectrometry (ToF-SIMS). In addition, respective Franz cell components were analysed using high performance liquid chromatography (HPLC). Analysis of porcine skin cross-sections demonstrated limited dermal permeation of 5% w/w imiquimod cream. Similarly, limited dermal permeation was also seen when 5% w/w imiquimod cream was applied to the skin that was pre-treated with the Dermapen ® , this is known as poke-and-patch. In contrast, when the formulation was applied first to the skin prior to Dermapen ® application, this is known as patch-and-poke, we observed a significant increase in intradermal permeation of imiquimod. Such enhancement occurs immediately upon microneedle application, generating an intradermal depot that persists for up to 24 hours. Intradermal colocalization of isostearic acid, an excipient in the cream, with imiquimod within microneedle channels was also demonstrated. However, such enhancement in intradermal delivery of imiquimod was not observed when the patch-and-poke strategy used a non-oscillating microneedle applicator, the Dermastamp TM . The current work highlights that using the patch-andpoke approach with an oscillating microneedle pen may be a viable approach to improve the current treatment in BCC patients who would prefer a less invasive intervention relative to surgery.
The protection provided by the human skin is mostly attributed to the stratum corneum. However, this barrier also limits the range of molecules that can be delivered into and across the skin. One of the methods to overcome this physiological barrier and improve the delivery of molecules into and across the skin is via the use of microneedles. This work evaluates the mechanical insertion of two different commercially available microneedle systems, Dermapen® and Dermastamp TM . The influence of biaxial skin strain on the penetration of the two microneedle systems was evaluated ex vivo using a biaxial stretch rig. From the skin insertion study, it was apparent that for all levels of biaxial strain investigated, the Dermapen® required less force than the Dermastamp TM to puncture the skin. In addition, it was observed that the oscillating microneedle system, the Dermapen®, resulted in deeper skin insertion ex vivo in comparison to the Dermastamp™. The use of this new biaxial stretch rig and the ex vivo skin insertion depth study highlights that the oscillating Dermapen® required less force to perforate the skin at varying biaxial strain whilst resulting in deeper skin penetration ex vivo in comparison to the Dermastamp TM . Although the Dermapen® punctured the skin deeper than the Dermastamp TM , such difference in penetration did not influence the permeation profile of the model drug, imiquimod across the skin as evidenced from a 24-hour ex vivo permeation study.
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