TNF was originally described as a circulating factor that can cause necrosis of tumours, but has since been identified as a key regulator of the inflammatory response This review describes the known signalling pathways and cell biological effects of TNF, and our understanding of the role of TNF in human disease TNF interacts with two different receptors, designated TNFR1 and TNFR2, which are differentially expressed on cells and tissues and initiate both distinct and overlapping signal transduction pathways These diverse signalling cascades lead to a range of cellular responses, which include cell death, survival, differentiation, proliferation and migration Vascular endothelial cells respond to TNF by undergoing a number of pro-inflammatory changes, which increase leukocyte adhesion, transendothelial migration and vascular leak and promote thrombosis The central role of TNF in inflammation has been demonstrated by the ability of agents that block the action of TNF to treat a range of inflammatory conditions, including rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease and psoriasis The increased incidence of infection in patients receiving anti-TNF treatment has highlighted the physiological role of TNF in infectious diseases

https://onlinelibrary.wiley.com/doi/pdf/10.1002/path.2287

TNF‐mediated inflammatory disease

Context.—Pain is the most disturbing symptom of
diabetic peripheral neuropathy. As many as 45% of patients with
diabetes mellitus develop peripheral neuropathies.Objective.—To evaluate the effect of gabapentin monotherapy
on pain associated with diabetic peripheral neuropathy.Design.—Randomized, double-blind, placebo-controlled,
8-week trial conducted between July 1996 and March 1997.Setting.—Outpatient clinics at 20 sites.Patients.—The 165 patients enrolled had a 1- to 5-year
history of pain attributed to diabetic neuropathy and a minimum 40-mm
pain score on the Short-Form McGill Pain Questionnaire visual analogue
scale.Intervention.—Gabapentin (titrated from 900 to 3600
mg/d or maximum tolerated dosage) or placebo.Main Outcome Measures.—The primary efficacy measure was
daily pain severity as measured on an 11-point Likert scale (0, no
pain; 10, worst possible pain). Secondary measures included sleep
interference scores, the Short-Form McGill Pain Questionnaire scores,
Patient Global Impression of Change and Clinical Global Impression of
Change, the Short Form–36 Quality of Life Questionnaire scores, and
the Profile of Mood States results.Results.—Eighty-four patients received gabapentin and 70
(83%) completed the study; 81 received placebo and 65 (80%) completed
the study. By intent-to-treat analysis, gabapentin-treated patients'
mean daily pain score at the study end point (baseline, 6.4; end point,
3.9; n = 82) was significantly lower (P<.001) compared with
the placebo-treated patients' end-point score (baseline, 6.5; end
point, 5.1; n = 80). All secondary outcome measures of pain were
significantly better in the gabapentin group than in the placebo group.
Additional statistically significant differences favoring gabapentin
treatment were observed in measures of quality of life (Short Form–36
Quality of Life Questionnaire and Profile of Mood States). Adverse
events experienced significantly more frequently in the gabapentin
group were dizziness (20 [24%] in the gabapentin group vs 4
[4.9%] in the control group; P<.001) and somnolence (19
[23%] in the gabapentin group vs 5 [6%] in the control group;
P = .003). Confusion was also more frequent in the gabapentin
group (7 [8%] vs 1 [1.2%]; P = .06).Conclusion.—Gabapentin monotherapy appears to be
efficacious for the treatment of pain and sleep interference associated
with diabetic peripheral neuropathy and exhibits positive effects on
mood and quality of life.

/pdf/gabapentin-for-the-symptomatic-treatment-of-painful-3hioh8gzer.pdf

Gabapentin for the Symptomatic Treatment of Painful Neuropathy in Patients With Diabetes Mellitus: A Randomized Controlled Trial

New studies of the treatment of neuropathic pain have increased the need for an updated review of randomized, double-blind, placebo-controlled trials to support an evidence based algorithm to treat neuropathic pain conditions. Available studies were identified using a MEDLINE and EMBASE search. One hundred and five studies were included. Numbers needed to treat (NNT) and numbers needed to harm (NNH) were used to compare efficacy and safety of the treatments in different neuropathic pain syndromes. The quality of each trial was assessed. Tricyclic antidepressants and the anticonvulsants gabapentin and pregabalin were the most frequently studied drug classes. In peripheral neuropathic pain, the lowest NNT was for tricyclic antidepressants, followed by opioids and the anticonvulsants gabapentin and pregabalin. For central neuropathic pain there is limited data. NNT and NNH are currently the best way to assess relative efficacy and safety, but the need for dichotomous data, which may have to be estimated retrospectively for old trials, and the methodological complexity of pooling data from small cross-over and large parallel group trials, remain as limitations.

Algorithm for neuropathic pain treatment:: an evidence based proposal.

Studies of oral corticosteroid dose and loss of bone mineral density have reported inconsistent results. In this meta-analysis, we used information from 66 papers on bone density and 23 papers on fractures to examine the effects of oral corticosteroids on bone mineral density and risk of fracture. Strong correlations were found between cumulative dose and loss of bone mineral density and between daily dose and risk of fracture. The risk of fracture was found to increase rapidly after the start of oral corticosteroid therapy (within 3 to 6 months) and decrease after stopping therapy. The risk remained independent of underlying disease, age and gender. We conclude that oral corticosteroid treatment using more than 5 mg (of prednisolone or equivalent) daily leads to a reduction in bone mineral density and a rapid increase in the risk of fracture during the treatment period. Early use of preventive measures against corticosteroid-induced osteoporosis is recommended.

/pdf/the-epidemiology-of-corticosteroid-induced-osteoporosis-a-4ra3qtx7u3.pdf

The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis.

Tricyclic antidepressants and carbamazepine have become the mainstay in the treatment of neuropathic pain. Within the last decade, controlled trials have shown that numerous other drugs relieve such pain. We identified all placebo-controlled trials and calculated numbers needed to treat (NNT) to obtain one patient with more than 50% pain relief in order to compare the efficacy with the current treatments, and to search for relations between mechanism of pain and drug action. In diabetic neuropathy, NNT was 1.4 in a study with optimal doses of the tricyclic antidepressant imipramine as compared to 2.4 in other studies on tricyclics. The NNT was 6.7 for selective serotonin reuptake inhibitors, 3.3 for carbamazepine, 10.0 for mexiletine, 3.7 for gabapentin, 1.9 for dextromethorphan, 3.4 for tramadol and levodopa and 5.9 for capsaicin. In postherpetic neuralgia, the NNT was 2.3 for tricyclics, 3.2 for gabapentin, 2.5 for oxycodone and 5.3 for capsaicin, whereas dextromethorphan was inactive. In peripheral nerve injury, NNT was 2.5 for tricyclics and 3.5 for capsaicin. In central pain, NNT was 2.5 for tricyclics and 3. 4 for carbamazepine, whereas selective serotonin reuptake inhibitors, mexiletine and dextromethorphan were inactive. There were no clear relations between mechanism of action of the drugs and the effect in distinct pain conditions or for single drug classes and different pain conditions. It is concluded that tricyclic antidepressants in optimal doses appear to be the most efficient treatment of neuropathic pain, but some of the other treatments may be important due to their better tolerability. Relations between drug and pain mechanisms may be elucidated by studies focusing on specific neuropathic pain phenomena such as pain paroxysms and touch-evoked pain.

Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action.

OBJECTIVE To prove the efficacy of mexiletine in painful diabetic neuropathy.

RESEARCH DESIGN AND METHODS Treatment was provided in three dosages. For pain measurements, a VAS and McGill's verbal rating scale were chosen. Ninety-five patients were included in the study.

RESULTS A global assessment of the VAS among patients showed no differences between mexiletine treatment and placebo. The total evaluation (PRIT) of the McGill scale fell just below the level of significance. More specific exploratory evaluations of subclasses of the McGill scale, representing different degrees of pain, gave remarkable differences between mexiletine and placebo in sensory and miscellaneous items. In special subgroups, which were formed according to types and courses of complaints compiled at the beginning of this evaluation, the substantial advantages of the mexiletine treatment were shown with both the VAS and the McGill scale.

CONCLUSIONS Evidence strongly indicates that, in particular, those patients with stabbing or burning pain, heat sensations, or formication will benefit most by mexiletine therapy. Concerning the dosage, a medium regimen of 450 mg/day seems to be appropriate. With an increase in the antiarryhthmic dosage level, the efficacy does not rise proportionally. Mexiletine proved to be a safe therapy with negligible side effects at the medium dose range, even < placebo; and remarkably, no cardiovascular side effects were noted. Further studies should avoid global assessments and pay more attention to the variety of complaints and quality of life.

Mexiletine in the Treatment of Diabetic Neuropathy

Aim Efficacy and safety of benfotiamine in treatment of diabetic polyneuropathy. Methods Double blind, placebo-controlled, phase-III-study. 181 patients were screened. 165 patients with symmetrical, distal diabetic polyneuropathy were randomised to one of three treatment groups entering the wash-out phase and 133/124 patients were analysed in the ITT/PP analysis: Benfotiamine 600 mg per day (n=47/43), benfotiamine 300 mg per day (n=45/42) or placebo (n=41/39). Results After 6 weeks of treatment, the primary outcome parameter NSS (Neuropathy Symptom Score) differed significantly between the treatment groups (p=0.033) in the PP (per protocol) population. In the ITT (intention to treat) population, the improvement of NSS was slightly above significance (p=0.055). The TSS (Total Symptom Score) showed no significant differences after 6 weeks of treatment. The improvement was more pronounced at the higher benfotiamine dose and increased with treatment duration. In the TSS, best results were obtained for the symptom "pain". Treatment was well tolerated in all groups. Conclusion Benfotiamine may extend the treatment option for patients with diabetic polyneuropathy based on causal influence on impaired glucose metabolism. Further studies should confirm the positive experiences.

Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study.

In a double-blind, randomized, controlled study, the effectiveness of treatment with a combination of Benfotiamine (an Allithiamine, a lipid-soluble derivative of vitamin B1 with high bioavailability) plus vitamin B6/B12 on objective parameters of neuropathy was studied over a period of 12 weeks on 24 diabetic patients with diabetic polyneuropathy. The results showed a significant improvement (p = 0.006) of nerve conduction velocity in the peroneal nerve and a statistical trend toward improvement of the vibration perception threshold. Long-term observation of 9 patients with verum over a period of 9 months support the results. Therapy-specific adverse effects were not seen. The results of this double-blind investigation, of the long-term observation and of the reports in the literature support the contention that the neurotropic benfotiamine-vitamin B combination represents a starting point in the treatment of diabetic polyneuropathy.

A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy.

Osteopenia in HIV-infected women prior to highly active antiretroviral therapy.

In rats with streptozotocin (STZ) induced diabetes the effect of (watersoluble) thiamine nitrate and of (lipidsoluble) benfotiamine on peripheral nerve function (motor nerve conduction velocity) as well as on the formation of advanced glycation end-products in peripheral nerve tissue was studied. In one group of animals drug administration was started immediately after diabetes induction (prevention study) and in another group two months after diabetes induction (treatment study). Motor nerve conduction velocity (NCV) dropped by 10.5% in diabetic animals, carboxymethyl-lysine (CML) rose to a 3.5fold concentration, deoxyglucosone (3DG)-type AGE formation was increased 5.1fold compared with controls. After three months preventive administration of both vitamin B(1) preparations NCV had increased substantially compared with results in diabetic controls. It was nearly normal after six months with benfotiamine, while the administration of thiamine nitrate resulted in no further amelioration. NCV was nearly normalized after six months of benfotiamine application but not with thiamine. Furthermore, benfotiamine induced a major inhibition of neural imidazole-type AGE formation and completely prevented diabetes induced glycoxidation products (CML). Treatment with thiamine did not significantly affect AGE or cmL levels. Unlike treatment with water-soluble thiamine nitrate timely administration of liposoluble prodrug benfotiamine was effective in the prevention of functional damage and of AGE and cmL formation in nerves of diabetic rats.

H. Stracke

Papers

Mexiletine in the Treatment of Diabetic Neuropathy

Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study.

A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy.

Osteopenia in HIV-infected women prior to highly active antiretroviral therapy.

Efficacy of benfotiamine versus thiamine on function and glycation products of peripheral nerves in diabetic rats