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Pain Medicine 2012; 13: 915–918Wiley Periodicals, Inc. NEUROPATHIC PAIN SECTION
Case Report
Successful Treatment of Refractory
Postherpetic Neuralgia with Topical Gallium
Maltolate: Case Reportpme_1404915.918

Lawrence R. Bernstein, PhD
nale to study topical gallium maltolate in patients
with refractory peripheral neuropathic pain.

Words. Postherpetic
Neuralgia;
Trigeminal
Reprint requests to: Lawrence R. Bernstein, Neuralgia; Neuropathic Pain; Gallium Maltolate;
PhD, Terrametrix, 285 Willow Rd., Menlo Park, CA 94025, USA. Tel: 650-324-3344; E-mail:[email protected]
Introduction
Abstract
Postherpetic neuralgia (PHN) is a neuropathic pain thatpersists following the resolution of an occurrence of Introduction. Postherpetic neuralgia is a common
herpes zoster (shingles). The virus that causes herpes sequela of herpes zoster (shingles), in which chronic
zoster, varicella-zoster virus, remains latent in dorsal root pain may last for weeks to years. Currently, available
or trigeminal ganglia following an earlier varicella (chicken- treatments include systemic opioid analgesics, tricy-
pox) infection, and may become reactivated with age or clic antidepressants, corticosteroids, and anticon-
the weakening of immune responses. Following reactiva- vulsants, as well as topical capsaicin and lidocaine.
tion, viral particles travel down neuronal axons to the skin, These treatments are commonly unsatisfactory, with
producing painful, vesicular cutaneous lesions that are fewer than half of treated patients experiencing more
dermasomally distributed. Pain is usually also present than a 50% reduction in pain.
before the skin lesions form (prodromal pain), when themultiplying virus is already damaging neurons. PHN Case. A 99-year-old woman had a 4-year history of
occurs in about 40% of herpes zoster patients who are severe postherpetic (trigeminal) neuralgia on the left
older than 50 years and about 75% of those over 75 [1].
side of her face. During those 4 years, numerous
The duration of PHN ranges from weeks to years; both treatments were tried, including systemic opioid
the incidence and duration of PHN are strongly positively analgesics
anticonvulsants,
lidocaine and capsaicin, all with unsatisfactory
results. The topical application of gallium maltolate,

The etiology and pathophysiology of PHN are not fully at a concentration of 0.5% in an emulsion of water
understood. Fields et al. [3] suggested two broad types of and hydrophilic petrolatum, was found to relieve the
PHN: 1) severe allodynia caused by abnormal hypersen- severe pain within about 10 minutes, with the relief
sitivity and activation of C (unmyelinated) primary afferent lasting for about 6–8 hours. The patient has been
nociceptor neurons, with no loss of sensation; and 2) using this treatment for more than 5 years, with no
variable degrees of allodynia associated with partial loss of adverse effects and a highly significant improvement
C-nociceptors, resulting in partial loss of sensation, in in her quality of life.
which the pain is caused by spontaneous discharge ofdeafferented central neurons. Patients having the first type Discussion. Gallium
significant
of pain (“irritable nociceptor”) would tend to respond to inflammatory activity, inhibiting the activation and
local anesthetic treatment, whereas those with the second proliferation of pro-inflammatory T cells. Because
type (“deafferentiation”) would not. Other studies, based gallium is chemically similar to zinc, it can interfere
on autopsy results, have found that viral replication and/or with the activity of matrix metalloproteinases (zinc-
proteins may persist in sensory neurons following herpes bearing proteases), which have been implicated in
zoster resolution, potentially causing persistent pain [1]. All the etiology of neuropathic pain, and it may sup-
current information indicates that the pathophysiology of press the secretion of substance P. Gallium may
PHN is complex, multifactorial, and variable, accounting also inhibit viral replication and the inflammatory
for the variable and commonly resistant nature of PHN to activity of viral proteins. This case provides ratio-
Bernstein
The development of herpes zoster, and of consequent The patient experienced essentially no remission in her PHN, is significantly reduced in immunocompetent indi- left-side facial pain over the following 4 years. During that viduals who receive herpes zoster vaccine [4]. Treatment time, the patient tried numerous treatments in an attempt to of herpes zoster with oral nucleoside antiviral agents (e.g., relieve the pain. Systemic therapeutics that were used acyclovir, valacyclovir, and famciclovir), if initiated within 72 included amitriptyline 25 mg bid, methadone 5 mg bid, hours of lesion onset, can reduce viral shedding, speed carbamazepine 100 mg bid, gabapentin 200 mg qd, oxy- healing of cutaneous lesions, and reduce acute pain [5].
Such treatment may reduce the incidence, duration, and acetaminophen 500 mg qid, naproxen, acetaminophen, severity of PHN, though a meta-analysis of six randomized and intravenous hydrogen peroxide; topical therapeutics controlled trials found no significant difference in the inci- included lidocaine 5% patches, capsaicin 0.025% cream, dence of PHN (at 4 or 6 months after herpes zoster rash geranium oil, and emu oil. None of these treatments pro- onset) between patients who took acyclovir and those vided significant, satisfactory pain relief, and the patient was hospitalized several times due to severe pain. After 4years, her left-side facial pain was still severe and there was Available systemic treatments for PHN include opioid noticeable left-side facial erythema. The patient, who had analgesics, tricyclic antidepressants (particularly amitrip- been highly active before the onset of PHN (playing tennis tyline), corticosteroids, and the anticonvulsants gabapen- at the age of 95), was depressed and discouraged due to tin and pregabalin. Topical treatments include capsaicin, her chronic PHN and her consequent reduction in activity.
lidocaine, acetylsalicylic acid, and geranium oil. All of thesetherapeutics have limited efficacy, and most can produce Four years and 2 months after initiation of the patient’s significant adverse effects [5]. Current PHN therapy is PHN, the patient was given, by the patient’s son, a topical generally considered unsatisfactory, with less than half of cream consisting of 0.5% gallium maltolate in an emulsion treated patients experiencing pain reduction of greater of 50% water and 50% Aquaphor® (Beiersdorf Inc., Wilton, than 50% [7]. As PHN afflicts an estimated 800,000 Connecticut, USA) (hydrophilic petrolatum). The gallium people in the United States alone [2], new, more effective maltolate had been synthesized under cGMP protocols by Regis Technologies, Inc., of Morton Grove, Illinois. Thepatient utilized the cream by gently applying a thin coatingto the painful area on the left side of her face.
Case Report
The patient said that when the gallium maltolate cream was This case report describes the course and treatment of first applied, her facial pain was virtually eliminated within PHN in a female patient who was 95 years old at the time about 10 minutes. This effect lasted for about 6–8 hours.
of initial presentation, and is currently 105. The patient After several days of applying the cream three times per initially presented with severe pain on the left side of her day, her facial erythema had gone away. Since that time, face and moderate edema of her lips. Because she had more than 5 years ago, the patient has applied the cream dental work performed earlier the same day (an upper left two to four times per day nearly every day for pain relief. Her molar crown was repaired), and other signs of disease severe pain is nearly eliminated by the cream, though mild were not noted, it was hypothesized that her pain and allodynia sometimes still remains. When offered the chance edema were likely related to the dental work, and she was to try new analgesic treatments, she has refused, saying that she is doing fine on her gallium maltolate cream. Fromthe time that the patient started using the topical cream, Two days later, the patient’s facial pain had worsened.
she has returned to an active lifestyle with a greatly She went to the emergency room, where she received improved quality of life. No adverse effects were noted by x-rays of her head. The attending physician concluded the patient, and none were observed during physical that the patient had an infected root canal, and she was examination or by routine tests. The patient has noted that referred to an endodontist. The endodontist drilled out the the gallium maltolate cream has also rapidly relieved pain presumably infected tooth, but no obvious infection was from insect bites, spider bites, abrasions, and minor burns.
found; no drainage ensued from the tooth and pain reliefdid not occur.
A placebo effect in this patient is considered unlikely. Nosignificant pain relief had occurred during 4 years in which On the evening of the third day after initial presentation, numerous drugs were tried, most having been prescribed the patient returned to the emergency room with severe by her physician, but some also obtained from alternative left-side facial pain. At that time, the patient received the medical sources. Furthermore, a week before receiving correct diagnosis of herpes zoster (a vesicular rash had the gallium maltolate cream, the patient tried a topical appeared), and was sedated with morphine. She began a formulation, given to her by her son, consisting of the 4-day course of acyclovir, a 3-day course of prednisone, same vehicle used for the gallium maltolate cream, but and was told to apply lidocaine 5% patches and capsaicin containing a trace of a germanium compound; this formu- 0.025% cream to the affected area for 3 days. The herpes lation produced no pain relief. The gallium maltolate cream zoster rash resolved in about a week, but severe PHN has consistently provided temporary pain relief, which persisted, affecting the dermatome corresponding to the lasts for several hours following administration, over a mandibular branch of the left trigeminal nerve.
Gallium Maltolate Treatment of Postherpetic Neuralgia
Discussion
viral replication, or at least the continued presence of viralproteins, may persist in sensory ganglia long after rash resolution, causing inflammation and pain [1]. Interference inflammatory, and anti-bone-resorptive activities [8,9], and with viral replication, interactions with inflammatory viral topically applied gallium nitrate has been reported effec- proteins, or general anti-inflammatory activity are possible tive in relieving arthritis pain [10]. During small clinical means by which gallium could ameliorate PHN.
anticancer trials, significant pain relief was noted in pros-tate cancer patients [11] and multiple myeloma patients Gallium may also inhibit neuronal inflammation by acting [12] who received parenteral gallium nitrate. Severe right as a mimic of zinc, thus interfering with matrix metallopro- abdominal pain was relieved following oral administration teinase (MMP) activity (MMPs are zinc-dependent pro- of gallium maltolate in a patient with advanced hepatocel- teases). The ability of gallium to inhibit MMP activity has lular carcinoma [13]. We here present the first published been suggested previously [8], and has been demon- report of topically applied gallium having an analgesic strated in vitro [17]. MMPs, particularly MMP-9 [18,19], effect other than on inflammatory arthritis, and the first MMP-2 [19], and MMP-5 [20], have been strongly impli- published report of topically applied gallium showing effi- cated in the pathogenesis of neuropathic pain. Zinc is also known to modulate the secretion of the pain-associatedneuropeptide substance P in afferent rat neurons [21], The antiproliferative activity of gallium appears due mainly with high zinc concentrations strongly inhibiting the to its chemical mimicry of ferric iron (Fe3+) [8]. Fe3+ is release of substance P. It is possible that gallium has a present in the active site of ribonucleotide reductase, an enzyme essential for DNA synthesis. Because gallium(which occurs in solution as Ga3+) is an irreducible analog Limited evidence suggests that inflammation may be of ferric iron, it interferes with cellular uptake and usage of directly related to at least some PHN-associated pain. A Fe3+, consequently inhibiting ribonucleotide reductase randomized clinical trial found that intrathecally adminis- activity and DNA synthesis. Like Fe3+, gallium binds to tered methylprednisolone (an anti-inflammatory corticos- serum transferrin and is then taken up by pathological teroid) together with lidocaine was effective in relieving rapidly proliferating cells that overexpress transferrin PHN pain (though patients with trigeminal-associated pain receptor, such as cancer cells and bacteria. The inhibition were not included in the study); patients receiving of DNA synthesis in these cells prevents replication and lidocaine alone or no treatment did not experience pain relief [22]. Interleukin-8, which is associated with neutro-phil recruitment and with inflammation-associated pain, Some of the observed anti-inflammatory activity of gallium was elevated in the cerebrospinal fluid of the PHN is also likely related to gallium being an irreducible mimic of patients, and was reduced significantly by the intrathecal Fe3+. Several animal and in vitro studies found gallium to methylprednisolone. These results suggest that anti- be a potent inhibitor of T cell activation and proliferation inflammatory action on neuronal tissue can, at least in [8]. T-helper type 1 (Th-1) cells, which generally act to stimulate macrophages and are predominately pro-inflammatory, are much more sensitive to inactivation by Gallium’s analgesic activity in PHN thus likely involves iron deprivation than Th-2 cells, which act mainly on B gallium’s anti-inflammatory properties as well as other cells to stimulate antibody production and are predomi- modalities. Because gallium maltolate is moderately nately anti-inflammatory [14]. The presence of gallium, by soluble in both water and lipids (octanol : water partition competitively inhibiting iron, would tend to cause inactiva- coefficient of 0.41; [23]), it is expected to readily penetrate tion of Th-1 cells relative to Th-2 cells.
skin and neurons. Gallium maltolate thus appears particu-larly able to deliver gallium directly to skin, underlying The varicella-zoster virus itself is dependent upon ribo- tissues, and neurons when applied topically to the skin or nucleotide reductase (and therefore Fe3+) to synthesize DNA and multiply; unlike most viruses, it produces itsown ribonucleotide reductase [15]. By interfering with Based on observations in the case reported here, there is Fe3+ uptake and utilization, gallium may inhibit viral ribo- justification to study topical gallium maltolate in other nucleotide reductase activity, and thus viral replication patients with refractory peripheral neuropathic pain. Labo- (similar to gallium’s activity against the proliferation of ratory research on the analgesic properties of gallium may cancer cells and bacteria). Gallium has shown antiviral elucidate its mechanisms of action; complementarily, such activity against human immunodeficiency virus in labora- studies may open up new avenues of studying pain and Because the neurological and biochemical mechanismsthat produce PHN are not fully understood, any hypoth- References
eses regarding the amelioration of PHN by gallium remain 1 Gowrishankar K, Steain M, Cunningham AL, et al.
speculative. Studies of neurons and surrounding tissue Characterization of the host immune response in from individuals who died within a few months of having human ganglia after herpes zoster. J Virol 2010;84: herpes zoster (though who did not die of it) suggest that Bernstein
2 Schmader KE. Epidemiology and impact on quality subsequent treatment by gallium maltolate: Rationale of life of postherpetic neuralgia and painful diabetic and case study. Anticancer Agents Med Chem neuropathy. Clin J Pain 2002;18:350–4.
3 Fields HL, Rowbotham M, Baron R. Postherpetic 14 Thorson JA, Smith KM, Gomez F, Naumann PW, neuralgia: Irritable nociceptors and deafferentation.
Kemp JD. Role of iron in T cell activation: TH1 clones differ from TH2 clones in their sensitivity to inhibition ofDNA synthesis caused by IgG Mabs against the trans-ferrin receptor and the iron chelator deferoxamine. Cell 4 Tseng HF, Smith N, Harpaz R, et al. Herpes zoster vaccine in older adults and the risk of subsequentherpes zoster disease. JAMA 2011;305:160–6.
15 Heineman TC, Cohen JI. Deletion of the varicella- zoster virus large subunit of ribonucleotide reductase 5 Whitley RJ, Volpi A, McKendrick M, Wijck A, Oak- impairs growth of virus in vitro. J Virol 1994;68:3317– lander AL. Management of herpes zoster and post- herpetic neuralgia now and in the future. J Clin Virol2010;48(suppl 1):S20–8.
16 Stapleton JT, Klinzman D, Olakanmi O, et al. Gallium nitrate: A potent inhibitor of HIV-1 infection in vitro.
6 Li Q, Chen N, Yang J, et al. Antiviral treatment for Abstracts, 39th ICAAC Meeting, San Francisco 1999; preventing postherpetic neuralgia. Cochrane Data- 17 Panagakos FS, Kumar E, Venescar C, Guidon P. The effect of gallium nitrate on synoviocyte MMP activity.
7 Johnson RW. Herpes zoster and postherpetic neural- gia. Expert Rev Vaccines 2010;9(3 suppl):21–6.
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8 Bernstein LR. Mechanisms of therapeutic activity for Cytokine regulation of MMP-9 in peripheral glia: Impli- gallium. Pharmacol Rev 1998;50:665–82.
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9 Bernstein LR. Therapeutic gallium compounds. In: 19 Ji RR, Xu ZZ, Wang X, Lo EH. Matrix metalloprotease Gielen M, Tiekink ERT, eds. Metallotherapeutic Drugs regulation of neuropathic pain. Trends Pharmacol Sci and Metal-Based Diagnostic Agents: The Use of Metals in Medicine. New York: Wiley; 2005:259–77.
20 Komori K, Nonaka T, Okada A, et al. Absence 10 Eby G. Elimination of arthritis pain and inflammation for of mechanical allodynia and A-beta-fiber sprouting over 2 years with a single 90 min, topical 14% gallium after sciatic nerve injury in mice lacking membrane- nitrate treatment: Case reports and review of actions type 5 matrix metalloproteinase. FEBS Lett 2004;557: of gallium III. Med Hypotheses 2005;65:1136–41.
11 Scher HI, Curley T, Geller N, et al. Gallium nitrate 21 Tang HB, Miyano K, Nakata Y. Modulation of the in prostatic cancer: Evaluation of antitumor activity substance P release from cultured rat primary afferent and effects on bone turnover. Cancer Treat Rep neurons by zinc ions. J Pharmacol Sci 2009;110:397– 22 Kotani N, Kushikata T, Hashimoto H, et al. Intrathecal 12 Warrell RP Jr, Lovett D, Dilmanian FA, Schneider R, methylprednisolone for intractable postherpetic neu- Heelan RT. Low-dose gallium nitrate for prevention of ralgia. N Engl J Med 2000;343:1514–9.
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23 Bernstein LR, Tanner T, Godfrey C, Noll B. Chemistry and pharmacokinetics of gallium maltolate, a com- 13 Bernstein LR, van der Hoeven JJM, Boer RO. Hepa- pound with high oral gallium bioavailability. Met Based tocellular carcinoma detection by gallium scan and

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